CA2413186A1 - Extracellular matrix and cell adhesion molecules - Google Patents

Abstract

The invention provides human extracellular matrix and cell adhesion molecules (ECMCAD) and polynucleotides which identify and encode ECMCAD. The invention also provides expression vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with aberrant expression of ECMCAD.

Description

EXTRACELLULAR MATRIX AND CELL ADHESION MOLECULES
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of extracellular matrix and cell adhesion molecules and to the use of these sequences in the diagnosis, treatment, and prevention of genetic, immune/inflammatory, developmental, neurological, connective tissue, and cell proliferative disorders, including cancer and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of extracellular matrix and cell adhesion molecules.
BACKGROUND OF THE INVENTION
Extracellular Matrix Proteins The extracellular matrix (ECM) is a complex network of glycoproteins, polysaccharides, proteoglycans, and other macromolecules that are secreted from the cell into the extracellular space.
The ECM remains in close association with the cell surface and provides a suppoi~ive meshwork that profoundly influences cell shape; motility, strength, flexibility, and adhesion. In fact, adhesion of a cell to its surrounding matrix is required for cell survival except in the case of metastatic tumor cells, which have overcome the need for cell-ECM anchorage. This phenomenon suggests that the ECM plays a critical role in the molecular mechanisms of growth control and metastasis.
(Reviewed in Ruoslahti, E. (1996) Sci. Am. 275:72-77.) Furthermore, the ECM determines the structure and physical properties of connective tissue and is particularly important for morphogenesis and other processes associated with embryonic development and pattern formation.
The collagens comprise a family of ECM proteins that provide structure to bone, teeth, skin, ligaments, tendons, cartilage, blood vessels, and basement membranes. Multiple collagen proteins have been identified. Three collagen molecules fold together in a triple helix stabilized by interchain disulfide bonds. Bundles of these triple helices then associate to form fibrils.
Elastin and related proteins confer elasticity to tissues such as skin, blood vessels, and lungs.
Elastin is a highly hydrophobic protein of about 750 amino acids that is rich in proline and glycine residues. Elastin molecules are highly cross-linked, forming an extensive extracellular network of fibers and sheets. Elastin fibers are surrounded by a sheath of microfibrils which are composed of a number of glycoproteins, including fibrillin.
Fibronectin is a large ECM glycoprotein found in all vertebrates. Fibronectin exists as a dimer of two subunits, each containing about 2,500 a,rnino acids. Each subunit folds into a rod-like structure containing multiple domains. The domains each contain multiple repeated modules, the most common of which is the type III fibronectin repeat. The type III fibronectin repeat is about 90 amino acids in length and is also found in other ECM proteins and in some plasma membrane and cytoplasmic proteins. Furthermore, some type III fibronectin repeats contain a characteristic tripeptide consisting of Arginine-Glycine-Aspartic acid (RGD). ~ The RGD sequence is recognized by the integrin family of cell surface receptors and is also found in other ECM proteins. (Reviewed in Alberts, et al. (1994) Molecular Biology of the Cell, Garland Publishing, New York, NY, pp. 986-987.) Laminin is a major glycoprotein component of the basal lamina which underlies and supports epithelial cell sheets. Laminin is one of the first ECM proteins synthesized in the developing embryo.
1o Laminin is an 850 kilodalton protein composed of three polypeptide chains joined in the shape of a cross by disulfide bonds. Laminin is especially important for angiogenesis and, in particular, for guiding the formation of capillaries. (Reviewed in Alberts, supra, pp. 990-991.) Many proteinaceous ECM components are proteoglycans. Proteoglycans are composed of unbranched polysaccharide chains (glycosaminoglycans) attached to protein cores. Common proteoglycans include aggrecan, betaglycan, decorin, perlecan, serglycin, and syndecan-1. Some of these molecules not only provide mechanical support, but also bind to extracellular signaling molecules, such as fibroblast growth factor and transforming growth factor (3, suggesting a role for proteoglycans in cell-cell communication. (Reviewed in Alberts, supra, pp. 973-978.) Dentin phosphoryn (DPP) is a major component of the dentin ECM. DPP is a proteoglycan that is synthesized and expressed by odontoblasts (Gu, K., et al. (1998) Eur.
J. Oral Sci. 106:1043 1047). DPP is believed to nucleate or modulate the formation of hydroxyapatite crystals.
Mucins are highly glycosylated glycoproteins that are the major structural component of the mucus gel. The physiological functions of mucins are cytoprotection, mechaxlical protection, maintenance of viscosity in secretions, and cellular recognition. MUC6 is a human gastric mucin that is also found in gall bladder, pancreas, seminal vesicles, and female reproductive tract (Toribara,~
N.W., et al. (1997) J. Biol. Chem. 272:16398-16403). The MUC6 gene has been mapped to human chromosome 11 (Toribara, N.W., et al. (1993) J. Biol. Chem. 268:5879-5885).
Hemomucin is a novel Drosophila surface mucin that may be involved in the induction of antibacterial effector molecules (Theopold, U., et al. (1996) J. Biol. Chem. 217:12708-12715).
Olfactomedin was originally identified as the major component of the mucus layer surrounding the chemosensory dendrites of olfactory neurons. Olfactomedin-related proteins are secreted glycoproteins with conserved C-terminal motifs. The TIGR/myocilin protein, an olfactomedin-related protein expressed in the eye, is associated with the pathogenesis of glaucoma (Kulkarni, N.H. et al.

(2000) Genet. Res. 76:41-50).
Ankyrin (ANK) repeats mediate protein-protein interactions associated with diverse intracellular functions. ANK repeats are composed of about 33 amino acids that form a helix-turn-helix core preceded by a protruding "tip." These tips are of variable sequence and may play a role in protein protein interactions. The helix-turn-helix region of the ANK repeats stack on top of one another and are stabilized by hydrophobic interactions (Yang, Y. et al. (1998) Structure 6:619-626).
Sushi repeats, also called short consensus repeats (SCR), are found in a number of proteins that share the common feature of binding to other proteins. For example, in the C-terminal domain of versican, the sushi domain is important for heparin binding. Sushi domains contain basic amino acid residues, which may play a role in binding (Oleszewski, M. et al. (2000) J.
Biol. Chem. 275:34478-34485).
Link, or X-link, modules are hyaluronan-binding domains found in proteins involved in the assembly of extracellular matrix, cell adhesion, and migration. The Link module superfamily includes CD44, cartilage link protein, and aggrecan. There is close similarity between the Link module and the ~15 C-type lectin domain, with the predicted hyaluronan-binding site at an analogous position to the carbohydrate-binding pocket in E-selectin (Kohda, D. et al. (1996) Cell, Vol.
86, 767-775).
Multidomain or mosaic proteins play an important role in the diverse functions of the extracellular matrix (Engel, J. et al. (1994) Development (Carob.) S35-42).
ECM proteins are frequently characterized by the presence of one or more domains which may contain a number of potential intracellular disulfide bridge motifs. For example, domains which match the epidermal growth factor (EGF) tandem repeat consensus are present within several known extracellular proteins that promote cell growth, development, and cell signaling. This signature sequence is about forty amino acid residues in length and includes six conserved cysteine residues, and a calcium-binding site near the N-terminus of the signature sequence. The main structure is a two-stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet. Subdomains between the conserved cysteines vary in length (Davis, C.G. New Biol (1990) May;2(5):410-9). Post-translational hydroxylation of aspartic acid or asparagine residues has been associated with EGF-like domains in several proteins (Prosite PDOC00010 Aspartic acid and asparagine hydroxylation site).
A number of proteins that contain calcium-binding EGF-like domain signature sequences are 3o involved in growth and differentiation. Examples include bone morphogenic protein 1, which induces the formation of cartilage and bone; crumbs, which is a Drosonhila epithelial development protein;
Notch and a number of its homologs,. which are involved in neural growth and differentiation, and transforming growth factor beta-1 binding protein (Expasy PROSITE document PDOC00913; Soler, C. and Carpenter, G., in Nicola, N.A. (1994) The Cytokine Facts Book, Oxford University Press, Oxford, UK, pp 193-197). EGF-like domains mediate protein-protein interactions for a variety of proteins. For example, EGF-like domains in the ECM glycoprotein fibulin-1 have been shown to mediate both self association and binding to fibronectin (Tram H. et al.
(1997) J. Biol. Chem.
272:22600-22606). Point mutations in the EGF-like domains of ECM proteins have been identified as the cause of human disorders such as Marfan syndrome and pseudochondroplasia (Maurer, P. et al.
(1996) Curr. Opin. Cell Biol. 8:609-617).
The CUB domain is an extracellular domain of approximately 110 amino acid residues found mostly in developmentally regulated proteins. The CUB domain contains four conserved cysteine l0 residues and is predicted to have a structure similar to that of immunoglobulins. Vertebrate bone morphogenic protein 1, which induces cartilage and bone formation, and fibropellins I and III from sea urchin, which form the apical lamina component of the ECM, are examples of proteins that contain both CUB and EGF domains (PROSITE PDOC00908 CUB domain profile).
Other ECM proteins are members of the type A domain of von Willebrand factor (vWFA)-like module superfamily, a diverse group of proteins with a module sharing high sequence similarity.
The vWFA-like module is found not only in plasma proteins but also in plasma membrane and ECM
proteins (Colombatti, A. and Bonaldo, P. (1991) Blood 77:2305-2315). Crystal structure analysis of an integrin vWFA-like module shows a classic "Rossmann" fold and suggests a metal ion-dependent adhesion site for binding protein ligands (Lee, J.-O. et al. (1995) Cell 80:631-638). This family includes the protein matrilin-2, an extracellular matrix protein that is expressed in a broad range of mammalian tissues and organs. Matxilin-2 is thought to play a role in ECM
assembly by bridging collagen fibrils and the aggrecan network (beak, F. et al. (1997) J. Biol.
Chem. 272:9268-9274).
The thrombospondins are muItimeric, calcium-binding extracellular glycoproteins found widely in the embryonic extracellular matrix. These proteins are expressed in the developing nervous system or at specific sites in the adult nervous system after injury. Thrombospondins contain multiple EGF-type repeats, as well as a motif known as the thrombospondin type 1 repeat (TSR). The TSR is approximately 60 amino acids in length and contains six conserved cysteine residues. Motifs within TSR domains are involved in mediating cell adhesion through binding to proteoglycans and sulfated glycolipids. Thrombospondin-1 inhibits angiogenesis and modulates endothelial cell adhesion, motility, and growth. TSR domains are found in a diverse group of other proteins, most of which are expressed in the developing nervous system and have potential roles in the guidance of cell and growth cone migration. Proteins that share TSRs include the F-spondin gene family, the semaphorin 5 family, UNC-5, and SCO-spondin. The TSR superfamily includes the ADAMTS proteins which contain an ADAM (A Disintegrin and Metalloproteinase) domain as well as one or more TSRs.
The ADAMTS
proteins have roles in regulating the turnover of cartilage matrix, regulation of blood vessel growth, and possibly development of the nervous system. (Reviewed in Adams, J.C. and Tucker, R. P. (2000) Dev. Dyn. 218:280-299).
Fibrinogen, the principle protein of vertebrate blood clotting, is a hexamer consisting of two sets of three different chains (alpha, beta, and gamma). The C-terminal domain of the beta and gamma chains comprises about 270 amino acid residues and contains four cysteines involved in two disulfide bonds. This domain has also been found in mammalian tenascin-X, an ECM protein that appears to be involved in cell adhesion (Prosite PDOC00445 Fibrinogen beta and gamma chains C-terminal domain signature).
Adhesion-Associated Proteins The surface of a cell is rich in transmembrane proteoglycans, glycoproteins, glycolipids, and receptors. These macromolecules mediate adhesion with other cells and with components of the ECM. The interaction of the cell with its surroundings profoundly influences cell shape, strength, flexibility, motility, and adhesion. These dynamic properties are intimately associated with signal transduction pathways controlling cell proliferation and differentiation, tissue construction, and embryonic development. Families of cell adhesion molecules include the cadherins, integrins, lectins, neural cell adhesion proteins, and some members of the proline-rich proteins.
Cadherins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually all solid tissues of multicellular organisms.
These proteins share multiple repeats of a cadherin-specific motif, and the repeats form the folding units of the cadherin extracellular domain. Cadherin molecules cooperate to form focal contacts, or adhesion plaques, between adjacent epithelial cells. The cadherin family includes the classical cadherins and protocadherins. Classical cadherins include the E-cadherin, N-cadherin, and P-cadherin subfamilies.
E-cadherin is present on many types of epithelial cells and is especially important for embryonic rlo.rolr,.-.mor,+ TvT ...,rlho.-;., ;~ ~....~~o..+ ~.. ........., ,..-..~.,~.le .,~..11 1....., ....77., ,....,7 :.. .,1,... ....:+:..~7 .F .. .._..-.L~_..._:_ Integrins are ubiquitous transmembrane adhesion molecules that link the ECM to the internal cytoskeleton. lntegrins are composed of two noncovalently associated transmembrane glycoprotein subunits called a and (3. Integrins function as receptors that play a role in signal transduction. For example, binding of integrin to its extxacellular ligand may stimulate changes in intracellular calcium levels or protein kinase activity (Sjaastad, M.D. and Nelson, W.J. (1997) BioEssays 19:47-55). At least ten cell surface receptors of the integrin family recognize the ECM
component fibronectin, which is involved in many different biological processes including cell migration and embryogenesis (Johansson, S. et al. (1997) Front. Biosci. 2:D126-D146).
Lectins comprise a ubiquitous family of extracellular glycoproteins which bind cell surface carbohydrates specifically and reversibly, resulting in the agglutination of cells (reviewed in Drickamer, I~. and Taylor, M. E. (1993) Annu. Rev. Cell Biol. 9:237-264). This function is particularly important for activation of the immune response. Lectins mediate the agglutination and mitogenic stimulation of lymphocytes at sites of inflammation (Lasky, L. A.
(1991) J. Cell. Biochem.
45:139-146; Paietta, E, et al. (1989) J. Immunol. 143:2850-2857).
Lectins are further classified into subfamilies based on carbohydrate-binding specificity and other criteria. The galectin subfamily, in particular, includes lectins that bind (3-galactoside carbohydrate moieties in a thiol-dependent manner (reviewed in Hadari, Y. R.
et al. (1998) J. Biol.
Chem. 270:3447-3453). Galectins are widely expressed and developmentally regulated. Galectins contain a characteristic carbohydrate recognition domain (CRD). The CRD is about 140 amino acids and contains several stretches of about 1 - 10 amino acids which are highly conserved among all galectins. A particular 6-amino acid motif within the CRD contains conserved tryptophan and arginine residues which are critical for carbohydrate binding. The CRD of some galectins also contains cysteine residues which may be important for disulfide bond formation.
Secondary strncture predictions indicate that the CRD forms several (3-sheets.
Galectins play a number of roles in diseases and conditions associated with cell-cell and cell-matrix interactions. For example, certain galectins associate with sites of inflammation and bind to cell surface immunoglobulin E molecules. In addition, galectins may play an important role in cancer metastasis. Galectin overexpression is correlated with the metastatic potential of cancers in humans and mice. Moreover, anti-galectin antibodies inhibit processes associated with cell transformation, 3o such as cell aggregation and anchorage-independent growth (see, for example, Su, Z.-Z. et al. (1996) Proc. Natl. Acad. Sci. USA 93:7252-7257).
Selectins, or LEC-CAMs, comprise a specialized lectin subfamily involved primarily in inflammation and leukocyte adhesion (Reviewed in Lasky, supra). Selectins mediate the recruitment of leukocytes from the circulation to sites of acute inflammation and are expressed on the surface of vascular endothelial cells in response to cytokine signaling. Selectins bind to specific ligands on the leukocyte cell membrane and enable the leukocyte to adhere to and migrate along the endothelial surface. Binding of selectin to its ligand leads to polarized rearrangement of the actin cytoskeleton and stimulates signal transduction within the leukocyte (Brenner, B. et al.
(1997) Biochem. Biophys.
Res. Commun. 231:802-807; Hidari, K. I. et al. (1997) J. Biol. Chem. 272:28750-28756). Members of the selectin family possess three characteristic motifs: a lectin or carbohydrate recognition domain; an epidermal growth factor-like domain; and a variable number of short consensus repeats (scr or "sushi"
repeats) which are also present in complement regulatory proteins.
l0 Neural cell adhesion proteins (NCAPs) play roles in the establishment of neural networks during development and regeneration of the nervous system (Uyemura et al.
(1996) Essays Biochem.
31:37-48~; Bmnmendorf and Rathjen (1996) Curr. Opin. Neurobiol. 6:584-593).
NCAP participates in neuronal cell migration, cell adhesion, neurite outgrowth, axonal fasciculation, pathfinding, synaptic target-recognition, synaptic formation, myelination and regeneration. NCAPs are expressed on the surfaces of neurons associated with learning and memory. Mutations in genes encoding NCAPS are linked with neurological diseases, including hereditary neuropathy Charcot-Marie-Tooth disease, Dejerine-Sottas disease, X-linked hydrocephalus, MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs), and spastic paraplegia type I. In some cases, expression of NCAP is not restricted to the nervous system. L1 , for example, is expressed in melanoma sells and hematopoietic tumor cells where it is implicated in cell spreading and migration, and may play a role in tumor progression (Montgomery et al. (1996) J. Cell Biol. 132:475-485).
NCAPs have at least one immunoglobulin constant or variable domain (Uyemura et al., s_~ra). They are generally linked to the plasma membrane through a transmembrane domain and/or a glycosyl-phosphatidylinositol (GPI) anchor. The GPI linkage can be cleaved by GPI phospholipase C.
Most NCAPs consist of an extracellular region made up of one or more immunoglobulin domains, a membrane spanning domain, and an intracellular region. Many NCAPs contain post-translational modifications including covalently attached oligosaccharide, glucuronic acid, and sulfate. NCAPs fall into three subgroups: simple-type, complex-type, and mixed-type. Simple-type NCAPs contain one or more variable or constant immunoglobulin domains, but lack other types of domains. Members of the simple-type subgroup include Schwann cell myelin protein (SMP), limbic system-associated membrane protein (LAMP), opiate-binding cell-adhesion molecule (OBCAM), and myelin-associated glycoprotein (MAG). The complex-type NCAPs contain fibronectin type III domains in addition to the immunoglobulin domains. The complex-type subgroup includes neural cell-adhesion molecule (NCAM), axonin-1, Fl l, Bravo, and Ll. Mixed-type NCAPs contain a combination of immunoglobulin domains and other motifs such as tyrosine kinase and epidermal growth factor-like domains. This subgroup includes Trk receptors of nerve growth factors such as nerve growth factor (NGF) and neurotropin 4 (NT4), Neu differentiation factors such as glial growth factor II (GGFII) and acetylcholine receptor-inducing factor (ARIA), and the semaphorin/collapsin family such as semaphorin B and collapsin.
Semaphorins are a large group of axonal guidance molecules consisting of at least 30 different members and are found in vertebrates, invertebrates, and even certain viruses.
All semaphorins contain the sema domain which is approximately 500 amino acids in length.
Neuropilin, a semaphorin receptor has been shown to promote neurite outgrowth in vitro. The extracellular region of neuropilins consists of three different domains: CUB, discoidin, and MAM domains. The CUB
and the MAM
motifs of neuropilin have been suggested as having roles in protein-protein interactions and are suggested to be involved in the binding of semaphorins through the sema and the C-terminal domains (reviewed in Raper, J.A. (2000) Curr. Opin. Neurobiol. 10:88-94).
An NCAP subfamily, the NCAP-LON subgroup, includes cell adhesion proteins expressed on distinct subpopulations of brain neurons. Members of the NCAP-LON subgroup possess three immunoglobulin domains and bind to cell membranes through GPI anchors. Kilon (a kindred of NCAP-LON), for example, is expressed in the brain cerebral cortex and hippocampus (Funatsu et al.
(1999) J. Biol. Chem. 274:8224-8230). Immunostaining localizes Kilon to the dendrites and soma of pyramidal neurons. Kilon has three C2 type immunoglobulin-like domains, six predicted glycosylation sites, and a GPI anchor. Expression of Kilon is developmentally regulated. It is expressed at higher levels in adult brain in comparison to embryonic and early postnatal brains.
Confocal microscopy shows the presence of Kilon in dendrites of hypothalamic magnocellular neurons secreting neuropeptides, oxytocin or arginine vasopressin (Miyata et al. (2000) J. Comp.
Neurol. 424:74-85).
Arginine vasopressin regulates body fluid homeostasis, extracellular osmolarity and intravascular volume. Oxytocin induces contractions of uterine smooth muscle during child birth and of myoepithelial cells in mammary glands during lactation. In magnocellular neurons, Kilon. is proposed to play roles in the reorganization of dendritic connections during neuropeptide secretion.
Cell adhesion proteins also include some members of the proline-rich proteins (PRPs). PRPs 3o are defined by a high frequency of proline, ranging from 20-50% of the total amino acid content.
Some PRPs have short domains which are rich in proline. These proline-rich regions are associated with protein-protein interactions. One family of PRPs are the proline-rich synapse-associated proteins (ProSAPs) which have been shown to bind to members of the postsynaptic density (PSD) protein family and subtypes of the somatostatin receptor (Yao, I. et al. (1999) J.
Biol. Chem. 274:
27463-27466; Zitzer, H. et al. (1999) J. Biol. Chem. 274:32997-33001). Members of ProSAP contain at the N-terminus six to seven ankyrin repeats, followed by an SH3 domain, a PDZ domain, then by seven proline-rich regions and a SAM domain at the C terminus. Several groups of ProSAP are important structural constituents of synaptic structures in human brain (Zitzer et al., supra). Another member of PRP is the HLA-B-associated transcript 2 protein (BAT2) which is xich in proline and include short tracts of polyproline, polyglycine, and charged amino acids. BAT2 also contains four RGD (Arg-Gly-Asp) motifs typical of integrins (Banerji, J. et al. (1990) Proc. Natl.
Acad. Sci. USA 87:2374-2378).
There are additional specific domains char acteristic of cell adhesion proteins. One such domain is the MAM domain, a domain of about 170 amino acids found in the extracellular region of diverse proteins. These proteins all share a receptor-like architecture comprising a signal peptide, followed by a large N-terminal extracellular domain, a transmembrane region, and an intracellular domain. (PROSTTE document PDOC00604 MAM domain signature and profile). MAM
domain proteins include zonadhesin, a sperm-specific membrane protein that binds to the zona pellucida of the egg; neuropilin, a cell adhesion molecule that functions during the formation of certain neuronal circuits, and Xenopus laevis thyroid hormone induced protein B, which contains four MAM domains and is involved in metamorphosis (Brown, D.D. et al. (1996) Proc. Natl. Acad.
Sci. USA 93:1924-1929).
The WSC domain was originally found in the yeast WSC (cell-wall integrity and stress response component) proteins which act as sensors of environmental stress. The WSC domains are extracellular and are thought to possess a carbohydrate binding role (Ponting, C.P. et al. (1999) Curr.
Biol. 9:S1-S2). A WSC domain has recently been identified in polycystin-l, a human plasma membrane protein. Mutations in polycystin-1 are the cause of the commonest form of autosomal dominant polycystic kidney disease (Ponting, C.P. et al. (1999) C~rr. Biol.
9:8585-8588).
Toposome is a cell-adhesion glycoprotein isolated from mesenchyme-blastula embryos.
Toposome precursors including vitellogenin promote cell adhesion of dissociated blastula cells.
Leucine rich repeats (L88) are short motifs found in numerous proteins from a wide range of species. LRR motifs are of variable length, most commonly 20-29 amino acids and multiple repeats 3o are typically present in tandem. LRR is important for proteinlprotein interactions and cell adhesion, and LRR proteins are involved in cell/cell interactions, morphogenesis, and development (Kobe, B. and Deisenhofer, J. (1995) Gtr. Opin. Struct. Biol. 5:409-416). The human ISLR
(immunoglobulin superfamily containing leucine-rich repeat) protein contains'a C2-type immunoglobulin domain as well as LRR. The ISLR gene is linked to the critical region for Bardet-Biedl syndrome, a developmental disorder of which the most common feature is retinal dystrophy (Nagasawa, A.
et al. (1999) Genomics 61:37-43).
The sterile alpha motif (SAM) domain is a conserved protein binding domain, approximately 70 amino acids in length, and is involved in the regulation of many developmental processes in many eukaryotes. The SAM domain can potentially function as a protein interaction module through its ability to form homo- or hetero-oligomers with other SAM domains (Schultz, J.
et al. (1997) Protein Sci. 6:249-253).
The discovery of new extracellular matrix and cell adhesion molecules and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of genetic, immune/inflammatory, developmental, neurological, connective tissue, and cell proliferative disorders, including cancer, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of extracellular matrix and cell adhesion molecules.
SUMMARY OF THE INVENTION
The invention features purified polypeptides, extracellular matrix and cell adhesion molecules, referred to collectively as "ECMCAD" and individually as "ECMCAD-l," "ECMCAD-2,"
"ECMCAD-3," "ECMCAD-4," "ECMCAD-5," "ECMCAD-6," "ECMCAD-7," "ECMCAD-8,"
"ECMCAD-9," "ECMCAD-10," "ECMCAD-11," "ECMCAD-12," "ECMCAD-13," "ECMCAD-14," "ECMCAD-15," "ECMCAD-16," "ECMCAD-17," "ECMCAD-18," "ECMCAD-19,"
"ECMCAD-20," "ECMCAD-21," "ECMCAD-22," "ECMCAD-23," "ECMCAD-24," "ECMCAD-25," "ECMCAD-26," "ECMCAD-27," "ECMCAD-28," "ECMCAD-29," "ECMCAD-30,"
"ECMCAD-31," "ECMCAD-32," "ECMCAD-33," "ECMCAD-34," "ECMCAD-35," and "ECMCAD-36." In one aspect, the invention provides an isolated polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ 117 N0:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ 1D N0:1-36. In one alternative, the invention provides an isolated polypeptide comprising the amino acid sequence of SEQ ~ N0:1-36.
The invention further provides an isolated polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ
D7 N0:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:l-36. In one alternative, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ ID
N0:1-36. In another alternative, the polynucleotide is selected from the group consisting of SEQ m N0:37-72.
Additionally, the invention provides a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ 1D N0:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-36. In one alternative, the invention provides a cell transformed with the recombinant polynucleodde. In another alternative, the invention provides a transgenic organism comprising the recombinant polynucleotide.
The invention also provides a method for producing a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:I-36. The method comprises a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding the polypeptide, and b) recovering the polypeptide so expressed.
Additionally, the invention provides an isolated antibody which specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID N0:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ )D N0:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
)17 N0:1-36.
The invention further provides an isolated polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ
1D N0:37-72, b) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:37-72, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). In one alternative, the polynucleotide comprises at least 60 contiguous nucleotides.
Additionally, the invention provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ
1D N0:37-72, b) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:37-72, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and optionally, if present, the amount thereof. In one alternative, the probe comprises at least 60 contiguous nucleotides.
The invention further provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ 1D
N0:37-72, b) a naturally occurnng polynucleotide comprising a polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:37-72, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.
The. invention further provides a composition comprising an effective amount of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ 1D NO:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID N0:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ 1D N0:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, and a pharmaceutically acceptable excipient. In one embodiment, the composition comprises an amino acid sequence selected from the group consisting of SEQ ID N0:1-36. The invention additionally provides a method of treating a disease or condition associated with decreased expression of functional ECMCAD, comprising administering to a patient in need of such treatment the composition.
The invention also provides a method for screening a compound for effectiveness as an agonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ 1D N0:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-36. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. In one alternative, the invention provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with decreased expression of functional ECMCAD, comprising administering to a patient in need of such treatment the composition.
Additionally, the invention provides a method for screening a compound for effectiveness as an antagonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ 1D N0:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ )D N0:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ 1D N0:1-36. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample.
In one alternative, the invention provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with overexpression of functional ECMCAD, comprising administering to a patient in need of such treatment the composition.
The invention further provides a method of screening for a compound that specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ m NO:l-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from to the group consisting of SEQ ID NO:l-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ )D N0:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
1D N0:1-36. The method comprises a) combining the polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide to the test compound, thereby identifying a compound that specifically binds to the polypeptide.
The invention further provides a method of screening for a compound that modulates the activity of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ 1D NO:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ )D N0:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ )D NO:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ 1D N0:1-36. The method comprises a) combining the polypeptide with at least one test compound under conditions permissive for the activity of the polypeptide, b) assessing the activity of the polypeptide in the presence of the test compound, and c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide.
The invention further provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence selected from the group consisting of SEQ )D N0:37-72, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, and b) detecting altered expression of the target polynucleotide.

The invention further provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound; b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ
m N0:37-72, ii) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ 1D N0:37-72, iii) a polynucleotide having a sequence complementary to i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:37-72, ii) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ 1D N0:37-72, iii) a polynucleotide complementary to the polynucleotide of i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Alternatively, the target polynucleotide comprises a fragment of a polynucleotide sequence selected from the group consisting of i)-v) above; c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.
BRIEF DESCRIPTION OF THE TABLES
Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide sequences of the present invention.
Table 2 shows the GenBank identification number and annotation of the nearest GenBank homolog for polypeptides of the invention. The probability score for the match between each polypeptide and its GenBank homolog is also shown.
Table 3 shows structural features of polypeptide sequences of the invention, including predicted motifs and domains, along with the methods, algorithms, and searchable databases used for analysis of the polypeptides.
Table 4 lists the cDNA and/or genomic DNA fragments which were used to assemble polynucleotide sequences of the invention, along with selected fragments of the polynucleotide sequences.
Table S shows the representative cDNA library for polynucleotides of the invention.
Table 6 provides an appendix which describes the tissues and vectors used for construction of the cDNA libraries shown in Table 5.
Table 7 shows the tools, programs, and algorithms used to analyze the polynucleotides and polypeptides of the invention, along with applicable descriptions, references, and threshold parameters.
DESCRIPTION OF THE INVENTION
Before the present proteins, nucleotide sequences, and methods a.re described, it is understood l0 that this invention is not limited to the particular machines, materials and methods described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
It must be noted that as used herein and in the appended claims, the singular forms "a," "an,"
15 and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a host cell" includes a plurality of such host cells, and a reference to "an antibody" is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same 20 meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.
Although any machines, materials, and methods similar or equivalent to those described herein can be used to practice or test the present invention, the preferred machines, materials and methods are. now described. All publications mentioned herein are cited for the purpose of describing and disclosing the cell lines, protocols, reagents and vectors which are reported in the publications and which might be 25 used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
DEFINITIONS
"ECMCAD" refers to the amino acid sequences of substantially purified ECMCAD
obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, marine, equine, 30 and human, and from any source, whether natural, synthetic, semi-synthetic, or recombinant.
The teen "agonist" refers to a molecule which intensi~xes or mimics the biological aetivity of ECMCAD. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of ECMCAD either by directly interacting with ECMCAD or by acting on components of the biological pathway in which ECMCAD
participates.
An "allelic variant" is an alternative form of the gene encoding ECMCAD.
Allelic variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. A
gene may have none, one, or many allelic variants of its naturally occurring form. Common mutational changes which give rise to allelic variants are generally ascribed to natural deletions, additions, or substitutions of nucleotides. Each of these types of changes may occur alone, or in combination with the others, one or more times in a given sequence.
"Altered" nucleic acid sequences encoding ECMCAD include those sequences with deletions, 1o insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as ECMCAD or a polypeptide with at least one functional characteristic of ECMCAD. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding ECMCAD, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide sequence IS encoding ECMCAD. The encoded protein may also be "altered," and may contain deletions, insertions, or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent ECMCAD. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, chaxge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological or immunological activity of ECMCAD is retained. For example, 2o negatively chaxged amino acids may include aspartic acid and glutamic acid, and positively charged amino acids may include lysine and arginine. Amino acids with uncharged polar side chains having similar hydrophilicity values may include: asparagine and glutamine; and serine and threonine. Amino acids with uncharged side chains having similar hydrophilicity values may include: leucine, isoleucine, and valine; glycine and alanine; and phenylalanine and tyrosine.
25 The terms "amino acid" and "amino acid sequence" refer to an oligopeptide, peptide, polypeptide, or protein sequence, or a fragment of any of these, and to naturally occurring or synthetic molecules. Where "amino acid sequence" is recited to refer to a sequence of a naturally occurring protein molecule, "amino acid sequence" and like terms are not meant to limit the amino acid sequence to the complete native amino acid sequence associated with the recited protein molecule.
30 "Amplification" relates to the production of additional copies of a nucleic acid sequence.
Amplification is generally carried out using polymerase chain reaction (PCR) technologies well known in the art.
The term "antagonist" refers to a molecule which inhibits or attenuates the biological activity of ECMCAD. Antagonists may include proteins such as antibodies, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of ECMCAD
either by directly interacting with ECMCAD or by acting on components of the biological pathway in which ECMCAD participates.
The term "antibody" refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab, F(ab')2, and Fv fragments, which are capable of binding an epitopic determinant.
Antibodies that bind ECMCAD polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired.
Commonly used carriers that are chemically coupled to peptides include bovine senun albumin, thyroglobulin, and keyhole limpet hemocyanin (KLI~. The coupled peptide is then used to immunize the animal.
The term "antigenic determinant" refers to that region of a molecule (i.e., an epitope) that makes contact with a particular antibody. When a protein or a fragment of a protein is used to immunize a host animal, numerous regions of the protein may induce the production of antibodies which bind specifically to antigenic determinants (particular regions or three-dimensional structures on the protein). An antigenic determinant may compete with the intact antigen (i.e., the immunogen used to elicit the immune response) for binding to an antibody.
The term "antisense" refers to any composition capable of base-pairing with the "sense"
(coding) strand of a specific nucleic acid sequence. Antisense compositions may include DNA; RNA;
peptide nucleic acid (PNA); oIigonucleotides having modified backbone linkages such as phosphorothioates, methylphosphonates, or benzylphosphonates; oligonucleotides having modified sugar groups such'as 2'-methoxyethyl sugars or 2'-methoxyethoxy sugars; or oligonucleotides having modified bases such as 5-methyl cytosine, 2'-deoxyuracil, or 7-deaza-2'-deoxyguanosine. Antisense molecules may be produced by any method including chemical synthesis or transcription. Once introduced into a cell, the complementary antisense molecule base-pairs with a naturally occurring nucleic acid sequence produced by the cell to form duplexes which block either transcription or translation. The designation "negative" or "minus" can refer to the antisense strand, and the designation "positive" or "plus" can refer to the sense strand of a reference DNA molecule.
The term "biologically active" refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise, "immunologically active" or "immunogenic"
refers to the capability of the natural, recombinant, or synthetic ECMCAD, or of any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.
"Complementary" describes the relationship between two single-stranded nucleic acid sequences that anneal by base-pairing. For example, 5'-AGT-3' pairs with its complement, 3'-TCA-5'.
A "composition comprising a given polynucleotide sequence" and a "composition comprising a given amino acid sequence" refer broadly to any composition containing the given polynucleotide or amino acid sequence. The composition may comprise a dry formulation or an aqueous solution.
Compositions comprising polynucleotide sequences encoding ECMCAD or fragments of ECMCAD
l0 may be employed as hybridization probes. The probes may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In hybridizations, the probe may be deployed in an aqueous solution containing salts (e.g., NaCI), detergents (e.g., sodium dodecyl sulfate;
SDS), and other components (e.g., Denhardt's solution, dry milk, salmon sperm DNA, etc.).
"Consensus sequence" refers to a nucleic acid sequence which has been subjected to repeated DNA sequence analysis to resolve uncalled bases, extended using the XLrPCR kit (Applied Biosystems, Foster City CA) in the 5' and/or the 3' direction, and resequenced, or which has been assembled from one or more overlapping cDNA, EST, or genomic DNA fragments using a computer program for fragment assembly, such as the GELVIEW fragment assembly system (GCG, Madison Wl7 or Phrap (University of Washington, Seattle WA). Some sequences have been both extended and assembled to produce the consensus sequence.
"Conservative amino acid substitutions" are those substitutions that axe predicted to least interfere with the properties of the original protein, i.e., the structure and especially the function of the protein is conserved and not significantly changed by such substitutions. The table below shows amino acids which may be substituted for an original amino acid in a protein and which are regarded as conservative amino acid substitutions.
Original Residue Conservative Substitution Ala Gly, Ser Arg His, Lys Asn Asp, Gln, His Asp Asn, Glu Cys Ala, Ser Gln Asn, Glu, His Glu Asp, Gln, His Gly Ala His Asn, Arg, Gln, Glu Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Thr Thr Ser, Val Trp Phe, Tyr Tyr His, Phe, Trp Val Ile, Leu, Thr to Conservative amino acid substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta sheet or alpha helical conformation, (b) the charge or hydrophobicity of the molecule at the site of the substitution, and/or (c) the bulk of the side chain.
A "deletion" refers to a change in the amino acid or nucleotide sequence that results in the 15 absence of one or more amino acid residues or nucleotides.
The term "derivative" refers to a chemically modified polynucleotide or polypeptide.
Chemical modifications of a polynucleotide can include, for example, replacement of hydrogen by an alkyl, acyl, hydroxyl, or amino group. A derivative polynucleotide encodes a polypeptide which retains at least one biological or immunological function of the natural molecule. A
derivative polypeptide is 20 one modified by glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the polypeptide from which it was derived.
A "detectable label" refers to a reporter molecule or enzyme that is capable of generating a measurable signal and is covalently ar noncovalently joined to a polynucleotide or polypeptide.
"Differential expression" refers to increased or upregulated; or decreased, downregulated, or 25 absent gene or protein expression, determined by comparing at least two different samples. Such comparisons may be carried out between, for example, a treated and an untreated sample, or a diseased and a normal sample.
A "fragment" is a unique portion of ECMCAD or the polynucleotide encoding ECMCAD
which is identical in sequence to but shorter in length than the parent sequence. A fragment may 30 comprise up to the entire length of the defined sequence, minus one nucleotide/amino acid residue.
For example, a fragment may comprise from 5 to 1000 contiguous nucleotides or amino acid residues.
A fragment used as a probe; primer, antigen, therapeutic molecule, or for other purposes, may be at least 5, 10, 15, 16, 20, 25, 30, 40, 50, 60, 75, 100, 150, 250 or at least 500 contiguous nucleotides or amino acid residues in length. Fragments may be preferentially selected from certain regions of a 35 molecule. For example, a polypeptide fragment may comprise a certain length of contiguous amino acids selected from the first 250 or 500 amino acids (or first 25% or 50°Io) of a polypeptide as shown 2o in a certain defined sequence. Clearly these lengths are exemplary, and any length that is supported by the specification, including the Sequence Listing, tables, and figures, may be encompassed by the present embodiments.
A fragment of SEQ ID N0:37-72 comprises a region of unique polynucleotide sequence that specifically identifies SEQ ID N0:37-72, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ ID N0:37-72 is useful, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ
ID N0:37-72 from related polynucleotide sequences. The precise length of a fragment of SEQ ID
N0:37-72 and the region of SEQ ID N0:37-72 to which the fragment corresponds are routinely l0 determinable by one of ordinary skill in the art based on the intended purpose for the fragment.
A fragment of SEQ ID NO:l-36 is encoded by a fragment of SEQ ID N0:37-72. A
fragment of SEQ ID NO:1-36 comprises a region of unique amino acid sequence that specifically identifies SEQ ID NO:1-36. For example, a fragment of SEQ ID NO:1-36 is useful as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID NO:1-36.
The precise length of a fragment of SEQ 1D N0:1-36 and the region of SEQ ID
N0:1-36 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.
A "full length" polynucleotide sequence is one containing at Ieast a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon. A "full length" polynucleotide sequence encodes a "full length" polypeptide sequence.
"Homology" refers to sequence similarity or, interchangeably, sequence identity, between two or more polynucleotide sequences or two or more polypeptide sequences.
The terms "percent identity" and "% identity," as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.
Percent identity between polynucleotide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e sequence alignment program. This program is part of the LASERGENE software package, a suite of molecular biological analysis programs (DNASTAR, Madison WI). CLUSTAL V is described in Higgins, D.G. and P.M. Sharp (1989) CABIOS 5:151-153 and in Higgins, D.G. et al. (1992) CABIOS
8:189-191. For pairwise alignments of polynucleotide sequences, the default parameters are set as follows: I~tuple=2, gap penalty=5, window=4, and "diagonals saved"=4. The "weighted" residue weight table is selected as the default. Percent identity is reported by CLUSTAL V as the "percent similarity" between aligned polynucleotide sequences.
Alternatively, a suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S.F. et al. (1990) J. Mol. Biol. 215:403-410), which is available from several sources, including the NCBI, Bethesda, MD, and on the Internet at http://www.ncbi.nlm.nih.govBLAST/. The BLAST software suite includes various sequence analysis programs including "blastn," that is used to align a known polynucleotide sequence with other l0 polynucleotide sequences from a variety of databases. Also available is a tool called "BLAST 2 Sequences" that is used for direct pairwise comparison of two nucleotide sequences. "BLAST 2 Sequences" can be accessed and used interactively at http:/lwww.ncbi.nlm.nih.gov/gorf/bl2.html. The "BLAST 2 Sequences" tool can be used for both blastn and blastp (discussed below). BLAST
programs are commonly used with gap and other parameters set to default settings. For example, to compare two nucleotide sequences, one may use blastn with the "BLAST 2 Sequences" tool Version 2Ø12 (April-21-2000) set at default parameters. Such default parameters may be, for example:
Matrix: BLOSUM62 Reward for match: 1 Penalty for mismatch: -2 Open Gap: 5 and Extension Gap: 2 penalties Gap x drop-off. 50 Expect: l0 Word Size: 11 Filter: on Percent identity may be measured over the length of an entire defined sequence, for example, as defined by a particular SEQ 1D number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures, or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein.
The phrases "percent identity" and "% identity," as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions. Such conservative substitutions, explained in more detail above, generally preserve the charge and hydrophobicity at the site.of substitution, thus preserving the structuxe (and therefore function) of the polypeptide.
Percent identity between polypeptide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e sequence alignment program (described and referenced above). For pairwise alignments of polypeptide sequences using CLUSTAL V, the default parameters are set as follows: I~tuple=1, gap penalty=3, window=5, and "diagonals saved"=5. The PAM250 matrix is selected as the default residue weight table. As with polynucleotide alignments, the percent identity is reported by CLUSTAL V as the "percent similarity" between aligned polypeptide sequence pairs.
Alternatively the NCBI BLAST software suite may be used. For example, for a pairwise comparison of two polypeptide sequences, one may use the "BLAST 2 Sequences"
tool Version 2Ø12 (April-21-2000) with blastp set at default parameters. Such default parameters ray be, for example:
Matrix: BLOSUM62 Opera Gap: 11 and Extefasioyz Gap: I penalties Gap x drop-off. 50 Expect: 10 Word Size: 3 Filter: ofi Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID nwnber, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
"Human artificial chromosomes" (HACs) are linear microchromosomes which may contain DNA 'sequences of about 6 kb to 10 Mb in size and which contain all of the elements required for chromosome replication, segregation and maintenance.
The term "humanized antibody" refers to an antibody molecule in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely resembles a human antibody, and still retains its original binding ability.
"Hybridization" refers to the process by which a polynucleotide strand anneals with a complementary strand through base pairing under defined hybridization conditions. Specific hybridization is an indication that two nucleic acid sequences share a high degree of complementarity.
Specific hybridization complexes form under permissive annealing conditions and remain hybridized l0 after the "washing" step(s). The washing steps) is particularly important in determining the stringency of the hybridization process, with more stringent conditions allowing less non-specific binding, i.e., binding between pairs of nucleic acid strands that axe not perfectly matched. Permissive conditions for annealing of nucleic acid sequences are routinely determinable by one of ordinary skill in the art and may be consistent among hybridization experiments, whereas wash conditions may be varied among experiments to achieve the desired stringency, and therefore hybridization specificity.
Permissive annealing conditions occur, for example, at 68°C in the presence of about 6 x SSC, about 1 % (w/v) SDS, and about 100 ~ g/ml sheared, denatured salmon sperm DNA.
Generally, stringency of hybridization is expressed, in part, with reference to the temperature under which the wash step is carried out. Such wash temperatures are typically selected to be about 5°C to 20°C lower than the thermal melting point (T~ for the specific sequence at a defined ionic strength and pH. The Tm i5 the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating Tm and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Cold Spring Harbor Press, Plainview NY;
specifically see volume 2, chapter 9.
High stringency conditions for hybridization between polynucleotides of the present invention include~'wash conditions of 68°C in the presence of about 0.2 x SSC and about 0.1 % SDS, for 1 hour.
Alternatively, temperatures of about 65°C, 60°C, 55°C, or 42°C may be used. SSC concentration may be varied from about 0.1 to 2 x SSC, with SDS being present at about 0.1 %.
Typically, blocking reagents are used to block non-specific hybridization. Such blocking reagents include, for instance, sheared and denatured salmon sperm DNA at about 100-200 ~.g/ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, may also be used under particular circumstances, such as for RNA:DNA hybridizations. Useful variations on these wash conditions will be readily apparent to those of ordinary skill in the art. Hybridization, particularly under high stringency conditions, may be suggestive of evolutionary similarity between the nucleotides. Such similarity is strongly indicative of a similar role for the nucleotides and their encoded polypeptides.
The term "hybridization complex" refers to a complex formed between two nucleic acid sequences by virtue of the formation of hydrogen bonds between complementary bases. A
hybridization complex may be formed in solution (e.g., Cot or Rot analysis) or foamed between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (e.g., paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells or their nucleic acids have been fixed).
The words "insertion" and "addition" refer to changes in an amino acid or nucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides, respectively.
"immune response" can refer to conditions associated with inflammation, trauma, immune disorders, or infectious or genetic disease, etc. These conditions can be characterized by expression of various factors, e.g., cytokines, chemokines, and other signaling molecules, which may affect cellular and systemic defense systems.
An "immunogenic fragment" is a polypeptide or oligopeptide fragment of ECMCAD
which is capable of eliciting an immune response when introduced into a living organism, for example, a mammal. The term "immunogenic fragment" also includes any polypeptide or oligopeptide fragment of ECMCAD which is useful in any of the antibody production methods disclosed herein or known in the art.
The term "microarray" refers to an arrangement of a plurality of polynucleotides, polypeptides, or other chemical compounds on a substrate.
The terms "element" and "array element" refer to a polynucleotide, polypeptide, or other chemical compound having a unique and defined position on a microarray.
The term "modulate" refers to a change in the activity of ECMCAD. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of ECMCAD.
The phrases "nucleic acid" and "nucleic acid sequence" refer to a nucleotide, oligonucleotide, polynucleotide, or any fragment thereof. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-like matexial.
"Operably linked" refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with a second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences may be in close proximity or contiguous and, where necessary to join two protein coding regions, in the same reading frame.
"Peptide nucleic acid" (PNA) refers to an antisense molecule or anti-gene agent which comprises an oligonucleotide of at least about 5 nucleotides in length linked to a peptide backbone of amino acid residues ending in lysine. The terminal lysine confers solubility to the composition. PNAs preferentially bind complementary single stranded DNA or RNA and stop transcript elongation, and may be pegylated to extend their lifespan in the cell.
"Post-translational modification" of an ECMCAD may involve lipidation, glycosylation, l0 phosphorylation, acetylation, racemization, proteolytic cleavage, and other modifications known in the art. These processes may occur synthetically or biochemically. Biochemical modifications will vary by cell type depending on the enzymatic milieu of ECMCAD.
"Probe" refers to nucleic acid sequences encoding ECMCAD, their complements, or fragments thereof, which are used to detect identical, allelic or related nucleic acid sequences. Probes are isolated oligonucleotides or polynucleotides attached to a detectable label or reporter molecule.
Typical labels include radioactive isotopes, ligands, chemiluminescent agents, and enzymes. "Primers'.' are short nucleic acids, usually DNA oligonucleotides, which may be annealed to a target polynucleotide by complementary base-pairing. The primer may then be extended along the target DNA strand by a DNA polymerase enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid sequence, e.g., by the polymerase chain reaction (PCR).
Probes and primers as used in the present invention typically comprise at least 15 contiguous nucleotides of a known sequence. In order to enhance specificity, longer probes and primers may also be employed, such as probes and primers that comprise at least 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, or at least 150 consecutive nucleotides of the disclosed nucleic acid sequences. Probes and primers may be considerably longer than these examples, and it is understood that any length supported by the specification, including the tables, figures, and Sequence Listing, may be used.
Methods for preparing and using probes and primers are described in the references, for example Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Cold Spring Haxbor Press, Plainview NY; Ausubel, F.M. et al. (1987) Current Protocols in Molecular Biolo~v, Greene Publ. Assoc. & Wiley-Intersciences, New York NY; Innis, M. et al. (1990) PCR
Protocols, A Guide to Methods and Applications, Academic Press, San Diego CA.
PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose such as Primer (Version 0.5, 1991, Whitehead Institute for Biomedical Research, Cambridge MA).
Oligonucleotides for use as primers are selected using software known in the art for such purpose. For example, OLIGO 4.06 software is useful for the selection of PCR
primer pairs of up to 100 nucleotides each, and for the analysis of oligonucleotides and larger polynucleotides of up to 5,000 nucleotides from an input polynucleotide sequence of up to 32 kilobases.
Similar primer selection programs have incorporated additional features for expanded capabilities. For example, the PrimOU
primer selection program (available to the public from the Genome Center at University of Texas South West Medical Center, Dallas TX) is capable of choosing specific primers from megabase sequences and is thus useful for designing primers on a genome-wide scope. The Primer3 primer selection program (available to the public from the Whitehead Institute/MIT
Center for Genome Research, Cambridge MA) allows the user to input a "mispriming library," in which sequences to avoid as primer binding sites are user-specified. Primer3 is useful, in particular, for the selection of oligonucleotides for microarrays. (The source code for the latter two primer selection programs may also be obtained from their respective sources and modified to meet the user's specific needs.) The PrimeGen program (available to the public from the UK Human Genome Mapping Project Resource Centre, Cambridge UK) designs primers based on multiple sequence alignments, thereby allowing selection of primers that hybridize to either the most conserved or least conserved regions of aligned nucleic acid sequences. Hence, this program is useful for identification of both unique and conserved oligonucleotides and polynucleotide fragments. The oligonucleotides and polynucleotide fragments identified by any of the above selection methods are useful in hybridization technologies, for example, as PCR or sequencing primers, microarray elements, or specific probes to identify fully or partially complementary polynucleotides in a sample of nucleic acids. Methods of oligonucleotide selection are not limited to those described above.
A "recombinant nucleic acid" is a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two or more otherwise separated segments of sequence.
This, artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques , such as those described in Sambrook, supra. The term recombinant includes nucleic acids that have been altered solely by addition, substitution, or deletion of a portion of the nucleic acid. Frequently, a 3o recombinant nucleic acid may include a nucleic acid sequence operably linked to a promoter sequence.
Such a recombinant nucleic acid may be part of a vector that is used, for example, to transform a cell.
Alternatively, such recombinant nucleic acids may be part of a viral vector, e.g., based on a vaccinia virus, that could be use to vaccinate a mammal wherein the recombinant nucleic acid is expressed, inducing a protective immunological response in the mammal.
A "regulatory element" refers to a nucleic acid sequence usually derived from untranslated regions of a gene and includes enhancers, promoters, introns, and 5' and 3' untranslated regions (UTRs). Regulatory elements interact with host or viral proteins which control transcription, translation, or RNA stability.
"Reporter molecules" are chemical or biochemical moieties used for labeling a nucleic acid, amino acid, or antibody. Reporter molecules include radionuclides; enzymes;
fluorescent, chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors;
magnetic particles; and other moieties known in the art.
An "RNA equivalent," in reference to a DNA sequence, is composed of the same linear sequence of nucleotides as the reference DNA sequence with the exception that all occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.
The term "sample" is used in its broadest sense. A sample suspected of containing ECMCAD, nucleic acids encoding ECMCAD, or fragments thereof may comprise a bodily fluid; an extract from a cell, chromosome, organelle, or membrane isolated from a cell;
a cell; genomic DNA, RNA, or cDNA, in solution or bound to a substrate; a tissue; a tissue print;
etc.
The terms "specific binding" and "specifically binding" refer to that interaction between a protein or peptide and an agonist, an antibody, an antagonist, a small molecule, or any natural or synthetic binding composition. The interaction is dependent upon the presence of a particular structure of the protein, e.g., the antigenic determinant or epitope, recognized by the binding molecule. For example, if an antibody is specific for epitope "A," the presence of a polypeptide comprising the epitope A, or the presence of free unlabeled A, in a reaction containing free labeled A and the antibody will reduce the amount of labeled A that binds to the antibody.
The term "substantially purified" refers to nucleic acid or amino acid sequences that are removed from their natural environment and are isolated or separated, and are at least 60% free, preferably at least 75% free, and most preferably at least 90% free from other components with which they are naturally associated.
A "substitution" refers to the replacement of one or more amino acid residues or nucleotides by different amino acid residues or nucleotides, respectively.
"Substrate" refers to any suitable rigid or semi-rigid support including membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing, plates, polymers, microparticles and capillaries. The substrate can have a variety of surface forms, such as wells, trenches, pins, channels and pores, to which polynucleotides or polypeptides are bound.
A "transcript image" refers to the collective pattern of gene expression by a particular cell type or tissue under given conditions at a given time.
"Transformation" describes a process by which exogenous DNA is introduced into a recipient cell. Transformation may occur under natural or artificial conditions according to various methods well known in the art, and may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method for transformation is selected based on the type of host cell being transformed and may include, but is not limited to, bacteriophage or viral infection, electroporation, heat shock, lipofection, and particle bombardment.
The term "transformed 1o cells" includes stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome, as well as transiently, transformed cells which express the inserted DNA or RNA for limited periods of time.
A "txansgenic organism," as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by txansgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA
molecule. The transgenic organisms contemplated in accordance with the present invention include bacteria, cyanobacteria, fungi, plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or transconjugation.
Techniques for transferring the DNA of the present invention into such organisms a~~e widely known and provided in references such as Sambrook et al. (1989), supra.
A "variant" of a particular nucleic acid sequence is defined as a nucleic acid sequence having at least 40% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such a pair of nucleic acids may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length. A variant may be described as, for example, an "allelic" (as defined above), "splice," "species," or "polymorphic" variant. A
splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternative splicing of exons during mRNA processing.
The corresponding polypeptide may possess additional functional domains or lack domains that are present in the reference molecule. Species variants are polynucleotide sequences that vary from one species to another. The resulting polypeptides will generally have significant amino acid identity relative to each other. A polymorphic variant is a variation in the polynucleotide sequence of a particular gene between individuals of a given species. Polymoiphic variants also may encompass "single nucleotide polymorphisms" (SNPs) in which the polynucleotide sequence varies by one nucleotide base. The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.
A "variant" of a particular polypeptide sequence is defined as a polypeptide sequence having at least 40% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such a pair of polypeptides may show, for example, at least 50%, at least 60%, at Least 70%, at least 80%, at Ieast 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%
or greater sequence identity over a certain defined length of one of the polypeptides.
THE INVENTION
The invention is based on the discovery of new human extxacellular matrix and cell adhesion molecules (ECMCAD), the polynucleotides encoding ECMCAD, and the use of these compositions for the diagnosis, treatment, or prevention of genetic, immune/inflammatory, developmental, .
neurological, connective tissue, and cell proliferative disorders, including cancer.
Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide sequences of the invention. Each polynucleotide and its corresponding polypeptide are correlated to a single Incyte project identification number (Incyte Project 1D). Each polypeptide sequence is denoted by both a polypeptide sequence identification number (Polypeptide SEQ 117 NO:) and an Incyte polypeptide sequence number (Incyte Polypeptide ID) as shown. Each polynucleotide sequence is denoted by both a polynucleotide sequence identification number (Polynucleotide SEQ )D NO:) and an Incyte polynucleotide consensus sequence number (Incyte Polynucleotide 1D) as shown.
Table 2 shows sequences with homology to the polypeptides of the invention as identified by BLAST analysis against the GenBank protein (genpept) database. Columns 1 and 2 show the polypeptide sequence identification number (Polypeptide SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for polypeptides of the invention. Column 3 shows the GenBank identification number (Genbank ID NO:) of the nearest GenBank homolo8.
Column 4 shows the probability score for the match between each polypeptide and its GenBank homolog. Column 5 shows the annotation of the GenBankhomolog along with relevant citations where applicable, all of which are expressly incorporated by reference herein.
Table 3 shows various structural features of the polypeptides of the invention. Columns l and 2 show the polypeptide sequence identification number (SEQ m NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide m) for each polypeptide of the invention. Column 3 shows the number of amino acid residues in each polypeptide. Column 4 shows potential phosphorylation sites, and column 5 shows potential glycosylation sites, as determined by the MOTIFS
to program of the GCG sequence analysis software package (Genetics Computer Group, Madison WI).
Column 6 shows amino acid residues comprising signature sequences, domains, and motifs. Column 7 shows analytical methods for protein structure/function analysis and in some cases, searchable databases to which the analytical methods were applied.
Together, Tables 2 and 3 summarize the properties of polypeptides of the invention, and these properties establish that the claimed polypeptides are extracellular matrix and cell adhesion molecules.
For example, SEQ ID N0:2 is 48% identical over 46.% of its length to mouse procollagen type I alpha chain, (GenBank ID 8192264) as determined by the Basic Local Alignment Search Tool (BLAST).
(See Table 2.) The BLAST probability score is 6.9e-46, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:2 also contains a collagen triple helix repeat, as determined by searching for statistically significant matches in the PFAM database.
(See Table 3.) HMMER and SPSCAN analyses indicate the presence of a signal peptide at the N-terminus of SEQ ID N0:2. Data from BLAST analysis of the PRODOM and DOMO
databases, as well as MOTIFS analysis, provide further corroborative evidence that SEQ ID
N0:2 is a cellular matrix protein associated with cell adhesion. In an alternative example, SEQ
ID N0:6 is 64%
identical to frog MAM domain protein (GenBank ID 81234793) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 4.2e-254, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ
ID N0:6 also contains four MAM domains as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family 3o domains. (See Table 3.) Data from MOTIFS analysis provide further corroborative evidence that SEQ ID N0:6 is a MAM domain cell adhesion protein. In an alternative example, SEQ 1D N0:10 is 80% identical to marine semaphorin B (GenBank ID 8854326) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 6.0e-66, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ
ID N0:10 also contains a sema domain as determined by searching for statistically significant matches in the hidden Markov model (I3MM)-based PFAM database of conserved protein family domains.
(See Table 3.) The BLAST and HMMER analyses provide evidence that SEQ ID N0:10 is a semaphorin. SEQ ID N0:12 is 44% identical to human cadherin superfamily protein VR4-11 (GenBank )D 89622240) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 9.9e-170, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:12 also contains a cadherin domain as deternuned by searching for statistically significant matches in the hidden Markov model (HIvIM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ ID N0:12 is a cadherin. SEQ 1D N0:14 is 91 % identical to marine neuronal glycoprotein (GenBank ID
8200057) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ B? N0:14 also contains fibronectin type III
and immunoglobulin domains as determined by searching for statistically significant matches in the hidden Markov model .
(HMM)-based PFAM database of conserved protein family domains. (See Table 3.) The BLAST
and HMMER analyses provide evidence that SEQ ID N0:14 is a cell adhesion molecule. In an alternative example, SEQ D7 N0:22 is 79% identical to mouse laminin 5 alpha chain (GenBank ID
82599232) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The .
BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide s sequence alignment by chance. SEQ ID N0:22 also contains a laminin N-terminal domain, multiple laminin EGF-like domains, a laminin B domain, and laminin G domains, as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM
database of conserved protein family domains. (See Table 3.) Data from BLIMPS, and MOTIFS
analyses provide further corroborative evidence that SEQ ID N0:22 is a laminin. In an alternative example, SEQ ID N0:24 is 89% identical to Bos taurus brevican (GenBank ID 8452821) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance.
SEQ 1D N0:24 also contains a lectin C-type domain, an extracellular link domain, an EGF-like domain, a sushi domain, and an immunoglobulin domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ m N0:24 is a c-type lectin. In an alternative example, SEQ
)D N0:31 is 87% identical to a mouse semaphorin homolog (GenBank ID 81110599) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:31 also contains a Sema domain and a plexin repeat as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein fanuly domains. (See Table 3.) Data from BLAST analyses against the DOMO
and PRODOM databases provide further corroborative evidence that SEQ ID N0:31 is a semaphorin. In an alternative example, SEQ ID N0:35 is 61 % identical to marine C-type lectin l0 (GenBank 1D 84159801) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 2.9e-75, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ~Il7 N0:35 also eontains a lectin C-type domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS and PROFIL,ESCAN analyses provide further corroborative evidence that SEQ ID NO:35 is a lectin. SEQ ID N0:1, SEQ >D N0:3-5, SEQ )D N0:7-9, SEQ )D NO:11, SEQ ID
N0:13, SEQ
ID NO:15-21, SEQ m NO:23, SEQ ID NO:25-30, SEQ ID N0:32-34 and SEQ 1D N0:36 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ
ID NO:1-36 are described in Table 7.
As shown in Table 4, the full length polynucleotide sequences of the present invention were assembled using cDNA sequences or coding (exon) sequences derived from genomic DNA, or any combination of these two types of sequences. Columns 1 and 2 list the polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and the corxesponding Incyte polynucleotide consensus sequence number (Incyte Polynucleotide 1D) for each polynucleotide of the invention.
Column 3 shows the length of each polynucleotide sequence in basepairs. Column 4 lists fragments of the polynucleotide sequences which are useful, for example, in hybridization or amplification technologies that identify SEQ ID N0:37-72 or that distinguish between SEQ ID
NO:37-72 and related polynucleotide sequences. Column. 5 shows identification numbers corresponding to cDNA
sequences, coding sequences (exons) predicted from genomic DNA, and/or sequence assemblages 3o comprised of both cDNA and genomic DNA. These sequences were used to assemble the full length polynucleotide sequences of the invention. Columns 6 and 7 of Table 4 show the nucleotide start (5') and stop (3') positions of the cDNA and/or genomic sequences in column 5 relative to their respective full length sequences.

The identification numbers in Column 5 of Table 4 may refer specifically, for example, to Incyte cDNAs along with their corresponding cDNA libraries. For example, 7347284H1 is the identification number of an Incyte cDNA sequence, and LLTNLTLTE01 is the cDNA
library from which it is derived. Incyte cDNAs for which cDNA libraries are not indicated were derived from pooled cDNA libraries (e.g., 71699406V1). Alternatively, the identification numbers in column 5 may refer to GenBank cDNAs or ESTs (e.g., g1242437) which contributed to the assembly of the full length polynucleotide sequences. Alternatively, the identification numbers in column 5 may refer to coding regions predicted by Genscan analysis of genomic DNA. For example, GNN.g7923864_002 is the identification number of a Genscan-predicted coding sequence, with g7923864 being the GenBank 1o identification number of the sequence to which Genscan was applied. The Genscan-predicted coding sequences may have been edited prior to assembly. (See Example IV.) Alternatively, the identification numbers in column 5 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an "exon stitching" algorithm. (See Example V.) Alternatively, the identification numbers in column 5 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an "exon-stretching" algorithm. For example, FL2428715_g6815043 000026_g8052237_1_3_4.edit is the identification number of a "stretched"
sequence, with 2428715 being the Incyte project identification number, g6815043 being the GenB ank identification number of the human genomic sequence to which the "exon-stretching" algorithm was .
applied, and g8052237 being the GenBank identification number of the nearest GenBank protein homolog. (See Example V.) In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in column 5 was obtained to confirm the final consensus polynucleotide sequence, but the relevant Incyte cDNA identification numbers are not shown.
Table 5 shows the representative cDNA libraries for those full length polynucleotide sequences which were assembled using Incyte cDNA sequences. The representative cDNA library is the Incyte cDNA library which is most frequently represented by the Incyte cDNA sequences which were used to assemble and confirm the above polynucleotide sequences.
The tissues and vectors which were used to construct the cDNA libraries shown in Table 5 are described in Table 6.
The invention also encompasses ECMCAD variants. A preferred ECMCAD variant is one which has at least about 80%, or alternatively at least about 90%, or even at least about 95% amino acid sequence identity to the ECMCAD amino acid sequence, and which contains at least one functional or structural characteristic of ECMCAD.
The invention also encompasses polynucleotides which encode ECMCAD. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID N0:37-72, which encodes ECMCAD. The polynucleotide sequences of SEQ ID N0:37-72, as presented in the Sequence Listing, embrace the equivalent RNA
sequences, wherein occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.
The. invention also encompasses a variant of a polynucleotide sequence encoding ECMCAD.
In particular, such a variant polynucleotide sequence will have at least about 70%, or alternatively at least about 85%, ox even at least about 95% polynucleotide sequence identity to the polynucleotide sequence encoding ECMCAD. A particular aspect of the invention encompasses a variant of a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ )D N0:37-72 which has at least about 70%, or alternatively at least about 85%, or even at least about 95%
polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ
ID N0:37-72. Any one of the polynucleotide variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of ECMCAD.
It will be appreciated by those skilled in the art that as a result of the degeneracy of the genetic code, a multitude of polynucleotide sequences encoding ECMCAD, some bearing minimal similarity to the polynucleotide sequences of any known and naturally occurring gene, may be produced. Thus, the invention contemplates each and every possible variation of polynucleotide sequence that could be made by selecting combinations based on possible codon choices. These combinations are made in accordance with the standard triplet genetic code as applied to the polynucleotide sequence of naturally occurring ECMCAD, and all such variations are to be considered as being specifically disclosed.
Although nucleotide sequences which encode ECMCAD and its variants are generally capable of hybridizing to the nucleotide sequence of the naturally occurring ECMCAD under appropriately selected conditions of stringency, it may be advantageous to produce nucleotide sequences encoding ECMCAD or its derivatives possessing a substantially different codon usage, e.g., inclusion of non-naturally occurring codons. Codons may be selected to increase the rate at which expression of the peptide occurs in a particular prokaryotic or eukaryotic host in accordance with the frequency with which particular codons are utilized by the host. Other reasons for substantially altering the nucleotide sequence encoding ECMCAD and its derivatives without altering the encoded amino acid sequences include the production of RNA transcripts having more desirable properties, such as a greater half life, than transcripts produced from the naturally occurring sequence.
The invention also encompasses production of DNA sequences which encode ECMCAD
and ECMCAD derivatives, or fragments thereof, entirely by synthetic chemistry.
After production, the synthetic sequence may be inserted into any of the many available expression vectors and cell systems using reagents well known in the art. Moreover, synthetic chemistry may be used to introduce mutations into a sequence encoding ECMCAD or any fragment thereof.
Also encompassed by the invention are polynucleotide sequences that are capable of hybridizing to the claimed polynucleotide sequences, and, in particular, to those shown in SEQ ID
N0:37-72 and fragments thereof under various conditions of stringency. (See, e.g., Wahl, G.M. and S.L. Berger (1987) Methods Enzymol. 152:399-407; I~immel, A.R. (1987) Methods Enzymol. 152:507-511.) Hybridization conditions, including annealing and wash conditions, are described in "Definitions."
Methods for DNA sequencing are well known in the art and may be used to practice any of the embodiments of the invention. The methods may employ.such enzymes as the Klenow fragment of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland OH), Taq polymerase (Applied Biosystems), thermostable T7 polymerase (Amersham Pharmacia Biotech, Piscataway NJ), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE
amplification system (Life Technologies, Gaithersburg MD). Preferably, sequence preparation is automated with machines such as the MICROLAB 2200 liquid transfer system (Hamilton, Reno NV), PTC200 thermal cycler (MJ Research, Watertown MA) and ABI CATALYST 800 thermal cycler (Applied Biosystems). Sequencing is then carried out using either the ABI 373 or 377 DNA
sequencing system (Applied Biosystems), the MEGABACE 1000 DNA sequencing system (Molecular Dynamics, Sunnyvale CA), or other systems known in the art. The resulting sequences are analyzed using a variety of algorithms which are well known in the art.
(See, e.g., Ausubel, F.M.
(1997) Short Protocols in Molecular Biolo~y, John Wiley & Sons, New York NY, unit 7.7; Meyers, R.A. (1995) Molecular Biolo~v and Biotechnology, Wiley VCH, New York NY, pp.
856-853.) The nucleic acid sequences encoding ECMCAD may be extended utilizing a partial nucleotide sequence and employing various PCR-based methods known in the art to detect upstream sequences, such as promoters and regulatory elements. For example, one method which may be employed, restriction-site PCR, uses universal and nested primers to amplify unknown sequence from genomic DNA within a cloning vector. (See, e.g., Sarkar, G. (1993) PCR Methods Applic.
2:318-322.) Another method, inverse PCR, uses ,primers that extend in divergent directions to amplify unknown sequence from a circularized template. The template is derived from restriction fragments comprising a known genomic locus and surrounding sequences. (See, e.g., Triglia, T. et al. (1988) Nucleic Acids Res. 16:8186.) A third method, capture PCR, involves PCR amplification of DNA
fragments adjacent to known sequences in human and yeast artificial chromosome DNA. (See, e.g., Lagerstrom, M. et al, (1991) PCR Methods Applic. 1:111-119.) In this method, multiple restriction enzyme digestions and ligations may be used to insert an engineered double-stranded sequence into a region of unlmown sequence before performing PCR. Other methods which may be used to retrieve unknown sequences are known in the art. (See, e.g., Parker, J.D. et al. (1991) Nucleic Acids Res. 19:3055-3060).
Additionally, one may use PCR, nested primers, and PROMOTERFINDER libraries (Clontech, Palo Alto CA) to walk genomic DNA. This procedure avoids the need to screen libraries and is useful in finding intron/exon junctions. For all PCR-based methods, primers may be designed using commercially available software, such as OLIGO 4.06 primer analysis software (National Biosciences, Plymouth MN) or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the template at temperatures of about i0 68°C to 72°C.
When screening for full length cDNAs, it is preferable to use libraries that have been size-selected to include larger cDNAs. In addition, random-primed libraries, which often include sequences containing the 5' regions of genes, are preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomic libraries may be useful for extension of sequence into S' non-transcribed regulatory regions.
Capillary electrophoresis systems which are commercially available may be used to analyze the size or confirm the nucleotide sequence of sequencing or PCR products. In particular, capillary sequencing may employ flowable polymers for electrophoretic separation, four different nucleotide-specific, laser-stimulated fluorescent dyes, and a charge coupled device camera for detection of the emitted wavelengths. Outputllight intensity may be converted to electrical signal using appropriate software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Applied Biosystems), and the entire process from loading of samples to computer analysis and electronic data display may be computer controlled. Capillary electrophoresis is especially preferable for sequencing small DNA fragments which may be present in limited amounts in a particular sample.
In another embodiment of the invention, polynucleotide sequences or fragments thereof which encode ECMCAD may be cloned in recombinant DNA molecules that direct expxession of ECMCAD, or fragments or functional equivalents thereof, in appropriate host cells. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be produced and used to express ECMCAD.
The nucleotide sequences of the present invention can be engineered using methods generally known in the art in order to alter ECMCAD-encoding sequences for a variety of purposes including, but not limited to, modification of the cloning, processing, and/or expression of the gene product. DNA
shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. For example, oIigonucleotide-mediated site-directed mutagenesis may be used to introduce mutations that create new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth.
The nucleotides of the present invention may be subjected to DNA shuffling techniques such as MOLECULARBREEDING (Maxygen Inc., Santa Clara CA; described in U.S. Patent Number 5,837,458; Chang, C.-C. et al. (1999) Nat. Biotechnol. 17:793-797; Christians, F.C. et al. (1999) Nat.
Biotechnol. 17:259-264; arid Crameri, A. et al. (1996) Nat. Biotechnol. 14:315-319) to alter or improve the biological properties of ECMCAD, such as its biological or enzymatic activity or its ability to bind to other molecules or compounds. DNA shuffling is a process by which a library of gene variants is l0 produced using PCR-mediated recombination of gene fragments. The library is then subjected to selection or screening procedures that identify those gene variants with the desired properties. These preferred variants may then be pooled and further subjected to recursive rounds of DNA shuffling and selection/screening. Thus, genetic diversity is created through "artificial"
breeding and rapid molecular evolution. For example, fragments of a single gene containing random point mutations may be recombined, screened, and then reshuffled until the desired properties are optimized. Alternatively, fragments of a given gene may be recombined with fragments of homologous genes in the same gene family, either from the same or different species, thereby maximizing the genetic diversity of multiple naturally occuW ng genes in a directed and controllable manner.
In another embodiment, sequences encoding ECMCAD may be synthesized, in whole or in part, using chemical methods well known in the art. (See, e.g., Caruthers, M.H. et al. (1980) Nucleic Acids Symp. Ser. 7:215-223; and Horn, T. et al. (1980) Nucleic Acids Symp.
Ser. 7:225-232.) Alternatively, ECMCAD itself or a fragment thereof may be synthesized using chemical methods.
For example, peptide synthesis can be performed using various solution-phase or solid-phase techniques. (See, e.g., Creighton, T. (1984) Proteins, Structures and Molecular Properties, WH, Freeman, New York NY, pp. 55-60; and Roberge, J.Y. et al. (1995) Science 269:202-204.) Automated synthesis may be achieved using the ABI 431A peptide synthesizer (Applied Biosystems).
Additionally, the amino acid sequence of ECMCAD, or any part thereof, may be altered during direct synthesis and/or combined with sequences from other proteins, or any part thereof, to produce a variant polypeptide or a polypeptide having a sequence of a naturally occurring polypeptide.
The peptide may be substantially purified by preparative high performance liquid chromatography. (See, e.g., Chiez, R.M. and F.Z. Regnier (1990) Methods Enzymol. 182:392-421.) The composition of the synthetic peptides may be confirmed by amino acid analysis or by sequencing.
(See, e.g., Creighton, supra, pp, 28-53.) In order to express a biologically active ECMCAD, the nucleotide sequences encoding ECMCAD or derivatives thereof may be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for transcriptional and translational control of the inserted coding sequence in a suitable host. These elements include regulatory sequences, such as enhancers, constitutive and inducible promoters, and 5' and 3' untranslated regions in the vector and in polynucleotide sequences encoding ECMCAD. Such elements may vary in their strength and specificity. Specific initiation signals may also be used to achieve more efficient translation of sequences encoding ECMCAD. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where sequences encoding ECMCAD
and its initiation l0 codon and upstream regulatory sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed.
However, in cases where only coding sequence, or a fragment thereof, is inserted, exogenous translational control signals including an in-frame ATG initiation codon should be provided by the vector.
Exogenous translational elements and initiation codons may be of various origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of enhancers appropriate for the particular host cell system used. (See, e.g., Scharf, D. et al. (1994} Results Probl. Cell Differ.
20:125-162.) Methods which are well known to those skilled in the art may be used to construct expression vectors containing sequences encoding ECMCAD and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. (See, e.g., Sambrook, J. et al. (1989) Molecular Cloning, A
Laborator~i Manual, Cold Spring Harbor Press, Plainview NY, ch. 4, 8, and 16-17; Ausubel, F.M. et al. (1995) Current Protocols in Molecular Biolo~y, John Wiley & Sons, New York NY, ch. 9, 13, and 16.) A variety of expression vector/host systems may be utilized to contain and express sequences encoding ECMCAD, These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with viral expression vectors (e.g., baculovirus); plant cell systems transformed with viral expression vectors (e.g., cauliflower mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g., Ti or pBR322 plasmids); or animal cell systems. (See, e.g., 'Sambrook, supra;
Ausubel, supra; Van Heeke, G. and S.M. Schuster (1989) J. Biol. Chem. 264:5503-5509; Engelhard, E.K. et aI. (1994) Proc. Natl.
Acad. Sci. LTSA 91:3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther. 7:1937-1945; Takamatsu, N.
(1987) EMBO J. 6:307-311; The McGraw Hill Yearbook of Science and Technolo~y (1992) McGraw Hill, New York NY, pp. 191-196; Logan, J. and T. Shenk (1984) Proc. Natl.
Acad. Sci. USA
81:3655-3659; and Harrington, J.J. et al. (1997) Nat. Genet. 15:345-355.) Expression vectors derived from retroviruses, adenoviruses, or herpes or vaccinia viruses, or from various bacterial plasmids, may be used fox delivery of nucleotide sequences to the targeted organ, tissue, or cell population. (See, e.g., Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5(6):350-356; Yu, M. et al. (1993) Proc. Natl.
Acad. Sci. USA 90(13):6340-6344; Buller, R.M. et aI. (1985) Nature 317(6040):813-815; McGregor, D.P. et al. (1994) Mol. Immunol. 31(3):219-226; and Verma, LM. and N. Somia (1997) Nature 389:239-242.) The invention is not limited by the host cell employed.
In bacterial systems, a number of cloning and expression vectors may be selected depending i0 upon the use intended for polynucleotide sequences encoding ECMCAD. For example, routine cloning, subcloning, and propagation of polynucleotide sequences encoding ECMCAD can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla CA) or PSPORTl plasmid (Life Technologies). Ligation of sequences encoding ECMCAD
into the vector's multiple cloning site disrupts the lacZ gene, allowing a colorimetric screening procedure for identification of transformed bacteria containing recombinant molecules. In addition, these vectors may be useful for in vitro transcription, dideoxy sequencing, single strand rescue with helper phage, and creation of nested deletions in the cloned sequence. (See, e.g., Van Heeke, G. and S.M. Schuster (1989) J. Biol. Chem. 264:5503-5509.) When large quantities of ECMCAD are needed, e.g. for the production of antibodies, vectors which direct high level expression of ECMCAD
may be used. For example, vectors containing the strong, inducible SP6 or T7 bacteriophage promoter may be used.
Yeast expression systems may be used for production of ECMCAD. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH
promoters, may be used in the yeast Saccharomvces cerevisiae or Pichia pastoris. In addition, such vectors direct either the secretion ox intracellular retention of expressed proteins and enable integration of foreign sequences into the host genome for stable propagation. (See, e.g., Ausubel, 1995, supra;
Bitter, G.A. et al. (1987) Methods Enzymol. 153:516-544; and Scorer, C.A. et al. (1994) BiolTechnology 12:181-184.) Plant systems may also be used for expression of ECMCAD. Transcription of sequences encoding ECMCAD may be driven by viral promoters, e.g., the 35S and 19S
promoters of CaMV
used alone or in combination with the omega leader sequence from TMV
(Takamatsu, N. (1987) EMBO J. 6:307-311). Alternatively, plant promoters such as the small subunit of RUBISCO or heat shock promoters may be used. (See, e.g., Coruzzi, G. et al. (1984) EMBO J.
3:1671-1680; Brogue, R.
et al. (1984) Science 224:838-843; and Winter, J. et al. (1991) Results Probl.
Cell Differ. 17:85-105.) These constructs can be introduced into plant cells by direct DNA
transformation or pathogen-mediated transfection. (See, e.g., The McGraw Hill Yearbook of Science and Technolo~y (1992) McGraw Hill, New York NY, pp. 191-196.) In mammalian cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, sequences encoding ECMCAD
may be ligated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader sequence. Insertion in a non-essential El or E3 region of the viral genome may be used to obtain infective virus which expresses ECMCAD in host cells. (See, e.g., Logan, J.
and T. Shenk (1984) Proc. Natl. Acad. Sci. USA 81:3655-3659.) In addition, transcription enhancers, such as the Rous l0 sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells. SV40 or EBV-based vectors may also be used for high-level protein expression.
Human artificial chromosomes (HACs) may also be employed to deliver larger fragments of DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb to 10 Mb are constructed and delivered via conventional delivery methods (liposomes, polycationic amino polymers, or vesicles) for therapeutic purposes. (See, e.g., Harrington, J.J. et al.
(1997) Nat. Genet. 15:345-355.) For long term production of recombinant proteins in mammalian systems, stable expression of ECMCAD in cell lines is preferred. For example, sequences encoding ECMCAD can be transformed into cell lines using expression vectors which may contain viral origins of replication and/or 2o endogenous expression elements and a selectable marker gene on the same or on a separate vector.
Following the introduction of the vector, cells may be allowed to grow for about 1 to 2 days in enriched media before being switched to selective media. The purpose of the selectable marker is to confer resistance to a selective agent, and its presence allows growth and recovery of cells which successfully express the introduced sequences. Resistant clones of stably transformed cells may be propagated using tissue culture techniques appropriate to the cell type.
Any number of selection systems may be used to recover transformed cell lines.
These include, but are not limited to, the herpes simplex virus thymidine kinase and adenine phosphoribosyltransferase genes, for use in tl~ and apr cells, respectively.
(See, e.g., Wigler, M. et al. (1977) Cell 11:223-232; Lowy, I. et al. (1980) Cell 22:817-823.) Also, antimetabolite, antibiotic, or herbicide resistance can be used as the basis for selection. For example, dhfr confers resistance to methotrexate; neo confers resistance to the aminoglycosides neomycin and G-418; and als and pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively. (See, e.g., Wigler, M. et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1-14.) Additional selectable genes have been described, e.g., trpB and hisD, which alter cellular requirements for metabolites. (See, e.g., Hartman, S.C. and R.C. Mulligan (1988) Proc.
Nail. Acad. Sci. USA 85:8047-8051.) Visible markers, e.g., anthocyanins, green fluorescent proteins (GFP; Clontech),13 glucuronidase and its substrate J3-glucuronide, or luciferase and its substrate luciferin may be used. These markers can be used not only to identify transformants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system.
(See, e.g., Rhodes, C.A. (1995) Methods Mol. Biol. 55:121-131.) Although the presence/absence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be confirmed. For example, if the sequence encoding ECMCAD is inserted within a marker gene sequence, transformed cells containing sequences encoding ECMCAD can be identified by the absence of marker gene function.
Alternatively, a marker gene can be placed in tandem with a sequence encoding ECMCAD under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
In general, host cells that contain the nucleic acid sequence encoding ECMCAD
and that express ECMCAD may be identified by a variety of procedures known to those of skill in the art.
These procedures include, but are not limited to, DNA-DNA or DNA-RNA
hybridizations, PCR
amplification, and protein bioassay or immunoassay techniques which include membrane, solution, or chip based technologies for the detection andlor quantification of nucleic acid or protein sequences.
2o T_m_m__unological methods for detecting and measuring the expression of ECMCAD using either specific polyclonal or monoclonal antibodies are known in the art. Examples of such techniques include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and fluorescence activated cell sorting (FACS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on ECMCAD is preferred, but a competitive binding assay may be employed. These and other assays are well known in the art. (See, e.g., Hampton, R. et al. (1990) Serological Methods, a Laboratory Manual, APS
Press, St. Paul MN, Sect. IV; Coligan, J.E. et al. (1997) Current Protocols in Immunolo~v, Greene Pub. Associates and Wiley-Interscience, New York NY; and Pound, J.D. (1998) Immunochemical Protocols, Humana Press, Totowa NJ.) A wide variety of labels and conjugation techniques are known by those skilled in the art and may be used in various nucleic acid and amino acid assays. Means for producing labeled hybridization or PCR probes for detecting sequences related to polynucleotides encoding ECMCAD include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide.

Alternatively, the sequences encoding ECMCAD, or any fragments thereof, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of an appropriate RNA
polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures may be conducted using a variety of commercially available kits, such as those provided by Amersham Pharmacia Biotech, Promega (Madison WI), and LTS Biochemical. Suitable reporter molecules or labels which may be used for ease of detection include radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles, and the like.
Host cells transformed with nucleotide sequences encoding ECMCAD may be cultured under conditions suitable for the expression and recovery of the protein from cell culture. The protein produced by a transformed cell may be secreted or retained intracellularly depending on the sequence and/or the vector used. As will be understood by those of skill in the art, expression vectors containing polynucleotides which encode ECMCAD may be designed to contain signal sequences which direct secretion of ECMCAD through a prokaryotic or eukaryotic cell membrane.
In addition, a host cell strain may be chosen for its ability to modulate expression of the inserted sequences or to process the expressed protein in the desired fashion.
Such modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. Post-translational processing which cleaves a "prepro" or "pro" form of the protein may also be used to specify protein targeting, folding, and/or activity. Different host cells which have specific cellular machinery and characteristic mechanisms for post-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and WI38) are available from the American Type Culture Collection (ATCC, Manassas VA) and may be chosen to ensure the correct modification and processing of the foreign protein.
In another embodiment of the invention, natural, modified, or recombinant nucleic acid sequences encoding ECMCAD may be ligated to a heterologous sequence resulting in translation of a fusion protein in any of the aforementioned host systems. For example, a chimeric ECMCAD protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of ECMCAD
activity. Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but are not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), 6-His, FLAG, c-nzyc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable purification of their cognate fusion proteins on immobilized glutathione, maltose, phenylarsine oxide, calmodulin, and metal-chelate resins, respectively. FLAG, c-nayc, and hemagglutinin (HA) enable immunoaffinity purification of fusion proteins using commercially available monoclonal and polyclonal antibodies that speciEcally recognize these epitope tags. A fusion protein may also be engineered to contain a proteolytic cleavage site located between the ECMCAD encoding sequence and the heterologous protein sequence, so that ECMCAD may be cleaved away from the heterologous moiety following purification. Methods for fusion protein expression and purification are discussed in Ausubel (1995, supra, ch. 10). A variety of commercially available kits may also be used to facilitate expression and purification of fusion proteins.
In a further embodiment of the invention, synthesis of radiolabeled ECMCAD may be l0 achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract system (Promega).
These systems couple transcription and translation of protein-coding sequences operably associated with the T7, T3, or SP6 promoters. Translation takes place in the presence of a radiolabeled amino acid precursor, for example, 35S-methionine.
ECMCAD of the present invention or fragments thereof may be used to screen for compounds that specifically bind to ECMCAD. At least one and up to a plurality of test compounds may be screened for specific binding to ECMCAD. Examples of test compounds include antibodies, oligonucleotides, proteins (e.g., receptors), or small molecules.
In one embodiment, the compound thus identified is closely related to the natural ligand of ECMCAD, e.g., a ligand or fragment thereof, a natural substrate, a structural or functional mimetic, or a natural binding partner. (See, e.g., Coligan, J.E. et al. (1991) Current Protocols in Immunolo~y 1 (2):
Chapter 5.) Similarly, the compound can be closely related to the natural receptor to which ECMCAD binds, or to at least a fragment of the receptor, e.g., the ligand binding site. In either case, the compound can be rationally designed using known techniques. In one embodiment, screening for these compounds involves producing appropriate cells which express ECMCAD, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E.
coli. Cells expressing ECMCAD or cell membrane fractions which contain ECMCAD
are then contacted with a test compound and binding, stimulation, or inhibition of activity of either ECMCAD or the compound is analyzed.
An assay may simply test binding of a test compound to the polypeptide, wherein binding is detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable label. For example, the assay may comprise the steps of combining at least one test compound with ECMCAD, either in solution or affixed to a solid support, and detecting the binding of ECMCAD to the compound.
Alternatively, the assay may detect or measure binding of a test compound in the presence of a labeled competitor. Additionally, the assay may be carried out using cell-free preparations, chemical libraries, or natural product mixtures, and the test compounds) may be free in solution or affixed to a solid support.
ECMCAD of the present invention or fragments thereof may be used to screen for compounds that modulate the activity of ECMCAD. Such compounds may include agonists, antagonists, or partial or inverse agonists. In one embodiment, an assay is performed under conditions permissive for ECMCAD activity, wherein ECMCAD is combined with at least one test compound, and the activity of ECMCAD in the presence of a test compound is compared with the activity of ECMCAD in the absence of the test compound. A change in the activity of ECMCAD
in the presence of the test compound is indicative of a compound that modulates the activity of ECMCAD.
Alternatively, a test compound is combined with an in vitro or cell-free system comprising ECMCAD
under conditions suitable for ECMCAD activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of ECMCAD may do so indirectly and need not come in direct contact with the test compound. At least one and up to a plurality of test compounds may be screened.
In another embodiment, polynucleotides,encoding ECMCAD or their mammalian homologs may be "knocked out" in an animal model system using homologous recombination in embryonic stem (ES) cells. Such techniques are well known in the art and are useful for the generation of animal models of human disease. (See, e.g., U.S. Patent Number 5,175,383 and U.S.
Patent Number 5,767,337.) For example, mouse ES cells, such as the mouse 1291SvJ cell line, are derived from the early mouse embryo and grown in culture. The ES cells are transformed with a vector containing the gene of interest disrupted by a marker gene, e.g., the neomycin phosphotransferase gene (neo;
Capecchi, M.R. (1989) Science 244:1288-1292). The vector integrates into the corresponding region of the host genome by homologous recombination. Alternatively, homologous recombination takes place using the Cre-loxP system to knockout a gene of interest in a tissue- or developmental stage-specific manner (March, J.D. (1996) Clin. Invest. 97:1999-2002; Wagner, K.U.
et al. (1997) Nucleic Acids Res. 25:4323-4330). Transformed ES cells are identified and microinjected into mouse cell blastocysts such as those from the C57BL16 mouse strain. The blastocysts are surgically transferred to pseudopregna,nt dams, and the resulting chimeric progeny are genotyped and bred to produce heterozygous or homozygous strains. Transgenic animals thus generated may be tested with potential therapeutic or toxic agents. , Polynucleotides encoding ECMCAD may also be manipulated in vitro in ES cells derived from human blastocysts. Human ES cells have the potential to differentiate into at least eight separate cell lineages including endoderm, mesoderm, and ectodermal cell types. These cell lineages differentiate into, for example, neural cells, hematopoietic fineages, and cardiomyocytes (Thomson, J.A. et al.
(1998) Science 282:1145-1147).
Polynucleotides encoding ECMCAD can also be used to create "knockin" humanized animals (pigs) or transgenic animals (mice or rats) to model human disease. With knockin technology, a region of a polynucleotide encoding ECMCAD is injected into animal ES cells, and the injected sequence integrates into the animal cell genome. Transformed cells are injected into blastulae, and the blastulae are implanted as described above. Transgenic progeny or inbred lines are studied and treated with potential pharmaceutical agents to obtain information on treatment of a human disease. Alternatively, a mammal inbred to overexpress ECMCAD, e.g., by secreting ECMCAD in its milk, may also serve as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol.
Annu. Rev. 4:55-74).
THERAPEUTICS
Chemical and structural similarity, e.g., in the context of sequences and motifs, exists between regions of ECMCAD and extracellular matrix and cell adhesion molecules. ~ In addition, the expression of ECMCAD is closely associated with brain, prostate, atrial myxoma, cerebellum, cervical dorsal root ganglion, cardiac muscle, mesentery fat, kidney epithelium, thymus, endothelium, ovary, placenta, smooth muscle, fallopian tube, breast, cartilage, bladder, rib, colon, spine, gall bladder, blood granulocytes, submandibular gland, seminal vesicle, and intestine tissues;
with tumors of the brain, prostate, rib, and fallopian tube; and with dermal nlicrovascular endothelial cells, hNT2 cells derived from a human teratocarcinoma, and 293-EBNA transformed embryonal cells derived from kidney epithelial tissue. Therefore, ECMCAD appears to play a role in genetic, immune/inflammatory, developmental, neurological, connective tissue, and cell proliferative disorders, including cancer. In the treatment of disorders associated with increased ECMCAD expression or activity, it is desirable to decrease the expression or activity of ECMCAD. In the treatment of disorders associated with decreased ECMCAD expression or activity, it is desirable to increase the expression or activity of ECMCAD.
Therefore, in one embodiment, ECMCAD or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of ECMCAD. Examples of such disorders include, but are not limited to, a genetic disorder such as adrenoleukodystrophy, Alport's syndrome, choroideremia, Duchenne and Becker muscular dystrophy, Down's syndrome, cystic fibrosis, chronic granulomatous disease, Gaucher's disease, Huntington's chorea, Marfan's syndrome, muscular dystrophy, myotonic dystrophy, pycnodysostosis, Refsum's syndrome, retinoblastoma, sickle cell anemia, thalassemia, Werner syndrome, von Willebrand's disease, Wilms' tumor, Zellweger syndrome, peroxisomal acyl-CoA
oxidase deficiency, peroxisomal thiolase deficiency, peroxisomal bifunctional protein deficiency, mitochondrial carnitine palmitoyl transferase and carnitine deficiency, mitochondrial very-long-chain acyl-CoA dehydrogenase deficiency, rnitochondrial medium-chain acyl-CoA dehydrogenase deficiency, mitochondrial short-s chain acyl-CoA dehydrogenase deficiency, mitochondrial electron transport flavoprotein and electron transport fiavoprotein:ubiquinone oxidoreductase deficiency, mitochondrial trifunctional protein deficiency, and mitochondrial short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; an immune/inflammatory disorder such as acquired immunodeficiency syndrome (AIDS), X-linked agammaglobinemia of Breton, common variable immunodeficiency (CVI], DiGeorge's syndrome l0 (thymic hypoplasia), thymic dysplasia, isolated IgA deficiency, severe combined immunodeficiency disease (SC1D), immunodeficiency with thrombocytopenia and eczema (Wiskott-Aldrich syndrome), Chediak-Higashi syndrome, chronic granulomatous diseases, hereditary angioneurotic edema, immunodeficiency associated with Cushing's disease, Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune 15 hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodeimal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, eiythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, 2o multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic 25 infections, and trauma; a developmental disorder such as renal tubular acidosis, anemia, C~shing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome {Wilins' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and 30 neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss; a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system including Down syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; a connective tissue disorder such as osteogenesis irnperfecta, Ehlers-Danlos syndrome, chondrodysplasias, Marfan syndrome, Alport syndrome, familial aortic aneurysm, achondroplasia, mucopolysaccharidoses, osteoporosis, osteopetrosis, Paget's disease, rickets, osteomalacia, hyperparathyroidism, renal osteodystrophy, osteonecrosis, osteomyelitis, osteoma, osteoid osteoma, osteoblastoma, osteosarcoma, osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, chondrosarcoma, fibrous cortical defect, nonossifying fibroma, fibrous dysplasia, fibrosarcoma, malignant fibrous histiocytoma, Ewing's sarcoma, primitive neuroectodermal tumor, giant cell tumor, osteoarthritis, rheumatoid arthritis, ankylosing spondyloarthritis, Reiter's syndrome, psoriatic arthritis, enteropathic arthritis, infectious arthritis, gout, gouty arthritis, calcium pyrophosphate crystal deposition disease, ganglion, synovial cyst, villonodular synovitis, systemic sclerosis, Dupuytren's contracture, hepatic fibrosis, lupus erythematosus, mixed connective tissue disease, epidermolysis bullosa simplex, bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis), non-epidermolytic and epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, pachyonychia congenita, and white sponge nevus; and a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart,.kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus.
In another embodiment, a vector capable of expressing ECMCAD or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of ECMCAD including, but not limited to, those described above.
In a further embodiment, a composition comprising a substantially purified ECMCAD in conjunction with a suitable pharmaceutical carrier may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of ECMCAD
including, but not limited to, l0 those provided above.
In still another embodiment, an agonist which modulates the activity of ECMCAD
may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of ECMCAD including, but not limited to, those listed above.
In a fiuther embodiment, an antagonist of ECMCAD may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of ECMCAD. Examples of such disorders include, but are not limited to, those genetic, immune/inflammatory, developmental, neurological, connective tissue, and cell proliferative disorders, including cancer described above. In one aspect, an antibody which specifically binds ECMCAD may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissues which express ECMCAD.
In an additional embodiment, a vector expressing the complement of the polynucleotide encoding ECMCAD may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of ECMCAD including, but not limited to, those described above.
In other embodiments, any of the proteins, antagonists, antibodies, agonists, complementary sequences, or vectors of the invention may be administered in combination with other appropriate therapeutic agents. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic;
efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
An antagonist of ECMCAD may be produced using methods which are generally known in the art. In particular, purified ECMCAD may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind ECMCAD.
Antibodies to ECMCA,D

may also be generated using methods that are well known in the art. Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, and single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. Neutralizing antibodies (i.e., those which inhibit dimer formation) are generally preferred for therapeutic use.
For the production of antibodies, various hosts including goats, rabbits, rats, mice, humans, and others may be immunized by injection with ECMCAD or with any fragment or oligopeptide thereof which has immunogenic propeWes. Depending on the host species, various adjuvants may be used to increase immunological response. Such adjuvants include, but are not limited to, Freund's, mineral gels such as aluminum hydroxide, and surface active substances such as lysolecithin, pluronic polyols, l0 polyanions, peptides, oil emulsions, KLH, and dinitrophenol. Among adjuvants used in humans, BCG
(bacilli Calmette-Guerin) and Corvnebacterium parvum are especially preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to ECMCAD have an amino acid sequence consisting of at least about 5 amino acids, and generally will consist of at least about 10 amino acids. Tt is also preferable that these oligopeptides, peptides, or fragments are identical to a portion of the amino acid sequence of the natural protein. Short stretches of ECMCAD amino acids may be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.
Monoclonal antibodies to ECMCAD may be prepared using any technique which provides for , the production of antibody molecules by continuous cell lines in culture.
These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EB V-hybridoma technique. (See, e.g., Kohler, G. et al. (1975) Nature 256:495-497; Kozbor, D.
et al. (1985) J.
Immunol. Methods 81:31-42; Cote, R.J. et al. (1983) Proc. Natl. Acad. Sci. USA
80:2026-2030; and Cole, S.P. et al. (1984) Mol. Cell Biol. 62:109-120.) In addition, techniques developed for the production of "chimeric antibodies,"
such as the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used. (See, e.g., Morrison, S.L. et al. (1984) Proc.
Natl. Acad. Sci. USA 81:6851-6855; Neuberger, M.S. et al. (1984) Nature 312:604-608; and Takeda, S. et al. (1985) Nature 314:452-454.) Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce ECMCAD-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries. (See, e.g., Burton, D.R. (1991) Proc. Natl. Acad. Sci. USA 88:10134-10137.) Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents as disclosed in the literature. (See, e.g., Orlandi, R. et al. (1989) Proc. Natl. Acad. Sci.
USA 86:3833-3837; Winter, G. et al. (1991) Nature 349:293-299.) Antibody fragments which contain specific binding sites for ECMCAD may also be generated. For example, such fragments include, but are not limited to, F(ab~2 fragments produced by pepsin digestion of the antibody molecule and Fab fragments generated by reducing the disulfide bridges of the F(ab~2 fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity. (See, e.g., Huse, W.D. et al. (1989) Science 246:1275-1281.) Various immunoassays may be used for screening to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificities are well known in the art. Such immunoassays typically involve the measurement of complex formation between ECMCAD and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering ECMCAD epitopes is generally used, but a competitive binding assay may also .
be employed (Pound, supra).
Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for ECMCAD. Affinity is expressed as an association constant, I~, which is defined as the molar concentration of ECMCAD-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions.
The I~ determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple ECMCAD epitopes, represents the average affinity, or avidity, of the antibodies for ECMCAD. The I~ determined for a preparation of monoclonal antibodies, which are monospecific for a particular ECMCAD epitope, represents a true measure of affinity. High-affinity antibody preparations with I~ ranging from about 109 to 1012 L/mole are preferred for use in immunoassays in which the ECMCAD-antibody complex must withstand rigorous manipulations.
Low-affinity antibody preparations with I~ ranging from about 106 to 10' L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of ECMCAD, preferably in active form, from the antibody (Catty, D. (1988) Antibodies, Volume I: A Practical Approach, IRL Press, Washington DC; Liddell, J.E. and A. Cryer (1991) A
Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York NY).
The titer and avidity of polyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for certain downstream applications. For example, a polyclonal antibody preparation containing at least 1-2 mg specific antibody/ml, preferably 5-10 mg specific antibody/ml, is generally employed in procedures requiring precipitation of ECMCAD-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines for antibody quality and usage in various applications, are generally available.
(See, e.g., Catty, supra, and Coligan et al. supra.) In another embodiment of the invention, the polynucleotides encoding ECMCAD, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, modifications of gene expression can be achieved by designing complementary sequences or antisense molecules (DNA, RNA, PNA, or modified oligonucleotides) to the coding or regulatory regions of the gene l0 encoding ECMCAD. Such technology is well known in the art, and antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding ECMCAD. (See, e.g., Agrawal, S., ed. (1996) Antisense Therapeutics, Humana Press Inc., Totawa NJ.) In therapeutic use, any gene delivery system suitable for introduction of the antisense sequences into appropriate target cells can be used. Antisense sequences can be delivered intracellularly in the form of an expression plasmid which, upon transcription, produces a sequence complementary to at least a portion of the. cellular sequence encoding the target protein. (See, e.g., Slater, J.E. et al. (1998) J. Allergy Cli. Immunol. 102(3):469-475; and Scanlon, K.J. et al. (1995) 9(13):1288-1296.) Antisense sequences can also be introduced intracellularly through the use of viral 2o vectors, such as retrovirus and adeno-associated virus vectors. (See, e.g., Miller, A.D. (1990) Blood 76:271; Ausubel, supra; Uekert, W, and W. Walther (1994) Pharmacol. Ther.
63(3):323-347.) Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art. (See, e.g., Rossi, J.J. (1995) Br. Med. Bull.
51(1):217-225; Boado, R.J. et al. (1998) J. Pharm. Sci. 87(11):1308-1315; and Morxis, M.C. et al. (1997) Nucleic Acids Res.
25(14):2730-2736.) In another embodiment of the invention, polynucleotides encoding ECMCAD may be used for somatic or germline gene therapy. Gene therapy may be performed to (i) correct a genetic deficiency (e.g., in the cases of severe combined immunodeficiency (SCID)-Xl disease characterized by X-linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288:669-672), severe combined immunodeficiency syndrome associated with an inherited adenosine deaminase (ADA) deficiency (Blaese, R.M. et al. (1995) Science 270:475-480; Bordignon, C. et al. (1995) Science 270:470-475), cystic fibxosis (Zabner, J. et al. (1993) Cell 75:207-216; Crystal, R.G. et al. (1995) Hum. Gene Therapy 6:643-666; Crystal, R.G. et al. (1995) Hum. Gene Therapy 6:667-703), thalassamias, familial hypercholesterolemia, and hemophilia resulting from Factor V)II or Factor IX
deficiencies (Crystal, R.G. (1995) Science 270:404-410; Verma, LM. and N. Somia (1997) Nature 389:239-242)), (ii) express a conditionally lethal gene product (e.g., in the case of cancers which result from unregulated cell proliferation), or (iii) express a protein which affords protection against intracellular paxasites (e.g., against human retroviruses, such as human immunodeficiency virus (HIV) (Baltimore, D. (1988) Nature 335:395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci. USA.
93:11395-11399), hepatitis B or C virus (HBV, HCV); fungal parasites, such as Candida albicans and Paracoccidioides brasiliensis; and protozoan parasites such as Plasmodium falciparum and Trvaanosoma cruzi). In the case where a genetic deficiency in ECMCAD expression or regulation causes disease, the expression of ECMCAD from an appropriate population of transduced cells may alleviate the clinical manifestations caused by the genetic deficiency.
In a further embodiment of the invention, diseases or disorders caused by deficiencies in ECMCAD axe treated by constructing mammalian expression vectors encoding ECMCAD and introducing these vectors by mechanical means into ECMCAD-deficient cells.
Mechanical transfer technologies for use with cells in vivo or ex vitro include (i) direct DNA
microinjection into individual Bells, (ii) ballistic gold particle delivery, (iii) liposome-mediated transfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA transposons (Morgan, R.A. and W.F.
Anderson (1993) Annu.
Rev. Biochem. 62:191-217; Ivics, Z. (1997) Cell 91:501-510; Boulay, J-L. and H. Recipon (1998) , C~rr. Opin. Bioteclmol. 9:445-450).
Expression vectors that may be effective for the expression of ECMCAD include, but are not limited to, the PCDNA 3.1, EPTTAG, PRCCMV2, PREP, PVAX vectors (Invitrogen, Carlsbad CA), PCMV-SCRIPT, PCMV-TAG, PEGSH/PERV (Stratagene, La Jolla CA), and PTET-OFF, PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto CA), ECMCAD may be expressed using (i) a constitutively active promoter, (e.g., from cytomegalovirus (CMV),.Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or (i-actin genes), (ii) an inducible promoter (e.g., the tetracycline-regulated promoter (Gossen, M. and H. Bujard (1992) Proc. Natl. Acad. Sci.
USA 89:5547-5551; Gossen, M. et al. (1995) Science 268:1766-1769; Rossi, F.M.V. and H.M. Blau (1998) Cur. Opin. Bioteclmol. 9:451-456), commercially available in the T-REX
plasmid (Invitrogen));
the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND;
Invitrogen); the FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F.M.V.
and Blau, H.M, supra)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding ECMCAD from a normal individual.
Commercially available liposome transformation kits (e.g., the PERFECT LIl'm TRANSFECTION KIT, available from Invitrogen) allow one with ordinary skill in the art to deliver polynucleotides to target cells in culture and require minimal effort to optimize experimental parameters. In the alternative, transformation is performed using the calcium phosphate method (Graham, F.L. and A.J. Eb (1973) Virology 52:456-467), or by electroporation (Neumann, E. et al.
(1982) EMBO J. 1:841-845). The introduction of DNA to primary cells requires modification of these standardized mammalian transfection protocols.
In another embodiment of the invention, diseases or disorders caused by genetic defects with respect to ECMCAD expression are treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding ECMCAD under the control of an independent promoter or the retrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals, and (iii) a Rev-responsive element (RRE) along with additional retrovirus cis-acting RNA
sequences and coding sequences required for efficient vector propagation. Retrovirus vectors (e.g., PFB and PFBNEO) are commercially available (Stratagene) and are based on published data (Riviere, I. et al. (1995) Proc.
Natl. Aced. Sci. USA 92:6733-6737), incorporated by reference herein. The vector is propagated in an appropriate vector producing cell line (VPCL) that expresses an envelope gene with a tropism for receptors on the target cells or a promiscuous envelope protein such as VSVg (Armentano, D. et al.
(1987) J. Virol. 61:1647-1650; Bender, M.A. et al. (1987) J. Virol. 61:1639-1646; Adam, M.A. and A.D. Miller (1988) J. Virol. 62:3802-3806; Dull, T. et al. (1998) J. Virol.
72:8463-8471; Zufferey, R. et al. (1998) J. Virol. 72:9873-9880). U.S. Patent Number 5,910,434 to Rigg ("Method for obtaining retrovirus packaging cell lines producing high transducing efficiency retroviral supernatant") discloses a method for obtaining retrovirus packaging cell lines and is hereby incorporated by reference.
Propagation of retrovirus vectors, transduction of a population of cells (e.g., CD4+ T-cells), and the return of transduced cells to a patient are procedures well known to persons skilled in the art of gene therapy and have been well documented (Range, U. et al. (1997) J. Virol.
71:7020-7029; Bauer, G. et al. (1997) Blood 89:2259-2267; Bonyhadi, M.L. (1997) J. Virol. 71:4707-4716;
Range, U. et al. (1998) Proc. Natl. Aced. Sci. USA 95:1201-1206; Su, L. (1997) Blood 89:2283-2290).
In the alternative, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding ECMCAD to cells which have one or more genetic abnormalities with respect to the expression of ECMCAD. The construction and packaging of adenovirus-based vectors are well known to those with ordinary skill in the art. Replication defective adenovirus vectors have proven to be versatile for importing genes encoding immunoregulatory proteins into intact islets in the pancreas (Csete, M.E. et al. (1995) Transplantation 27:263-268). Potentially useful adenoviral vectors are described in U.S. Patent Number 5,707,618 to Armentano ("Adenovirus vectors for gene therapy")> hereby incorporated by reference. For adenoviral vectors, see also Antinozzi, P.A, et al.
(1999) Annu. Rev. Nutr. 19:511-544 and Verma, LM. and N. Somia (1997) Nature 18:389:239-242, both incorporated by reference herein.
In another alternative, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding ECMCAD to target cells which have one or more genetic abnormalities with respect to the expression of ECMCAD. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing ECMCAD to cells of the central nervous system, for which HSV has a tropism. The construction and packaging of herpes-based vectors are well known to those with ordinary skill in the art. A replication-competent herpes simplex virus (HSV) type 1-based vector l0 has been used to deliver a reporter gene to the eyes of primates (Liu, X.
et al. ( 1999) Exp. Eye Res.
169:385-395). The construction of a HSV-1 virus vector has also been disclosed in detail in U.S.
Patent Number 5,804,413 to DeLuca ("Herpes simplex vims strains for gene transfer"), which is hereby incorporated by reference. U.S. Patent Number 5,804,413 teaches the use of recombinant HSV d92 which consists of a genome containing at least one exogenous gene to be transferred to a cell under the control of the appropriate promoter for purposes including human gene therapy. Also taught by this patent are the construction and use of recombinant HSV strains deleted for ICP4, ICP27 and ICP22. For HSV vectors, see also Goins, W.F. et al. (1999) J. Virol.
73:519-532 and Xu, H. et al. (1994) Dev. Biol. 163:152-161, hereby incorporated by reference. The manipulation of cloned herpesvirus sequences, the generation of recombinant virus following the transfection of multiple plasmids containing different segments of the large herpesvirus genomes, the growth and propagation of herpesvirus, and the infection of cells with herpesvirus are techniques well known to those of ordinary skill in the art.
In another alternative, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver polynucleotides encoding ECMCAD to target cells. The biology of the prototypic alphavirus, Semliki Forest Virus (SFV), has been studied extensively and gene transfer vectors have been based on the SFV genome (Garoff, H. and K.-J. Li (1998) Curr. Opin. Biotechnol.
9:464-469). During alphavirus RNA replication, a subgenomic RNA is generated that normally encodes the viral capsid proteins. This subgenomic RNA replicates to higher levels than the full length genomic RNA, resulting in the overproduction of capsid proteins relative to the viral proteins with enzymatic activity (e.g., protease and polymerase). Similarly, inserting the coding sequence for ECMCAD into the alphavirus genome in place of the capsid-coding region results in the production of a large number of ECMCAD-coding RNAs and the synthesis of high levels of ECMCAD in vector transduced cells.
While alphavirus infection is typically associated with cell lysis within a few days, the ability to establish a persistent infection in hamster normal kidney cells (BHK-21) with a variant of Sindbis virus (SIN) indicates that the lytic replication of alphaviruses can be altered to suit the needs of the gene therapy application (Dryga, S.A. et al. (1997) Virology 228:74-83). The wide host range of alphaviruses will allow the introduction of ECMCAD into a variety of cell types. The specific transduction of a subset of cells in a population may require the sorting of cells prior to transduction.
The methods of manipulating infectious cDNA clones of alphaviruses, performing alphavirus cDNA
and RNA transfections, and performing alphavirus infections, axe well known to those with ordinary skill in the art.
Oligonucleotides derived from the transcription initiation site, e.g., between about positions -10 1o and +10 from the start site, may also be employed to inhibit gene expression. Similarly, inhibition can be achieved using triple helix base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature. (See, e.g., Gee, J.E. et al. (1994) in Huber, B.E. and B.I. Carr, Molecular and Immunolo~ic Approaches, Futura Publishing, Mt. Kisco NY, pp. 163-177.) A
complementary sequence or antisense molecule may also be designed to block translation of mRNA
by preventing the transcript from binding to ribosomes.
Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific cleavage of .
RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
For example, engineered hammerhead motif ribozyme molecules may specifically and efficiently catalyze endonucleolytic cleavage of sequences encoding ECMCAD.
Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, including the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides, corresponding to the region of the target gene containing the cleavage site, may be evaluated for secondary structural features which may render the oligonucleotide inoperable.
The suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.
Complementary ribonucleic acid molecules and ribozymes of the invention may be prepared by any method known in the art for the synthesis of nucleic acid molecules.
These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis.
Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA

sequences encoding ECMCAD. Such DNA sequences may be incorporated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6.
Alternatively, these cDNA
constructs that synthesize complementary RNA, constitutively or inducibly, can be introduced into cell lines, cells, or tissues.
RNA molecules may be modified to increase intracellular stability and half life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine which are not as easily recognized by endogenous endonucleases.
An additional embodiment of the invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding ECMCAD.
Compounds which may be effective in altering expression of a specific polynucleotide may include, but are not limited to, oligonucleotides, antisense oligonucleotides, triple helix-forming oligonucleotides, transcription factors and other polypeptide transcriptional regulators, and non-macromolecular chemical entities which are capable of interacting with specific polynucleotide sequences. Effective compounds may alter polynucleotide expression by acting as either inhibitors or promoters of polynucleotide expression. Thus, in the treatment of disorders associated with increased ECMCAD
expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding ECMCAD may be therapeutically useful, and in the treatment of disorders associated with decreased ECMCAD expression or activity, a compound which specifically promotes expression of the polynucleotide encoding ECMCAD may be therapeutically useful.
At least one, and up to a plurality, of test compounds may be screened for effectiveness in altering expression of a specific polynucleotide. A test compound may be obtained by any method commonly known in the art, including chemical modification of a compound known to be effective in altering polynucleotide expression; selection from an existing, commercially-available or proprietary library of naturally-occurring or non-natural chemical compounds; rational design of a compound based on chemical and/or structural properties of the target polynucleotide;
and selection from a library of chemical compounds created combinatorially or randomly. A sample comprising a polynucleotide encoding ECMCAD is exposed to at least one test compound thus obtained. The sample may comprise, for example, an intact or permeabilized cell, or an in vitro cell-free'or reconstituted biochemical system. Alterations in the expression of a polynucleotide encoding ECMCAD are assayed by any method commonly known in the art. Typically, the expression of a specific nucleotide is detected by hybridization with a probe having a nucleotide sequence complementary to the sequence of the polynucleotide encoding ECMCAD. The amount of hybridization may be quantified, thus forming the basis for a comparison of the expression of the polynucleotide both with and without exposure to one or more test compounds.
Detection of a change in the expression of a polynucleotide exposed to a test compound indicates that the test compound is effective in altering the expression of the polynucleotide. A screen for a compound effective in altering expression of a specific polynucleotide can be carried out, fox example, using a Schizosacchaxomvces pombe gene expression system (Atkins, D. et al. (1999) U.S. Patent No.
5,932,435; Arndt, G.M. et al. (2000) Nucleic Acids Res. 28:E15) or a human cell line such as HeLa cell (Clarke, M.L. et al. (2000) Biochem. Biophys. Res. Common. 268:8-13). A
particular embodiment of the present invention involves screening a combinatorial library of oligonucleotides (such as deoxyribonucleotides; ribonucleotides, peptide nucleic acids, and modified oligonucleotides) for antisense activity against a specific polynucleotide sequence (Bruice, T.W, et al. (1997) U.S.
Patent No. 5,686,242; Bruice, T.W. et al. (2000) U.S. Patent No. 6,022,691).
Many methods for introducing vectors into cells or tissues are available and equally suitable fox use in vivo, in vitro, and ex vivo. For ex vivo therapy, vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient.
Delivery by transfection, by liposome injections, or by polycationic amino polymers may be achieved using methods which are well known in the art. (See, e.g., Goldman, C.K. et al. (1997) Nat.
Biotechnol. 15:462-466.) Any of the therapeutic methods described above may be applied to any subject in need of such therapy, including, for example, mammals such as humans, dogs, cats, cows, horses, rabbits, and monkeys.
An additional embodiment of the invention relates to the administration of a composition which generally comprises an active ingredient formulated with a pharmaceutically acceptable excipient.
Excipients may include, for example, sugars, starches, celluloses, gums, and proteins. Various formulations are commonly known and are thoroughly discussed in the latest edition of Remin on's Pharmaceutical Sciences (Maack Publishing, Easton PA). Such compositions may consist of ECMCAD, antibodies to ECMCAD, and mimetics, agonists, antagonists, or inhibitors of ECMCAD.
The compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, infra-arterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.
Compositions for pulmonary administration may be prepared in liquid or dry powder form.
These compositions are generally aerosolized immediately prior to inhalation by the patient. In the case of small molecules (e.g. traditional low molecular weight organic drugs), aerosol delivery of fast-s acting formulations is well-known in the art. In the case of macromolecules (e.g. larger peptides and proteins), recent developments in the field of pulmonary delivery via the alveolar region of the lung have enabled the practical delivery of drugs such as insulin to blood circulation (see, e.g., Patton, J.S.
et al., U.S. Patent No. 5,997,848). Pulmonary delivery has the advantage of administration without needle injection, and obviates the need for potentially toxic penetration enhancers.
Compositions suitable for use in the invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
Specialized forms of compositions may be prepared for direct intracellular delivery of macromolecules comprising ECMCAD or fragments thereof. For example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, ECMCAD or a fragment thereof may be joined to a short cationic N-terminal portion from the HIV Tat-1 protein. Fusion proteins thus generated have been found to transduce into the cells of all tissues, including the brain, in a mouse model system (Schwarze, S.R. et al. (1999) Science 285:1569-1572).
For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models such as mice, rats, rabbits, dogs, monkeys, or pigs. An animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
A therapeutically effective dose refers to that amount of active ingredient, for example ECMCAD or fragments thereof, antibodies of ECMCAD, and agonists, antagonists or inhibitors of ECMCAD, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating the EDso (the dose therapeutically effective in 50% of the population) or LDSO (the dose lethal to 50% of the population) statistics. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LDSO/EDSO ratio. Compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used to formulate a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that includes the EDso with little or no toxicity.
The dosage varies within this range depending upon the dosage form employed,,the sensitivity of the patient, and the route of administration.
The exact dosage will be determined by the practitioner, in light of factors related to the subject requiring treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, time and frequency of administration, drug combination(s), reaction sensitivities, and response to therapy. Long-acting compositions may be.administered every 3 to 4 days, every week, or biweekly depending on the half life and clearance rate of the particular formulation.
Normal dosage amounts may vary from about 0.1 ,ug to 100,000 fig, up to a total dose of about 1 gram, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.
DIAGNOSTICS
In another embodiment, antibodies which specifically bind ECMCAD may be used for fine diagnosis of disorders characterized by expression of ECMCAD, or in assays to monitor patients being treated with ECMCAD or agonists, antagonists, or inhibitors of ECMCAD.
Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics.
Diagnostic assays for ECMCAD include methods which utilize the antibody and a label to detect ECMCAD in human body fluids or in extracts of cells or tissues. The antibodies may be used with or without modification, and may be labeled by covalent or non-covalent attachment of a reporter molecule. A wide variety of reporter molecules, several of which are described above, are known in the art and may be used.
A variety of protocols for measuring ECMCAD, including ELISAs, RTAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of ECMCAD
expression. Normal or standard values for ECMCAD expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to ECMCAD under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of ECMCAD expressed in subject, control, and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease.
In another embodiment of the invention, the polynucleotides encoding ECMCAD
may be used for diagnostic purposes. The polynucleotides which may be used include oligonucleotide sequences, complementary RNA and DNA molecules, and PNAs. The polynucleotides may be used to detect and quantify gene expression in biopsied tissues in which expression of ECMCAD
may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of ECMCAD, and to monitor regulation of ECMCAD levels during therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting polynucleotide sequences, including genomic sequences, encoding ECMCAD or closely related molecules may be used to identify nucleic acid sequences which encode ECMCAD. The specificity of the probe, whether it is made from a highly specific region, e.g., the 5' regulatory region, or from a less specific region, e.g., a conserved motif, and the stringency of the hybridization or amplification will determine whether the probe identifies only naturally occurring sequences encoding ECMCAD, allelic variants, or related sequences.
Probes may also be used for the detection of related sequences, and may have at least 50%
sequence identity to any of the ECMCAD encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ 1D N0:37-72 or from genomic sequences including promoters, enhancers, and introns of the ECMCAD gene.
Means for producing specific hybridization probes for DNAs encoding ECMCAD
include the cloning of polynucleotide sequences encoding ECMCAD or ECMCAD derivatives into vectors for the production of mRNA probes. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes~in vitro by means of the addition of the appropriate RNA
polymerases and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionuclides such as 32P or 355, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.
Polynucleotide sequences encoding ECMCAD may be used for the diagnosis of disorders associated with expression of ECMCAD. Examples of such disorders include, but are not limited to, a genetic disorder such as adrenoleukodystrophy, Alport's syndrome, choroideremia, Duchenne and Becker muscular dystrophy, D'own's syndrome, cystic fibrosis, chronic granulomatous disease, Gaucher's disease, Huntington's chorea, Marfan's syndrome, muscular dystrophy, myotonic dystrophy, pycnodysostosis, Refsum's syndrome, retinoblastoma, sickle cell anemia, thalassemia, Werner syndrome, von Willebrand's disease, Wilms' tumor, Zellweger syndrome, peroxisomal acyl-CoA oxidase deficiency, peroxisomal thiolase deficiency, peroxisomal bifunctional protein deficiency, mitochondria) carnitine palmitoyl transferase and carnitine deficiency, mitochondriaI very-Iong-chain acyl-CoA dehydrogenase deficiency, mitochondria) medium-chain acyl-CoA
dehydrogenase deficiency, mitochondria) short-chain acyl-CoA dehydrogenase deficiency, mitochondria) electron transport flavoprotein and electron transport flavoprotein:ubiquinone oxidoreductase deficiency, mitochondria) trifunctional protein deficiency, and mitochondria) short-chain 3-hydroxyacyl-CoA
dehydrogenase deficiency; an immune/inflammatory disorder such as acquired immunodeficiency syndrome (AIDS), X-linked agammaglobinemia of Bruton, common variable immunodeficiency (CV)), DiGeorge's syndrome (thymic hypoplasia), thymic dysplasia, isolated IgA
deficiency, severe combined immunodeficiency disease (SCID), immunodeficiency with thrombocytopenia and eczema (Wiskott-Aldrich syndrome), Chediak-Higashi syndrome, chronic granulomatous diseases, hereditary angioneurotic edema, immunodeficiency associated with Cushing's disease, Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracoiporeal circulation, viral, bacterial, fungal, parasitic, protozoa), and helminthic infections, and trauma; a developmental disorder such as renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such ' as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss; a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia> Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Sixaussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the centt~al nervous system including Down syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postheipetic neuralgia, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; a connective tissue disorder such as osteogenesis imperfecta, Ehlers-Danlos syndrome, chondrodysplasias, Marfan syndrome, Alport syndrome, familial aortic aneurysm, achondroplasia, mucopolysaccharidoses, osteoporosis, osteopetrosis, Paget's disease, rickets, osteomalacia, hypeiparathyroidism, renal osteodystrophy, osteonecrosis, osteomyelitis, osteoma, osteoid osteoma, osteoblastoma, osteosarcoma, osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, chondrosarcoriia, fibrous cortical defect, nonossifying fibroma, fibrous dysplasia, fibrosarcoma, malignant fibrous histiocytoma, Ewing's sarcoma, primitive neuroectodermal tumor, giant cell tumor, osteoarthritis, rheumatoid arthritis, ankylosing spondyloarthritis, Reiter's syndrome, psoriatic arthritis, enteropathic arthritis, infectious arthritis, gout, gouty arthritis, calcium pyrophosphate crystal deposition disease, ganglion, synovial cyst, villonodulax synovitis, systemic sclerosis, Dupuytren's contracture, hepatic fibrosis, lupus erythematosus, mixed connective tissue disease, epidermolysis bullosa simplex, bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis), non-epidermolytic and epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, pachyonychia congenita, and white sponge nevus; and a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus.
The polynucleotide sequences encoding ECMCAD may be used in Southern or northern analysis, dot blot, or other membrane-based technologies; in PCR technologies; in dipstick, pin, and multiformat ELISA-like assays; and in microarrays utilizing fluids or tissues from patients to detect altered ECMCAD expression. Such qualitative or quantitative methods are well known in the art.
In a particular aspect, the nucleotide sequences encoding ECMCAD may be useful in assays that detect the presence of associated disorders, particularly those mentioned above. The nucleotide sequences encoding ECMCAD may be labeled by standard methods and added to a fluid or tissue sample from a patient under conditions suitable for the formation of hybridization complexes. After a suitable incubation period, the sample is washed and the signal is quantified and compaxed with a standard value. If the amount of signal in the patient sample is significantly altered in comparison to a control sample then the presence of altered levels of nucleotide sequences encoding ECMCAD in the sample indicates the presence of the associated disorder. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials, or to monitor the treatment of an individual patient.
In order to provide a basis for the diagnosis of a disorder associated with expression of ECMCAD, a normal or standard profile for expression is established. This may be accomplished by combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding ECMCAD, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with values from an experiment in which a known amount of a substantially purified polynucleotide is used. Standard values obtained in this manner may be compared with values obtained from samples from patients who are symptomatic for a disorder.
Deviation from standard values is used to establish the presence of a disorder.
Once the presence of a disorder is established and a treatment protocol is initiated, hybridization assays may be repeated on a regular basis to determine if the level of expression in the patient begins to approximate that which is observed in the normal subject.
The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to months.
With respect to cancer, the presence of an abnormal amount of transcript (either under- or overexpressed) in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.
Additional diagnostic uses for oligonucleotides designed from the sequences encoding ECMCAD may involve the use of PCR. These oligomers may be chemically synthesized, generated enzymatically, or produced in vitro. Oligomers will preferably contain a fragment of a polynucleotide encoding ECMCAD, or a fragment of a polynucleotide complementary to the polynucleotide encoding ECMCAD, and will be employed under optimized conditions for identification of a specific gene or to condition. Oligomers may also be employed under less stringent conditions for detection or quantification of closely related DNA or RNA sequences.
In a particular aspect, oligonucleotide primers derived from the polynucleotide sequences encoding ECMCAD may be used to detect single nucleotide polymorphisms (SNPs).
SNPs are substitutions, insertions and deletions that are a frequent cause of inherited or acquired genetic disease in humans. Methods of SNP detection include, but are not limited to, single-stranded conformation polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from the polynucleotide sequences encoding ECMCAD are used to amplify DNA using the polymerase chain reaction (PCR). The DNA may be derived, for example, from diseased or normal tissue, biopsy samples, bodily fluids, and the like. SNPs in the DNA cause differences in the secondary and tertiary structures of PCR products in single-stranded form, and these differences are detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the oligonucleotide primers are fluorescently labeled, which allows detection of the amplimers in high-throughput equipment such as DNA sequencing machines. Additionally, sequence database analysis methods, termed in silico SNP
(isSNP), are capable of identifying polymorphisms by comparing the sequence of individual overlapping DNA fragments which assemble into a common consensus sequence.
These computer-based methods filter out sequence variations due to laboratory preparation of DNA and sequencing errors using statistical models and automated analyses of DNA sequence chromatograms. In the alternative, SNPs may be detected and characterized by mass spectrometry using, for example, the high throughput MASSARRAY system (Sequenom, Inc., San Diego CA).
Methods which may also be used to quantify the expression of ECMCAD include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standard curves. (See, e.g., Melby, P.C. et al. (1993) J.
Immunol. Methods 159:235-244;
Duplaa, C. et al. (1993) Anal. Biochem. 212:229-236.) The speed of quantitation of multiple samples may be accelerated by running the assay in a high-throughput format where the oligomer or polynucleotide of interest is presented in various dilutions and a spectrophotometric or colorimetric response gives rapid quantitation.
In further embodiments, oligonucleotides or longer fragments derived from any of the polynucleotide sequences described herein may be used as elements on a microarray. The microarray can be used in transcript imaging techniques which monitor the relative expression levels of large numbers of genes simultaneously as described below. The microarray may also be used to identify genetic variants, mutations, and polymorphisms. This information may be used to determine gene function, to understand the genetic basis of a disorder, to diagnose a disorder, to monitor progression/regression of disease as a function of gene expression, and to develop and monitor the activities of therapeutic agents in the treatment of disease. In particular, this information may be used to develop a pharmacogenomic profile of a patient in order to select the most appropriate and effective treatment regimen for that patient. For example, therapeutic agents which are highly effective and display the fewest side effects may be selected for a patient based on his/her pharmacogenomic profile.
In another embodiment, ECMCAD, fragments of ECMCAD, or antibodies specific for ECMCAD may be used as elements on a microarray. The microarray may be used to monitor or measure protein-protein interactions, drug-target interactions, and gene expression profiles, as described above.
A particular embodiment relates to the use of the polynucleotides of the present invention to generate a transcript image of a tissue or cell type. A transcript image represents the global pattern of gene expression by a particular tissue or cell type. Global gene expression patterns are analyzed by quantifying the number of expressed genes and their relative abundance under given conditions and at a given time. (See Seilhamer et al., "Comparative Gene Transcript Analysis,"
U.S. Patent Number 5,840,484, expressly incorporated by reference herein.) Thus a transcript image may be generated by hybridizing the polynucleotides of the present invention or their complements to the totality of transcripts or reverse transcripts of a particular tissue or cell type. In one embodiment, the hybridization takes place in high-throughput format, wherein the polynucleotides of the present invention or their complements comprise a subset of a plurality of elements on a microarray. The resultant transcript image would provide a profile of gene activity.
Transcript images may be generated using transcripts isolated from tissues, cell lines, biopsies, or other biological samples. The transcript image may thus reflect gene expression in vivo, as in the case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.

Transcript images which profile the expression of the polynucleotides of the present invention may also be used in conjunction with in vitro model systems and preclinical evaluation of pharmaceuticals, as well as toxicological testing of industrial and naturally-occurring environmental compounds. All compounds induce characteristic gene expression patterns, frequently termed molecular fingerprints or toxicant signatures, which are indicative of mechanisms of action and toxicity (Nuwaysir, E.F. et al. (1999) Mol. Carcinog. 24:153-159; Steiner, S. and N.L.
Anderson (2000) Toxicol. Lett. 112-113:467-471, expressly incorporated by reference herein).
If a test compound has a signature similar to that of a compound with known toxicity, it is likely to share those toxic properties.
These fingerprints or signatures are most useful and refined when they contain expression information from a large number of genes and gene families. Ideally, a genome-wide measurement of expression provides the highest quality signature. Even genes whose expression is not altered by any tested compounds are important as well, as the levels of expression of these genes are used to normalize the rest of the expression data. The normalization procedure is useful for comparison of expression data after treatment with different compounds. While the assignment of gene function to elements of a toxicant signature aids in interpretation of toxicity mechanisms, knowledge of gene function is not necessary for the statistical matching of signatures which leads to prediction of toxicity. (See, for example, Press Release 00-02 from the National Institute of Environmental Health Sciences, released February 29, 2000, available at http://www.niehs.nih.gov/oc/news/toxchip.htm.) Therefore, it is important and desirable in toxicological screening using toxicant signatures to include all expressed gene sequences.
In one embodiment, the toxicity of a test compound is assessed by treating a biological sample containing nucleic acids with the test compound. Nucleic acids that are expressed in the treated biological sample are hybridized with one or more probes specific to the polynucleotides of the present invention, so that transcript levels corresponding to the polynucleotides of the present invention may be quantified. The transcript levels in the treated biological sample are compared with levels in an untreated biological sample. Differences in the transcript levels between the two samples axe indicative of a toxic response caused by the test compound in the treated sample.
Another particular embodiment relates to the use of the polypeptide sequences of the present invention to analyze the proteome of a tissue or cell type. The term proteome refers to the global pattern of protein expression in a particular tissue or cell type. Each protein component of a proteome can be subjected individually to further analysis. Proteome expression patterns, or profiles, are analyzed by quantifying the number of expressed proteins and their relative abundance under given conditions and at a given time. A profile of a cell's proteome may thus be generated by separating and analyzing the polypeptides of a particular tissue or cell type. In one embodiment, the separation is achieved using two-dimensional gel electrophoresis, in which proteins from a sample are separated by isoelectric focusing in the first dimension, and then according to molecular weight by sodium dodecyl sulfate slab gel electrophoresis in the second dimension (Steiner and Anderson, supra). The proteins are visualized in the gel as discrete and uniquely positioned spots, typically by staining the gel with an agent such as Coomassie Blue or silver or fluorescent stains. The optical density of each protein spot is generally proportional to the level of the protein in the sample. The optical densities of equivalently positioned protein spots from different samples, for example, from biological samples either treated or untreated with a test compound or therapeutic agent, are compared to identify any changes in protein spot density related to the treatment. The proteins in the spots are partially sequenced using, for example, standard methods employing chemical or enzymatic cleavage followed by mass spectrometry. The identity of the protein in a spot may be determined by comparing its partial sequence, preferably of at least 5 contiguous amino acid residues, to the polypeptide sequences of the present invention. In some cases, further sequence data may be obtained for definitive protein identification.
A proteomic profile may also be generated using antibodies specific for ECMCAD
to quantify the levels of ECMCAD expression. In one embodiment, the antibodies are used as elements on a microarray, and protein expression levels are quantified by exposing the microarray to the sample and detecting the levels of protein bound to each array element (Lueking, A. et al. ( 1999) Anal. Biochem.
270:103-111; Mendoze, L.G. et al. (1999) Biotechniques 27:778-788). Detection may be performed by a variety of methods known in the art, for example, by reacting the proteins in the sample with a thiol-or amino-reactive fluorescent compound and detecting the amount of fluorescence bound at each array element.
Toxicant signatures at the proteome level are also useful for toxicological screening, and should be analyzed in parallel with toxicant signatures at the transcript level. There is a poor correlation between transcript and protein abundances for some proteins in some tissues (Anderson, N.L. and J. Seilhamer (1997) Electrophoresis 18:533-537), so proteome toxicant signatures may be useful in the analysis of compounds which do not significantly affect the transcript image, but which alter the proteomic profile. In addition, the analysis of transcripts in body fluids is difficult, due to rapid degradation of mRNA, so proteomic profiling may be more reliable and informative in such cases.
In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins that are expressed in the treated biological sample are separated so that the amount of each protein can be quantified. The amount of each protein is compared to the amount of the corresponding protein in an untreated biological sample.
A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample. Individual proteins are identified by sequencing the amino acid residues of the individual proteins and comparing these partial sequences to the polypeptides of the present invention.
In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins from the biological sample are incubated with antibodies specific to the polypeptides of the present invention. The amount of protein recognized by the antibodies is quantified. The amount of protein in the treated biological sample is compared z0 with the amount in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample.
Microarrays may be prepared, used, and analyzed using methods known in the art. (See, e.g., Brennan, T.M. et al. (1995) U.S. Patent No. 5,474,796; Schena, M. et al.
(1996) Proc. Natl. Acad.
Sci. USA 93:10614-10619; Baldeschweiler et al. (1995) PCT application W095/251116; Shalom D. et al. (1995) PCT application W095/35505; Heller, R.A. et al. (1997) Proc. Natl.
Acad. Sci. USA
94:2150-2155; and Heller, M.J. et al. (1997) U.S. Patent No. 5,605,662.) Various types of microarrays are well known and thoroughly described in DNA Microarravs: A
Practical Approach, M, Schena, ed. (1999) Oxford University Press, London, hereby expressly incorporated by reference.
In another embodiment of the invention, nucleic acid sequences encoding ECMCAD
may be z0 used to generate hybridization probes useful in mapping the naturally occurring genomic sequence.
Either coding or noncoding sequences may be used, and in some instances, noncoding sequences may be preferable over coding sequences. For example, conservation of a coding sequence among members of a mufti-gene family may potentially cause undesired cross hybridization during chromosomal mapping. The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to artificial chromosome constructions, e.g., human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial P1 constructions, or single chromosome cDNA libraries. (See, e.g., Harnngton, J.J. et aI. (1997) Nat.
Genet. 15:345-355; Price, C.M. (1993) Blood Rev. 7:127-134; and Trask, B.J.
(1991) Trends Genet.

7:149-154.) Once mapped, the nucleic acid sequences of the invention may be used to develop genetic linkage maps, for example, which correlate the inheritance of a disease state with the inheritance of a particular chromosome region or restriction fragment length polymorphism (RFLP).
(See, for example, Lander, E.S. and D. Botstein (1956) Proc. Natl. Acad. Sci.
USA 53:7353-7357.) Fluorescent in situ hybridization (FISH) may be correlated with other physical and genetic map data. (See, e.g., Heinz-Utrich, et al. (1995) in Meyers, supra, pp. 965-968.) Examples of genetic map data can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OM1M) World Wide Web site. Correlation between the location of the gene encoding ECMCAD on a physical map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA associated with that disorder and thus may further positional cloning efforts.
In situ hybridization of chromosomal preparations and physical mapping techniques, such as linkage analysis using established chromosomal markers, may be used for extending genetic maps.
Often the placement of a gene on the chromosome of another mammalian species, such as mouse, may reveal associated markers even if the exact chromosomal locus is not known. This information is l0 valuable to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the gene or genes responsible for a disease or syndrome have been crudely localized by genetic linkage to a particular genomic region, e.g., ataxia-telangiectasia to 11 q22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation.
(See, e.g., Gatti, R.A. et al. (1988) Nature 336:577-580.) The nucleotide sequence of the instant invention may also be used to detect differences in the chromosomal location due to translocation, inversion, etc., among normal, carrier, or affected individuals.
In another embodiment of the invention, ECMCAD, its catalytic or immunogenic fragments, or oligopeptides thereof can be used for screening libraries of compounds in any of a variety of drug screening techniques. The fragment employed in such screening may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The formation of binding complexes between ECMCAD and the agent being tested may be measured.
Another technique for drug screening provides for high throughput screening of compounds having suitable binding affinity to the protein of interest. (See, e.g., Geysen, et al. (1984) PCT
application W084/03564.) In this method, large numbers of different small test compounds are synthesized on a solid substrate. The test compounds are reacted with ECMCAD, or fragments thereof, and washed. Bound ECMCAD is then detected by methods well known in the art. Purified ECMCAD can also be coated directly onto plates for use in the aforementioned drug screening techniques. Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support.
In another embodiment, one may use competitive drug screening assays in which neutralizing antibodies capable of binding ECMCAD specifically compete with a test compound for binding ECMCAD. In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with ECMCAD.

In additional embodiments, the nucleotide sequences which encode ECMCAD may be used in any molecular biology techniques that have yet to be developed, provided the new techniques rely on properties of nucleotide sequences that are currently known, including, but not limited to, such properties as the triplet genetic code and specific base pair interactions.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The disclosures of all patents, applications, and publications mentioned above and below, 1o including U.S. Ser. No. 60/215,454, U.S. Sex. No. 601219,462, U.S. Ser. No.
60/240,111, U.S. Ser.
No. 60/240,106, U.S. Ser. No. 601244,021, U.S. Ser. No. 60/248,887, and U.S.
Ser. No. 60/249,570 are hereby expressly incorporated by reference.
EXAMPLES
I. Construction of cDNA Libraries Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD
database (Incyte Genomics, Palo Alto CA) and shown in Table 4, column 5. Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL (Life Technologies), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCI
cushions or extracted with chloroform. RNA was precipitated from the lysates with either isopropanol or sodium acetate and ethanol, or by other routine methods.
Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA
purity. In some cases, RNA was treated with DNase. For most libraries, poly(A)+ RNA was isolated using oligo d(T)-coupled paramagnetic particles (Promega), OLIGOTEX
latex particles (QIAGEN, Chatsworth CA), or an OLIGOTEX mRNA purification kit (QIAGEN).
Alternatively, RNA was isolated directly from tissue lysates using other,RNA isolation kits, e.g., the POLY(A)PURE mRNA purification kit (Ambion, Austin TX).
In some cases, Stratagene was provided with RNA and constructed the corresponding cDNA
libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed with the UNIZAP vector system (Stratagene) or SUPERSCRIPT plasmid system (Life Technologies), using the recommended procedures or similar methods known in the art. (See, e.g., Ausubel, 1997, supra, units 5.1-6.6.) Reverse transcription was initiated using oligo d(T) or random primers. Synthetic oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA
was digested with the appropriate restriction enzyme or enzymes. For most libraries, the cDNA was size-selected (300-1000 bp) using SEPHACRYL S 1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Pharmacia Biotech) or preparative agarose gel electrophoresis. cDNAs were ligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), PSPORTl plasmid (Life Technologies), PCDNA2.1 plasmid (Invitrogen, Carlsbad CA), PBK-CMV plasmid (Stxatagene), or pINCY (Incyte Genomics, Palo Alto CA), or derivatives thereof. Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XLl-BlueMRF, or SOLR from Stratagene or DHSa, DHlOB, or ElectroMAX
l0 DH10B from Life Technologies.
II. Isolation of cDNA Clones Plasmids obtained as described in Example I were recovered from host cells by in vivo excision using the UNIZAP vector system (Stratagene) or by cell lysis.
Plasmids were purified using at least one of the following: a Magic or WIZARD Minipreps DNA purification system (Promega); an AGTC Miniprep purification kit (Edge Biosystems, Gaithersburg MD); and QIAWELL

8 Plasmid, QIAWELL 8 Plus Plasmid, QIAWELL 8 Ultra Plasmid purification systems or the R.E.A.L. PREP
96 plasmid purification kit from QIAGEN. Following precipitation, plasmids were resuspended in 0.1 ml of distilled water and stored, with or without lyophilization, at 4°C.
Alternatively, plasmid DNA was amplified from host cell lysates using direct link PCR in a high-throughput format (Rao, V.B. (1994) Anal. Biochem. 216:1-14). Host cell lysis and thermal cycling steps were carried out in a single reaction mixture. Samples were processed and stored in 384-well plates, and the concentration of amplified plasmid DNA was quantified fluorometrically using PICOGREEN dye (Molecular Probes, Eugene OR) and a FLUOROSKAN II fluorescence scanner (Labsystems Oy, Helsinki, Finland).
III. Sequencing and Analysis Incyte cDNA recovered in plasmids as described in Example II were sequenced as follows.
Sequencing reactions were processed using standaxd methods or high-throughput instrumentation such as the ABI CATALYST 800 (Applied Biosystems) thermal cycler or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientifc) or the MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions were prepared using reagents provided by Amersham Pharmacia Biotech or supplied in ABI
sequencing kits such as the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).
Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carried out using the MEGABACE 1000 DNA sequencing system (Molecular Dynamics); the ABI PRISM 373 or 377 sequencing system (Applied Biosystems) in conjunction with standard ABI
protocols and base calling software; or other sequence analysis systems known in the art. Reading frames within the cDNA sequences were identified using standard methods (reviewed in Ausubel, 1997, supra, unit 7.7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example VIII.
The polynucleotide sequences derived from Incyte cDNAs were validated by removing vector, linker, and poly(A) sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programming, and dinucleotide nearest neighbor analysis. The l0 Incyte cDNA sequences or translations thereof were then queried against a selection of public databases such as the GenBankprimate, rodent, mammalian, vertebrate, and eukaryote databases, and BLOCKS, PRINTS, DOMO, PRODOM, and hidden Markov model (HMM)-based protein family databases such as PFAM. (HMM is a probabilistic approach which analyzes consensus primary structures of gene families. See, for example, Eddy, S.R. (1996) Curr. Opin.
Struct. Biol. 6:361-365.) The queries were performed using programs based on BLAST, FASTA, BLIMPS, and HMMER.
The Incyte cDNA sequences were assembled to produce full length polynucleotide sequences.
Alternatively, GenBank cDNAs, GenBank ESTs, stitched sequences, stretched sequences, or Genscan-predicted coding sequences (see Examples IV and V) were used to extend Incyte cDNA
assemblages to full length. Assembly was performed using programs based on Phred, Phrap, and Consed, and cDNA assemblages were screened for open reading frames using programs based on GeneMark, BLAST, and FASTA. The full length polynucleotide sequences were translated to derive the corresponding full length polypeptide sequences. Alternatively, a polypeptide of the invention may begin at any of the methionine residues of the full length translated polypeptide. Full length polypeptide sequences were subsequently analyzed by querying against databases such as the GenBankprotein databases (genpept), SwissProt, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, and hidden Markov model (HMM)-based protein family databases such as PFAM. Full length polynucleotide sequences are also analyzed using MACDNASIS PRO software (Hitachi Software Engineering, South San Francisco CA) and LASERGENE software (DNASTAR). Polynucleotide and polypeptide sequence alignments are generated using default parameters specified by the CLUSTAL algorithm as incorporated into the MEGALIGN multisequence alignment program (DNASTAR), which also calculates the percent identity between aligned sequences.
Table 7 summarizes the tools, programs, and algorithms used for the analysis and assembly of Incyte cDNA and full length sequences and provides applicable descriptions, references, and threshold parameters. The first column of Table 7 shows the tools, programs, and algorithms used, the second column provides brief descriptions thereof, the third column presents appropriate references, all of which are incorporated by reference herein in their entirety, and the fourth column presents, where applicable, the scores, probability values, and other parameters used to evaluate the strength of a match between two sequences (the higher the score or the lower the probability value, the greater the identity between two sequences).
The programs described above for the assembly and analysis of full length polynucleotide and polypeptide sequences were also used to identify polynucleotide sequence fragments from SEQ ID
N0:37-72. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and 1o amplification technologies are described in Table 4, column 4.
IV. Identification and Editing of Coding Sequences from Genomic DNA
Putative extracellular matrix and cell adhesion molecules were initially identified by running the Genscan gene identification program against public genomic sequence databases (e.g., gbpri and gbhtg). Genscan is a general-purpose gene identification program which analyzes genomic DNA
sequences from a variety of organisms (See Burge, C. and S. Karlin (1997) J.
Mol. Biol. 268:78-94, and Burge, C. and S. Karlin (1998) Curr. Opin. Struct. Biol. 8:346-354). The program concatenates predicted exons to form an assembled cDNA sequence extending from a methionine to a stop codon.
The output of Genscan is a FASTA database of polynucleotide and polypeptide sequences. The maximum range of sequence for Genscan to analyze at once was set to 30 kb. To determine which of these Genscan predicted cDNA sequences encode extracellular matrix and cell adhesion molecules, the encoded polypeptides were analyzed by querying against PFAM models for extracellulax matrix and cell adhesion molecules. Potential extracellular matrix and cell adhesion molecules were also identified by homology to Incyte cDNA sequences that had been annotated as extracellular matrix and cell adhesion molecules. These selected Genscan-predicted sequences were then compared by BLAST analysis to the genpept and gbpri public databases. Where necessary, the Genscan-predicted sequences were then edited by comparison to the top BLAST hit from genpept to correct errors in the sequence predicted by Genscan, such as extra or omitted exons. BLAST analysis was also used to fmd any Incyte cDNA or public cDNA coverage of the Genscan-predicted sequences, thus providing evidence for transcription. When Incyte cDNA coverage was available, this information was used to correct or confirm the Genscan predicted sequence. Full length polynucleotide sequences were obtained by assembling Genscan-predicted coding sequences with Incyte cDNA
sequences and/or public cDNA sequences using the assembly process described in Example III.
Alternatively, full length polynucleotide sequences were derived entirely from edited or unedited Genscan-predicted coding sequences.
V. Assembly of Genomic Sequence Data with cDNA Sequence Data "Stitched" Sequences .
Partial cDNA sequences were extended with exons predicted by the Genscan gene identification program described in Example IV. Partial cDNAs assembled as described in Example IIT were mapped to genomic DNA and parsed into clusters containing related cDNAs and Genscan exon predictions from one or more genomic sequences. Each cluster was analyzed using an algorithm based on graph theory and dynamic programming to integrate cDNA and genomic information, generating possible splice variants that were subsequently confirmed, edited, or extended to create a full length sequence. Sequence intervals in which the entire length of the interval was present on more than one sequence in the cluster were identified, and intervals thus identified were considered to be equivalent by transitivity. For example, if an interval was present on a cDNA and two genomic sequences, then all three intervals were considered to be equivalent. This process allows unrelated but consecutive genomic sequences to be brought together, bridged by cDNA
sequence. Intervals thus identified were then "stitched" together by the stitching algorithm in the order that they appear along their parent sequences to generate the longest possible sequence, as well as sequence variants.
Linkages between intervals which proceed along one type of parent sequence (cDNA to cDNA or genomic sequence to genomic sequence) were given preference over linkages which change parent type (cDNA to genomic sequence). The resultant stitched sequences were translated and compared 2o by BLAST analysis to the genpept and gbpri public databases. Incorrect exons predicted by Genscan were corrected by comparison to the top BLAST hit from genpept. Sequences were further extended with additional cDNA sequences, or by inspection of genomic DNA, when necessary.
"Stretched" Sequences Partial DNA sequences were extended to full length with an algorithm based on BLAST
analysis. First, partial cDNAs assembled as described in Example DI were queued against public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases using the BLAST program. The nearest GenBank protein homolog was then compared by BLAST
analysis to either Incyte cDNA sequences or GenScan exon predicted sequences described in Example IV. A chimeric protein was generated by using the resultant high-scoring segment pairs (HSPs) to map the translated sequences onto the GenB auk protein homolog.
Insertions or deletions may occur in the chimeric protein with respect to the original GenB auk protein homolog. The GenBank protein homolog, the chimeric protein, or both were used as probes to search for homologous genomic sequences from the public human genome databases. Partial DNA
sequences were therefore "stretched" or extended by the addition of homologous genomic sequences. The resultant stretched sequences were examined to determine whether it contained a complete gene.
VI. Chromosomal Mapping of ECMCAD Encoding Polynucleotides The sequences which were used to assemble SEQ ID N0:37-72 were compared with sequences from the Incyte LIFESEQ database and public domain databases using BLAST and other implementations of the Smith-Waterman algorithm. Sequences from these databases that matched SEQ ID N0:37-72 were assembled into clusters of contiguous and overlapping sequences using assembly algorithms such as Phrap (Table 7). Radiation hybrid and genetic mapping data available from public resources such as the Stanford Human Genome Center (SHGC), Whitehead Institute for 1o Genome Research (WIGR), and Genethon were used to determine if any of the clustered sequences had been previously mapped. Inclusion of a mapped sequence in a cluster resulted in the assignment of all sequences of that cluster, including its particular SEQ ID NO:, to that map location.
Map locations are represented by ranges, or intervals, of human chromosomes.
The map position of an interval, in centiMorgans; is measured relative to the terminus of the chromosome's p-arm. (The centiMorgan (cM) is a unit of measurement based on recombination frequencies between chromosomal markers. On average, 1 cM is roughly equivalent to 1 megabase (Mb) of DNA in humans, although this can vary widely due to hot and cold spots of recombination.) The cM distances are based on genetic markers mapped by G6n~thon which provide boundaries for radiation hybrid markers whose sequences were included in each of the clusters. Human genome maps and other resources available to the public, such as the NCBI "GeneMap' 99" World Wide Web site (http:Jlwww.ncbi.nlm.nih.govJgenemap!), can be employed to determine if previously identified disease genes map within or in proximity to the intervals indicated above.
In this manner, SEQ )D N0:47 was mapped to chromosome 3 within the interval from 162.00 to 168.30 centiMorgans. SEQ 1D N0:49 was mapped to chromosome 4 within the interval from 63.90 to 88.50 centiMorgans.
VII. Analysis of Polynucleotide Expression Northern analysis is a laboratory technique used to detect the presence of a transcript of a gene and involves the hybridization of a labeled nucleotide sequence to a membrane on which RNAs from a particular cell type or tissue have been bound. (See, e.g., Sambrook, supra, ch. 7; Ausubel (1995) supra, ch. 4 and 16.) Analogous computer techniques applying BLAST were used to search for identical or related molecules in cDNA databases such as GenBank or LIFESEQ (Incyte Genomics). This analysis is much faster than multiple membrane-based hybridizations. In addition, the sensitivity of the computer search can be modified to determine whether any particular match is categorized as exact or similar.
The basis of the search is the product score, which is defined as:
BLAST Score x Percent Identity x minimum {length(Seq. 1), length(Seq. 2) }
The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. The product score is a normalized value between 0 and 100, and is calculated as follows: the BLAST score is multiplied by the percent nucleotide identity and the product is divided by (5 times the length of the shorter of the two sequences). The BLAST score is calculated by assigning a score of +5 for every base that matches in a high-scoring segment pair (HSP), and -4 for every mismatch. Two sequences may share more than one HSP
(separated by gaps). If there is more than one HSP, then the pair with the highest BLAST
score is used to calculate the product score. The product score represents a balance between fractional overlap and quality in a BLAST alignment. For example, a product score of 100 is produced only for 100%
identity over the entire length of the shorter of the two sequences being compared. A product score of 70 is produced either by 100% identity and 70% overlap at one end, or by 88% identity and 100% overlap at the other. A product score of SO is produced either by 100% identity and 50%
overlap at one end, or 79%
identity and 100% overlap.
2o Alternatively, polynucleotide sequences encoding ECMCAD are analyzed with respect to the tissue sources from which they were derived. For example, some full length sequences are assembled, at least in part, with overlapping Incyte cDNA sequences (see Example III). Each cDNA
sequence is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following organltissue categories: cardiovascular system; connective tissue;
digestive system; embryonic structures; endocrine system; exocrine glands;
genitalia, female; genitalia, male; germ cells; heroic and immune system; liver; musculoskeletal system;
nervous system;
pancreas; respiratory system; sense organs; skin; stomatognathic system;
unclassified/mixed; or urinary tract. The number of libraries in each category is counted and divided by the total number of libraries across all categories. Similarly, each human tissue is classified into one of the following disease/condition categories: cancer, cell line, developmental, inflammation, neurological, trauma, cardiovascular, pooled, and other, and the number of libraries in each category is counted and divided by the total number of libraries across all categories. The resulting percentages reflect the tissue- and disease-specific expression of cDNA encoding ECMCAD, cDNA sequences and cDNA

library/tissue information are found in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto CA).
VIII. Extension of ECMCAD Encoding Polynucleotides Full length polynucleotide sequences were also produced by extension of an appropriate fragment of the full length molecule using oligonucleotide primers designed from this fragment. One primer was synthesized to initiate 5' extension of the known fragment, and the other primer was synthesized to initiate 3' extension of the known fragment. The initial primers were designed using OLIGO 4.06 software (National Biosciences), or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the target sequence at temperatures of about 68 °C to about 72°C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations was avoided.
Selected human cDNA libraries were used to extend the sequence. If more than one extension was necessary or desired, additional or nested sets of primers were designed.
high fidelity amplification was obtained by PCR using methods well known in the art. PCR
was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research, Inc.). The reaction mix contained DNA template, 200 nmol of each primer, reaction buffer containing Mg2+, (NH4)2504, and 2-mercaptoethanol, Taq DNA polymerase (Amersham Pharmacia Biotech), ELONGASE
enzyme (Life Technologies), and Pfu DNA polymerase (Stratagene), with the following parameters for primer pair PCI A and PCI B: Step 1: 94°C, 3 min; Step 2:
94°C, 15 sec; Step 3: 60°C, 1 min;
Step 4: 68°C, 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68°C, 5 min; Step 7: storage at 4°C. In the alternative, the parameters for primer pair T7 and SK.+
were as follows: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3: 57°C, 1 min; Step 4:
68°C, 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68 °C, 5 min; Step 7: storage at 4 °C.
The concentration of DNA in each well was determined by dispensing 100 ~1 PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR) dissolved in 1X TE
and 0.5 ~1 of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Costar, Acton MA), allowing the DNA to bind to the reagent. The plate was scanned in a Fluoroskan II
(Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample and to quantify the concentration of DNA. A 5 ,u1 to 10 ~l aliquot of the reaction mixture was analyzed by electrophoresis on a 1 % agarose gel to determine which reactions were successful in extending the sequence.
The extended nucleotides were desalted and concentrated, transferred to 384-well plates, digested with CviJI cholera virus endonuclease (Molecular Biology Research, Madison WI), and sonicated or sheared prior to relegation into pUC 18 vector (Amersham Pharmacia Biotech). For shotgun sequencing, the digested nucleotides were separated on low concentration (0.6 to 0.8%) agarose gels, fragments were excised, and agar digested with Agar ACE
(Promega). Extended clones were relegated using T4 ligase (New England Biolabs, Beverly MA) into pUC 18 vector (Amersham Pharmacia Biotech), treated with Pfu DNA polymerase (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells were selected on antibiotic-containing media, and individual colonies were picked and cultured overnight at 37 °C in 384-well plates in LB/2x carb liquid media.
The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerase l0 (Amersham Pharmacia Biotech) and Pfu DNA polymerase (Stratagene) with the following parameters: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3;
60°C, 1 min; Step 4: 72°C, 2 min; Step 5: steps 2, 3, and 4 repeated 29 times; Step 6: 72°C, 5 min; Step 7:
storage at 4°C. DNA was quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples with low DNA
recoveries were reamplified using the same conditions as described above.
Samples were diluted with 20% dimethysulfoxide (1:2, v/v), and sequenced using DYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit (Amersham Pharmacia Biotech) or the ABI
PRISM
BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).
In like manner, full length polynucleotide sequences are verified using the above procedure or are used to obtain 5' regulatory sequences using the above procedure along with oligonucleotides designed for such extension,' and an appropriate genomic library.
IX. Labeling and Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID NO:37-72 are employed to screen cDNAs, genomic DNAs, or mRNAs. Although the labeling of oligonucleotides, consisting of about 20 base pairs, is specifically described, essentially the same procedure is used with larger nucleotide fragments. Oligonucleotides are designed using state-of-the-art software such as OLIGO 4,06 software (National Biosciences) and labeled by combining 50 pmol of each oligomer, 250 ~Ci of ~,~ 32P1 adenosine- triphosphate (Amersham Pharmacia Biotech), and T4 polynucleotide kinase (DuPont NEN, Boston MA). The labeled oligonucleotides are substantially purifted using a SEPHADEX G-25 supexfine size exclusion dextran bead column (Amersham Pharmacia Biotech).
An aliquot containing 10' counts per minute of the labeled probe is used in a typical membrane-based hybridization analysis of human genomic DNA digested with one of the following endonucleases: Ase I, Bgl II, Eco RI, Pst I, Xba I, or Pvu II (DuPont NEN).
The DNA from each digest is fractionated on a 0.7% agarose gel and transferred to nylon membranes (Nytran Plus, Schleicher & SchueIl, Durham NH). Hybridization is carried out for 16 hours at 40°C. To remove nonspecific signals, blots are sequentially washed at room temperature under conditions of up to, for example, 0.1 x saline sodium citrate and 0.5%
sodium dodecyl sulfate.
Hybridization patterns are visualized using autoradiography or an alternative imaging means and compared.
X. Microarrays The linkage or synthesis of array elements upon a microarray can be achieved utilizing photolithography, piezoelectric printing (ink jet printing, See, e.g., Baldeschweiler, su ra.), mechanical microspotting technologies, and derivatives thereof. The substrate in each of the aforementioned technologies should be uniform and solid with a non-porous surface (Schena (1999), supra).
Suggested substrates include silicon, silica, glass slides, glass chips, and silicon wafers. Alternatively, a procedure analogous to a dot or slot blot may also be used to arrange and link elements to the surface of a substrate using thermal, LTV, chemical, or mechanical bonding procedures.
A typical array may be produced using available methods arid machines well known to those of ordinary skill in the art and may contain any appropriate number of elements. (See, e.g., Schena, M. et al.
(1995) Science 270:467-470; Shalom D. et al. (1996) Genome Res. 6:639-645; Marshall, A. and J. Hodgson (1998) Nat. Biotechnol. 16:27-31.) Full length cDNAs, Expressed Sequence Tags (ESTs), or fragments or oligomers thereof may comprise the elements of the microarray. Fragments or oligomers suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). The array elements are hybridized with polynucleotides in a biological sample. The polynucleotides in the biological sample are conjugated to a fluorescent label or other molecular tag for ease of detection.
After hybridization, nonhybridized nucleotides from the biological sample are removed, and a fluorescence scanner is used to detect hybridization at each array element.
Alternatively, laser desorbtion and mass spectrometry may be used for detection of hybridization.
The degree of complementaxity and the relative abundance of each polynucleotide which hybridizes to an element on the microarray may be assessed. In one embodiment, microarray preparation and usage is described in detail below.
Tissue or Cell Sample Preparation Total RNA is isolated from tissue samples using the guanidinium thiocyanate method and poly(A)* RNA is purified using the oligo-(dT) cellulose method. Each poly(A)+
RNA sample is reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/~1 oligo-(dT) primer (2lmer), 1X first strand buffer, 0.03 units/~1 RNase inhibitor, 500 pM dATP, 5001tM dGTP, 500 ~M
dTTP, 40 pM

dCTP, 40 ~M dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Pharmacia Biotech). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng poly(A)+ RNA with GEMBRIGHT kits (Incyte). Specific control poly(A)+ RNAs are synthesized by in vitro transcription from non-coding yeast genomic DNA. After incubation at 37° C for 2 hr, each reaction sample (one with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of O.SM sodium hydroxide and incubated for 20 minutes at 85° C to the stop the reaction and degrade the RNA. Samples are purified using two successive CHROMA SPIN 30 gel filtration spin columns (CLONTECH
Laboratories, Inc.
(CLONTECH), Palo Alto CA) and after combining, both reaction samples are ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100%
ethanol. The sample is then dried to completion using a SpeedVAC (Savant Instruments Inc., Holbrook NY) and resuspended in 14 ~l SX SSC/0.2% SDS.
Microarray Preparation Sequences of the present invention are used to generate array elements. Each array element is amplified from bacterial cells containing vectors with cloned cDNA inserts.
PCR amplification uses primers complementary to the vector sequences flanking the cDNA insert. Array elements are amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a final quantity greater than 5 dug.
Amplified array elements are then purified using SEPHACRYL-400 (Amersham Pharmacia Biotech).
Purified array elements are immobilized on polymer-coated glass slides. Glass microscope slides (Corning) are cleaned by ultrasound in 0.1 %o SDS and acetone, with extensive distilled water washes between and after treatments. Glass slides are etched in 4%
hydrofluoric acid (VWR
Scientific Products Corporation (VWR), West Chester PA), washed extensively in distilled water, and coated with 0.05% aminopropyl silane (Sigma) in 95% ethanol. Coated slides are cured in a 110°C
oven.
Array elements are applied to the coated glass substrate using a procedure described in US
Patent No. 5,807,522, incorporated herein by reference. 1 ~1 of the array element DNA, at an average concentration of 100 ng/~1, is loaded into the open capillary printing element by a high-speed robotic apparatus. The apparatus then deposits about 5 n1 of array element sample per slide.
Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker (Stratagene).
Microarrays are washed at room temperature once in 0.2% SDS and three times in distilled water.
Non-specific binding sites are blocked by incubation of microarrays in 0.2%
casein in phosphate buffered saline (PBS) (Tropix, Inc., Bedford MA) for 30 minutes at 60°
C followed by washes in 0.2%
SDS and distilled water as before.
Hybridization Hybridization reactions contain 9 ~ l of sample mixture consisting of 0.2 p g each of Cy3 and Cy5 labeled cDNA synthesis products in 5X SSC, 0.2% SDS hybridization buffer.
The sample mixture is heated to 65° C for S minutes and is aliquoted onto the microarray surface and covered with an 1.8 cm2 coverslip. The arrays are transferred to a waterproof chamber having a cavity just slightly larger than a microscope slide. The chamber is kept at 100% humidity internally by the addition of 140 p1 of 5X SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6.5 hours at 60° C. The arrays are washed for 10 min at 45° C in a first wash buffer (1X SSC, 0.1%
SDS), three times for 10 minutes each at 45° C in a second wash buffer (0.1X SSC), and dried.
Detection Reporter-labeled hybridization complexes are detected with a microscope equipped with an Innova 70 mixed gas 10 W laser (Coherent, Inc., Santa Clara CA) capable of generating spectral lines at 488 nm for excitation of Cy3 and at 632 nm for excitation of CyS. The excitation laser light is focused on the array using a 20X microscope objective (Nikon, Inc., Melville NY). The slide containing the array is placed on a computer-controlled X-Y stage on the microscope and raster-scanned past the objective. The 1.8 cm x 1.8 em array used in the present example is scanned with a resolution of 20 micrometers.
In two separate scans, a mixed gas multiline laser excites the two fluorophores sequentially. , Emitted light is split, based on wavelength, into two photomultiplier tube detectors (PMT 81477, Hamamatsu Photonics Systems, Bridgewater NJ) corresponding to the two fluorophores. Appropriate, filters positioned between the array and the photomultiplier tubes are used to filter the signals. The emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for CyS. Each array is typically scanned twice, one scan per fluorophore using the appropriate filters at the laser source, although the apparatus is capable of recording the spectra from both fluorophores simultaneously.
The sensitivity of the scans is typically calibrated using the signal intensity generated by a cDNA control species added to the sample mixture at a known concentration. A
specific location on the array contains a complementary DNA sequence, allowing the intensity of the signal at that location to be correlated with a weight ratio of hybridizing species of 1:100,000. When two samples from different sources (e.g., representing test and control cells), each labeled with a different fluorophore, are hybridized to a single array for the purpose of identifying genes that are differentially expressed, the calibration is done by labeling samples of the calibrating cDNA with the two fluorophores and adding identical amounts of each to the hybridization mixture.
The output of the photomultiplier tube is digitized using a 12-bit RTI-835H
analog-to-digital (A/D) conversion board (Analog Devices, Inc., Norwood MA) installed in an IBM-compatible PC

computer. The digitized data are displayed as an image where the signal intensity is mapped using a linear 20-color transformation to a pseudocolor scale ranging from blue (low signal) to red (high signal). The data is also analyzed quantitatively. Where two different fluorophores are excited and measured simultaneously, the data are first corrected for optical crosstalk (due to overlapping emission S spectra) between the fluorophores using each fluorophore's emission spectrum.
A grid is superimposed over the fluorescence signal image such that the signal from each spot is centered in each element of the grid. The fluorescence signal within each element is then integrated to obtain a numerical value corresponding to the average intensity of the signal. The software used for signal analysis is the GEMTOOLS gene expression analysis program (Incyte).
l0 XI. Complementary Polynucleotides Sequences complementary to the ECMCAD-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring ECMCAD.
Although use of oligonucleotides comprising from about 15 to 30 base pairs is described, essentially the same procedure is used with smaller or with larger sequence fragments. Appropriate oligonucleotides are 15 designed using OLIGO 4.06 software (National Biosciences) and the coding sequence of ECMCAD.
To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5' sequence and used to prevent promoter binding to the coding sequence. To inhibit translation, a complementary oligonucleotide is designed to prevent ribosomal binding to the ECMCAD-encoding transcript.
XII. Expression of ECMCAD
20 Expression and purification of ECMCAD is achieved using bacterial or virus-based expression systems. For expression of ECMCAD in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA
transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the TS or T7 bacteizophage promoter in conjunction with the lac operator regulatory 25 element. Recombinant vectors are transformed into suitable bacterial hosts, e.g., BL21 (DE3).
Antibiotic resistant bacteria express ECMCAD upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of ECMCAD in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant Auto~raphica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is 30 replaced with cDNA encoding ECMCAD by either homologous recombination or bacterial-mediated transposition involving transfer plasmid intermediates. Viral infectivity is maintained and the strong polyhedrin promoter drives high levels of cDNA transcription. Recombinant baculovirus is used to infect Spodoptera fru~iperda (Sf9) insect cells in most cases, or human hepatocytes, in some cases.

Infection of the latter requires additional genetic modifications to baculovirus. (See Engelhard, E.K. et al. (1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther.
7:1937-1945.) In most expression systems, ECMCAD is synthesized as a fusion protein with, e.g., glutathione S-transferase (GST) or a peptide epitope tag, such as FLAG or 6-His, permitting rapid, single-step, affinity-based purification of recombinant fusion protein from crude cell lysates. GST, a 26-kilodalton enzyme from Schistosoma japonicum, enables the purification of fusion proteins on immobilized glutathione under conditions that maintain protein activity and antigenicity (Amersham Pharmacia Biotech). Following purification, the GST moiety can be proteolytically cleaved from 1o ECMCAD at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffinity purification using commercially available monoclonal and polyclonal anti-FLAG
antibodies (Eastman Kodak). 6-His, a stretch of six consecutive histidine residues, enables purification on metal-chelate resins (QIAGEN). Methods for protein expression and purification are discussed in Ausubel (1995, supra, ch. 10 and 16). Purified ECMCAD obtained by these methods can be used directly in the assays shown in Examples XVI and XVII where applicable.
XIII. Functional Assays ECMCAD function is assessed by expressing the sequences encoding ECMCAD at physiologically elevated levels in mammalian cell culture systems. cDNA is subcloned into a mammalian expression vector containing a strong promoter that drives high levels of cDNA
expression. Vectors of choice include PCMV SPORT (Life Technologies) and PCR3.1 (Invitrogen, Carlsbad CA), both of which contain the cytomegalovirus promoter. 5-10 ,ug of recombinant vector are transiently transfected into a human cell line, for example, an endothelial or hematopoietic cell Line, using either liposome formulations or electroporation. 1-2 ~cg of an additional plasmid containing sequences encoding a marker protein are co-transfected. Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA
expression from the recombinant vector. Maxker proteins of choice include, e.g., Green Fluorescent Protein (GFP; Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), an automated, laser optics-based technique, is used to identify transfected cells expressing GFP or CD64-GFP and to evaluate the apoptotic state of the cells and other cellular properties. FCM detects and quantifies the uptake of fluorescent molecules that diagnose events preceding or coincident with cell death. These events include changes in nuclear DNA content as measured by staining of DNA with propidium iodide; changes in cell size and granularity as measured by forward light scatter and 90 degree side light scatter; down-regulation of DNA synthesis as measured by decrease in bromodeoxyuridine uptake; alterations in expression of cell surface and intracellular proteins as measured by reactivity with specific antibodies; and alterations in plasma membrane composition as measured by the binding of fluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M.G. (1994) Flow C, ometry, Oxford, New York NY.
The influence of ECMCAD on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding ECMCAD and either CD64 or CD64-GFP.
CD64 and CD64-GFP are expressed on the surface of transfected cells and bind to conserved regions of human immunoglobulin G (IgG). Transfected cells are efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CD64 (DYNAL, Lake l0 Success NY). mRNA can be purified from the cells using methods well known by those of skill in the art. Expression of mRNA encoding ECMCAD and other genes of interest can be analyzed by northern analysis or microarray techniques.
XIV. Production of ECMCAD Specific Antibodies ECMCAD substantially purified using polyacrylamide gel electrophoresis (PAGE;
see, e.g., Harrington, M.G. (1990) Methods Enzymol. 182:488-495), or other purification techniques, is used to immunize rabbits and to produce antibodies using standard protocols.
Alternatively, the ECMCAD amino acid sequence is analyzed using LASERGENE
software (DNASTAR) to determine regions of high immunogenicity, and a corresponding oligopeptide is synthesized and used to raise antibodies by means known to those of skill in the art. Methods for selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions are well described in the art. (See, e.g., Ausubel, 1995, supra, ch. 11.) ' Typically, oligopeptides of about 15 residues in length are synthesized using an ABI 431A
peptide synthesizer (Applied Biosystems) using FMOC chemistry and coupled to KLH (Sigma-Aldrich, St. Louis MO) by reaction with N-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) to increase immunogenicity. (See, e.g., Ausubel, 1995, su ra.) Rabbits are immunized with the oligopeptide-KI,H complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-ECMCAD activity by, for example, binding the peptide or ECMCAD to a substrate, blocking with 1 % BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.
XV. Purification of Naturally Occurring ECMCAD Using Specific Antibodies Naturally occurring or recombinant ECMCAD is substantially purified by immunoa~nity chromatography using antibodies specific for ECMCAD. An immunoaffinity column is constructed by covalently coupling anti-ECMCAD antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Pharmacia Biotech). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.
Media containing ECMCAD are passed over the immunoaffnity column, and the column is washed under conditions that allow the preferential absorbance of ECMCAD
(e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/ECMCAD binding (e.g., a buffer of pH 2 to pH 3, or a high concentration,of a chaotrope, such as urea or thiocyanate ion), and ECMCAD is collected.
XVI. Identification of Molecules Which Interact with ECMCAD
ECMCAD, or biologically active fragments thereof, are labeled with 12s1 Bolton-Hunter l0 reagent. (See, e.g., Bolton A.E. and W.M. Hunter (1973) Biochem. J. 133:529-539.) Candidate molecules previously arrayed in the wells of a mufti-well plate are incubated with the labeled ECMCAD, washed, and any wells with labeled ECMCAD complex are assayed. Data obtained using different concentrations of ECMCAD are used to calculate values for the number, affinity, and association of ECMCAD with the candidate molecules.
Alternatively, molecules interacting with ECMCAD are analyzed using the yeast two-hybrid system as described in Fields, S. and O. Song (1989) Nature 340:245-246, or using commercially available kits based on the two-hybrid system, such as the MATCHMAKER system (Clontech).
ECMCAD may also be used in the PATHCALLING process (CuraGen Corp., New Haven CT) which employs the yeast two-hybrid system in a high-throughput manner to determine all interactions between the proteins encoded by two large libraries of genes (Nandabalan, K. et al.
(2000) U.S. Patent No. 6,057,101).
XVII. Demonstration of ECMCAD Activity An assay for ECMCAD activity measures the expression of ECMCAD on the cell surface.
cDNA encoding ECMCAD is transfected into a non-leukocytic cell line. Cell surface proteins are labeled with biotin (de la Fuente, M.A. et al. (1997) Blood 90:2398-2405).
Irnmunoprecipitations are performed using ECMCAD-speciftc antibodies, and immunoprecipitated samples are analyzed using SDS-PAGE and immunoblotting techniques. The ratio of labeled immunoprecipitant to unlabeled immunoprecipitant is proportional to the amount of ECMCAD expressed on the cell surface.
Alternatively, an assay for ECMCAD activity measures the amount of cell aggregation induced by overexpression of ECMCAD. In this assay, cultured cells such as NIH3T3 are transfected with cDNA encoding ECMCAD contained within a suitable mammalian expression vector under control of a strong promoter. Cotransfection with cDNA encoding a fluorescent marker protein, such as Green Fluorescent Protein (CLONTECH), is useful for identifying stable transfectants. The amount of cell agglutination, or clumping, associated with transfected cells is compared with that associated with untransfected cells. The amount of cell agglutination is a direct measure of ECMCAD activity.
Alternatively, an assay for ECMCAD activity measures the disruption of cytoskeletal filament networks upon overexpression of ECMCAD in cultured cell lines (Rezniczek, G.
A. et al. (1998) J.
Cell Biol. 141:209-225). cDNA encoding ECMCAD is subcloned into a mammalian expression vector that drives high levels of cDNA expression. This construct is transfected into cultured cells, such as rat kangaroo PtK2 or rat bladder carcinoma 8046 cells. Actin filaments and intermediate filaments such as keratin and vimentin are visualized by immunofluorescence microscopy using antibodies and techniques well known in the art. The configuration and abundance of cyoskeletal filaments can be assessed and quantified using confocal imaging techniques. In particular, the bundling and collapse of cytoskeletal filament networks is indicative of ECMCAD activity.
Alternatively, cell adhesion activity in ECMCAD is measured in a 96-well microtiter assay in which wells are first coated with ECMCAD by adding solutions of ECMCAD of varying concentrations to the wells. Excess ECMCAD is washed off with saline, and the wells incubated with a solution of 1 % bovine serum albumin to block non-specific cell binding.
Aliquots of a cell suspension of a suitable cell type are then added to the micortiter wells and incubated for a period of time at 37 °C. Non-adhered cells are washed off with saline and the cells stained with a suitable cell stain such as Coomassie blue. The intensity of staining is measured using a variable wavelength microtiter plate reader and compared to a standard curve to determine the number of cells adhering to the ECMCAD
coated plates. The degree of cell staining is proportional to the cell adhesion activity of ECMCAD in the sample.
Various. modifications and variations of the described methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention.
Although the invention has been described in connection with certain embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments.
Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims.

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<110> INCYTE GENOMICS, INC.
TANG, Y. Tom YUE, Henry AZIMZAI, Yalda HE, Ann BATRA, Sajeev L0, Terence P.
NGUYEN, Danniel B.
BURRILL, John D.
MARCUS, Gregory A.
ZINGLER, Kurt A.
GANDHI, Ameena R.
LAL, Preeti KEARNEY, Liam BURFORD, Neil YAO, Monique G.
WALIA, Narinder K.
ELLIOT, Vicki S.
PATTERSON, Chandra KHAN, Farrah A.
BAUGHN, Mariah R.
HAFALIA, April, J.A.
POLICKY, Jennifer L.
AU-YOUNG, Janice LU, Yan BOROWSKY, Mark L.
LU, Dyung Aina M.
RAMKUMAR, JayalaHIni YANG, Junming GURURAJAN, Rajagopal WARREN, Bridget A.
GIETZEN, Kimberly XU, Yuming KALLICK, Deborah A.
LEE, Ernestine A.
THANGAVELU, Kavitha DELEGEANE, Angelo M.
LEE, Sally <120> EXTRACELLULAR MATRIX AND CELL ADHESION MOLECULES
<130> PF-0794 PCT
<140> To Be Assigned <141> Herewith <150> 60/215,454; 60/219,462; 60/240,111; 60/240,106; 60/244,021;
60/248,887; 60/249,570 <151> 2000-06-30; 2000-07-18; 2000-10-12; 2000-10-12; 2000-10-27;
2000-11-14; 2000-11-16 <160> 72 <170> PERL Program <210> 1 <211> 234 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1888682CD1 <400> 1 Met Pro Ser Gly Cys His Ser Ser Pro Pro Ser Gly Leu Arg Gly Asp Met Ala Ser Leu Val Pro Leu Ser Pro Tyr Leu Ser Pro Thr Val Leu Leu Leu Val Ser Cys Asp Leu Gly Phe Val Arg Ala Asp Arg Pro Pro Ser Pro Val Asn Val Thr Val Thr His Leu Arg Ala Asn Ser Ala Thr Val Ser Trp Asp Val Pro Glu Gly Asn Ile Va1 Ile Gly Tyr Ser Ile Ser Gln Gln Arg Gln Asn Gly Pro Gly Gln Arg Val Ile Arg Glu Val Asn Thr Thr Thr Arg Ala Cys Ala Leu Trp Gly Leu Ala G1u Asp Ser Asp Tyr Thr Val Gln Val Arg Ser Ile Gly Leu Arg Gly Glu Ser Pro Pro Gly Pro Arg Val His Phe Arg Thr Leu Lys Gly Ser Asp Arg Leu Pro Ser Asn Ser Ser Ser Pro Gly Asp Ile Thr Val Glu G1y Leu Asp Gly Glu Arg Pro Leu Gln Thr Gly Glu Val Val Ile Ile Val Val Val Leu Leu Met Trp Ala Ala Val Ile Gly Leu Phe Cys Arg Gln Tyr Asp Ile Ile Lys Asp Asn Asp Ser Asn Asn Asn Pro Lys Glu Lys Gly Lys Gly Pro Glu Gln Ser Pro Gln Gly Arg Pro Val Gly Thr Arg Gln Lys Lys Ser Pro Ser Ile Asn Thr Ile Asp Val <210> 2 <211> 443 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature <223> 2ncyte ID No: 1794980CD1 <400> 2 Met Gly Gly Pro Arg Ala Trp Ala Leu Leu Cys Leu Gly Leu Leu Leu Pro Gly Gly Gly Ala Ala Trp Ser Ile Gly Ala Ala Pro Phe Ser Gly Arg Arg Asn Trp Cys Ser Tyr Val Val Thr Arg Thr Ile Ser Cys His Val Gln Asn Gly Thr Tyr Leu Gln Arg Val Leu Gln 50 . 55 60 Asn Cys Pro Trp Pro Met Ser Cys Pro Gly Ser Ser Tyr Arg Thr Val Val Arg Pro Thr Tyr Lys Val Met Tyr Lys Ile Val Thr Ala Arg Glu Trp Arg Cys Cys Pro Gly His Ser Gly Val Ser Cys Glu Glu Val Ala Ala Ser Ser Ala Ser Leu Glu Pro Met Trp Ser Gly 110 1l5 120 Ser Thr Met Arg Arg Met Ala Leu Arg Pro Thr Ala Phe Ser Gly Cys Leu Asn Cys Ser Lys Val Ser Glu Leu Thr Glu Arg Leu Lys Val Leu Glu Ala Lys Met Thr Met Leu Thr Val Ile Glu Gln Pro Val Pro Pro Thr Pro Ala Thr Pro Glu Asp Pro Ala Pro Leu Trp Gly Pro Pro Pro Ala Gln Gly Ser Pro Gly Asp Gly Gly Leu Gln Asp Gln Val Gly Ala Trp Gly Leu Pro Gly Pro Thr Gly Pro Lys Gly Asp Ala Gly Ser Arg Gly Pro Met Gly Met Arg Gly Pro Pro Gly Pro Gln Gly Pro Pro Gly Ser Pro Gly Arg Ala Gly Ala Val Gly Thr Pro Gly Glu Arg Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Ala Pro Val Gly Pro Pro His Ala Arg Ile Ser Gln His Gly Asp Pro Leu Leu Ser Asn Thr Phe Thr Glu Thr Asn Asn His Trp Pro Gln Gly Pro Thr Gly Pro Pro Gly Pro Pro Gly Pro Met Gly Pro Pro Gly Pro Pro Gly Pro Thr Gly Val Pro Gly Ser Pro Gly His Ile Gly Pro Pro Gly Pro Thr Gly Pro Lys Gly Ile Ser Gly His Pro Gly Glu Lys Gly Glu Arg Gly Leu Arg Gly Glu Pro Gly Pro Gln Gly Ser Ala Gly Gln Arg Gly Glu Pro Gly Pro Lys Gly Asp Pro Gly Glu Lys Ser His Trp Gly Glu Gly Leu His Gln Leu Arg Glu Ala Leu Lys Ile Leu Ala Glu Arg Val Leu Ile Leu Glu Thr Met Ile Gly Leu Tyr Glu Pro Glu Leu Gly Ser Gly Ala Gly Pro Ala Gly Thr G1y Thr Pro Ser Leu Leu Arg Gly Lys Arg Gly Gly His Ala Thr Asn Tyr Arg Ile Val Ala Pro Arg Ser Arg Asp Glu Arg Gly <210> 3 <211> 261 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5533958CD1 <400> 3 Met Gly Gly Ala Gly Ile Leu Leu Leu Leu Leu Ala Gly Ala Gly Val Val Val Ala Trp Arg Pro Pro Lys Gly Lys Cys Pro Leu Arg Cys Ser Cys Ser Lys Asp Ser Ala Leu Cys Glu Gly Ser Pro Asp Leu Pro Val Ser Phe Ser Pro Thr Leu Leu Ser Leu Ser Leu Val Arg Thr Gly Val Thr Gln Leu Lys Ala Gly Ser Phe Leu Arg Ile Pro Ser Leu His Leu Leu Leu Phe Thr Ser Asn Ser Phe Ser Val Ile Glu Asp Asp Ala Phe Ala Gly Leu Ser His Leu Gln Tyr Leu Phe Ile Glu Asp Asn Glu Ile Gly Ser Ile Ser Lys Asn Ala Leu Arg Gly Leu Arg Ser Leu Thr His Leu Ser Leu Ala Asn Asn His Leu Glu Thr Leu Pro Arg Phe Leu Phe Arg Gly Leu Asp Thr Leu Thr His Val Asp Leu Arg Gly Asn Pro Phe Gln Cys Asp Cys Arg Val Leu Trp Leu Leu Gln Trp Met Pro Thr Val Asn Ala Ser Val Gly Thr Gly Ala Cys Ala Gly Pro Ala Ser Leu Ser His Met Gln Leu His His Leu Asp Pro Lys Thr Phe Lys Cys Arg Ala Ile Gly Gly Gly Leu Ser Arg Trp Gly Gly Arg Arg Glu Ile Trp Gly Lys Gly Cys G1n Gly Gln Glu Ala Arg Leu Thr Pro Cys Pro Ala Ile Ser Arg Ser Gly Lys Thr Leu Ser Lys Gln His Cys Leu Pro Glu Pro Gln Phe Ser His Leu <210> 4 <211> 643 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 60210196CD1 <400> 4 Met Glu Pro Val Pro Leu Gln Asp Phe Val Arg Ala Leu Asp Pro Ala Ser Leu Pro Arg Val Leu Arg Val Cys Ser Gly Val Tyr Phe Glu Gly Ser Ile Tyr Glu Ile Ser Gly Asn Glu Cys Cys Leu Ser Thr Gly Asp Leu Ile Lys Val Thr Gln Val Arg Leu Gln Lys Val Val Cys Glu Asn Pro Lys Thr Ser Gln Thr Met Glu Leu Ala Pro Asn Phe Gln Gly Tyr Phe Thr Pro Leu Asn Thr Pro Gln Ser Tyr Glu Thr Leu Glu Glu Leu Val Ser Ala Thr Thr Gln Ser Ser Lys Gln Leu Pro Thr Cys Phe Met Ser Thr His Arg Ile Val Thr Glu Gly Arg Val Val Thr Glu Asp Gl.n Leu Leu Met Leu Glu Ala Val Val Met His Leu Gly Ile Arg Ser Ala Arg Cys Val Leu Gly Met Glu G1y G1n Gln Val Ile Leu His Leu Pro Leu Ser Gln Lys Gly 155 ~ 160 165 Pro Phe Trp Thr Trp Glu,Pro Ser Ala Pro Arg Thr Leu Leu Gln Val Leu Gln Asp Pro Ala Leu Lys Asp Leu Val Leu Thr Cys Pro Thr Leu Pro Trp His Ser Leu Ile Leu Arg Pro G1n Tyr Glu Ile GIn Ala I1e Met His Met Arg Arg Thr Ile Val Lys Ile Pro Ser Thr Leu Glu Val Asp Val Glu Asp Val Thr Ala Ser Sex Arg His Val His Phe Ile Lys Pro Leu Leu Leu Ser Glu Val Leu Ala Trp Glu Gly Pro Phe Pro Leu Ser Met G1u Ile Leu Glu Val Pro Glu Gly Arg Pro Ile Phe Leu Ser Pro Trp Val Gly Ser Leu Gln Lys Gly Gln Arg Leu Cys Val Tyr Gly Leu Ala Ser Pro Pro Trp Arg Val Leu Ala Ser Ser Lys Gly Arg Lys Val Pro Arg His Phe Leu Val Ser Gly Gly Tyr Gln Gly Lys Leu Arg Arg Arg Pro Arg Glu Phe Pro Thr Ala Tyr Asp Leu Leu Gly Ala Phe Gln Pro Gly Arg 335 340 ' 345 Pro Leu Arg Val Val Ala Thr Lys Asp Cys Glu Gly Glu Arg Glu y Glu Asn Pro Glu Phe Thr Ser Leu Ala Val Gly Asp Arg Leu Glu Val Leu Gly Pro Gly Gln Ala His Gly Ala Gln Gly Ser Asp Val Asp Val Leu Val Cys Gln Arg Leu Ser Asp Gln Ala Gly Glu Asp Glu Glu G1u Glu Cys Lys Glu Glu Ala G1u Ser Pro Glu Arg Val Leu Leu Pro Phe His Phe Pro Gly Ser Phe Val Glu Glu Met Ser Asp Ser Arg Arg Tyr Ser Leu Ala Asp Leu Thr Ala Gln Phe Ser Leu Pro Cys Glu Val Lys Val Val Ala Lys Asp Thr Ser His Pro Thr Asp Pro Leu Thr Ser Phe Leu Gly Leu Arg Leu Glu Glu Lys Ile Thr Glu Pro Phe Leu Val Val Ser Leu Asp Ser G1u Pro Gly Met Cys Phe Glu Ile Pro Pro Arg Trp Leu Asp Leu Thr Val Val Lys Ala Lys Gly Gln Pro Asp Leu Pro Glu Gly Ser Leu Pro Ile Ala Thr Val Glu Glu Leu Thr Asp Thr Phe Tyr Tyr Arg Leu Arg Lys Leu Pro Ala Cys Glu Ile Gln Ala Pro Pro Pro Arg Pro Pro Lys Asn Gln Gly Leu Ser Lys Gln Arg Arg His Ser Ser Glu Gly Gly Val Lys Ser Ser Gln Va1 Leu Gly Leu Gln Gln His Ala Arg Leu Pro Lys Pro Lys Ala Lys Thr Leu Pro Glu Phe Ile Lys Asp Gly Ser Ser Thr Tyr Ser Lys Ile Pro Ala His Arg Lys Gly His Arg Pro Ala Lys Pro Gln Arg Gln Asp Leu Asp Asp Asp Glu His Asp Tyr Glu Glu Ile Leu Glu Gln Phe Gln Lys Thr Ile <210> 5 <211> 628 <212> PRT
<213> Homo sapiens <220>
<221> misc feature <223> Incyte ID No: 815125CD1 <400> 5 Met Gly Ser Cys Ala Arg Leu Leu Leu Leu Trp Gly Cys Thr Val 1 ~ 5 10 15 Val Ala Ala Gly Leu Ser Gly Val Ala Gly Val Ser Ser Arg Cys Glu Lys Ala Cys Asn Pro Arg Met Gly Asn Leu Ala Leu Gly Arg 35 40 . 45 Lys Leu Trp Ala Asp Thr Thr Cys Gly Gln Asn Ala Thr Glu Leu Tyr Cys Phe Tyr Ser Glu Asn Thr Asp Leu Thr Cys Arg Gln Pro Lys Cys Asp Lys Cys Asn Ala Ala Tyr Pro His Leu Ala His Leu Pro Ser Ala Met Ala Asp Ser Ser Phe Arg Phe Pro Arg Thr Trp Trp Gln Ser Ala Glu Asp Val His Arg Glu Lys Val Gln Leu Asp Leu Glu Ala Glu Phe Tyr Phe Thr His Leu Ile Val Met Phe Lys Ser Pro Arg Pro Ala Ala Met Va1 Leu Asp Arg Ser Gln Asp Phe Gly Lys Thr Trp Lys Pro Tyr Lys Tyr Phe Ala Thr Asn Cys Ser Ala Thr Phe Gly Leu Glu Asp Asp Val Val Lys Lys Gly Ala Ile Cys Thr Ser Lys Tyr Ser Ser Pro Phe Pro Cys Thr Gly Gly Glu Va1 Ile Phe Lys Ala Leu Ser Pro Pro Tyr Asp Thr Glu Asn Pro Tyr Ser Ala Lys Val Gln Glu Gln Leu Lys Ile Thr Asn Leu Arg Val Gln Leu Leu Lys Arg Gln Ser Cys Pro Cys Gln Arg Asn Asp Leu Asn Glu Glu Pro Gln His Phe Thr His Tyr Ala Ile Tyr Asp Phe Ile Va1 Lys Gly Ser Cys Phe Cys Asn Gly His Ala Asp Gln Cys Ile Pro Va1 His Gly Phe Arg Pro Val Lys Ala Pro Gly Thr Phe His Met Val His Gly Lys Cys Met Cys Lys His Asn Thr Ala Gly Ser His Cys Gln His Cys Ala Pro Leu Tyr Asn Asp Arg Pro Trp Glu Ala Ala Asp Gly Lys Thr Gly Ala Pro Asn Glu Cys Arg Thr Cys Lys Cys Asn Gly His Ala Asp Thr Cys His Phe Asp Val 335 340 , 345 Asn Val Trp Glu Ala Ser Gly Asn Arg Ser Gly Gly Val Cys Asp Asp Cys Gln His Asn Thr Glu Gly Gln Tyr Cys Gln Arg Cys Lys Pro Gly Phe Tyr Arg Asp Leu Arg Arg Pro Phe Ser Ala Pro Asp Ala Cys Lys Pro Cys Ser Cys His Pro Val Gly Ser Ala.Val Leu Pro Ala Asn Ser Val Thr Phe Cys Asp Pro Ser Asn Gly Asp Cys Pro Cys Lys Pro Gly Val Ala G1y Arg Arg Cys Asp Arg Cys Met Val Gly Tyr Trp Gly Phe Gly Asp Tyr Gly Cys Arg Pro Cys Asp Cys Ala Gly Ser Cys Asp Pro I1e Thr Gly Asp Cys Ile Ser Ser His Thr Asp Ile Asp Trp Tyr His Glu Val Pro Asp Phe Arg Pro Val His Asn Lys Ser Glu Pro Ala Trp G1u Trp Glu Asp Ala Gln Gly Phe Ser Ala Leu Leu His Ser Gly Lys Cys Glu Cys Lys Glu Gln Thr Leu Gly Asn Ala Lys Ala Phe Cys Gly Met Lys Tyr Ser Tyr Val Leu Lys Ile Lys Ile Leu Ser Ala His Asp Lys Gly Thr His Val Glu Val Asn Val Lys Ile Lys Lys Val Leu Lys Ser Thr Lys Leu Lys Ile Phe Arg Gly Lys Arg Thr Leu Tyr Pro Glu Ser Trp Thr Asp Arg Gly Cys Thr Cys Pro Ile Leu Asn Pro Gly Leu Glu Tyr Leu Val Ala Gly His Glu Asp Ile Arg Thr Gly Lys Leu Ile Val Asn Met Lys Ser Phe Val G1n His Trp Lys Pro Ser Leu Gly Arg Lys Val Met Asp Ile Leu Lys Arg Glu Cys Lys <210> 6 <211> 686 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1386915CD1 <400> 6 Met Leu Leu Arg Gly Val Leu Leu Ala Leu Gln Ala Leu Gln Leu Ala Gly Ala Leu Asp Leu Pro Ala Gly Ser Cys Ala Phe Glu Glu Ser Thr Cys Gly Phe Asp Ser VaI Leu Ala Ser Leu Pro Trp Ile 35 40 ~ 45 Leu Asn Glu Glu Gly His Tyr.Ile Tyr Val Asp Thr Ser Phe Gly Lys Gln Gly Glu Lys Ala Val Leu Leu Ser Pro Asp Leu Gln Ala Glu Gl.u Trp Ser Cys Leu Arg Leu Val Tyr Gln Ile Thr Thr Ser Ser Glu Ser Leu Ser Asp Pro Ser Gln Leu Asn Leu Tyr Met Arg 95 l00 105 Phe Glu Asp Glu Ser Phe Asp Arg Leu Leu Trp Ser Ala Lys Glu Pro Ser Asp Ser Trp Leu Ile Ala Ser Leu Asp Leu Gln Asn Ser Ser Lys Lys Phe Lys Ile Leu Ile Glu Gly Val Leu Gly Gln Gly Asn Thr Ala Ser Ile Ala Leu Phe Glu Ile Lys Met Thr Thr Gly Tyr Cys Ile Glu Cys Asp Phe Glu Glu Asn His Leu Cys Gly Phe Val Asn Arg Trp Asn Pro Asn Val Asn Trp Phe Val Gly Gly Gly Ser Ile Arg Asn Val His Ser Ile Leu Pro Gln Asp His Thr Phe Lys Ser Glu Leu G1y His Tyr Met Tyr Val Asp Ser Val Tyr Val Lys His Phe Gln Glu Val Ala Gln Leu Ile Ser Pro Leu Thr Thr Ala Pro Met Ala Gly Cys Leu Ser Phe Tyr Tyr Gln Ile Gln Gln Gly Asn Asp Asn Val Phe Ser Leu Tyr Thr Arg Asp Val Ala Gly Leu Tyr Glu Glu Ile Trp Lys Ala Asp Arg Pro Gly Asn Ala Ala Trp Asn Leu Ala Glu Val Glu Phe Asn Ala Pro Tyr Pro Met Glu Val Ile Phe Glu Val Ala Phe Asn Gly Pro Lys Gly Gly Tyr Val Ala Leu Asp Asp Ile Ser Phe Ser Pro Val His Cys Gln Asn Gln Thr Glu Leu Leu Phe Ser Ala Val Glu Ala Ser Cys Asn Phe Glu Gln Asp Leu Cys Asn Phe Tyr Gln Asp Lys Glu Gly Pro Gly Trp Thr Arg Val Lys Val Lys Pro Asn Met Tyr Arg Ala Gly Asp His Thr Thr Gly Leu G1y Tyr Tyr Leu Leu Ala Asn Thr Lys Phe Thr 380 ~ 385 390 Ser Gln Pro Gly Tyr Ile Gly Arg Leu Tyr Gly Pro Ser Leu Pro Gly Asn Leu Gln Tyr Cys Leu Arg Phe His Tyr Ala Ile Tyr Gly Phe Leu Lys Met Ser Asp Thr Leu Ala Val Tyr Ile Phe Glu Glu Asn His Val Val Gln Glu Lys Ile Trp Ser Val Leu Glu Ser Pro Arg G1y Val Trp Met Gln Ala G1u Ile Thr Phe Lys Lys Pro Met Pro Thr Lys Val Val Phe Met Ser Leu Cys Lys Ser Phe Trp Asp Cys Gly Leu Val Ala Leu Asp Asp Ile Thr Ile Gln Leu Gly Ser Cys Ser Ser Ser Glu Lys Leu Pro Pro Pro Pro Gly Glu Cys Thr Phe Glu Gln Asp G1u Cys Thr Phe Thr Gln Glu Lys Arg Asn Arg Ser Ser Trp His Arg Arg Arg Gly Glu Thr Pro Thr Ser Tyr Thr 530 535, 540 Gly Pro Lys Gly Asp His Thr Thr Gly Val Gly Tyr Tyr Met Tyr Ile Glu A1a Ser His Met Val Tyr Gly Gln Lys Ala Arg Leu Leu Ser Arg Pro Leu Arg Gly Val Ser Gly Lys His Cys Leu Thr Phe Phe Tyr His Met Tyr Gly Gly Gly Thr Gly Leu Leu Sex Val Tyr Leu Lys Lys Glu Glu Asp Ser Glu Glu Ser Leu Leu Trp Arg Arg Arg Gly Glu Gln Ser Ile Ser Trp Leu Arg Ala Leu I1e Glu Tyr Ser Cys Glu Arg Gln His Gln Ile Ile Phe Glu Ala Ile Arg Gly Val Ser Ile Arg Ser Asp Ile Ala Ile Asp Asp Val Lys Phe Gln Ala Gly Pro Cys Gly Glu Met Glu Asp Thr Thr Gln Gln Ser Ser Gly Tyr Ser Glu Asp Leu Asn Glu Ile Glu Tyr <210> 7 <211> 296 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1344495CD1 <400> 7 Met Arg His Glu Glu Leu Leu Thr Lys Thr Phe Gln Gly Pro~Ala Val Val Cys Gly Thr Pro Thr Ser His Val Tyr Met Phe Lys Asn Gly Ser Gly Asp Ser Gly Asp Ser Ser Glu Glu Glu Ser His Arg Val Val Leu Arg Pro Arg Gly Lys Glu Arg His Lys Ser Gly Val His Gln Pro Pro Gln Ala Gly Ala Gly Asp Val Val Leu Leu Gln Arg Glu Leu Ala Gln Glu Asp Ser Leu Asn Lys Leu Ala Leu Gln 80 ' 85 90 Tyr Gly Cys Lys Val Ala Asp Tle Lys Lys Val Asn Asn Phe Ile 95 100 ~ 105 Arg Glu Gln Asp Leu Tyr Ala Leu Lys Ser Val Lys Ile Pro Val Arg Asn His Gly Ile Leu Met G1u Thr His Lys Glu Leu Lys Pro 125 130 ' 135 Leu Leu Ser Pro Ser Ser Glu Thr Thr Val Thr Val Glu Leu Pro Glu Ala Asp Arg Ala G1y Ala Gly Thr Gly Ala G1n Ala Gly Gln Leu Met Gly Phe Phe Lys Gly Ile Asp Gln Asp Ile Glu Arg Ala Va1 GIn Ser Glu Ile Phe Leu His Glu Ser Tyr Cys Met Asp Thr Ser His Gln Pro Leu Leu Pro Ala Pro Pro Lys Thr Pro Met Asp Gly Ala Asp Cys Gly Ile Gln Trp Trp Asn Ala Val Phe Ile Met Leu Leu Ile Gly Ile Val Leu Pro Val Phe Tyr Leu Val Tyr Phe Lys Ile Gln Ala Ser Gly Glu Thr Pro Asn Ser Leu Asn Thr Thr Val Ile Pro Asn Gly Ser Met Ala Met Gly Thr Val Pro Gly Gln Ala Pro Arg Leu Ala Val Ala Val Pro Ala Val Thr Ser Ala Asp Ser Gln Phe Ser Gln Thr Thr Gln Ala Gly Ser <210> 8 <211> 575 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1485774CD1 <400> 8 Met Ala Lys Pro Phe Phe Arg Leu Gln Lys Phe Leu Arg Arg Thr Gln Phe Leu Leu Phe Phe Leu Thr Ala Ala Tyr Leu Met Thr Gly Ser Leu Leu Leu Leu Gln Arg Val Arg Val Ala Leu Pro Gln Gly Pro Arg Ala Pro Gly Pro Leu Gln Thr Leu Pro Val Ala Ala Val Ala Leu Gly Val Gly Leu Leu Asp Ser Arg Ala Lieu His Asp Pro Arg Val Ser Pro Glu Leu Leu Leu Gly Val Asp Met Leu Gln Ser Pro Leu Thr Arg Pro Arg Pro G1y Pro Arg Trp Leu Arg Ser Arg Asn Ser Glu Leu Arg Gln Leu Arg Arg Arg Trp Phe His His Phe Met Ser Asp Ser Gln Gly Pro Pro Ala Leu Gly Pro Glu Ala Ala Arg Pro Ala Ile His Ser Arg Gly Thr Tyr Ile Gly Cys Phe Ser Asp Asp Gly His Glu Arg Thr Leu Lys G1y Ala Val Phe Tyr Asp Leu Arg Lys Met Thr Val Ser His Cys Gln Asp Ala Cys Ala Glu Arg Ser Tyr Val Tyr Ala Gly Leu Glu Ala Gly Ala Glu Cys Tyr Cys Gly Asn Arg Leu Pro Ala Val Ser Val Gly Leu Glu Glu Cys Asn His Glu Cys Lys Gly Glu Lys Gly Ser Val Cys Gly Ala Va1 Asp Arg Leu Ser Val Tyr Arg Val Asp Glu Leu Gln Pro Gly Ser Arg Lys Arg Arg Thr Ala Thr Tyr Arg Gly Cys Phe Arg Leu Pro Glu Asn Ile Thr His Ala Phe Pro Ser Ser Leu Ile Gln Ala Asn Val Thr Va1 Gly Thr Cys Ser Gly Phe Cys Ser Gln Lys Glu Phe Pro Leu Ala Ile Leu Arg Gly Trp Glu Cys Tyr Cys Ala Tyr Pro Thr Pro Arg Phe Asn Leu Arg Asp Ala Met Asp Ser Ser Va1 Cys Gly Gln Asp Pro Glu Ala Gln Arg Leu Ala Glu Tyr Cys Glu Val 320 ,325 330 Tyr Gln Thr Pro Val Gln Asp Thr Arg Cys Thr Asp Arg Arg Phe Leu Pro Asn Lys Ser Lys Val Phe Val Ala Leu Ser Ser Phe Pro Gly Ala Gly Asn Thr Trp Ala Arg His Leu Ile Glu His Ala Thr Gly Phe Tyr Thr Gly Ser Tyr Tyr Phe Asp Gly Thr Leu Tyr Asn Lys Gly Phe Lys Gly Glu Lys Asp His Trp Arg Ser Arg Arg Thr Ile Cys Val Lys Thr His Glu Ser Gly Arg Arg Glu Ile Glu Met Ser Asp Ser Ala Ile Leu Leu Ile Arg Asn Pro Tyr Arg Ser Leu Val Ala Glu Phe Asn Arg Lys Cys Ala Gly His Leu Gly Tyr Ala Ala Asp Arg Asn Trp Lys Ser Lys Glu Trp Pro Asp Phe Val Asn Ser Tyr Ala Ser Trp Trp Ser Ser His Val Leu Asp Trp Leu Lys Tyr Gly Lys Arg Leu Leu Val Val His Tyr Glu Glu Leu Arg Arg Ser Leu Val Pro Thr Leu Arg Glu Met Val Ala Phe Leu Asn Val Ser Val Ser Glu Glu Arg Leu Leu Cys Val Glu Asn Asn Lys Glu Gly Ser Phe Arg Arg Arg Gly Arg Arg Ser His Asp Pro Glu Pro Phe Thr Pro Glu Met Lys Asp Leu Ile Asn Gly Tyr Ile Arg Thr Val Asp Gln Ala Leu Arg Asp His Asn Trp Thr Gly Leu Pro Arg Glu Tyr Val Pro Arg <210> 9 <211> 592 <212> PRT
<2l3> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 7289372CD1 <400> 9 Met Phe Pro Leu Arg Ala Leu Trp Leu Val Trp Ala Leu Leu Gly Val Ala Gly Ser Cys Pro Glu Pro Cys Ala Cys Val Asp Lys Tyr Ala His Gln Phe Ala Asp Cys Ala Tyr Lys Glu Leu Arg Glu Val Pro Glu Gly Leu Pro Ala Asn Val Thr Thr Leu Ser Leu Ser Ala 50 ~ 55 60 Asn Lys Ile Thr Val Leu Arg Arg Gly Ala Phe Ala Asp Val Thr Gln Val Thr Ser Leu Trp Leu Ala His Asn Glu Val Arg Thr Val Glu Pro Gly Ala Leu Ala Val Leu Ser Gln Leu Lys Asn Leu Asp Leu Ser His Asn Phe Ile Ser Ser Phe Pro Trp Ser Asp Leu Arg Asn Leu Ser Ala Leu Gln Leu Leu Lys Met Asn His Asn Arg Leu Gly Ser Leu Pro Arg Asp Ala Leu Gly Ala Leu Pro Asp Leu Arg Ser Leu Arg Ile Asn Asn Asn Arg Leu Arg Thr Leu A1a Pro Gly Thr Phe Asp Ala Leu Ser Ala Leu Ser His Leu Gln Leu Tyr His Asn Pro Phe His Cys Gly Cys Gly Leu Va1 Trp Leu Gln Ala Trp Ala Ala Ser Thr Arg Val Ser Leu Pro Glu Pro Asp Ser Ile Ala Cys Ala Ser Pro Pro Ala Leu Gln Gly Va1 Pro Val Tyr Arg Leu Pro Ala Leu Pro Cys Ala Pro Pro Ser Val His Leu Ser Ala Glu Pro Pro Leu Glu Ala Pro Gly Thr Pro Leu Arg Ala Gly Leu Ala Phe Val Leu His Cys Ile Ala Asp Gly His Pro Thr Pro Arg Leu Gln Trp Gln Leu Gln Ile Pro Gly Gly Thr Val Val Leu Glu Pro Pro Val Leu Ser Gly Glu Asp Asp Gly Val Gly Ala Glu Glu Gly Glu Gly Glu Gly Asp Gly Asp Leu Leu Thr Gln Thr Gln Ala Gln Thr Pro Thr Pro Ala Pro Ala Trp Pro Ala Pro Pro Ala Thr Pro Arg Phe Leu Ala Leu Ala Asn Gly Ser Leu Leu Val Pro Leu Leu Ser Ala Lys Glu Ala Gly Val Tyr Thr Cys Arg Ala His Asn Glu Leu Gly Ala Asn Ser Thr Ser Ile Arg Val Ala Val Ala Ala Thr Gly Pro Pro Lys His Ala Pro Gly Ala Gly Gly Glu Pro Asp Gly Gln Ala Pro Thr Ser Glu Arg Lys Ser Thr Ala Lys Gly Arg Gly Asn Ser Val Leu Pro Ser Lys Pro Glu Gly Lys Ile Lys Gly Gln Gly Leu Ala Lys Val Ser Ile Leu G1y Glu Thr Glu Thr Glu Pro Glu Glu Asp Thr Ser Glu Gly Glu Glu Ala Glu Asp Gln Ile Leu Ala Asp Pro Ala Glu Glu Gln Arg Cys Gly Asn Gly Asp Pro Ser Arg Tyr Val Ser Asn His Ala Phe Asn Gln Ser Ala Glu Leu Lys Pro His Val Phe Glu Leu Gly Val Ile Ala Leu Asp Val Ala Glu Arg Glu Ala Arg Val Gln Leu Thr Pro Leu Ala Ala Arg Trp Gly Pro Gly Pro Gly Gly Ala Gly Gly Ala Pro Arg Pro Gly Arg Arg Pro Leu Arg Leu Leu Tyr Leu Cys Pro Ala Gly Gly Gly Ala Ala Val Gln Trp Ser Arg Val Glu Glu Gly Val Asn Ala Tyr Trp Phe Arg G1y Leu Arg Pro Gly Thr Asn Tyr Ser Val Cys Leu Ala Leu Ala Gly Glu Ala Cys His Va1 Gln Val Val Phe Pro Pro Arg Arg Ser Ser His Arg Cys Trp Ser <210> 10 <211> 255 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1672338CD1 <400> 10 Met Ala Leu Pro Ala Leu Gly Leu Asp Pro Trp Ser Leu Leu Gly Leu Phe Leu Phe Gln Leu Leu Gln Leu Leu Leu Pro Thr Thr Thr Ala Gly Gly Gly Gly Gln Gly Pro Met Pro Arg Val Arg Tyr Tyr Ala Gly Asp Glu Arg Arg Ala Leu Ser Phe Phe His Gln Lys Gly Leu Gln Asp Phe Asp Thr Leu Leu Leu Ser Gly Asp Gly Asn Thr Leu Tyr Val Gly Ala Arg Glu Ala Ile Leu A1a Leu Asp Ile Gln 80 85 ' 90 Asp Pro Gly Val Pro Arg Leu Lys Asn Met Ile Pro Trp Pro Ala Ser Asp Arg Lys Lys Ser Glu Cys Ala Phe Lys Lys Lys Ser Asn Glu Thr Gln Cys Phe Asn Phe Ile Arg Va1 Leu Val Ser Tyr Asn Val Thr His Leu Tyr Thr Cys Gly Thr Phe Ala Phe Ser Pro Ala Cys Thr Phe Ile Val Ser Ser Leu Val Pro Ser Ala Gln Ala Pro Lys His Pro Phe Ser His Leu Pro Thr Thr Phe Leu Cys Ser Ser Gly Lys Leu Trp Pro Ser Arg Cys Arg Thr Leu Met Asn Phe Leu Ala Pro Asp Gln Phe Pro Ser Met Ser Leu Ser Leu Pro Ser Ser Ser Pro Ser Phe Pro Arg Cys Glu Thr Leu Ala Phe Trp Pro Pro Ser Leu Ser Pro His Leu Gly Thr Ser Arg Phe Leu Pro Val Ala His Leu Gly Gly Gln Gly His Gly Gly Lys Arg Pro Lys Pro Leu <210> 11 <211> 641 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 184661CD1 <400> 11 Met Va1 Pro Gly Ala Arg Gly Gly Gly Ala Leu Ala Arg Ala Ala Gly Arg Gly Leu Leu Ala Leu Leu Leu Ala Val Ser Ala Pro Leu Arg Leu Gln Ala Glu Glu Leu Gly Asp Gly Cys Gly His Leu Val Thr Tyr Gln Asp Ser Gly Thr Met Thr Ser Lys Asn Tyr Pro Gly Thr Tyr Pro Asn His Thr Val Cys Glu Lys Thr Ile Thr Val Pro Lys Gly Lys Arg Leu Ile Leu Arg Leu Gly Asp Leu Asp Ile Glu Ser Gln Thr Cys Ala Ser Asp Tyr Leu Leu Phe Thr Ser Ser Ser Asp G1n Tyr Gly Pro Tyr Cys Gly Ser Met Thr Val Pro Lys Glu Leu Leu Leu Asn Thr Ser Glu Val Thr Val Arg Phe Glu Ser Gly Ser His Ile Ser Gly Arg Gly Phe Leu Leu Thr Tyr AIa Ser Ser Asp His Pro Asp Leu Ile Thr Cys Leu Glu Arg Ala Ser His Tyr Leu Lys Thr Glu Tyr Ser Lys Phe Cys Pro Ala Gly Cys Arg Asp Val Ala Gly Asp Ile Ser Gly Asn Met Val Asp Gly Tyr Arg Asp Thr Ser Leu Leu Cys Lys Ala Ala Ile His Ala Gly Ile Ile Ala Asp Glu Leu Gly Gly Gln Ile Ser Val Leu Gln Arg Lys Gly Ile Ser Arg Tyr Glu Gly Ile Leu Ala Asn Gly Val Leu Ser Arg Asp Gly Ser Leu Ser Asp Lys Arg Phe Leu Phe Thr Ser Asn Gly Cys Ser Arg Ser Leu Ser Phe Glu Pro Asp Gly Gln Ile Arg Ala Ser Ser Ser Trp Gln Ser Val Asn Glu Ser Gly Asp Gln Val His Trp Ser Pro Gly Gln Ala Arg Leu Gln Asp Gln Gly Pro Ser Trp Ala Ser Gly Asp Ser Ser Asn Asn His Lys Pro Arg Glu Trp Leu Glu Ile Asp Leu Gly Glu Lys Lys Lys Ile Thr Gly Ile Arg Thr Thr Gly Ser Thr Gln Ser Asn Phe Asn Phe Tyr Val Lys Ser Phe Val Met Asn Phe Lys Asn Asn Asn Ser Lys Trp Lys Thr Tyr Lys GIy Ile Va1 Asn Asri Glu Glu Lys Val Phe G1n Gly Asn Ser Asn Phe Arg Asp Pro Val Gln Asn Asn Phe Ile Pro Pro Ile Val Ala Arg Tyr Val Arg Val Val Pro Gln Thr Trp His Gln Arg Ile Ala Leu Lys Val Glu Leu Ile Gly Cys Gln Ile Thr Gln Gly Asn Asp Ser Leu Val Trp Arg Lys Thr Ser Gln Ser Thr Ser Val Ser Thr Lys Lys Glu Asp Glu Thr Ile Thr Arg Pro Ile Pro Ser Glu Glu Thr Ser Thr Gly Ile Asn Ile Thr Thr Val Ala Ile Pro Leu Val Leu Leu Val Val Leu Val Phe Ala Gly Met Gly Ile Phe Ala A1a Phe Arg Lys Lys Lys Lys Lys Gly Ser Pro Tyr Gly Ser Ala Glu Ala Gln Lys Thr Asp Cys Trp Lys Gln Ile Lys Tyr Pro Phe Ala Arg His Gln Ser Ala Glu Phe Thr Ile Ser Tyr Asp Asn Glu Lys Glu Met Thr Gln Lys Leu Asp Leu Ile Thr Ser Asp Met Ala Asp Tyr Gln Gln Pro Leu Met I1e Gly Thr Gly Thr Val Thr Arg Lys Gly Ser Thr Phe Arg Pro Met Asp Thr Asp Ala Glu Glu Ala Gly Val Ser Thr Asp Ala Gly Gly His Tyr Asp Cys Pro Gln Arg A1a Gly Arg His Glu Tyr Ala Leu Pro Trp Arg Pro Arg Ser Pro Ser Thr Pro Arg Pro Ser Trp Ser Gly Thr Cys Cys Ala Pro Thr Arg Ser Leu Arg Arg Ala Ala Thr Ala Ser Gln Gly Pro Ser Pro Ala Thr Asn Thr Pro Ser Pro Arg Ala Ala Ser Pro Pro 635 640 ,' <210> 12 <211> 924 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3719737CD1 <400> 12 Met Gly Arg Leu His Arg Pro Arg Ser Ser Thr Ser Tyr.Arg Asn Leu Pro His Leu Phe Leu Phe Phe Leu Phe Val Gly Pro Phe Ser Cys Leu Gly Ser Tyr Ser Arg Ala Thr Glu Leu Leu Tyr Ser Leu Asn Glu Gly Leu Pro A1a Gly Val Leu Ile Gly Ser Leu Ala Glu Asp Leu Arg Leu Leu Pro Arg Ser Ala Gly Arg Pro Asp Pro Gln Ser Gln Leu Pro Glu Arg Thr Gly Ala Glu Trp Asn Pro Pro Leu Ser Phe Ser Leu Ala Ser Arg Gly Leu Ser Gly Gln Tyr Val Thr 95 l00 105 Leu Asp Asn Arg Ser Gly Glu Leu His Thr Ser Ala Gln Glu Ile Asp Arg Glu Ala Leu Cys Val Glu Gly Gly Gly Gly Thr Ala Trp Ser Gly Ser Val Ser Ile Ser Ser Ser Pro Ser Asp Ser Cys Leu l40 145 150 Leu Leu Leu Asp Val Leu Val Leu Pro Gln Glu Tyr Phe Arg Phe Val Lys Val Lys I1e Ala Ile Arg Asp Ile Asn Asp Asn Ala Pro 170 175 l80 Gln Phe Pro Val Ser Gln Ile Ser Val Trp Val Pro Glu Asn Ala 185 l90 195 Pro Val Asn Thr Arg Leu Ala Ile Glu His4Pro Ala Val Asp Pro Asp Val Gly Ile Asn Gly Val Gln Thr Tyr Arg Leu Leu Asp Tyr His Gly Met Phe Thr Leu Asp Val Glu Glu Asn Glu Asn Gly Glu Arg Thr Pro Tyr Leu Ile Val Met Gly Ala Leu Asp Arg Glu Thr Gln Asp Gln Tyr Val Ser Ile Ile I1e Ala Glu Asp Gly Gly Ser Pro Pro Leu Leu Gly Ser Ala Thr Leu Thr Ile Gly Ile Ser Asp Ile Asn Asp Asn Cys Pro Leu Phe Thr Asp Ser Gln Ile Asn Val Thr Val Tyr Gly Asn Ala Thr Val G1y Thr Pro Ile Ala Ala 'Val Gln Ala Val Asp Lys Asp Leu Gly Thr Asn A1a Gln Ile Thr Tyr Ser Tyr Ser Gln Lys Val Pro Gln Ala Ser Lys Asp Leu Phe His Leu Asp Glu Asn Thr Gly Val Ile Lys Leu Phe Ser Lys I1e Gly Gly Ser Val Leu Glu Ser His Lys Leu Thr Ile Leu Ala Asn Gly Pro Gly Cys Ile Pro Ala Va1 Ile Thr Ala Leu Val Ser Ile Ile Lys Val Ile Phe Arg Pro Pro Glu Ile Val Pro Arg Tyr Ile Ala Asn Glu Ile Asp Gly Val Val Tyr Leu Lys Glu Leu Glu Pro Val Asn Thr Pro Ile Ala Phe Phe Thr Ile Arg Asp Pro Glu Gly Lys Tyr Lys Val Asn Cys Tyr Leu Asp Gly Glu Gly Pro Phe Arg Leu Ser Pro Tyr Lys Pro Tyr Asn Asn Glu Tyr Leu Leu Glu Thr Thr Lys Pro Met Asp Tyr Glu Leu Gln Gln Phe Tyr Glu Val Ala Val Val Ala Trp Asn Ser Glu Gly Phe His Val Lys Arg Val Ile Lys Val Gln Leu Leu Asp Asp Asn Asp Asn A1a Pro Ile Phe Leu Gln Pro Leu Ile Glu Leu Thr Tle Glu Glu Asn Asn Ser Pro Asn Ala Phe Leu Thr Lys Leu Tyr Ala Thr Asp Ala Asp Ser Glu Glu Arg Gly Gln Val Ser Tyr Phe Leu Gly Pro Asp Ala Pro Ser Tyr Phe Ser Leu Asp Ser Val Thr Gly Ile Leu Thr Val Ser Thr Gln Leu Asp Arg Glu Glu Lys Glu Lys Tyr Arg Tyr Thr Val Arg A1a Val Asp Cys Gly Lys Pro Pro Arg Glu Ser Va1 Ala Thr Val Ala Leu Thr Val Leu Asp Lys Asn Asp Asn Ser Pro Arg Phe Ile Asn Lys Asp Phe Ser Phe Phe Val Pro Glu Asn Phe Pro Gly Tyr Gly Glu Ile Gly Val Ile Ser Val Thr Asp Ala Asp Ala Gly Arg Asn Gly Trp Val Ala Leu Ser Val Val Asn Gln Ser Asp Ile Phe Val Ile Asp Thr Gly Lys Gly Met Leu Arg Ala Lys Val Ser Leu Asp Arg Glu Gln Gln Ser Ser Tyr Thr Leu Trp Val Glu Ala Val Asp Gly Gly Glu Pro Ala Leu Ser Ser Thr Ala Lys Ile Thr Ile Leu Leu Leu Asp Ile Asn Asp Asn Pro Pro Leu Val Leu Phe Pro Gln Ser Asn Met Ser Tyr Leu Leu Val Leu Pro Ser Thr Leu Pro Gly Ser Pro Val Thr Glu Val Tyr Ala Val Asp Lys Asp Thr Gly Met Asn Ala Val Ile Ala Tyr Ser Ile I1e Gly Arg Arg Gly Pro Arg Pro 755 760 7,65 Glu Ser Phe Arg Ile Asp Pro Lys Thr Gly Asn Ile Thr Leu Glu 770 775 i 780 Glu Ala Leu Leu Gln Thr Asp Tyr Gly Leu His Arg Leu Leu Val Lys Val Ser Asp His Gly Tyr Pro Glu Pro Leu His Ser Thr Val Met Va1 Asn Leu Phe Val Asn Asp Thr Val Ser Asn Glu Ser Tyr Ile Glu Ser Leu Leu Arg Lys Glu Pro Glu Ile Asn Ile Glu Glu Lys Glu Pro Gln Ile Ser Tle Glu Pro Thr His Arg Lys Val Glu Ser Val Ser Cys Met Pro Thr Leu Val Ala Leu Ser Val Ile Ser Leu G1y Ser Ile Thr Leu Val Thr Gly Met Gly Ile Tyr Ile Cys Leu Arg Lys Gly Glu Lys His Pro Arg G1u Asp Glu Asn Leu Glu Val Gln Ile Pro Leu Lys Gly Lys Ile Asp Leu His Met Arg Glu Arg Lys Pro Met Asp Ile Ser Asn Ile <210> 13 <211> 987 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5773251CD1 <400> 13 Met Arg Ile Ser Ser Cys Ser Asp Glu Ser Ser Asn Ser Asn Ser Ser Arg Lys Ser Asp Asn His Ser Pro Ala Val Val Thr Thr Thr Val Ser Ser Lys Lys Gln Pro Ser Val Leu Val Thr Phe Pro Lys Glu Glu Arg Lys Ser Val Ser Gly Lys Ala Ser Ile Lys Leu Ser Glu Thr I1e Ser G1u Gly Thr Ser Asn Ser Leu Ser Thr Cys Thr Lys Ser Gly Pro Ser Pro Leu Ser Ser Pro Asn Gly Lys Leu Thr Val Ala Ser Pro Lys Arg Gly Gln Lys Arg Glu Glu Gly Trp Lys Glu Val Val Arg Arg Ser Lys Lys Val Ser Val Pro Ser Thr Val Ile Ser Arg Val Ile Gly Arg Gly Gly Cys Asn Ile Asn Ala Ile Arg Glu Phe Thr Gly Ala His Ile Asp Ile Asp Lys Gln Lys Asp Lys Thr Gly Asp Arg Ile Ile Thr Ile Arg Gly Gly Thr Glu Ser Thr Arg Gln Ala Thr Gln Leu Ile Asn Ala Leu Ile Lys Asp Pro Asp Lys Glu Ile Asp Glu Leu Ile Pro Lys Asn Arg Leu Lys Ser Ser Ser Ala Asn Ser Lys Ile Gly Ser Ser Ala Pro Thr Thr Thr Ala A1a Asn Thr Ser Leu Met Gly Ile Lys Met Thr Thr Val A1a Leu Ser Ser Thr Ser Gln Thr Ala Thr Ala Leu Thr Val Pro Ala Ile Ser Ser Ala Ser Thr His Lys Thr Ile Lys Asn Pro Val Asn Asn Val Arg Pro Gly Phe Pro Val Ser Leu Pro Leu Ala Tyr Pro Pro Pro Gln Phe Ala His Ala Leu Leu Ala Ala Gln Thr Phe Gln Gln Ile Arg Pro Pro Arg Leu Pro Met Thr His Phe Gly Gly Thr Phe Pro Pro Ala Gln Ser Thr Trp Gly Pro Phe Pro Val Arg Pro Leu Ser Pro Ala Arg Ala Thr Asn Ser Pro Lys Pro His Met Val Pro Arg His Ser Asn Gln Asn Ser Ser Gly Ser Gln Val Asn Ser Ala Gly Ser Leu Thr Ser Ser Pro Thr Thr Thr Thr Ser Ser Ser Ala Ser Thr Val Pro Gly Thr Ser Thr Asn Gly Ser Pro Ser Ser Pro Ser Val Arg Arg Gln Leu Phe Val Thr Val Val Lys Thr Ser Asn Ala Thr Thr Thr Thr Val Thr Thr Thr Ala Ser Asn Asn Asn Thr Ala Pro Thr Asn Ala Thr Tyr Pro Met Pro Thr Ala Lys Glu His Tyr Pro Val Ser Ser Pro Ser Ser Pro Ser Pro Pro Ala Gln Pro Gly Gly Val Ser Arg Asn Ser Pro Leu Asp Cys Gly Ser Ala Ser Pro Asn Lys Val Ala Ser Ser Ser Glu Gln Glu Ala Gly Ser Pro Pro Val Val Glu Thr Thr Asn Thr Arg Pro Pro Asn Ser Ser Ser Ser Ser Gly Ser Ser Ser Ala His Ser Asn Gln Gln Gln Pro Pro Gly Ser Val Ser Gln Glu Pro Arg Pro Pro Leu Gln Gln Ser Gln Val Pro Pro Pro Glu Val Arg Met Thr Val Pro Pro Leu Ala Thr Ser Ser Ala Pro Val Ala Val Pro Ser Thr Ala Pro Val Thr Tyr Pro Met Pro Gln Thr Pro Met Gly Cys Pro Gln Pro Thr Pro Lys Met Glu Thr Pro Ala Ile Arg Pro Pro Pro His Gly Thr Thr Ala Pro His Lys Asn Ser Ala Ser Val Gln Asn Ser Ser Val Ala Val Leu Ser Val Asn His Ile Lys Arg Pro His Ser Val Pro Ser Ser Val Gln Leu Pro Ser Thr Leu Ser Thr Gln Ser Ala Cys Gln Asn Ser Val His Pro Ala Asn Lys Pro Ile Ala Pro Asn Phe Ser Ala Pro Leu Pro Phe Gly Pro Phe Ser Thr Leu Phe Glu Asn Ser Pro Thr Ser Ala His Ala Phe Trp Gly Gly Ser Val Val Ser Ser Gln Ser Thr Pro Glu Ser Met Leu Ser Gly Lys Ser Ser Tyr Leu Pro Asn Ser Asp Pro Leu His Gln Ser Asp Thr Ser Lys A1a Pro Gly Phe Arg Pro Pro Leu Gln Arg Pro Ala Pro Ser Pro Ser Gly Ile Val Asn Met Asp Ser Pro Tyr Gly Ser Val Thr Pro Ser Ser Thr His Leu Gly Asn Phe Ala Ser Asn Ile Ser Gly Gly Gln Met Tyr Gly Pro Gly Ala Pro Leu Gly Gly Ala Pro Ala Ala Ala Asn Phe Asn Arg Gln His Phe Ser Pro Leu Ser Leu Leu Thr Pro Cys Ser Ser Ala Ser Asn Asp Ser Ser Ala Gln Ser Val Sex Ser Gly Val Arg Ala Pro Ser Pro Ala Pro Ser Ser Val Pro Leu Gly Ser Glu Lys Pro Ser Asn Val Ser Gln Asp Arg Lys Val Pro Val Pro Ile Gly Thr Glu Arg Ser Ala Arg Ile Arg Gln Thr Gly Thr Ser Ala Pro Ser Val Ile Gly Ser Asn Leu Ser Thr Ser Val Gly His Ser Gly Ile Trp Ser Phe Glu Gly Ile Gly Gly Asn Gln Asp Lys Val Asp Trp Cys Asn Pro Gly Met Gly Asn Pro Met Ile His Arg Pro Met Ser Asp Pro Gly Val Phe Ser G1n His Gln Ala Met Glu Arg Asp Ser Thr Gly Ile Val Thr Pro Ser Gly Thr Phe His Gln His Val Pro Ala Gly Tyr Met Asp Phe Pro Lys Val Gly Gly Met Pro Phe Ser Val Tyr Gly Asn Ala Met Ile Pro Pro Val Ala Pro Ile Pro Asp Gly Ala Gly Gly Pro Ile Phe Asn Gly Pro His Ala Ala Asp Pro Ser Trp Asn Ser Leu Ile Lys Met Val Ser Ser Ser Thr Glu Asn Asn G1y Pro Gln Thr Val Trp Thr Gly Pro Trp Ala Pro His Met Asn Ser Val His Met Asn G1n Leu Gly <210> 14 <211> 1028 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature _.
<223> Incyte ID No: 5426470CD1 <400> 14 Met Met Phe Pro Trp Lys Gln Leu Ile Leu Leu Ser Phe Ile Gly Cys Leu Gly Gly Glu Leu Leu Leu Gln Gly Pro Val Phe Ile Lys Glu Pro Ser Asn Ser Ile Phe Pro Val Gly Ser Glu Asp Lys Lys Ile Thr Leu His Cys Glu Ala Arg Gly Asn Pro Ser Pro His Tyr Arg Trp Gln Leu Asn Gly Ser Asp Ile Asp Met Ser Met Glu His Arg Tyr Lys Leu Asn Gly Gly Asn Leu Val Val Ile Asn Pro Asn 80 , 85 90 Arg Asn Trp Asp Thr Gly Thr Tyr Gln Cys Phe Ala Thr Asn Ser Leu G1y Thr Ile Val Ser Arg Glu Ala Lys Leu Gln Phe Ala Tyr Leu Glu Asn Phe Lys Thr Lys Met Arg Ser Thr Val Ser Val Arg Glu Gly Gln Gly Val Val Leu Leu Cys Gly Pro Pro Pro His Ser Gly Glu Leu Ser Tyr Ala Trp Ile Phe Asn Glu Tyr Pro Ser Phe Val Glu Glu Asp Ser Arg Arg Phe Val Ser Gln Glu Thr Gly His Leu Tyr Ile Ser Lys Val Glu Pro Ser Asp Val Gly Asn Tyr Thr Cys Val Val Thr Ser Met Val Thr Asn Ala Arg Val Leu Gly Ser Pro Thr Pro Leu Val Leu Arg Ser Asp Gly Val Met Gly Glu Tyr Glu Pro Lys Ile Glu Val Gln Phe Pro Glu Thr Leu Pro Ala Ala Lys Gly Ser Thr Val Lys Leu Glu Cys Phe Ala Leu Gly Asn Pro Ile Pro Gln Ile Asn Trp Arg Arg Ser Asp Gly Leu Pro Phe Ser Ser Lys Ile Lys Leu Arg Lys Phe Ser Gly Val Leu Glu Ile Pro Asn Phe Gln Gln Glu Asp Ala Gly Ser Tyr Glu Cys Ile Ala Glu Asn Ser Arg Gly Lys Asn Val Ala Arg Gly Arg Leu Thr Tyr Tyr Ala Lys Pro His Trp Val Gln Leu Ile Lys Asp Val Glu Ile Ala Val Glu Asp Ser Leu Tyr Trp Glu Cys Arg Ala Ser Gly Lys Pro Lys Pro Ser Tyr Arg Trp Leu Lys Asn Gly A1a Ala Leu Val Leu Glu G1u Arg Thr G1n Ile Glu Asn Gly Ala Leu Thr Ile Ser Asn Leu Ser Val Thr Asp Ser Gly Met Phe Gln Cys Ile Ala Glu Asn Lys His Gly Leu Val Tyr Ser Ser Ala Glu Leu Lys Val Val AIa Ser Ala Pro Asp Phe Ser Lys Asn Pro Met Lys Lys Leu Val Gln Val Gln Val Gly Ser Leu Val Ser Leu Asp Cys Lys Pro Arg Ala Ser Pro Arg Ala Leu Ser Ser Trp Lys Lys Gly Asp Val Ser Val Gln Glu His Glu Arg Ile Ser Leu Leu Asn Asp Gly Gly Leu Lys Ile Ala Asn Val Thr Lys Ala Asp Ala Gly Thr Tyr Thr Cys Met Ala Glu Asn Gln Phe Gly Lys Ala Asn Gly Thr Thr His Leu Val Val Thr Glu Pro Thr Arg Ile Thr Leu Ala Pro Ser Asn Met Asp Val Ser Val Gly Glu Ser Val Ile Leu Pro Cys Gln Val Gln His Asp Pro Leu Leu Asp Ile Ile Phe Thr Trp Tyr Phe Asn Gly Ala Leu Ala Asp Phe Lys Lys Asp G1y Ser His Phe Glu Lys Val Gly Gly Ser Ser Ser Gly Asp Leu Met Ile Arg Asn Ile Gln Leu Lys His Ser Gly Lys Tyr Val Cys Met Val Gln Thr Gly Val Asp Ser Val Ser Ser Ala A1a Asp Leu Ile Val Arg Gly Ser Pro Gly Pro Pro Glu Asn Val Lys Val Asp Glu Ile Thr Asp Thr Thr Ala Gln Leu Ser Trp Lys Glu Gly Lys Asp Asn His Ser Pro Val Ile Ser Tyr Ser Ile Gln Ala Arg Thr Pro Phe Ser Val Gly Trp Gln Thr Val Thr Thr Val Pro Glu Val Ile Asp Gly Lys Thr His Thr Ala Thr Val Val Glu Leu Asn Pro Trp Val Glu Tyr Glu Phe Arg Val Val Ala Ser Asn Lys Ile Gly Gly Gly Glu Pro Ser Leu Pro Ser Glu Lys Val Arg Thr Glu Glu Ala Val Pro Glu Val Pro Pro Ser Glu Val Asn Gly Gly Gly Gly Ser Arg Ser Glu Leu Val Ile Thr Trp Asp Pro Val Pro Glu Glu Leu Gln Asn Gly Glu Gly Phe Gly Tyr Val Val Ala Phe Arg Pro Leu Gly Val Thr Thr Trp Ile Gln Thr Val Val Thr Ser Pro Asp Thr Pro Arg Tyr Val Phe Arg Asn Glu Ser Ile Val Pro Tyr Ser Pro Tyr Glu Val Lys Val Gly Val Tyr Asn Asn Lys Gly Glu Gly Pro Phe Ser Pro Val Thr Thr Val Phe Ser Ala Glu Glu Glu Pro Thr Val Ala Pro Ser Gln Val Ser Ala Asn Ser Leu Ser Ser Ser Glu Ile Glu Val Ser Trp Asn Thr 815 820 ' 825 Ile Pro Trp Lys Leu Ser Asn Gly His Leu Leu Gly Tyr Glu Val Arg Tyr Trp Asn Gly Gly Gly Lys Glu Glu Ser Ser Ser Lys Met Lys Val Ala Gly Asn Glu Thr Ser Ala Arg Leu Arg Gly Leu Lys Ser Asn Leu Ala Tyr Tyr Thr Ala Val Arg Ala Tyr Asn Ser Ala Gly Ala Gly Pro Phe Ser Ala Thr Val Asn Val Thr Thr Lys Lys Thr Pro Pro Ser Gln Pro Pro Gly Asn Val Val Trp Asn Ala Thr 905 9l0 915 Asp Thr Lys Val Leu Leu Asn Trp Glu Gln Val Lys Ala Met Glu Asn Glu Ser Glu Val Thr Gly Tyr Lys Val Phe Tyr Arg Thr Ser Ser Gln Asn Asn Val Gln Val Leu Asn Thr Asn Lys Thr Ser Ala Glu Leu Val Leu Pro Ile Lys Glu Asp Tyr Ile Ile Glu Val Lys Ala Thr Thr Asp Gly Gly Asp Gly Thr Ser Ser Glu Gln Ile Arg Ile Pro Arg Ile Thr Ser Met Asp Ala Arg Gly Ser Thr Ser Ala Ile Ser Asn Va1 His Pro Met Ser Ser Tyr Met Pro Ile Val Leu Phe Leu Ile Val Tyr Val Leu Trp <210> 15 <211> 354 <2l2> PRT
<2l3> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 7087904CD1 <400> 15 Met Asp Met Met Leu Leu Val Gln Gly Ala Cys Cys Ser Asn Gln 1 5 l0 15 Trp Leu Ala Ala Val Leu Leu Ser Leu Cys Cys Leu Leu Pro Ser Cys Leu Pro Ala Gly Gln Ser Val Asp Phe Pro Trp Ala Ala Val Asp Asn Met Met Val Arg Lys Gly Asp Thr Ala Val Leu Arg Cys Tyr Leu Glu Asp Gly Ala Ser Lys Gly Ala Trp Leu Asn Arg Ser Ser Ile Ile Phe Ala Gly Gly Asp Lys Trp Ser Val Asp Pro Arg Val Ser Ile Ser Thr Leu Asn Lys Arg Asp Tyr Ser Leu Gln Ile Gln Asn Val Asp Val Thr Asp Asp Gly Pro Tyr Thr Cys Ser Val Gln Thr Gln His Thr Pro Arg Thr Met Gln Val His Leu Thr Val Gln Val Pro Pro Lys Ile Tyr Asp Ile Ser Asn Asp Met Thr Val Asn Glu Gly Thr Asn Val Thr Leu Thr Cys Leu Ala Thr Gly Lys Pro Glu Pro Ser Ile Ser Trp Arg His Ile Ser Pro Ser Ala Lys Pro Phe Glu Asn Gly Gln Tyr Leu Asp Ile Tyr Gly Ile Thr Arg Asp Gln Ala Gly Glu Tyr Glu Cys Ser Ala Glu Asn Asp Val Ser Phe Pro Asp Val Arg Lys Val Lys Val Val Val Asn Phe Ala Pro Thr Ile Gln Glu Ile Lys Ser Gly Thr Val Thr Pro Gly Arg Ser Gly Leu Ile Arg Cys Glu Gly Ala Gly Val Pro Pro Pro Ala Phe Glu Trp Tyr Lys Gly Glu Lys Lys Leu Phe Asn Gly Gln Gln Gly Ile Ile Ile Gln Asn Phe Ser Thr Arg Ser Ile Leu Thr Val Thr Asn Val Thr Gln Glu His Phe Gly Asn Tyr Thr Cys Val Ala Ala Asn Lys Leu Gly Thr Thr Asn Ala Ser Leu Pro Leu Asn Pro Pro Ser Thr Ala G1n Tyr Gly Ile Thr Gly Ser Ala Asp Val Leu Phe Ser Cys Trp Tyr Leu Val Leu Thr Leu Ser Ser Phe Thr Ser Ile Phe Tyr Leu Lys Asn Ala Ile Leu Gln <210> 16 <211> 1829 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477312CD1 <400> 16 Met Gln Leu Ser Arg Ala Ala Ala Ala Ala Ala Ala Ala Pro Ala Glu Pro Pro Glu Pro Leu Ser Pro Ala Pro Ala Pro Ala Pro Ala Pro Pro Gly Pro Leu Pro Arg Ser Ala Ala Asp Gly Ala Pro Ala Gly Gly Lys Gly Gly Pro Gly Arg Arg Ala Arg Ser Pro Arg Ala Leu Arg Ser Pro Ala Arg Ala A1a Pro Ala Arg Ala Pro Ala Arg Gly Trp Thr Ala Pro Gly Pro Gly Ala Ser Ala Val Val Val Arg Val Gly Ile Pro Asp Leu Gln Gln Thr Lys Cys Leu Arg Leu Asp Pro Ala Ala Pro Val Trp Ala Ala Lys Gln Arg Val Leu Cys Ala Leu Asn His Ser Leu Gln Asp Ala Leu Asn Tyr Gly Leu Phe Gln Pro Pro Ser Arg Gly Arg Ala Gly Lys Phe Leu Asp Glu Glu Arg Leu Leu Gln Glu Tyr Pro Pro Asn Leu Asp Thr Pro Leu Pro Tyr Leu Glu Phe Arg Tyr Lys Arg Arg Val Tyr Ala Gln Asn Leu Ile Asp Asp Lys Gln Phe Ala Lys Leu His Thr Lys Ala Asn Leu Lys Lys Phe Met Asp Tyr Val Gln Leu His Ser Thr Asp Lys Val Ala Arg Leu Leu Asp Lys Gly Leu Asp Pro Asn Phe His Asp Pro Asp Ser Gly Glu Cys Pro Leu Ser Leu A1a Ala Gln Leu Asp Asn Ala Thr Asp Leu Leu Lys Val Leu Lys Asn Gly Gly Ala His Leu Asp Phe Arg Thr Arg Asp Gly Leu Thr Ala Val His Cys Ala Thr Arg Gln Arg Asn Ala Ala Ala Leu Thr Thr Leu Leu Asp Leu Gly Ala Ser Pro Asp Tyr Lys Asp Ser Arg Gly Leu Thr Pro Leu Tyr His Ser Ala Leu Gly Gly Gly Asp Ala Leu Cys Cys Glu Leu Leu Leu His Asp His Ala Gln Leu Gly Thr Thr Asp Glu Asn Gly Trp Gln Glu Ile His Gln Ala Cys Arg Phe Gly His Val Gln His Leu Glu His Leu Leu Phe Tyr Gly Ala Asp Met Gly Ala Gln Asn Ala Ser G1y Asn Thr Ala Leu His Ile Cys Ala Leu Tyr Asn Gln Glu Ser Cys Ala Arg Val Leu Leu Phe Arg Gly Ala Asn Arg Asp Val Arg Asn Tyr Asn Ser Gln Thr A1a Phe Gln Val Ala Ile Ile Ala Gly Asn Phe Glu Leu Ala Glu Val Ile Lys Thr His Lys Asp Ser Asp Val Gly Gln Asp Ser His Asp Leu Leu His Pro Met Pro Thr Gly Val Pro Glu Trp G1y Leu Tyr Thr Glu Glu Glu Leu Glu Gly Gly Ala Ala Phe Ser Val Pro Phe Arg Glu Thr Pro Ser Tyr A1a Lys Arg Arg Arg Leu Ala Gly Pro Ser Gly Leu Ala Ser Pro Arg Pro Leu Gln Arg Ser Ala Ser Asp Ile Asn Leu Lys Gly Glu Ala Gln Pro Ala Ala Ser Pro Gly Pro Ser Leu Arg Ser Leu Pro His Gln Leu Leu Leu Gln Arg Leu Gln Glu Glu Lys Asp Arg Asp Arg Asp Ala Asp Gln Glu Ser Asn Ile Ser Gly Pro Leu Ala Gly Arg Ala 530 . 535 540 Gly Gln Ser Lys I1e Arg Ser Cys Ile Arg Ile Arg Ala Arg Phe Pro Ala Pro Pro Ala Pro Pro Ala Pro Pro Pro Arg Gly Pro Lys Arg Lys Leu Tyr Ser Ala Val Pro Gly Arg Lys Phe Ile Ala Val Lys Ala His Ser Pro Gln Gly Glu Gly Glu Ile Pro Leu His Arg Gly Glu Ala Val Lys Val Leu Ser Ile Gly Glu Gly Gly Phe Trp Glu Gly Thr Val Lys Gly Arg Thr Gly Trp Phe Pro Ala Asp Cys Val Glu Glu Val G1n Met Arg Gln His Asp Thr Arg Pro Glu Thr Arg Glu Asp Arg Thr Lys Arg Leu Phe Arg His Tyr Thr Val Gly Ser Tyr Asp Ser Leu Thr Ser His Ser Asp Tyr Val Ile Asp Asp Lys Val Ala Val Leu Gln Lys Arg Asp His Glu Gly Phe Gly Phe Val Leu Arg Gly Ala Lys Ala G1u Thr Pro Ile Glu Glu Phe Thr Pro Thr Pro Ala Phe Pro Ala Leu Gln Tyr Leu Glu Ser Val Asp Val Glu Gly Val Ala Trp Arg Ala Gly Leu Arg Thr Gly Asp Phe Leu Ile Glu Val Asn Gly Val Asn Val Val Lys Val Gly His Lys Gln Val Val Ala Leu Ile Arg Gln Gly Gly Asn Arg Leu Val Met Lys Val Val Ser Val Thr Arg Lys Pro Glu Glu Asp Gly Ala Arg Arg Arg Ala Pro Pro Pro Pro Lys Arg Ala Pro Ser Thr Thr Leu Thr Leu Arg Ser Lys Ser Met Thr Ala Glu Leu Glu Glu Leu Glu Lys Leu Asp Glu Met Leu Ala Ala Ala A1a Glu Pro Thr Leu Arg Pro Asp Ile Ala Asp Ala Asp Ser Arg Ala Ala Thr Val Lys Gln Arg Pro Thr Ser Arg Arg Ile Thr Pro~Ala Glu Ile Ser Ser Leu Phe Glu Arg Gln Gly Leu Pro Gly Pro Glu Lys Leu Pro Gly Ser Leu Arg Lys Gly Ile Pro Arg Thr Lys Ser Val Gly Glu Asp Glu Lys Leu Ala Ser Leu Leu Glu Gly Arg Phe Pro Arg Ser Thr Ser Met Gln Asp Pro Val Arg Glu Gly Arg Gly Ile Pro Pro Pro Pro Gln Thr Ala Pro Pro Pro Pro Pro Ala Pro Tyr Tyr Phe Asp Ser Gly Pro Pro Pro Ala Phe Ser Pro Pro Pro Pro Pro G1y Arg Ala Tyr Asp Thr Val Arg Ser Ser Phe Lys Pro Gly Leu Glu Ala Arg Leu Gly Ala Gly Ala Ala Gly Leu Tyr Glu Pro Gly Ala Ala Leu Gly Pro Leu Pro Tyr Pro Glu Arg Gln Lys Arg Ala Arg Ser Met Ile Ile Leu Gln Asp Ser Ala Pro Glu Ser Gly Asp Ala Pro Arg 27/l23 Pro Pro Pro Ala Ala Thr Pro Pro Glu Arg Pro Lys Arg Arg Pro Arg Pro Pro Gly Pro Asp Ser Pro Tyr Ala Asn Leu Gly Ala Phe Ser Ala Ser Leu Phe Ala Pro Ser Lys Pro Gln Arg Arg Lys Ser Pro Leu Val Lys Gln Leu Gln Val Glu Asp Ala Gln GIu Arg Ala Ala Leu Ala Val Gly Ser Pro Gly Pro Gly Gly Gly Ser Phe Ala Arg Glu Pro Ser Pro Thr His Arg Gly Pro Arg Pro Gly Gly Leu Asp Tyr Gly Ala Gly Asp Gly Pro Gly Leu Ala Phe Gly Gly Pro Gly Pro Ala Lys Asp Arg Arg Leu Glu Glu Arg Arg Arg Ser Thr Val Phe Leu Ser Val Gly Ala Ile Glu Gly Ser Ala Pro Gly Ala Asp Leu Pro Ser Leu Gln Pro Ser Arg Ser Ile Asp Glu Arg Leu Leu Gly Thr Gly Pro Thr Ala Gly Arg Asp Leu Leu Leu Pro Ser 1160 1165 1170' Pro Val Ser Ala Leu Lys Pro Leu Val Ser Gly Pro Ser Leu Gly Pro Ser Gly Ser Thr Phe Ile His Pro Leu Thr Gly Lys Pro Leu Asp Pro Ser Ser Pro Leu Ala Leu Ala Leu Ala Ala Arg Glu Arg Ala Leu Ala Ser Gln Ala Pro Ser Arg Ser Pro Thr Pro Val His Ser Pro Asp Ala Asp Arg Pro Gly Pro Leu Phe Val Asp Va1 Gln Ala Arg Asp Pro G1u Arg Gly Ser Leu Ala Ser Pro Ala Phe Ser Pro Arg Ser Pro Ala Trp Ile Pro Val Pro Ala Arg Arg Glu Ala G1u Lys Val Pro Arg Glu Glu Arg Lys Ser Pro Glu Asp Lys Lys Ser Met Ile Leu Ser Val Leu Asp Thr Ser Leu Gln Arg Pro Ala Gly Leu Ile Val Val His Ala Thr Ser Asn Gly Gln Glu Pro Ser Arg Leu Gly Gly Ala Glu Glu Glu Arg Pro Gly Thr Pro Glu Leu Ala Pro A1a Pro Met Gln Ser Ala Ala Val Ala Glu Pro Leu Pro Ser Pro Arg Ala Gln Pro Pro Gly Gly Thr Pro Ala Asp Ala Gly Pro Gly Gln Gly Ser Ser Glu~Glu Glu Pro Glu Leu Val Phe Ala Val Asn Leu Pro Pro Ala Gln Leu Ser Ser Ser Asp Glu Glu Thr Arg Glu Glu Leu Ala Arg Ile Gly Leu Val Pro Pro Pro Glu Glu Phe Ala Asn Gly Val Leu Leu Ala Thr Pro Leu Ala Gly Pro Gly Pro Ser Pro Thr Thr Val Pro Ser Pro Ala Ser Gly Lys Pro Ser Ser Glu Pro Pro Pro Ala Pro Glu Ser Ala Ala Asp Ser Gly Val Glu Glu Ala Asp Thr Arg Ser Ser Ser Asp Pro His Leu Glu Thr Thr Ser Thr Ile Ser Thr Val Ser Ser Met Ser Thr Leu Ser Ser Glu Ser Gly Glu Leu Thr Asp Thr His Thr Ser Phe Ala Asp Gly His Thr Phe Leu Leu Glu Lys Pro Pro Val Pro Pro Lys Pro Lys Leu Lys Ser Pro Leu Gly Lys Gly Pro Val Thr Phe Arg Asp Pro Leu Leu Lys Gln Ser Ser Asp Ser Glu Leu Met Ala Gln Gln His His Ala Ala Ser Ala Gly Leu Ala Ser Ala Ala Gly Pro Ala Arg Pro Arg Tyr Leu Phe Gln Arg Arg Ser Lys Leu Trp Gly Asp Pro Val Glu Ser Arg Gly Leu Pro Gly Pro Glu Asp Asp Lys Pro Thr 1580 ' 1585 1590 Val Ile Ser Glu Leu Ser Ser Arg Leu Gln Gln Leu Asn Lys Asp Thr Arg Ser Leu Gly Glu Glu Pro Val Gly Gly Leu Gly Ser Leu Leu Asp Pro Ala Lys Lys Ser Pro Ile Ala Ala Ala Arg Leu Phe Ser Ser Leu Gly Glu Leu Ser Ser Ile Ser Ala Gln Arg Ser Pro Gly Gly Pro Gly Gly Gly Ala Ser Tyr Ser Val Arg Pro Ser Gly Arg Tyr Pro Val Ala Arg Arg Ala Pro Ser Pro Val Lys Pro Ala Ser Leu Glu Arg Val Glu GIy Leu Gly Ala Gly Ala Gly Gly Ala Gly Arg Pro Phe Gly Leu Thr Pro Pro Thr Ile Leu Lys Ser Ser Ser Leu Ser Ile Pro His Glu Pro Lys Glu Val Arg Phe Val Val Arg Ser Val Ser Ala Arg Ser Arg Ser Pro Ser Pro Ser Pro Leu Pr'o Ser Pro Ala Ser Gly Pro Gly Pro G1y Ala Pro G1y Pro Arg Arg Pro Phe Gln Gln Lys Pro Leu Gln Leu Trp Ser Lys Phe Asp Val Gly Asp Trp Leu Glu Ser Ile His Leu Gly Glu His Arg Asp Arg Phe Glu Asp His Glu Ile Glu Gly Ala His Leu Pro Ala Leu Thr Lys Asp Asp Phe Val Glu Leu G1y Val Thr Arg Val Gly His Arg Met Asn Ile Glu Arg Ala Leu Arg Gln Leu Asp Gly Ser <210> 17 <211> 323 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2739431CD1 <400> 17 Met Met Ser Pro Ser Gln Ala Ser Leu Leu Phe Leu Asn Val Cys Ile Phe Ile Cys Gly Glu Ala Val Gln Gly Asn Cys Val His His Ser Thr Asp Ser Ser Va1 Val Asn Ile Val Glu Asp Gly Ser Asn Ala Lys Asp Glu Ser Lys Ser Asn Asp Thr Val Cys Lys G1u Asp Cys Glu Glu Ser Cys Asp Val Lys Thr Lys Ile Thr Arg Glu Glu Lys His Phe Met Cys Arg Asn Leu Gln Asn Ser Ile Val Ser Tyr Thr Arg Ser Thr Lys Lys Leu Leu Arg Asn Met Met Asp Glu Gln 95 . 100 105 Gln Ala Ser Leu Asp Tyr Leu Ser Asn Gln Val Met Cys Asp Met Asp Tyr Arg Gly Gly Gly Trp Thr Val Ile Gln Lys Arg Ile Asp Gly Ile Ile Asp Phe Gln Arg Leu Trp Cys Asp Tyr Leu Asp Gly Phe Gly Asp Leu Leu Gly Glu Phe Trp Leu Gly Leu Lys Lys Ile Phe Tyr Ile Val Asn Gln Lys Asn Thr Ser Phe Met Leu Tyr Val Ala Leu Glu Ser Glu Asp Asp Thr Leu Ala Tyr Ala Ser Tyr Asp Asn Phe Trp Leu Glu Asp Glu Thr Arg Phe Phe Lys Met His Leu Gly Arg Tyr Ser Gly Asri A1a Gly Asp Ala Phe Arg Gly Leu Lys Lys Glu Asp Asn Gln Asn Ala Met Pro Phe Ser Thr Ser Asp Val Asp Asn Asp Gly Cys Arg Pro Ala Cys Leu Val Asn Gly Gln Ser , Val Lys Ser Cys Ser His Leu His Asn Lys Thr Gly Trp Trp Phe Asn Glu Cys Gly Leu Ala Asn Leu Asn Gly I1e His His Phe Ser Gly Lys Leu Leu Ala Thr Gly Ile Gln Trp Gly Thr Trp Thr Lys Asn Asn Ser Pro Val Lys Ile Lys Ser Val Ser Met Lys Ile Arg Arg Met Tyr Asn Pro Tyr Phe Lys <210> l8 <211> 644 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 7473606CD1 <400> 18 Met Asp G1y Arg Gly A1a Phe Trp Thr Val Ala Ile Pro Arg Ala Arg Gln Glu Gly Leu Gly Arg Leu Gly Leu Pro Phe Pro Val Lys Arg Thr Pro Pro Ala Pro Gln Asn Pro Gly Gly Ser Thr Gln Ala Pro Gln Arg Val Val Gly Lys Ser His Ser Gly Ile Arg Met Pro Ala Lys Ser Arg Asn Leu Arg Leu Glu Ser Lys Leu Asn Arg Lys Val Val Lys Tyr Lys Trp Gly Lys Gln Gly Ser Gly Ala Gly Arg Glu Leu Val Pro Ala Phe Pro Thr Asn Ala Gly Leu G1y Arg Arg Asp Arg Cys Arg Pro Pro Pro Ala Gly Gly Asp Val A1a Ser His Gly Leu Pro Gly Ser Gly Val Gly Tyr Ser Cys Asn Gln Arg Glu Glu Gly Leu Arg Gly Gly Cys Gly Gly Ile Pro His Val Pro Leu Phe Leu Ser Pro Leu Pro Leu Asp Ala Ser Gly Gln Arg Pro Ser Ser Thr Tyr Arg Gln Ser Leu Arg Arg Gly Leu Gly Thr Arg Ala His Gln Ser Pro Ala Asn Glu Ile Pro Glu Leu Gly Asp Leu Arg Gly Ser Arg Leu Ala Gln Glu Pro Ala Val Leu Phe Gly Leu Arg Pro Ser Ile Ser Lys Arg Gly Leu Leu Ala Arg Arg Leu Trp Ala Gln Pro Met Leu Leu Ser Gly Trp Val Val Ser Thr Thr Thr Thr Ile Ile Thr Val Thr Val Thr Phe Thr Pro Thr Gly Leu Leu Cys Val Lys His Ser Arg Gly Pro Leu Gln Pro Thr Cys Gln Glu Ser Ala Pro Glu Asn Arg Val Gly Lys Ala Leu Ile Thr Phe Ser Lys Gly Trp Arg Ala Ser Leu Arg Leu Ala Pro Pro Pro Ser Ala Leu Leu Leu Arg Arg His Gly Pro Gly Gly Leu Pro Val Pro Gly Thr 305 310 ~ 315 Met Cys Asp Gly Ala Leu Leu Pro Pro Leu Val Leu Pro Val Leu Leu Leu Leu Val Trp Gly Leu Asp Pro Gly Thr Gly Ser Ala Pro Ser His Ser Pro Leu His Pro Ala Ser Cys Gly Tyr Leu Pro Ser Ala Phe Ser Arg Arg Pro Gly Gly Pro Gly Ala Ala Ala Gly Pro Leu Thr Ala Pro Glu Arg Arg Arg Arg Gly Pro Arg Pro Glu Tyr Gly Asn Arg Val Ala Pro Trp Gln Ala Arg Arg Arg Arg Val Ser Ala Arg Arg Cys Ala Ala Pro Phe Arg Glu Val Leu Ala Arg Leu Arg Arg Arg Pro Ser Pro Gly Gly Ala Gly Gln Arg Gly Ala Val Gly Asp Ala Ala Ala Asp Val Glu Val Val Leu Pro Trp Arg Val 440 . 445 450 Arg Pro Asp Asp Val His Leu Pro Pro Leu Pro Ala Ala Pro Gly Pro Arg Arg Arg Arg Arg Pro Arg Thr Pro Pro Ala Ala Pro Arg Ala Arg Pro Gly Glu Arg Ala Leu Leu Leu His Leu Pro Ala Phe Gly Arg Asp Leu Tyr Leu Gln Leu Arg Arg Asp Leu Arg Phe Leu Ser Arg Gly Phe Glu Va1 Glu Glu Ala Gly Ala Ala Arg Arg Arg Gly Arg Pro Ala Glu Leu Cys Phe Tyr Ser Gly Arg Val Leu Gly His Pro Gly Ser Leu Val Ser Leu Ser Ala Cys Gly Ala Ala Gly Gly Leu Val Gly Leu Ile Gln Leu Gly Gln Glu Gln Val Leu I1e Gln Pro Leu Asn Asn Ser Gln Gly Pro Phe Ser G1y Arg Glu His Leu Ile Arg Arg Lys Trp Ser Leu Thr Pro Ser Pro Ser Ala Glu Ala Gln Arg Pro Glu Gln Leu Cys Lys Val Leu Thr Val Pro Gln Cys Leu Gly Leu Thr Trp Glu Asp Leu Lys Ser Gly Gly Trp Ser Asp Leu Glu Val Pro His Ser Cys Val Trp Pro Gly Gly Gly <210> 19 <211> 881 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 3534918CD1 <400> 19 Met Glu His Gly Ala Leu Gly Ser Leu Gly Glu His Ala Ala Lys 1 ~ 5 10 15 Val Val Gly Lys Val Leu Arg Gln Glu Gln Asp Phe Val Ile Thr His His Gln Arg Leu Val Gly Pro Thr Val Met Glu Gln Lys His Arg Cys Lys Phe Ala Met Lys Glu Ile Val Gln Phe Met Ala Ser Gly Arg Leu Gly Pro Val Gly Val Pro Val Leu Cys His Val Glu Glu Val Pro Asp Arg Glu Gln Gly A1a Ala Pro Thr Leu Cys Pro Ser Met Glu Glu Gly Asn Ala Lys Gly Val Met Ser Arg Val Ile Phe Ala Thr Val Thr Leu Ala Gln Val Ser Val Gly Asn Thr His Gly Asn Trp Ser Pro Trp Ser Gly Trp Gly Thr Cys Ser Arg Thr Cys Asn Gly G1y Gln Met Arg Arg Tyr Arg Thr Cys Asp Asn Pro Pro Pro Ser Asn Gly Gly Arg A1a Cys Gly Gly Pro Asp Ser Gln l55 160 165 Ile Gln Arg Cys Asn Thr Asp Met Cys Pro Val Asp Gly Ser Trp Gly Ser Trp His Ser Trp Ser Gln Cys Ser Ala Ser Cys Gly Gly Gly Glu Lys Thr Arg Lys Arg Leu Cys Asp His Pro Val Pro Va1 Lys G1y Gly Arg Pro Cys Pro Gly Asp Thr Thr Gln Val Thr Arg Cys Asn Val G1n Ala Cys Pro Gly Gly Pro Gln Arg A1a Arg Gly Ser Val Ile Gly Asn Ile Asn Asp Val Glu Phe Gly Ile Ala Phe Leu Asn Ala Thr Ile Thr Asp Ser Pro Asn Ser Asp Thr Arg Ile Ile Arg Ala Lys Ile Thr Asn Va1 Pro Arg Ser Leu Gly Ser Ala Met Arg Lys Ile Val Ser Ile Leu Asn Pro Ile Tyr Trp Thr Thr Ala Lys Glu Ile Gly Glu Ala Val Asn Gly Phe Thr Leu Thr Asn Ala Val Phe Lys Arg Glu Thr Gln Val Glu Phe Ala Thr Gly Glu Ile Leu Gln Met Ser His Tle Ala Arg Gly Leu Asp Ser Asp Gly Ser Leu Leu Leu Asp Ile Va1 Val Ser Gly Tyr Val Leu Gln Leu Gln Ser Pro Ala Glu Val Thr Val Lys Asp Tyr Thr Glu Asp Tyr Ile Gln Thr Gly Pro Gly Gln Leu Tyr Ala Tyr Ser Thr Arg Leu Phe Thr Ile Asp Gly Ile Ser Ile Pro Tyr Thr Trp Asn His Thr Val Phe Tyr Asp Gln Ala Gln Gly Arg Met Pro Phe Leu Val Glu Thr Leu His Ala Ser Ser Val Glu Ser Asp Tyr Asn Gln Ile Glu Glu Thr Leu Gly Phe Lys Ile His A1a Ser Ile Ser Lys Gly Asp Arg Ser Asn Gln Cys Pro Ser Gly Phe Thr Leu Asp Ser Val Gly Pro Phe Cys Ala Asp Glu Asp Glu Cys Ala Ala Gly Asn Pro Cys Ser His Ser Cys His Asn Ala Met Gly Thr Tyr Tyr Cys Ser Cys Pro Lys Gly Leu Thr Ile Ala Ala Asp Gly Arg Thr Cys Gln Asp Ile Asp Glu Cys Ala Leu Gly Arg His Thr Cys His Ala Gly Gln Asp Cys Asp Asn Thr Ile Gly Ser Tyr Arg Cys Val Val Arg Cys Gly Ser Gly Phe Arg Arg Thr Ser Asp G1y Leu Ser Cys Gln Asp Ile Asn Glu Cys Gln Glu Ser Ser Pro Cys His Gln Arg Cys Phe Asn Ala Ile Gly Ser Phe His Cys Gly Cys Glu Pro G1y Tyr Gln Leu Lys Gly Arg Lys Cys Met Asp Val Asn Glu Cys Arg Gln Asn Val Cys Arg Pro Asp Gln His Cys Lys Asn Thr Arg Gly Gly Tyr Lys Cys Ile Asp Leu Cys Pro Asn Gly Met Thr Lys Ala Glu Asn Gly Thr Cys Ile Asp Ile Asp Glu Cys Lys Asp Gly Thr His Gln Cys Arg Tyr Asn Gln Ile Cys Glu Asn Thr Arg Gly Ser Tyr Arg Cys Val Cys Pro Arg Gly Tyr Arg Ser Gln Gly Val Gly Arg Pro Cys Met Asp I1e Asp Glu Cys G1u Asn Thr Asp Ala Cys Gln His Glu Cys Lys Asn Thr Phe Gly Ser Tyr Gln Cys Ile Cys Pro Pro Gly Tyr Gln Leu Thr His Asn Gly Lys Thr Cys Gln Asp Ile Asp Glu Cys Leu Glu Gln Asn Val His Cys Gly Pro Asn Arg Met Cys Phe Asn Met Arg Gly Ser Tyr Gln Cys Ile Asp Thr Pro Cys Pro Pro Asn Tyr Gln Arg Asp Pro Val Ser Gly Phe Cys Leu Lys Asn Cys Pro Pro Asn Asp Leu Glu Cys Ala Leu Ser Pro Tyr Ala Leu Glu Tyr Lys Leu Val Ser Leu Pro Phe Gly Ile Ala Thr Asn Gln Asp Leu Ile Arg Leu Val Ala Tyr Thr Gln Asp Gly Val Met His Pro Arg Thr Thr Phe Leu Met Val Asp Glu Glu Gln Thr Val Pro Phe Ala Leu Arg Asp Glu Asn Leu Lys Gly Val Val Tyr Thr Thr Arg Pro Leu Arg Glu Ala Glu Thr Tyr Arg Met Arg Val Arg Ala Ser Ser Tyr Ser Ala Asn Gly Thr Ile Glu Tyr Gln Thr Thr Phe Ile Val Tyr Ile Ala Val Ser Ala Tyr Pro Tyr <210> 20 <211> 957 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature <223> Inoyte ID No: 2428715CD1 <400> 20 Met Gly Ala Ala Ala Val Arg Trp His Leu Cys Val Leu Leu Ala Leu Gly Thr Arg Gly Arg Leu Ala Gly Gly Ser Gly Leu Pro Gly Ser Val Asp Val Asp Glu Cys Ser Glu Gly Thr Asp Asp Cys His' Ile Asp Ala Ile Cys Gln Asn Thr Pro Lys Ser Tyr Lys Cys Leu Cys Lys Pro Gly Tyr Lys Gly Glu Gly Lys Gln Cys Glu Asp Ile Asp Glu Cys Glu Asn Asp Tyr Tyr Asn Gly Gly Cys Val His Glu Cys Ile Asn Ile Pro Gly Asn Tyr Arg Cys Thr Cys Phe Asp Gly 95 100 ~ 105 Phe Met Leu Ala His Asp Gly His Asn Cys Leu Asp Val Asp Glu Cys Gln Asp Asn Asn Gly Gly Cys Gln Gln Ile Cys Val Asn Ala Met Gly Ser Tyr Glu Cys Gln Cys His Ser Gly Phe Phe Leu Ser Asp Asn GIn His Thr Cys Ile His Arg Ser Asn Glu Gly Met Asn Cys Met Asn Lys Asp His Gly Cys Ala His Ile Cys Arg Glu Thr Pro Lys Gly Gly Val Ala Cys Asp Cys Arg Pro Gly Phe Asp Leu Ala Gln Asn Gln Lys Asp Cys Thr Leu Thr Cys Asn Tyr Gly Asn Gly Gly Cys Gln His Ser Cys Glu Asp Thr Asp Thr Gly Pro Thr Cys Gly Cys His Gln Lys Tyr Ala Leu His Ser Asp Gly Arg Thr Cys Ile Glu Lys Asp Glu Ala Ala Ile Glu Arg Ser Gln Phe Asn Ala Thr Ser Val Ala Asp Val Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu Thr Cys Ala Val Asn Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr Ala Thr Gly Val Arg Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Pro Asp Gly Lys Thr Cys Lys Asp 21e Asn Glu Cys Leu Val Asn Asn Gly Gly Cys Asp His Phe Cys Arg Asn Thr Val Gly Ser Phe Glu Cys Gly Cys Arg Lys Gly Tyr Lys Leu Leu Thr Asp Glu Arg Thr Cys Gln Asp Ile Asp Glu Cys Ser Phe Glu Arg Thr Cys Asp His I1e Cys Ile Asn Ser Pro Gly Ser Phe Gln 365 ~ 370 375 Cys Leu Cys His Arg Gly Tyr Ile Leu Tyr Gly Thr Thr His Cys Gly Asp Val Asp Glu Cys Ser Met Ser Asn Gly Ser Cys Asp Gln 395 ~ 400 405 Gly Cys Val Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys Pro Pro 4l0 415 420 Gly Arg Arg Leu His Trp Asn Arg Lys Asp Cys Val Glu Thr Gly Lys Cys Leu Ser Arg Ala Lys Thr Ser Pro Arg Ala Gln Leu Ser Cys Ser Lys Ala Gly Gly Val Glu Ser Cys Phe Leu Ser Cys Pro Ala His Thr Leu Phe Val Pro Asp Ala Pro Thr Thr Pro Ile Lys Gln Lys Ala Arg Phe Lys Ile Arg Asp Ala Lys Cys His Leu Arg Pro His Ser Gln Ala Arg Ala Lys Glu Thr Ala Arg Gln Pro Leu Leu Asp His Cys His Va1 Thr Phe Val Thr Leu Lys Cys Asp Ser Ser Lys Lys Arg Arg Arg Gly Arg Lys Ser Pro Ser Lys Glu Val Ser His Ile Thr Ala Glu Phe Glu Ile Glu Thr Lys Met Glu Glu A1a Ser Asp Thr Cys Glu Ala Asp Cys Leu Arg Lys Arg Ala Glu Gln Ser Leu Gln Ala Ala Ile Lys Thr Leu Arg Lys Ser Ile Gly Arg Gln Gln Phe Tyr Val Gln Val Ser Gly Thr Glu Tyr Glu Val Ala Gln Arg Pro Ala Lys Ala Leu Glu Gly Gln Gly Ala Cys Gly Ala Gly Gln Val Leu Gln Asp Ser Lys Cys Val Ala Cys Gly Pro Gly Thr His Phe Gly Gly Glu Leu Gly Gln Cys Val Pro Cys Met Pro Gly Thr Tyr Gln Asp Met Glu Gly Gln Leu Ser Cys Thr Pro Cys Pro Ser Ser Asp Gly Leu Gly Leu Pro Gly Ala Arg Asn Val Ser Glu Cys Gly Gly Gln Cys Ser Pro Gly Phe Phe Ser Ala Asp Gly Phe Lys Pro Cys Gln Ala Cys Pro Val Gly Thr Tyr Gln Pro Glu Pro Gly Arg Thr Gly Cys Phe Pro Cys Gly Gly Gly Leu Leu Thr Lys His Glu Gly Thr Thr Ser Phe Gln Asp Cys Glu Ala Lys Val His Cys Ser Pro Gly His His Tyr Asn Thr Thr Thr His Arg Cys Ile Arg Cys Pro Val Gly Thr Tyr Gln Pro Glu Phe Gly Gln Asn His Cys Ile Thr Cys Pro Gly Asn Thr Ser Thr Asp Phe Asp Gly Ser Thr Asn Val Thr His Cys Lys Asn Gln His Cys Gly Gly Glu Leu Gly Asp Tyr Thr Gly Tyr Ile Glu Ser Pro Asn Tyr Pro Gly Asp Tyr Pro Ala Asn Ala Glu Cys Val Trp His Ile Ala Pro Pro Pro Lys Arg Arg Ile Leu Ile Val Val Pro Glu Ile Phe Leu Pro Ile Glu Asp Glu Cys Gly Asp Val Leu Val Met Arg Lys Ser Ala Ser Pro Thr Ser Ile Thr Thr Tyr Glu Thr Cys Gln Thr Tyr Glu Arg Pro Ile Ala Phe Thr Ser Arg Ser Arg Lys Leu Trp Ile Gln Phe Lys Ser Asri Glu Gly Asn Ser Gly Lys Gly Phe Gln VaI

Pro Tyr Val Thr Tyr Asp Glu Asp Tyr Gln Gln Leu Ile G1u Asp Ile Val Arg Asp Gly Arg Leu Tyr Ala Ser Glu Asn His Gln Glu Ile Leu Lys Asp Lys Lys Leu Ile Lys Ala Leu Phe Asp Val Leu Ala His Pro Gln Asn Arg Gly Leu Val Ser Ser Cys <2l0> 21 <211> 1393 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3351332CD1 <400> 21 ' Met Gly Ala Ser Arg Asap Arg Gly Leu Ala Ala Leu Trp Cys Leu 1 5 10 15~
Gly Leu Leu Gly Gly Leu A1a Arg Val Ala Gly Thr His Tyr Arg Tyr Leu Trp Arg Gly Cys Tyr Pro Cys His Leu Gly Gln A1a Gly Tyr Pro Val Ser Ala Gly Asp Gln Arg Pro Asp Val Asp Glu Cys Arg Thr His Asn Gly Gly Cys Gln His Arg Cys Val Asn Thr Pro Gly Ser Tyr Leu Cys Glu Cys Lys Pro Gly Phe Arg Leu His Thr Asp Ser Arg Thr Cys Leu Ala Ile Asn Ser Cys Ala Leu Gly Asn Gly Gly Cys Gln His His Cys Val Gln Leu Thr Ile Thr Arg His Arg Cys Gln Cys Arg Pro Gly Phe Gln Leu Gln Glu Asp Gly Arg His Cys Val Arg Arg Ser Pro Cys Ala Asn Arg Asn Gly Ser Cys 37/l23 Met His Arg Cys Gln Val Val Arg Gly Leu Ala Arg Cys Glu Cys His Val Gly Tyr Gln Leu Ala Ala Asp Gly Lys Ala Cys Pro Asp 170 ~ 175 180 Val Asp Glu Cys Ala Ala Gly Leu Ala Gln Cys Ala His Gly Cys Leu Asn Thr Gln Gly Ser Phe Lys Cys Val Cys His Ala Gly Tyr Glu Leu Gly Ala Asp Gly Arg Gln Cys Tyr Arg Ile Glu Met Glu Ile Val Asn Ser Cys Glu Ala Asn Asn Gly Gly Cys Ser His Gly Cys Ser His Thr Ser Ala Gly Pro Leu Cys Thr Cys Pro Arg Gly Tyr Glu Leu Asp Thr Asp Gln Arg Thr Cys Ile Asp Val Asp Asp Cys Ala Asp Ser Pro Cys Cys Gln Gln Val Cys Thr Asn Asn Pro Gly Gly Tyr Glu Cys Gly Cys Tyr Ala Gly Tyr Arg Leu Ser Ala Asp Gly Cys Gly Cys Glu Asp Val Asp Glu Cys Ala Ser Ser Arg Gly Gly Cys Glu His His Cys Thr Asn Leu Ala Gly Ser Phe Gln Cys Ser Cys Glu Ala G1y Tyr Arg Leu His Glu Asp Arg Arg Gly Cys Ser Pro Leu Glu Glu Pro Met Val Asp Leu Asp G1y G1u Leu Pro Phe Val Arg Pro Leu Pro His Ile Ala Val Leu Gln Asp Glu Leu Pro Gln Leu Phe Gln Asp Asp Asp Val Gly Ala Asp Glu Glu Glu Ala Glu Leu Arg Gly Glu His Thr Leu Thr Glu Lys Phe Val Cys Leu Asp Asp Ser Phe Gly His Asp Cys Ser Leu Thr Cys Asp Asp Cys Arg Asn Gly Gly Thr Cys Leu Leu Gly Leu Asp Gly Cys Asp Cys Pro Glu Gly Trp Thr Gly Leu Ile Cys Asn Glu Thr Cys Pro Pro Asp Thr Phe Gly Lys Asn Cys Ser Phe Ser Cys Ser Cys Gln Asn Gly Gly Thr Cys Asp Ser Val Thr Gly Ala Cys Arg Cys Pro Pro Gly Val Ser Gly Thr Asn Cys Glu Asp Gly Cys Pro Lys Gly Tyr Tyr Gly Lys His Cys Arg Lys Lys Cys Asn Cys Ala Asn Arg Gly Arg Cys His Arg Leu Tyr Gly Ala Cys Leu Cys Asp Pro Gly Lei Tyr Gly Arg Phe Cys His Leu Thr Cys Pro Pro Trp Ala Phe Gly Pro Gly Cys Ser Glu Glu Cys Gln Cys Val Gln Pro His Thr Gln Ser Cys Asp Lys Arg Asp Gly Ser Cys Ser Cys Lys Ala Gly Phe Arg Gly Glu Arg Cys Gln Ala Glu Cys Glu Leu Gly Tyr Phe Gly Pro Gly Cys Trp Gln Ala Cys Thr Cys Pro Val Gly Val Ala Cys Asp Ser Val Ser Gly Glu Cys Gly Lys Arg Cys Pro Ala Gly Phe Gln Gly Glu Asp Cys Gly Gln Glu Cys Pro Val Gly Thr Phe Gly Val Asn Cys Ser Ser Ser Cys Ser Cys Gly Gly Ala Pro Cys His Gly Val Thr Gly Gln Cys Arg Cys Pro Pro Gly Arg Thr Gly Glu Asp Cys Glu Ala Asp Cys Pro Glu Gly Arg Trp Gly Leu Gly Cys Gln Glu Ile Cys Pro Ala Cys Gln His Ala A1a Arg Cys Asp Pro Glu Thr G1y Ala Cys Leu Cys Leu Pro Gly Phe Val Gly Ser Arg Cys Gln Asp Val Cys Pro Ala Gly Trp Tyr Gly Pro Ser Cys Gln Thr Arg Cys Ser Cys Ala Asn Asp Gly His Cys His Pro ' Ala Thr Gly His Cys Ser Cys Ala Pro Gly Trp Thr Gly Phe Ser Cys Gln Arg Ala Cys Asp Thr Gly His Trp Gly Pro Asp Cys Ser His Pro Cys Asn Cys Ser Ala G1y His Gly Ser Cys Asp Ala Ile Ser Gly Leu Cys Leu Cys Glu Ala Gly Tyr Val Gly Pro Arg Cys Glu Gln Gln Cys Pro Gln Gly His Phe Gly Pro Gly Cys Glu Gln Leu Cys Gln Cys Gln His G1y Ala Ala Cys Asp His Val Ser Gly Ala Cys Thr Cys Pro Ala Gly Trp Arg Gly Thr Phe Cys Glu His Ala Cys Pro Ala Gly Phe Phe Gly Leu Asp Cys Arg Ser Ala Cys Asn Cys Thr Ala Gly Ala Ala Cys Asp Ala Val Asn Gly Ser Cys Leu Cys Pro Ala Gly Arg Arg Gly Pro Arg Cys Ala Glu Thr Cys Pro Ala His Thr Tyr Gly His Asn Cys Ser Gln Ala Cys Ala Cys Phe Asn Gly Ala Ser Cys Asp Pro Val His Gly Gln Cys His Cys 905 9l0 915 Ala Pro Gly Trp Met Gly Pro Ser Cys Leu Gln Glu Cys Leu Pro Arg Asp Val Arg Ala Gly Cys Arg His Ser Gly Gly Cys Leu Asn Gly Gly Leu Cys Asp Pro His Thr Gly Arg Cys Leu Cys Pro Ala Gly Trp Thr Gly Asp Lys Cys Gln Ser Pro Cys Leu Arg Gly Trp Phe Gly Glu Ala Cys Ala Gln Arg Cys Ser Cys Pro Pro Gly Ala Ala Cys His His Val Thr Gly Ala Cys Arg Cys Pro Pro Gly Phe Thr Gly Ser Gly Cys Glu Gln Ala Cys Pro Pro Gly Ser Phe Gly Glu Asp Cys Ala Gln Met Cys Gln Cys Pro Gly Glu Asn Pro Ala Cys His Pro Ala Thr Gly Thr Cys Ser Cys Ala Ala Gly Tyr His Gly Pro Ser Cys Gln Gln Arg Cys Pro Pro Gly Arg Tyr Gly Pro Gly Cys Glu Gln Leu Cys Gly Cys Leu Asn Gly Gly Ser Cys Asp Ala Ala Thr Gly Ala Cys Arg Cys Pro Thr Gly Phe Leu Gly Thr Asp Cys Asn Leu Thr Cys Pro Gln Gly Arg Phe Gly Pro Asn Cys Thr His Val Cys Gly Cys Gly Gln Gly Ala Ala Cys Asp Pro Val Thr Gly Thr Cys Leu Cys Pro Pro Gly Arg Ala Gly Va1 Arg Cys Glu Arg Gly Cys Pro Gln Asn Arg Phe Gly Val Gly Cys Glu His Thr Cys Ser Cys Arg Asn,Gly Gly Leu Cys His Ala Ser Asn Gly Ser Cys Ser Cys Gly Leu Gly Trp Thr Gly Arg His Cys Glu Leu Ala Cys Pro Pro Gly Arg Tyr Gly Ala Ala Cys His Leu Glu Cys Ser Cys His Asn Asn Ser Thr Cys Glu Pro Ala Thr Gly Thr Cys Arg Cys Gly Pro Gly Phe Tyr Gly Gln Ala Cys Glu His Pro Cys Pro Pro Gly Phe His Gly Ala Gly Cys Gln Gly Leu Cys Trp Cys Gln His Gly Ala Pro Cys Asp Pro Ile Ser Gly Arg Cys Leu Cys Pro Ala Gly Phe His Gly His Phe Cys Glu Arg Gly Cys G1u Pro Gly Ser Phe Gly Glu Gly Cys His Gln Arg Cys Asp Cys Asp Gly Gly Ala Pro Cys Asp Pro Val Thr Gly Leu Cys Leu Cys Pro Pro Gly Arg Ser Gly Ala Thr Cys Asn Leu Asp Cys Arg Arg Gly.Gln Phe Gly Pro Ser Cys Thr Leu His Cys Asp Cys Gly Gly Gly Ala Asp Cys Asp Pro Val Ser Gly Gln Cys His Cys Val Asp Gly Tyr Met Gly Pro Thr Cys Arg Glu Gly Gly Pro Leu Arg Leu Pro Glu Asn Pro Ser Leu Ala Gln Gly Ser Ala Gly Thr Leu Pro Ala Ser Ser Arg Pro Thr Ser Arg Ser Gly Gly Pro Ala Arg His <210> 22 <211> 3695 <212> PRT
<213> Homo sapiens <220>
<221> misc feature <223> Incyte ID No: 6382722CD1 <400> 22 Met Ala Lys Arg Leu Cys Ala Gly Ser Ala Leu Cys Val Arg Gly Pro Arg G1y Pro Ala Pro Leu Leu Leu Val Gly Leu Ala Leu Leu Gly Ala Ala Arg Ala Arg Glu Glu Ala Gly Gly Gly Phe Ser Leu His Pro Pro Tyr Phe Asn Leu Ala Glu Gly Ala Arg Ile Ala Ala Ser Ala Thr Cys Gly Glu Glu Ala Pro Ala Arg Gly Ser Pro Arg Pro Thr Glu Asp Leu Tyr Cys Lys Leu Val Gly G1y Pro Val Ala Gly Gly Asp Pro Asn Gln Thr Ile Arg Gly G1n Tyr Cys Asp Ile Cys Thr Ala Ala Asn Ser Asn Lys Ala His Pro Ala Ser Asn Ala Ile Asp Gly Thr Glu Arg Trp Trp Gln Ser Pro Pro Leu Ser Arg Gly Leu Glu Tyr Asn G1u Val Asn Val Thr Leu Asp Leu Gly Gln Val Phe His Val Ala Tyr Val Leu Ile Lys Phe Ala Asn Ser Pro Arg Pro Asp Leu Trp Val Leu Glu Arg Ser Met Asp Phe Gly Arg Thr Tyr Gln Pro Trp Gln Phe Phe Ala Ser Ser Lys Arg Asp Cys Leu Glu Arg Phe Gly Pro Gln Thr Leu Glu Arg Ile Thr Arg Asp Asp Ala Ala Ile Cys Thr Thr Glu Tyr Ser Arg Ile Val Pro Leu Glu Asn Gly Glu Ile Val Val Ser Leu Val Asn Gly Arg Pro Gly Ala Met Asn Phe Ser Tyr Ser Pro Leu Leu Arg Glu Phe Thr Lys Ala Thr Asn Val Arg Leu Arg Phe Leu Arg Thr Asn Thr Leu Leu Gly His Leu Met Gly Lys Ala Leu Arg Asp Pro Thr Val Thr Arg Arg Tyr Tyr Tyr Ser Ile Lys Asp Ile Ser Ile Gly Gly Arg Cys Val Cys His Gly His Ala Asp Ala Cys Asp Ala Lys Asp Pro Thr Asp Pro Phe Arg Leu GIn Cys Thr Cys Gln His Asn Thr Cys Gly Gly Thr Cys Asp Arg Cys Cys Pro Gly Phe Asn Gln Gln Pro Trp 335 340 ~ 345 Lys Pro Ala Thr Ala Asn Ser Ala Asn Glu Cys G1n Ser Cys Asn Cys Tyr Gly His Ala Thr Asp Cys Tyr Tyr Asp Pro Glu Val Asp Arg Arg Arg Ala Ser Gln Ser Leu Asp Gly Thr Tyr Gln Gly Gly Gly Val Cys Ile Asp Cys Gln His His Thr Ala Gly Val Asn Cys Glu Arg Cys Leu Pro Gly Phe Tyr Arg Ser Pro Asn His Pro Leu Asp Ser Pro His Val Cys Arg Arg Cys Asn Cys Glu Ser Asp Phe Thr Asp Gly Thr Cys Glu Asp Leu Thr Gly Arg Cys Tyr Cys Arg Pro Asn Phe Ser Gly Glu Arg Cys Asp Val Cys Ala Glu Gly Phe Thr Gly Phe Pro Ser Cys Tyr Pro Thr Pro Ser Ser Ser Asn Asp Thr Arg G1u Gln Val Leu Pro Ala Gly Gln Ile Val Asn Cys Asp Cys Ser Ala Ala Gly Thr Gln Gly Asn Ala Cys Arg Lys Asp Pro Arg Val Gly Arg Cys Leu Cys Lys Pro Asn Phe Gln Gly Thr His Cys Glu Leu Cys Ala Pro Gly Phe Tyr Gly Pro Gly Cys Gln Pro Cys Gln Cys Ser Ser Pro Gly Val A1a Asp Asp Arg Cys Asp Pro Asp Thr Gly Gln Cys Arg Cys Arg Val Gly Phe Glu Gly A1a Thr Cys Asp Arg Cys Ala Pro Gly Tyr Phe His Phe Pro Leu Cys Gln Leu Cys Gly Cys Ser Pro Ala Gly Thr Leu Pro Glu Gly Cys Asp Glu Ala Gly Arg Cys Leu Cys Gln Pro Glu Phe Ala Gly Pro His Cys Asp Arg Cys Arg Pro Gly Tyr His Gly Phe Pro Asn Cys Gln Ala Cys Thr Cys Asp Pro Arg Gly Ala Leu Asp Gln Leu Cys Gly Ala Gly Gly Leu Cys Arg Cys Arg Pro Gly Tyr Thr Gly Thr Ala Cys Gln Glu Cys Ser Pro Gly Phe His Gly Phe Pro Ser Cys Val Pro Cys His Cys Ser Ala Glu Gly Ser Leu His Ala Ala Cys Asp Pro Arg Ser Gly Gln Cys Ser Cys Arg Pro Arg Val Thr Gly Leu Arg Cys Asp Thr Cys Va1 Pro Gly Ala Tyr Asn Phe Pro Tyr Cys 710 ~ 715 720 Glu Ala Gly Ser Cys His Pro Ala Gly Leu Ala Pro Val Asp Pro Ala Leu Pro Glu Ala Gln Val Pro Cys Met Cys Arg Ala His Val Glu Gly Pro Ser Cys Asp Arg Cys Lys Pro Gly Phe Trp Gly Leu Ser Pro Ser Asn Pro Glu Gly Cys Thr Arg Cys Ser Cys Asp Leu Arg Gly Thr Leu Gly Gly Val Ala Glu Cys Gln Pro Gly Thr Gly Gln Cys Phe Cys Lys Pro His Val Cys Gly Gln Ala Cys Ala Ser Cys Lys Asp Gly Phe Phe Gly Leu Asp Gln Ala Asp Tyr Phe Gly Cys Arg Ser Cys Arg Cys Asp Ile Gly Gly Ala Leu Gly Gln Ser Cys Glu Pro Arg Thr Gly Val Cys Arg Cys Arg Pro Asn Thr Gln Gly Pro Thr Cys Ser Glu Pro Ala Arg Asp His Tyr Leu Pro Asp Leu His His Leu Arg Leu Glu Leu Glu Glu Ala Ala Thr Pro Glu Gly His Ala Val Arg Phe Gly Phe Asn Pro Leu Glu Phe Glu Asn Phe Ser Trp Arg Gly Tyr Ala Gln Met Ala Pro Val Gln Pro Arg Ile Val Ala Arg Leu Asn Leu Thr Ser Pro Asp Leu Phe Trp Leu Val Phe Arg Tyr Val Asn Arg Gly Ala Met Ser Val Ser Gly Arg Val Ser Val Arg Glu Glu Gly Arg Ser Ala Ala Cys Ala Asn Cys Thr Ala Gln Ser Gln Pro Val Ala Phe Pro Pro Ser Thr Glu Pro Ala Phe Ile Thr Val Pro Gln Arg Gly Phe G1y G1u Pro Phe Val Leu Asn Pro Gly Thr Trp Ala Leu Arg Val Glu Ala Glu Gly Val Leu Leu Asp Tyr Val Val Leu Leu Pro Ser Ala Tyr Tyr Glu Ala Ala Leu Leu Gln Leu Arg Val Thr G1u Ala Cys Thr Tyr Arg Pro Ser Ala Gln Gln Ser Gly Asp Asn Cys Leu Leu Tyr Thr His Leu Pro Leu Asp Gly Phe Pro Ser Ala Ala Gly Leu Glu Ala Leu Cys Arg Gln Asp Asn Ser Leu Pro Arg Pro Cys Pro Thr Glu Gln Leu Ser Pro Ser His Pro Pro Leu Ile Thr Cys Thr Gly Ser Asp Val Asp Val Gln Leu Gln Val Ala Val Pro Gln Pro Gly Arg Tyr Ala Leu Val Val Glu Tyr Ala Asn Glu Asp Ala Arg Gln Glu Val Gly Val Ala Val His Thr Pro Gln Arg Ala Pro Gln Gln Gly Leu Leu Ser Leu His Pro Cys Leu Tyr Ser Thr Leu Cys Arg Gly Thr Ala Arg Asp Thr Gln Asp His Leu Ala Val Phe His Leu Asp Ser Glu Ala Ser Val Arg Leu Thr Ala Glu Gln Ala Arg Phe Phe Leu His Gly Val Thr Leu Val Pro Ile Glu G1u Phe Ser Pro Glu Phe Val Glu Pro Arg Val Ser Cys Ile Ser Ser His Gly Ala Phe Gly Pro Asn Ser Ala Ala Cys Leu Pro Ser Arg Phe Pro Lys Pro Pro Gln Pro Ile Ile Leu Arg Asp Cys Gln Val Ile Pro Leu Pro Pro Gly Leu Pro Leu Thr His Ala Gln Asp Leu Thr Pro Ala Thr Ser Pro Ala Gly Pro Arg Pro Arg Pro Pro Thr Ala Val Asp Pro Asp Ala Glu Pro Thr Leu Leu Arg Glu Pro Gln Ala Thr Val Val Phe Thr Thr His Val Pro Thr Leu Gly Arg Tyr Ala Phe Leu Leu His Gly Tyr Gln Pro Ala His Pro Thr Phe Pro Val Glu Val Leu Ile Asn Ala Gly Arg Val Trp Gln Gly His Ala Asn Ala Ser Phe Cys Pro His Gly Tyr Gly Cys Arg Thr Leu Val Val Cys Glu Gly G1n Ala Leu Leu Asp Val Thr His Ser Glu Leu Thr Val Thr Val Arg Val Pro Glu Gly Arg Trp Leu Trp Leu Asp Tyr Val Leu Val Val Pro Glu Asn Val Tyr Ser Phe Gly Tyr Leu Arg Glu Glu Pro Leu Asp Lys Ser Tyr Asp Phe Ile Ser His Cys Ala Ala Gln Gly Tyr His Ile Ser Pro Ser Ser Ser Ser Leu Phe Cys Arg Asn Ala Ala A1a Ser Leu Ser Leu Phe Tyr Asn Asn Gly Ala Arg Pro Cys Gly Cys His Glu Val G1y Ala Thr Gly Pro Thr Cys Glu Pro Phe Gly Gly Gln Cys Pro Cys His Ala His Val Ile Gly Arg Asp Cys Ser Arg Cys Ala Thr Gly Tyr Trp Gly Phe Pro Asn Cys Arg Pro Cys Asp Cys Gly Ala Arg Leu Cys Asp Glu Leu Thr Gly G1n Cys Ile Cys Pro Pro Arg Thr Ile Pro Pro Asp Cys Leu Leu Cys Gln Pro Gln Thr Phe Gly Cys His Pro Leu Val Gly Cys Glu Glu Cys Asn Cys Ser Gly Pro Gly Ile Gln Glu Leu Thr Asp Pro Thr Cys Asp Thr Asp Ser Gly Gln Cys Lys Cys Arg Pro Asn Val Thr Gly Arg Arg Cys Asp Thr Cys Ser Pro Gly Phe His Gly Tyr Pro Arg Cys Arg Pro Cys Asp Cys His Glu Ala Gly Thr Ala Pro Gly Val Cys Asp Pro Leu Thr Gly Gln Cys Tyr Cys Lys Glu Asn Val Gln Gly Pro Lys Cys Asp Gln Cys Ser Leu Gly Thr Phe Ser Leu Asp Ala Ala 1610 ~ 1615 1620 Asn Pro Lys Gly Cys Thr Arg Cys Phe Cys Phe Gly Ala Thr Glu Arg Cys Arg Ser Ser Ser Tyr Thr Arg Gln Glu Phe Val Asp Met Glu Gly Trp Val Leu Leu Ser Thr Asp Arg Gln Val Val Pro His Glu Arg Gln Pro Gly Thr Glu Met Leu Arg Ala Asp Leu Arg His Val Pro G1u Ala Val Pro Glu Ala Phe Pro Glu Leu Tyr Trp Gln Ala Pro Pro Ser Tyr Leu Gly Asp Arg Val Ser Ser Tyr Gly Gly Thr Leu Arg Tyr Glu Leu His Ser Glu Thr Gln Arg Gly Asp Val Phe Val Pro Met Glu Ser Arg Pro Asp Val Val Leu Gln Gly Asn Gln Met Ser Ile Thr Phe Leu Glu Pro A1a Tyr Pro Thr Pro Gly His Val His Arg Gly Gln Leu Gln Leu Val Glu Gly Asn Phe Arg His Thr Glu Thr Arg Asn Thr Val Ser Arg Glu Glu Leu Met Met Val Leu Ala Ser Leu Glu Gln Leu G1n Ile Arg Ala, Leu Phe Ser Gln Ile Ser Ser Ala Val Ser Leu Arg Arg Val Ala Leu Glu Val 1805 1810 ' 1815 Ala Ser Pro Ala Gly Gln Gly Ala Leu Ala Ser Asn Val Glu Leu Cys Leu Cys Pro Ala Ser Tyr Arg Gly Asp Ser Cys Gln Glu Cys Ala Pro Gly Phe Tyr Arg Asp Val Lys Gly Leu Phe Leu Gly Arg Cys Val Pro Cys Gln Cys His Gly His Ser Asp Arg Cys Leu Pro Gly Ser Gly Val Cys Val Asp Cys Gln His Asn Thr Glu Gly Ala His Cys Glu Arg Cys Gln Ala Gly Phe Met Ser Ser Arg Asp Asp Pro Ser Ala Pro Cys Val Ser Cys Pro Cys Pro Leu Ser Val Pro Ser Asn Asn Phe Ala Glu Gly Cys Val Leu Arg Gly Gly Arg Thr Gln Cys Leu Cys Lys Pro Gly Tyr Ala Gly Ala Ser Cys Glu Arg Cys Ala Pro Gly Phe Phe Gly Asn Pro Leu Val Leu Gly Ser Ser Cys Gln Pro Cys Asp Cys Ser Gly Asn Gly Asp Pro Asn Leu Leu Phe Ser Asp Cys Asp Pro Leu Thr Gly Ala Cys Arg Gly Cys Leu Arg His Thr Thr Gly Pro Arg Cys Glu Ile Cys Ala Pro G1y Phe Tyr Gly Asn Ala Leu Leu Pro Gly Asn Cys Thr Arg Cys Asp Cys Thr Pro Cys Gly Thr Glu Ala Cys Asp Pro His Ser Gly His Cys Leu Cys Lys Ala Gly Val Thr Gly Arg Arg Cys Asp Arg Cys Gln Glu Gly His Phe Gly Phe Asn Gly Cys Gly Gly Cys Arg Pro Cys Ala Cys Gly Pro Ala Ala Glu Gly Ser Glu Cys His Pro Gln Ser Gly Gln Cys His Cys Arg Pro Gly Thr Met Gly Pro Gln Cys Arg Glu Cys Ala Pro Gly Tyr Trp Gly Leu Pro Glu Gln Gly Cys Arg Arg Cys Gln Cys Pro Gly Gly Arg Cys Asp Pro His Thr Gly Arg Cys Asn Cys Pro Pro Gly Leu Ser Gly Glu Arg Cys Asp Thr Cys Ser Gln Gln His Gln Val Pro Val Pro Gly Gly Pro Val Gly His Ser Ile His Cys Glu Val Cys Asp His Cys Val Va1 Leu Leu Leu Asp Asp Leu Glu Arg Ala Gly Ala Leu Leu Pro Ala Ile His Glu Gln Leu Arg Gly Ile Asn Ala Ser Ser Met Ala Trp Ala Arg Leu His Arg Leu Asn Ala Ser Ile Ala Asp Leu Gln Ser Gln Leu Arg Ser Pro Leu Gly Pro Arg His Glu Thr Ala Gln Gln Leu Glu Val Leu Glu Gln Gln Ser Thr Ser Leu Gly Gln Asp Ala Arg Arg Leu Gly Gly Gln Ala Val Gly Thr Arg Asp Gln Ala Ser Gln Leu Leu Ala Gly Thr Glu A1a Thr Leu Gly His Ala Lys Thr Leu Leu Ala Ala Ile Arg Ala Val Asp Arg Thr Leu Ser Glu Leu Met Ser Gln Thr Gly His Leu Gly Leu Ala Asn Ala Ser Ala Pro Ser Gly Glu Gln Leu Leu Arg Thr Leu Ala Glu Val Glu Arg Leu Leu Trp Glu Met Arg Ala Arg Asp Leu G1y Ala Pro Gln Ala Ala Ala Glu Ala Glu Leu Ala Ala Ala Gln Arg Leu Leu A1a Arg Va1 Gln Glu Gln Leu Ser Ser Leu,Trp Glu Glu Asn Gln Ala Leu Ala Thr Gln Thr Arg Asp Arg Leu Ala Gln His Glu Ala Gly Leu Met Asp Leu Arg Glu Ala Leu Asn Arg Ala Val Asp Ala Thr Arg Glu Ala Gln Glu Leu Asn Ser Arg Asn Gln Glu Arg Leu Glu Glu A1a Leu Gln Arg Lys Gln Glu Leu Ser Arg Asp Asn A1a Thr Leu Gln Ala Thr Leu His Ala Ala Arg Asp Thr Leu Ala Ser Val Phe Arg Leu Leu His Ser Leu Asp Gln Ala Lys Glu Glu Leu Glu Arg Leu Ala Ala Ser Leu Asp Gly Ala Arg Thr Pro Leu Leu Gln Arg Met Gln Thr Phe Ser Pro Ala Gly Ser Lys Leu Arg Leu Val Glu Ala Ala Glu Ala His Ala Gln Gln Leu Gly Gln Leu Ala Leu Asn Leu Ser Ser Ile Ile Leu Asp Val Asn Gln Asp Arg Leu Thr Gln Arg Ala Ile Glu Ala Ser Asn Ala Tyr Ser Arg Ile Leu Gln Ala Val Gln Ala Ala Glu Asp Ala Ala Gly Gln Ala Leu Gln Gln Ala Asp His Thr Trp Ala Thr Val Val Arg Gln Gly Leu Val Asp Arg Ala Gln Gln Leu Leu Ala Asn Ser Thr Ala Leu Glu Glu Ala Met Leu Gln G1u G1n Gln Arg Leu Gly Leu Val Trp Ala Ala Leu Gln Gly Ala Arg Thr Gln Leu Arg Asp Val Arg Ala Lys Lys Asp Gln Leu Glu Ala His Ile Gln Ala Ala Gln Ala Met Leu Ala Met Asp Thr Asp Glu Thr Ser Lys Lys Ile Ala His Ala Lys Ala Val Ala Ala Glu Ala Gln Asp Thr Ala Thr Arg Val Gln Ser Gln Leu Gln Ala Met G1n Glu Asn Va1 Glu Arg Trp Gln Gly Gln Tyr Glu G1y Leu Arg Gly Gln Asp Leu Gly Gln Ala Val Leu Asp Ala Gly His Ser Val Ser Thr 2675 2680 268'5 Leu Glu Lys Thr Leu Pro Gln Leu Leu A1a Lys Leu Ser I1e Leu Glu Asn Arg Gly Val His Asn Ala Ser Leu Ala Leu Ser Ala Ser Ile Gly Arg Val Arg Glu Leu Ile Ala Gln Ala Arg Gly Ala Ala Ser Lys Val Lys Val Pro Met Lys Phe Asn Gly Arg Ser Gly Val Gln Leu Arg Thr Pro Arg Asp Leu Ala Asp Leu Ala Ala Tyr Thr Ala Leu Lys Phe Tyr Leu Gln Gly Pro Glu Pro G1u Pro Gly Gln Gly Thr Glu Asp Arg Phe Val Met Tyr Met Gly Ser Arg Gln Ala Thr Gly Asp Tyr Met Gly Val Ser Leu Arg Asp Lys Lys Val His Trp Val Tyr Gln Leu Gly Glu Ala Gly Pro Ala Val Leu Ser Ile Asp Glu Asp Ile Gly Glu Gln.Phe Ala Ala Val Ser Leu Asp Arg Thr Leu Gln Phe Gly His Met Ser Val Thr Val Glu Arg Gln Met Ile Gln Glu Thr Lys Gly Asp Thr Val Ala Pro Gly Ala Glu Gly Leu Leu Asn Leu Arg Pro Asp Asp Phe Val Phe Tyr Val Gly Gly Tyr Pro Ser Thr Phe Thr Pro Pro Pro Leu Leu Arg Phe Pro Gly Tyr Arg Gly Cys Ile Glu Met Asp Thr Leu Asn Glu Glu Val Val Ser Leu Tyr Asn Phe Glu Arg Thr Phe Gln Leu Asp Thr Ala Val Asp Arg Pro Cys Ala Arg Ser Lys Ser Thr Gly Asp Pro Trp Leu Thr Asp Gly Ser Tyr Leu Asp Gly Thr Gly Phe Ala Arg Ile Ser Phe Asp Ser Gln Ile Ser Thr Thr Lys Arg Phe Glu Gln Glu Leu Arg Leu Val Ser Tyr Ser Gly Val Leu Phe Phe Leu Lys Gln Gln 2975 2980 ! 2985 Ser Gln Phe Leu Cys Leu Ala Val Gln Glu Gly Ser Leu Val Leu Leu Tyr Asp Phe Gly Ala Gly Leu Lys Lys Ala Val Pro Leu Gln Pro Pro Pro Pro Leu Thr Ser Ala Ser Lys Ala Ile Gln Val Phe Leu Leu Gly Gly Ser Arg Lys Arg Val Leu Val Arg Val Glu Arg Ala Thr Val Tyr Ser Val Glu Gln Asp Asn Asp Leu Glu Leu Ala Asp Ala Tyr Tyr Leu Gly Gly Val Pro Pro Asp Gln Leu Pro Pro Ser Leu Arg Arg Leu Phe Pro Thr Gly Gly Ser Val Arg Gly Cys Val Lys Gly Ile Lys Ala Leu Gly Lys Tyr Val Asp Leu Lys Arg Leu Asn Thr Thr Gly Val Ser Ala Gly Cys Thr Ala Asp Leu Leu Val Gly Arg Ala Met Thr Phe His Gly His Gly Phe Leu Arg Leu Ala Leu Ser Asn Val Ala Pro Leu Thr Gly Asn Val Tyr Ser Gly Phe Gly Phe His Ser Ala Gln Asp Ser Ala Leu Leu Tyr Tyr Arg A1a Ser Pro Asp Gly Leu Cys Gln Val Ser Leu Gln Gln Gly Arg Val Ser Leu Gln Leu Leu Arg Thr Glu Val Lys Thr Gln Ala Gly Phe Ala Asp Gly Ala Pro His Tyr Val Ala Phe Tyr Ser Asn Ala Thr Gly Val Trp Leu Tyr Val Asp Asp Gln Leu Gln Gln Met Lys Pro His Arg Gly Pro Pro Pro Glu Leu G1n Pro Gln Pro Glu Gly Pro Pro Arg Leu Leu Leu Gly Gly Leu Pro Glu Ser Gly Thr Ile Tyr Asn Phe Ser Gly Cys Ile Ser Asn Val Phe Val Gln Arg Leu Leu Gly Pro Gln Arg Val Phe Asp Leu Gln Gln Asn Leu Gly Ser Val Asn Val Ser Thr Gly Cys Ala Pro Ala Leu Gln Ala Gln Thr Pro Gly Leu Gly Pro Arg Gly Leu Gln Ala Thr Ala Arg Lys Ala Ser Arg Arg Ser Arg Gln Pro Ala Arg His Pro Ala Cys Met Leu Pro Pro His Leu Arg Thr Thr Arg Asp Ser Tyr Gln Phe Gly Gly Ser Leu Ser Ser His Leu Glu Phe Val Gly Ile Leu Ala Arg His 3350 3355 33&0 Arg Asn Trp Pro Ser Leu Ser Met His Val Leu Pro Arg Ser Ser Arg Gly Leu Leu Leu Phe Thr Ala Arg Leu Arg Pro Gly Ser Pro Ser Leu Ala Leu Phe Leu Ser Asn Gly His Phe Val Ala Gln Met Glu Gly Leu Gly Thr Arg Leu Arg Ala Gln Ser Arg Gln Arg Ser Arg Pro Gly Arg Trp His Lys Val Ser Val Arg Trp Glu Lys Asn Arg Ile Leu Leu Val Thr Asp Gly Ala Arg Ala Trp Ser Gln Glu Gly Pro His Arg Gln His Gln Gly Ala Glu His Pro Gln Pro His Thr Leu Phe Val Gly G1y Leu Pro Ala Ser Ser His Sex Ser Lys Leu Pro Val Thr Val Gly Phe Ser Gly Cys Val Lys Arg Leu Arg Leu His Gly Arg Pro Leu Gly A1a Pro Thr Arg Met Ala Gly Val Thr Pro Cys Ile Leu Gly Pro Leu Glu Ala Gly Leu Phe Phe Pro G1y Ser Gly Gly Val Ile Thr Leu Asp Leu Pro Gly Ala Thr Leu Pro Asp Val G1y Leu Glu Leu Glu Val Arg Pro Leu Ala Val Thr Gly Leu Ile Phe His Leu Gly Gln Ala Arg Thr Pro Pro Tyr Leu Gln Leu Gln Val Thr Glu Lys Gln Val Leu Leu Arg Ala Asp Asp Gly Ala Gly Glu Phe Ser Thr Ser Val Thr Arg Pro Ser Val Leu Cys Asp Gly Gln Trp His Arg Leu Ala Val Met Lys Ser Gly Asn Val Leu Arg Leu Glu Val Asp Ala Gln Ser Asn His Thr Val Gly Pro Leu Leu Ala Ala Ala Ala Gly Ala Pro Ala Pro Leu Tyr Leu Gly Gly Leu Pro Glu Pro Met Ala Val Gln Pro Trp Pro Pro Ala Tyr Cys Gly Cys Met Arg Arg Leu Ala Val Asn Arg Ser Pro Val Ala Met Thr Arg Ser Val Glu Val His Gly Ala Val Gly Ala Ser Gly Cys Pro Ala Ala <210> 23 <211> 1255 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 55022490CD1 <400> 23 Met Val Arg Gly Gly Arg Trp Glu Gln Ala His Lys Lys Glu Pro Leu Gly Val Trp Gly Pro Leu Pro Cys Val Arg Gly Ala Gln Gly Thr Leu Gly Asp Arg Asn Gly Gly Thr Gly Gly Trp Arg His Trp Gly Gly Cys Glu Gly Met Pro Met Pro Ser Ser Ser Gln Asn Val Cys Thr Asn Ser Gly Ala Ser Val Gly Thr Thr Cys His Ser Lys Leu Asp Ala Ala Va1 Asp Gly Thr Arg Cys Gly Glu Asn Lys Trp Cys Leu Ser Gly Glu Cys Val Pro Val Gly Phe Arg Pro Glu Ala Val Asp Gly Gly Trp Ser Gly Trp Ser Ala Trp Ser Ile Cys Ser Arg Ser Cys Gly Met Gly Val Gln Ser Ala Glu Arg Gln Cys Thr 12.5 13 0 13 5 Gln Pro Thr Pro Lys Tyr Lys Gly Arg Tyr Cys Val Gly Glu Arg Lys Arg Phe Arg Leu Cys Asn Leu Gln Ala Cys Pro Ala Gly His Pro Ser Phe Arg His Val Gln Cys Ser His Phe Asp Ala Met Leu Tyr Lys Gly G1n Leu His Thr Trp Val Pro Val Val Asn Asp Val Asn Pro Cys Glu Leu His Cys Arg Pro Ala Asn Glu Tyr Phe Ala Glu Lys Leu Arg Asp Ala Val Val Asp Gly Thr Pro Cys Tyr Gln Val Arg Ala Ser Arg Asp Leu Cys Ile Asn Gly Ile Cys Lys Asn Val Gly Cys Asp Phe Glu Ile Asp Ser Gly Ala Met Glu Asp Arg Cys Gly Va1 Cys His Gly Asn Gly Ser Thr Cys His Thr Val Ser Gly Thr Phe Glu Glu Ala Glu Gly Leu Gly Tyr Val Asp Val Gly Leu Ile Pro Ala Gly Ala Arg Glu Ile Arg Ile Gln Glu Val Ala Glu Ala Ala Asn Phe Leu Ala Leu Arg Ser Glu Asp Pro Glu Lys Tyr Phe Leu Asn Gly Gly Trp Thr Ile Gln Trp Asn Gly Asp Tyr Gln Val Ala Gly Thr Thr Phe Thr Tyr Ala Arg Arg G1y Asn Trp Glu Asn Leu Thr Ser Pro Gly Pro Thr Lys Glu Pro Val Trp Ile Gln Leu Leu Phe Gln Glu Ser Asn Pro Gly Val His Tyr Glu Tyr Thr Ile His Arg Glu Ala Gly Gly His Asp Glu Val Pro Pro Pro Val Phe Ser Trp His Tyr Gly Pro Trp Thr Lys Cys Thr Val Thr Cys Gly Arg Gly Val Gln Arg Gln Asn Val Tyr Cys Leu Glu Arg Gln Ala Gly Pro Val Asp Glu Glu His Cys Asp Pro Leu Gly Arg Pro Asp Asp Gln Gln Arg Lys Cys Ser Glu Gln Pro Cys Pro Ala Arg Trp Trp Ala Gly Glu Trp Gln Leu Cys Ser Ser Ser Cys Gly Pro Gly Gly Leu Ser Arg Arg Ala Val Leu Cys Ile Arg Ser Val Gly Leu Asp Glu Gln Ser Ala Leu GIu,Pro Pro Ala Cys Glu His Leu Pro Arg Pro Pro Thr Glu Thr Pro Cys Asn Arg His Val Pro Cys Pro Ala Thr,Trp Ala Val Gly Asn Trp Ser Gln Cys Ser Val Thr Cys Gly Glu Gly Thr Gln Arg Arg Asn Val Leu Cys Thr Asn Asp Thr Gly Val Pro Cys Asp Glu Ala Gln Gln Pro Ala Ser Glu Val Thr Cys Sex Leu Pro Leu Cys Arg Trp Pro Leu Gly Thr Leu Gly Pro Glu Gly Ser Gly Ser Gly Ser Ser Ser His Glu Leu Phe Asn Glu Ala Asp Phe I1e Pro His His Leu Ala Pro Arg Pro Ser Pro Ala Ser Sex Pro Lys Pro Gly Thr Met Gly Asn Ala Ile Glu Glu Glu Ala Pro Glu Leu Asp Leu Pro Gly Pro Val Phe Val Asp Asp Phe Tyr Tyr Asp Tyr Asn Phe Ile Asn Phe His Glu Asp Leu Ser Tyr Gly Pro Ser Glu Glu Pro Asp Leu Asp Leu Ala Gly Thr Gly Asp Arg Thr Pro Pro Pro His Ser Arg Pro Ala Ala Pro Ser Thr Gly Ser Pro Val Pro Ala Thr Glu Pro Pro Ala Ala Lys Glu Glu Gly Val Leu Gly Pro Trp Ser Pro Ser Pro Trp Pro Ser Gln Ala Gly Arg Ser Pro Pro Pro Pro Ser Glu Gln Thr Pro Gly Asn Pro Leu Ile Asn Phe Leu Pro Glu Glu Asp Thr Pro Ile Gly Ala Pro Asp Leu Gly Leu Pro Ser Leu Ser Trp Pro Arg Val Ser Thr Asp Gly Leu G1n Thr Pro Ala Thr Pro Glu Ser Gln Asn Asp Phe Pro Val Gly Lys Asp Ser Gln Ser Gln Leu Pro Pro Pro Trp Arg Asp Arg Thr Asn Glu Val Phe Lys Asp Asp Glu Glu Pro Lys Gly Arg Gly Ala Pro His Leu Pro Pro Arg Pro Ser Ser Thr Leu Pro 800. 805 8l0 Pro Leu Ser Pro Val Gly Ser Thr His Ser Ser Pro Ser Pro Asp Val Ala Glu Leu Trp Thr Gly G1y Thr Val Ala Trp Glu Pro Ala Leu Glu Gly Gly Leu Gly Pro Val Asp Ser Glu Leu Trp Pro Thr Val Gly Val Ala Ser Leu Leu Pro Pro Pro Ile Ala Pro Leu Pro Glu Met Lys Val Arg Asp Ser Ser Leu Glu Pro Gly Thr Pro Ser Phe Pro Thr Pro Gly Pro Gly Ser Trp Asp Leu Gln Thr Val Ala Val Trp Gly Thr Phe Leu Pro Thr Thr Leu Thr Gly Leu Gly His 905 910 9~.5 Met Pro Glu Pro Ala Leu Asn Pro GIy Pro Lys Gly Gln Pro Glu Ser Leu Ser Pro Glu Val Pro Leu Ser Ser Arg Leu Leu Ser Thr Pro Ala Trp Asp Ser Pro Ala Asn Ser His Arg Val Pro Glu Thr Gln Pro Leu Ala Pro Ser Leu Ala Glu Ala Gly Pro Pro Ala Asp Pro Leu Val Val Arg Asn Ala Ser Trp Gln Ala Gly Asn Trp Ser Glu Cys Ser Thr Thr Cys Gly Leu Gly A1a Val Trp Arg Pro Val Arg Cys Ser Ser Gly Arg Asp Glu Asp Cys Ala Pro A1a Gly Arg Pro Gln Pro Ala Arg Arg Cys His Leu Arg Pro Cys Ala Thr Trp His Ser Gly Asn Trp Ser Lys Cys Ser Arg Ser Cys Gly Gly Gly Ser Ser Val Arg Asp Val Gln Cys Val Asp Thr Arg Asp Leu Arg Pro Leu Arg Pro Phe His Cys Gln Pro Gly Pro A1a Lys Pro Pro Ala His Arg Pro Cys Gly Ala Gln Pro Cys Leu Ser Trp Tyr Thr 1085 ~ 1090 . 1095 Ser Ser Trp Arg Glu Cys Ser Glu Ala Cys Gly Gly Gly Glu Gln Gln Arg Leu Val Thr Cys Pro Glu Pro Gly Leu Cys Glu Glu Ala Leu Arg Pro Asn Thr Thr Arg Pro Cys Asn Thr His Pro Cys Thr Gln Trp Val Va1 Gly Pro Trp Gly Gln Cys Ser Ala Pro Cys Gly Gly Gly Val Gln Arg Arg Leu Val Lys Cys Val Asn Thr Gln Thr Gly Leu Pro Glu Glu Asp Ser Asp Gln Cys Gly His Glu Ala Trp Pro Glu Ser Ser Arg Pro Cys Gly Thr Glu Asp Cys Glu Pro Val Glu Pro Pro Arg Cys Glu Arg Asp Arg Leu Ser Phe Gly Phe Cys Glu Thr Leu Arg Leu Leu Gly Arg Cys Gln Leu Pro Thr Ile Arg Thr Gln Cys Cys Arg Ser Cys Ser Pro Pro Ser His Gly Ala Pro Ser Arg Gly His Gln Arg Val Ala Arg Arg <210> 24 <211> 911 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 6755002CD1 <400> 24 Met Ala Gln Leu Phe Leu Pro Leu Leu Ala Ala Leu Val Leu Ala Gln Ala Pro Ala Ala Leu Ala Asp Val Leu Glu Gly Asp Ser Ser Glu Asp Arg Ala Phe Arg Val Arg Ile Ala Gly Asp Ala Pro Leu Gln Gly Val Leu Gly G1y Ala Leu Thr Ile Pro Cys His Val His Tyr Leu Arg Pro Pro Pro Ser Arg Arg A1a Val Leu Gly Ser Pro Arg Val Lys Trp Thr Phe Leu Ser Arg Gly Arg Glu Ala Glu Val Leu Val Ala Arg Gly Va1 Arg Val Lys Val Asn Glu Ala Tyr Arg Phe Arg Val Ala Leu Pro Ala Tyr Pro Ala Ser Leu Thr Asp Val Ser Leu Ala Leu Ser Glu Leu Arg Pro Asn Asp Ser Gly Ile Tyr Arg Cys Glu Val Gln His Gly Ile Asp Asp Ser Ser Asp Ala Val Glu Val Lys Val Lys Gly Val Val Phe Leu Tyr Arg Glu Gly Ser Ala Arg Tyr Ala Phe Ser Phe Ser Gly Ala Gln G1u Ala Cys Ala Arg Ile Gly Ala His Ile Ala Thr Pro G1u Gln Leu Tyr Ala Ala Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Ser Asp Gln Thr Val Arg Tyr Pro Ile Gln Thr Pro Arg Glu Ala Cys Tyr Gly Asp Met Asp Gly Phe Pro Gly Val Arg Asn Tyr Gly Val Val Asp Pro Asp Asp Leu Tyr Asp Val Tyr Cys Tyr Ala Glu Asp Leu Asn Gly Glu Leu Phe Leu Gly Asp Pro Pro Glu Lys Leu Thr Leu Glu Glu Ala Arg Ala Tyr Cys Gln Glu Arg Gly Ala Glu Ile Ala 275 ~ 280 285 Thr Thr Gly Gln Leu Tyr Ala Ala Trp Asp Gly Gly Leu Asp His Cys Ser Pro Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Val Thr Pro Ser Gln Arg Cys Gly Gly Gly Leu Pro Gly Val Lys Thr Leu Phe Leu Phe Pro Asn Gln Thr Gly Phe Pro Asn Lys His Ser Arg Phe Asn Val Tyr Cys Phe Arg Asp Ser Ala Gln Pro Ser Ala Ile Pro Glu Ala Ser Asn Pro Ala Ser Asn Pro Ala Ser Asp Gly Leu Glu Ala Ile Val Thr Val Thr Glu Thr Leu Glu G1u Leu Gln Leu Pro Gln Glu Ala Thr Glu Ser Glu Ser Arg Gly Ala Ile Tyr Ser Ile Pro Ile Met Glu Asp Gly Gly Gly G1y Ser Ser Thr Pro Glu Asp Pro Ala Glu Ala Pro Arg Thr Leu Leu Glu Phe Glu 425 430 ' 435 Thr Gln Ser Met Val Pro Pro Thr G1y Phe Ser Glu Glu Glu Gly Lys Ala Leu Glu Glu Glu Glu Lys Tyr Glu Asp Glu Glu Glu Lys Glu Glu Glu G1u Glu Glu Glu Glu Val Glu Asp Glu Ala Leu Trp Ala Trp Pro Ser Glu Leu Ser Ser Pro Gly Pro Glu Ala Ser Leu Pro Thr Glu Pro Ala Ala Gln Glu Lys Ser Leu Ser Gln Ala Pro Ala Arg Ala Val Leu Gln Pro Gly Ala Ser Pro Leu Pro Asp Gly 5l5 520 525 Glu Ser Glu Ala Ser Arg Pro Pro Arg Val His Gly Pro Pro Thr Glu Thr Leu Pro Thr Pro Arg Glu Arg Asn Leu Ala Ser Pro Ser Pro Ser Thr Leu Val Glu Ala Arg Glu Val Gly Glu Ala Thr Gly Gly Pro Glu Leu Ser Gly Val Pro Arg Gly Glu Ser Glu Glu Thr Gly Ser Ser Glu Gly Ala Pro Ser Leu Leu Pro Ala Thr Arg Ala Pro Glu Gly Thr Arg Glu Leu Glu Ala Pro Ser Glu Asp Asn Ser Gly Arg Thr A1a Pro Ala Gly Thr Ser Val Gln Ala Gln Pro Val Leu Pro Thr Asp Ser Ala Ser Arg Gly Gly Val Ala Val Val Pro Ala Ser Gly Asp Cys Val Pro Ser Pro Cys His Asn Gly Gly Thr Cys Leu Glu Glu Glu Glu Gly Val Arg Cys Leu Cys Leu Pro Gly Tyr Gly G1y Asp Leu Cys Asp Val Gly Leu Arg Phe Cys Asn Pro Gly Trp Asp Ala Phe Gln Gly Ala Cys Tyr Lys His Phe Ser Thr 695 ~ 700 705 Arg Arg Ser Trp Glu Glu Ala Glu Thr Gln Cys.Arg Met Tyr Gly Ala His Leu Ala Ser Ile Ser Thr Pro Glu Glu Gln Asp Phe Ile Asn Asn Arg Tyr Arg Glu Tyr Gln Trp Ile Gly Leu Asn Asp Arg Thr Ile Glu Gly Asp Phe Leu Trp Ser Asp Gly Val Pro Leu Leu Tyr Glu Asn Trp Asn Pro Gly Gln Pro Asp Ser Tyr Phe Leu Ser Gly Glu Asn Cys Val Val Met Val Trp His Asp Gln Gly Gln Trp Ser Asp Val Pro Cys Asn Tyr His Leu Ser Tyr Thr Cys Lys Met Gly Leu Val Ser Cys Gly Pro Pro Pro Glu Leu Pro Leu Ala Gln Val Phe Gly Arg Pro Arg Leu Arg Tyr Glu Val Asp Thr Val Leu Arg Tyr Arg Cys Arg Glu Gly Leu Ala Gln Arg Asn Leu Pro Leu Ile Arg Cys Gln Glu Asn Gly Arg Trp Glu Ala Pro Gln Ile Ser Cys Val Pro Arg Arg Pro Ala Arg Ala Leu His Pro Glu Glu Asp Pro'Glu Gly Arg Gln Gly~Arg Leu Leu Gly Arg Trp Lys Ala Leu Leu Ile Pro Pro Ser Ser Pro Met Pro Gly Pro <210> 25 <211> 467 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7350907CD1 <400> 25 Met Pro Gly Arg Trp Arg Trp Gln Arg Asp Met His Pro Ala Arg Lys Leu Leu Ser Leu Leu Phe Leu Ile Leu Met Gly Thr Glu Leu Thr G1n Val Leu Pro Thr Asn Pro Glu Glu Ser Trp Gln Val Tyr Ser Ser Ala Gln Asp Ser Glu Gly Arg Cys Ile Cys Thr Val Val Ala Pro Gln Gln Thr Met Cys Ser Arg Asp Ala Arg Thr Lys Gln Leu Arg Gln Leu Leu Glu Lys Val Gln Asn Met Ser Gln Ser Ile Glu Val Leu Asp Arg Arg Thr Gln Arg Asp Leu Gln Tyr Val Glu Lys Met Glu Asn Gln Met Lys Gly Leu Glu Ser Lys Phe Lys Gln Val Glu Glu Ser His Lys Gln His Leu Ala Arg Gln Phe Lys Ala Ile Lys Ala Lys Met Asp Glu Leu Arg Pro Leu Tle Pro Val Leu Glu Glu Tyr Lys Ala Asp A1a Lys Leu Val Leu Gln Phe Lys Glu Glu Val Gln Asn Leu Thr Ser Val Leu Asn Glu Leu Gln Glu Glu Ile Gly Ala Tyr Asp Tyr Asp Glu Leu Gln Ser Arg Val Ser Asn Leu Glu Glu Arg Leu Arg Ala Cys Met Gln Lys Leu Ala Cys Gly 200 205 ' 210 Lys Leu Thr Gly Ile Ser Asp Pro Val Thr Val Lys Thr Ser Gly Ser Arg Phe Gly Ser Trp Met Thr Asp Pro Leu Ala Pro Glu Gly 230 ' 235 240 Asp Asn Arg Val Trp Tyr Met Asp Gly Tyr His Asn Asn Arg Phe Val Arg Glu Tyr Lys Ser Met Val Asp Phe Met Asn Thr Asp Asn Phe Thr Ser His Arg Leu Pro His Pro Trp Ser Gly Thr Gly Gln Val Val Tyr Asn Gly Ser Ile Tyr Phe Asn Lys Phe Gln Ser His Ile Ile Ile Arg Phe Asp Leu Lys Thr Glu Thr Ile Leu Lys Thr Arg Ser Leu Asp Tyr Ala Gly Tyr Asn Asn Met Tyr His Tyr Ala Trp Gly Gly His Ser Asp Ile Asp Leu Met Val Asp Glu Ser Gly Leu Trp Ala Val Tyr Ala Thr Asn Gln Asn Ala Gly Asn Ile Val Val Ser Arg Leu Asp Pro Val Ser Leu Gln Thr Leu Gln Thr Trp Asn Thr Ser Tyr Pro Lys Arg Ser Ala Gly Glu Ala Phe Ile Ile Cys Gly Thr Leu Tyr Val Thr Asn Gly Tyr Ser'Gly Gly Thr Lys Val His Tyr Ala Tyr Gln Thr Asn Ala Ser Thr Tyr Glu Tyr Ile Asp Ile Pro Phe Gln Asn Lys Tyr Ser His Ile Ser Met Leu Asp Tyr Asn Pro Lys Asp Arg Ala Leu Tyr Ala Trp Asn Asn Gly His Gln Ile Leu Tyr Asn Val Thr Leu Phe His Val Ile Arg Ser Asp Glu Leu <210> 26 <211> 1018 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7474411CD1 <400> 26 Met Val Ser His Phe Met Gly Ser Leu Ser Val Leu Cys Phe Leu Leu Leu Leu Gly Phe Gln Phe Val Cys Pro Gln Pro Ser Thr Gln His Arg Lys Val Pro Gln Arg Met Ala Ala Glu Gly Ala Pro Glu Asp Asp Gly Gly Gly Gly Ala Pro Gly Val Trp Gly Ala Trp Gly Pro Trp Ser Ala Cys Ser Arg Ser Cys Ser Gly Gly Val Met Glu Gln Thr Arg Pro Cys Leu Pro Arg Ser Tyr Arg Leu Arg Gly Gly Gln Arg Pro Gly Ala Pro Ala Arg Ala Phe Ala Asp His Val Val Ser Ala Val Arg Thr Ser Val Pro Leu His Arg Ser Arg Asp Glu Thr Pro Ala Leu Ala Gly Thr Asp Ala Ser Arg Gln Gly Pro Thr 125 130 ~ 135 Val Leu Arg Gly Ser Arg His Pro Gln Pro Gln Gly Leu Glu Val Thr Gly Asp Arg Arg Ser Arg Thr Arg Gly Thr I1e Gly Pro Gly Lys Tyr Gly Tyr Gly Lys Ala Pro Tyr Ile Leu Pro Leu G1n Thr Asp Thr Ala His Thr Pro Gln Arg Leu Arg Arg Gln Lys Leu Ser Ser Arg His Ser Arg Ser Gln Gly A1a Ser Ser Ala Arg His Gly Tyr Ser Ser Pro Ala His Gln Val Pro Gln His Gly Pro Leu Tyr G1n Ser Asp Ser Gly Pro Arg Ser Gly Leu Gln Ala Ala Glu Ala Pro Ile Tyr Gln Leu Pro Leu Thr His Asp Gln Gly Tyr Pro Ala Ala Ser Ser Leu Phe His Ser Pro Glu Thr Ser Asn Asn His Gly Val Gly Thr His Gly Ala Thr Gln Ser Phe Ser Gln Pro Ala Arg Ser Thr Ala Ile Ser Cys Ile Gly Ala Tyr Arg Gln Tyr Lys Leu 290 ~ 295 300 Cys Asn Thr Asn Val Cys Pro Glu Ser Ser Arg Ser Ile Arg Glu Val Gln Cys Ala Ser Tyr Asn Asn Lys Pro Phe Met Gly Arg Phe Tyr G1u Trp Glu Pro Phe Ala Glu Val Lys Gly Asn Arg Lys Cys Glu Leu Asn Cys Gln Ala Met Gly Tyr Arg Phe Tyr Val Arg Gln Ala Glu Lys Val Ile Asp Gly Thr Pro Cys Asp Gln Asn Gly Thr Ala Ile Cys Val Ser Gly Gln Cys Lys Ser Ile Gly Cys Asp Asp Tyr Leu Gly Ser Asp Lys Val Val Asp Lys Cys Gly Val Cys Gly Gly Asp Asn Thr Gly Cys Gln Val Val Ser Gly Val Phe Lys His Ala Leu Thr Ser Leu Gly Tyr His Arg Val Val Glu Ile Pro Glu 425 430 43,5 Gly Ala Thr Lys Ile Asn Ile Thr G1u Met Tyr Lys Ser Asn Asn Tyr Leu Ala Leu Arg Ser Arg Ser Gly Arg Ser Ile Ile Asn Gly 455 . 460 465 Asn Trp Ala Ile Asp Arg Pro Gly Lys Tyr Glu Gly Gly Gly Thr Met Phe Thr Tyr Lys Arg Pro Asn Glu Ile Ser Ser Thr Ala Gly Glu Ser Phe Leu Ala Glu Gly Pro Thr Asn Glu Ile Leu Asp Val Tyr Met Ile His Gln Gln Pro Asn Pro Gly Val His Tyr Glu Tyr Val Ile Met Gly Thr Asn A1a Ile Ser Pro Gln Val Pro Pro His Arg Arg Pro Gly Glu Pro Phe Asn Gly Gln Met Val Thr Glu Gly Arg Ser Gln Glu Glu Gly Glu Gln Lys Gly Arg Asn Glu Glu Lys Glu Asp Leu Arg Gly Glu Ala Pro Glu Met Phe Thr Ser Glu Ser 575 ~ 580 585 Ala Gln Thr Phe Pro Val Arg His Pro Asp Arg Phe Ser Pro His Arg Pro Asp Asn Leu Val Pro Pro Ala Pro Gln Pro Pro Arg Arg Ser Arg Asp His Asn Trp Lys G1n Leu Gly Thr Thr Glu Cys Ser Thr Thr Cys Gly Lys Gly Ser Gln Tyr Pro Ile Phe Arg Cys Val His Arg Ser Thr His Glu Glu Ala Pro Glu Ser Tyr Cys Asp Ser Ser Met Lys Pro Thr Pro Glu Glu Glu Pro Cys Asn Ile Phe Pro Cys Pro Ala Phe Trp Asp Ile Gly Glu Trp Ser G1u Cys Ser Lys Thr Cys Gly Leu Gly Met Gln His Arg Gln Val Leu Cys Arg Gln Val Tyr Ala Asn Arg Ser Leu Thr Val Gln Pro Tyr Arg Cys Gln His Leu Glu Lys Pro Glu Thr Thr Ser Thr Cys Gln Leu Lys Ile Cys Ser Glu Trp Gln Ile Arg Thr Asp Trp Thr Ser Cys Ser Val Pro Cys G1y Val Gly Gln Arg Thr Arg Asp Val Lys Cys Val Ser Asn Ile Gly Asp Va1 Val Asp Asp Glu Glu Cys Asn Met Lys Leu Arg Pro Asn Asp Tle Glu Asn Cys Asp Met Gly Pro Cys Ala Lys Ser Trp Phe Leu Thr Glu Trp Ser Glu Arg Cys Ser Ala Glu Cys Gly Ala Gly Val Arg Thr Arg Ser Val Val Cys Met Thr Asn His Val Ser Ser Leu Pro Leu Glu Gly Cys Gly Asn Asn Arg Pro Ala Glu Ala Thr Pro Cys Asp Asn Gly Pro Cys Thr Gly Lys Val Glu Trp Phe Ala Gly Ser Trp Ser Gln Cys Ser Ile Glu Cys Gly Ser Gly Thr Gln Gln Arg Glu Val Ile Cys Val Arg Lys Asn Ala Asp Thr Phe Glu Val Leu Asp Pro Ser Glu Cys Ser Phe Leu Glu Lys Pro Pro Ser Gln Gln Ser Cys His Leu Lys Pro Cys Gly Ala Lys Trp Phe Ser Thr Glu Trp Ser Met Cys Ser Lys Ser Cys Gln Gly Gly Phe Arg Val Arg Glu Val Arg Cys Leu Ser Asp Asp Met Thr . 935 940 945 Leu Ser Asn Leu Cys Asp Pro G1n Leu Lys Pro Glu Glu Arg Glu Ser Cys Asn Pro G1n Asp Cys Val Pro Glu Val Asp Glu Asn Cys Lys Asp Lys Tyr Tyr Asn Cys Asn Val Val Val Gln Ala Arg Leu Cys Val Tyr Asn Tyr Tyr Lys Thr Ala Cys Cys Ala Ser Cys Thr Arg Val Ala Asn Arg Gln Thr Gly Phe Leu Gly Ser Arg <210> 27 <211> 1458 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4755911CD1 <400> 27 Met Gly Lys Glu Gln Glu Leu Val Gln Ala Val Lys Ala Glu Asp l 5 10 15 Val Gly Thr Ala Gln Arg Leu Leu Gln Arg Pro Arg Pro Gly Lys Ala Thr Arg Ser Leu Pro Gly Gly Arg Arg Arg Trp Met Asp Gly Arg Val Asp Gln Pro Arg Val Arg Leu Arg Thr Tyr Ser Arg Val Ser Val Ser Gly His Leu Cys G1y His Gly Gln Gly Ser A1a Glu Leu Leu Gly Ser Thr Lys Lys Ile Asn Val Asn Phe Gln Asp Pro Asp Gly Val Gly Phe Gly Val Lys Gly Gln Leu Pro Ala Ser Pro Arg Pro Pro Gly Met Arg Pro Leu His Tyr Ala Ala Trp Gln Gly Arg Lys Glu Pro Met Lys Leu Val Leu Lys Ala Gly Ser Ala Val Asn Ile Pro Ser Asp Glu Gly His Ile Pro Leu His Leu Ala AIa Gln His Gly His Tyr Asp Val Ser Glu Met Leu Leu Gln His Gln Ser Asn Pro Cys Met Val Asp Asn Ser Gly Lys Thr Pro Leu Asp Leu Ala Cys Glu Phe Gly Arg Val Gly Val Val Gln Leu Leu Leu Ser Ser Asn Met Cys Ala Ala Leu Leu Glu Pro Arg Pro Gly Asp Ala Thr Asp Pro Asn Gly Thr Ser Pro Leu His Leu Ala Ala Lys Asn Gly His Ile Asp Ile Ile Arg Leu Leu Leu Gln Ala Gly Ile Asp Ile Asn Arg Gln Thr Lys Ser Gly Thr Ala Leu His Glu A1a Ala Leu Cys Gly Lys Thr Glu Val Val Arg Leu Leu Leu Asp Ser Gly Ile Asn Ala His Val Arg Asn Thr Tyr Ser Gln Thr Ala Leu Asp Ile Val His Gln Phe Thr Thr Ser Gln Ala Ser Arg Glu Ile Lys Gln Leu Leu Arg Glu Ala Ser Ala Ala Leu Gln Val Arg Ala Thr Lys Asp Tyr Cys Asn Asn Tyr Asp Leu Thr Ser Leu Asn Val Lys Ala Gly Asp I1e Ile Thr Val Leu Glu Gln His Pro Asp Gly Arg Trp Lys Gly Cys Ile His Asp Asn Arg Thr G1y Asn Asp Arg Val Gly Tyr Phe Pro Ser Ser Leu Gly Glu Ala Ile Val Lys Arg Ala Gly Ser Arg A1a Gly Thr Glu Pro Ser Leu Pro Gln Gly Ser Ser Ser Ser Gly Pro Ser Ala Pro Pro Glu Glu Ile Trp Val Leu Arg Lys Pro Phe Ala Gly Gly Asp Arg Ser Gly Ser Ile Ser Gly Met Ala Gly Gly Arg Gly Ser Gly Gly His Ala Leu His Ala Gly Ser Glu Gly Val Lys Leu Leu Ala Thr Val Leu Ser Gln Lys Ser Val Ser Glu Ser Gly Pro G1y Asp Ser Pro Ala Lys Pro Pro Glu Gly Ser Ala Gly Val Ala Arg Ser Gln Pro Pro Val A1a His Ala Gly Gln Val Tyr Gly G1u Gln Pro Pro Lys Lys Leu Glu Pro.Ala Ser Glu Gly Lys Ser Ser Glu Ala Va1 Ser Gln Trp Leu Thr Ala Phe Gln Leu Gln Leu Tyr A1a Pro Asn Phe Ile Ser Ala Gly Tyr Asp Leu Pro Thr Ile Ser Arg Met Thr Pro Glu Asp Leu Thr Ala Ile Gly Val Thr Lys Pro Gly His Arg Lys Lys Ile Ala Ala Glu Ile Ser Gly Leu Ser Ile Pro Asp Trp Leu Pro Glu His Lys Pro A1a Asn Leu Ala Val Trp Leu Ser Met Ile Gly Leu Ala Gln Tyr Tyr Lys Val Leu Val Asp Asn Gly Tyr Glu Asn Ile Asp Phe Ile Thr Asp Ile Thr Trp Glu Asp Leu Gln Glu Ile Gly Ile Thr Lys Leu Gly His Gln Lys Lys Leu Met Leu Ala Val Arg Lys Leu Ala Glu Leu Gln Lys Ala Glu Tyr Ala Lys Tyr Glu Gly Gly Pro Leu Arg Arg Lys Ala Pro Gln~Ser Leu Glu Val Met Ala Ile Glu Ser Pro Pro Pro Pro Glu Pro Thr Pro Ala Asp Cys Gln Ser Pro Lys Met Thr Thr Phe Gln Asp Ser Glu Leu Ser Asp Glu Leu Gln Ala Ala Met Thr Gly Pro Ala Glu Val Gly Pro Thr Thr Glu Lys Pro Ser Ser His Leu Pro Pro Thr Pro Arg Ala Thr Thr Arg Gln Asp Ser Ser Leu Gly Gly Arg Ala Arg His Met Ser Ser Sex Gln Glu Leu Leu Gly Asp Gly Pro Pro Gly Pro Ser Ser Pro Met Ser Arg Ser Gln Glu Tyr Leu Leu Asp Glu Gly Pro Ala Pro Gly Thr Pro Pro Arg Glu Ala Arg Pro Gly~Arg His Gly His Ser Ile Lys Arg 770 ~ 775 780 Ala Ser Val Pro Pro Val Pro G1y Lys Pro Arg Gln Val Leu Pro Pro Gly Thr Ser His Phe Thr Pro Pro Gln Thr Pro Thr Lys Thr Arg Pro Gly Ser Pro Gln Ala Leu Gly Gly Pro His Gly Pro Ala Pro Ala Thr Ala Lys Val Lys Pro Thr Pro Gln Leu Leu Pro Pro Thr Glu Arg Pro Met Ser Pro Arg Ser Leu Pro Gln Ser Pro Thr His Arg Gly Phe Ala Tyr Val Leu Pro Gln Pro Val Glu Gly G1u Val Gly Pro Ala Ala Pro Gly Pro Ala Pro Pro Pro Val Pro Thr Ala Val Pro Thr Leu Cys Leu Pro Pro Glu Ala Asp Ala Glu Pro Gly Arg Pro Lys Lys Arg Ala His Ser Leu Asn Arg Tyr Ala Ala Ser Asp Ser Glu Pro Glu Arg Asp Glu Leu Leu Val Pro Ala Ala Ala Gly Pro Tyr Ala Thr Val Gln Arg Arg Val Gly Arg Ser His Ser Val Arg Ala Pro Ala Gly Ala Asp Lys Asn Val Asn Arg Ser Gln,Ser Phe Ala Val Arg Pro Arg Lys Lys Gly Pro Pro Pro Pro Pro Pro Lys Arg Ser Ser Ser Ala Leu Ala Ser Ala Asn Leu Ala Asp Glu Pro Val Pro Asp Ala Glu Pro Glu Asp Gly Leu Leu Gly Val Arg Ala Gln Cys Arg Arg Ala Ser Asp Leu Ala Gly Ser Val Asp Thr Gly Ser Ala Gly Ser Val Lys Ser Ile Ala Ala Met Leu Glu Leu Ser Ser Ile Gly Gly Gly Gly Arg Ala Ala Arg Arg Pro 1040 ' 1045 1050 Pro Glu Gly His Pro Thr Pro Arg Pro Ala Ser Pro Glu Pro Gly Arg Val Ala Thr Val Leu Ala Ser Val Lys His Lys Glu Ala Ile Gly Pro Gly Gly Glu Val Val Asn Arg Arg Arg Thr Leu Ser Gly Pro Val Thr G1y Leu Leu Ala Thr Ala Arg Arg Gly Pro Gly Glu Ser~Ala Asp Pro Gly Pro Phe Val Glu Asp G1y Thr Gly Arg Gln Arg Pro Arg Gly Pro Ser Lys Gly Glu Ala Gly Val Glu Gly Pro Pro Leu Ala Lys Val Glu Ala Ser Ala Thr Leu Lys Arg Arg Ile Arg Ala Lys Gln Asn Gln Gln Glu Asn Val Lys Phe Ile Leu Thr Glu Ser Asp Thr Val Lys Arg Arg Pro Lys Ala Lys Glu Arg Glu Ala Gly Pro Glu Pro Pro Pro Pro Leu Ser Val Tyr His Asn Gly Thr Gly Thr Val Arg Arg Arg Pro A1a Ser Glu Gln Ala Gly Pro Pro Glu Leu Pro Pro Pro Pro Pro Pro Ala Glu Pro Pro Pro Thr Asp Leu Ala His Leu Pro Pro Leu Pro Pro Pro Glu Gly Glu Ala Arg Lys Pro Ala Lys Pro Pro Val Ser Pro Lys Pro Val Leu Thr Gln Pro Val Pro Lys Leu Gln Gly Ser Pro Thr Pro Thr Ser Lys Lys Val Pro Leu Pro Gly Pro Gly Ser Pro Glu Val Lys Arg Ala His Gly Thr Pro Pro Pro Val Ser Pro Lys Pro Pro Pro Pro Pro Thr Ala Pro Lys Pro Val Lys Ala Val Ala Gly Leu Pro Ser Gly Ser Ala Gly Pro Ser Pro Ala Pro Ser Pro Ala Arg Gln Pro Pro Ala Ala Leu Ala Lys Pro Pro Gly Thr Pro Pro Ser Leu Gly Ala Ser Pro Ala Lys Pro Pro Ser Pro Gly Ala Pro Ala Leu His Val Pro Ala Lys Pro Pro Arg Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Pro Pro A1a Pro Pro Glu Gly Ala Ser Pro Gly Asp Ser Ala Arg Gln Lys Leu Glu Glu Thr Ser Ala Cys Leu Ala Ala Ala Leu Gln Ala Va1 Glu Glu Lys Ile Arg Gln Glu Asp Ala Gln Gly Pro Arg Asp Ser Ala Ala Glu Lys Ser Thr Gly Ser Ile Leu Asp Asp Ile Gly Ser Met Phe Asp Asp Leu Ala Asp Gln Leu Asp Ala Met Leu Glu <210> 28 <211> 323 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 379766CD1 <400> 28 Met Ala Ser Trp Thr Ser Pro Trp Trp Val Leu Ile Gly Met Val Phe Met His Ser Pro Leu Pro Gln Thr Thr Ala Glu Lys Ser Pro Gly Ala Tyr Phe Leu Pro Glu Phe Ala Leu Ser Pro Gln G1y Ser Phe Leu Glu Asp Thr Thr Gly Glu Gln Phe Leu Thr Tyr Arg Tyr Asp Asp Gln Thr Ser Arg Asn Thr Arg Ser Asp Glu Asp Lys Asp Gly Asn Trp Asp Ala Trp Gly Asp Trp Ser Asp Cys Ser Arg Thr Cys Gly Gly Gly Ala Ser Tyr Ser Leu Arg Arg Cys Leu Thr Gly Arg Asn Cys Glu Gly Gln Asn Ile Arg Tyr Lys Thr Cys Ser Asn His Asp Cys Pro Pro Asp Ala Glu Asp Phe Arg Ala Gln G1n Cys Ser Ala Tyr Asn Asp Val Gln Tyr Gln Gly Arg Tyr Tyr G1u Trp Leu Pro Arg Tyr Asn Asp Pro Ala Ala Pro Cys Ala Leu Lys Cys His Ala Gln Gly Gln Asn Leu Val Val Glu Leu Ala Pro Lys Val Leu Asp Gly Thr Arg Cys Asn Thr Asp Ser Leu Asp Met Cys Ile Ser Gly Ile Cys Gln Ala Val Gly Cys Asp Arg Gln Leu Gly Ser Asn Ala Lys Glu Asp Asn Cys Gly Val Cys Ala Gly Asp Gly Ser Thr Cys Arg Leu Val Arg Gly Gln Ser Lys Ser His Val Ser Pro Glu Lys Arg Glu Glu Asn Val Ile Ala Val Pro Leu Gly Ser Arg Ser Val Arg Ile Thr Val Lys Gly Pro Ala Tyr Pro Val Ala Trp Ala Leu Ala Ile Ser Ser Asn Thr Asn Cys Leu Va1 Leu Leu Cys Lys Ala Asn Leu Ala Ser Ser Gly Pro Tyr Phe Ala Leu Ile Pro Val Asn Pro Thr Thr Met Ala Leu Asn Thr Ala Ile Val Ser Gln Ser Ala Val Leu Ile Asp Cys Leu <210> 29 <211> 234 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 553744CD1 <400> 29 Met Met Ile His Ser Cys Leu Phe Ser Pro Phe His Ile Ala Phe Ser Thr Pro Ala Ser Gln Leu Phe Ser Pro His Gly Ser Asn Pro Ser Thr Pro Ala Ala Thr Pro Val Pro Thr Ala Ser Pro Val Lys Ala I1e Asn His Pro Ser Ala Ser Ala Ala Ala Thr Val Ser Gly Met Asn Leu Leu Asn Thr Val Leu Pro Val Phe Pro Gly Gln Val Ser Ser Ala Val His Thr Pro Gln Pro Ser Ile Pro Asn Pro Thr Val Ile Arg Thr Pro Ser Leu Pro Thr Ala Pro Val Thr Ser Ile His Ser Thr Thr Thr Thr Pro Val Pro Ser Ile Phe Ser Gly Leu 1l0 115 120 Val Ser Leu Pro Gly Pro Ser Ala Thr Pro Thr Ala Ala Thr Pro Thr Pro Gly Pro Thr Pro Arg Ser Thr Leu Gly Ser Ser Glu Ala Phe Ala Ser Thr Ser Ala Pro Phe Thr Ser Leu Pro Phe Ser Thr Ser Ser Ser Ala Ala Ser Thr Ser Asn Pro Asn Ser Ala Ser Leu Ser Ser Val Phe Ala Gly Leu Pro Leu Pro Leu Pro Pro Thr Ser 185 ~ 190 195 Gln Gly Leu Ser Asn Pro Thr Pro Val Ile Ala Gly Gly Ser Thr Pro Ser Val Ala Gly Pro Leu Gly Val Asn Ser Pro Ser Phe Val Cys Val Lys Arg Phe Ser Asp Ile Gln <210> 30 <211> 377 <212> PRT
<213> Homo sapiens <220>
<221> misc-feature <223> Incyte ID No: 1825473CD1 <400> 30 Met Lys Thr Leu Pro Leu Phe Val Cys Ile Cys Ala Leu Ser Ala Cys Phe Ser Phe Ser Glu Gly Arg Glu Arg Asp His Glu Leu Arg His Arg Arg His His His Gln Ser Pro Lys Ser His Phe Glu Leu Pro His Tyr Pro Gly Leu Leu Ala His Gln Lys Pro Phe Ile Arg Lys Ser Tyr Lys Cys Leu His Lys Arg Cys Arg Pro Lys Leu Pro 65 ' 70 75 Pro Ser Pro Asn Asn Pro Pro Lys Phe Pro Asn Pro His Gln Pro Pro Lys His Pro Asp Lys Asn Ser Ser Val Val Asn Pro Thr Leu Val Ala Thr Thr Gln Ile Pro Ser Val Thr Phe Pro Ser Ala Ser Thr Lys Ile Thr Thr Leu Pro Asn Va1 Thr Phe Leu Pro Gln Asn Ala Thr Thr Ile Ser Ser Arg Glu Asn Val Asn Thr Ser Ser Ser Val Ala Thr Leu Ala Pro Val Asn Ser Pro Ala Pro Gln Asp Thr Thr Ala Ala Pro Pro Thr Pro Ser A1a Thr Thr Pro Ala Pro Pro Ser Ser Ser Ala Pro Pro G1u Thr Thr Ala Ala Pro Pro Thr Pro Ser Ala Thr Thr Gln Ala Pro Pro Ser Ser Ser Ala Pro Pro Glu Thr Thr A1a Ala Pro Pro Thr Pro Pro Ala Thr Thr Pro Ala Pro Pro Ser Ser Ser Ala Pro Pro Glu Thr Thr Ala Ala Pro Pro Thr Pro Ser Ala Thr Thr Pro Ala Pro Leu Ser Ser Ser Ala Pro Pro Glu Thr Thr Ala Val Pro Pro Thr Pro Ser Ala Thr Thr Leu Asp Pro Ser Ser Ala Ser Ala Pro Pro Glu Thr Thr Ala Ala Pro Pro Thr Pro Ser Ala Thr Thr Pro Ala Pro Pro Ser Ser Pro Ala Pro Gln Glu Thr Thr Ala Ala Pro Ile Thr Thr Pro Asn Ser Ser Pro Thr Thr Leu Ala Pro Asp Thr Ser Glu Thr Ser Ala Ala Pro Thr His Gln Thr Thr Thr Ser Va1 Thr Thr Gln Thr Thr Thr Thr Lys Gln Pro Thr Ser Ala Pro Gly Gln Asn Lys Ile Ser Arg Phe Leu Leu Tyr Met Lys Asn Leu Leu Asn Arg Ile Ile Asp Asp Met Val Glu Gln <210> 31 <211> 833 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 7950094CD1 <400> 31 Met Ala Pro His Trp Ala Val Trp Leu Leu Ala Ala Arg Leu Trp Gly Leu Gly Ile Gly Ala Glu Val Trp Trp Asn Leu Val Pro Arg Lys Thr Val Ser Ser Gly Glu Leu Ala Thr Val Val Arg Arg Phe Ser Gln Thr Gly Ile Gln Asp Phe Leu Thr Leu Thr Leu Thr Glu Pro Thr Gly Leu Leu Tyr Val Gly Ala Arg Glu Ala Leu Phe Ala Phe Ser Met Glu Ala Leu Glu Leu Gln Gly AIa Ile Ser Trp Glu Ala Pro Val Glu Lys Lys Thr Glu Cys Ile Gln Lys Gly Lys Asn Asn Gln Thr Glu Cys Phe Asn Phe Ile Arg Phe Leu Gln Pro Tyr Asn Ala Ser His Leu Tyr Val Cys Gly Thr Tyr Ala Phe Gln Pro Lys Cys Thr Tyr Val Asn Met Leu Thr Phe Thr Leu G1u His Gly 140° 145 150 Glu Phe Glu Asp Gly Lys Gly Lys Cys Pro Tyr Asp Pro Ala Lys Gly His Ala Gly Leu Leu Val Asp Gly Glu Leu Tyr Ser Ala Thr Leu Asn Asn Phe Leu Gly Thr Glu Pro Ile Ile Leu Arg Asn Met Gly Pro His His Ser Met Lys Thr Glu Tyr Leu Ala Phe Trp°Leu Asn Glu Pro His Phe Val Gly Ser Ala Tyr Val Pro Glu Ser Val Gly Ser Phe Thr Gly Asp Asp Asp Lys Val Tyr Phe Phe Phe Arg Glu Arg Ala Val Glu Ser Asp Cys Tyr Ala Glu Gln Val Val Ala Arg Val Ala Arg Va1 Cys Lys Gly Asp Met Gly Gly Ala Arg Thr Leu Gln Arg Lys Trp Thr Thr Phe Leu Lys Ala Arg Leu Ala Cys Ser Ala Pro Asn Trp Gln Leu Tyr Phe Asn Gln Leu Gln Ala Met His Thr Leu Gln Asp Thr Ser Trp His Asn Thr Thr Phe Phe Gly Val Phe Gln Ala Gln Trp Gly Asp Met Tyr Leu Ser Ala Ile Cys Glu Tyr Gln Leu Glu Glu Ile Gln Arg Val Phe Glu Gly Pro Tyr Lys Glu Tyr His Glu Glu Ala Gln Lys Trp Asp Arg Tyr Thr Asp Pro Val Pro Ser Pro Arg Pro Gly Ser Cys Ile Asn Asn Trp His Arg Arg His Gly Tyr Thr Ser Ser Leu Glu Leu Pro Asp Asn Ile Leu Asn Phe Val Lys'Lys His Pro Leu Met Glu Glu Gln Val Gly Pro Arg Trp Ser Arg Pro Leu Leu Val Lys Lys Gly Thr Asn Phe Thr His Leu Val Ala Asp Arg Val Thr Gly Leu Asp Gly Ala Thr Tyr Thr Val Leu Phe Ile Gly Thr Gly Asp Gly Trp Leu Leu Lys Ala Val Ser Leu Gly Pro Trp Val His Leu Ile Glu Glu Leu Gln Leu Phe Asp Gln Glu Pro Met Arg Ser Leu Val Leu Ser Gln Ser Lys Lys Leu Leu Phe Ala Gly Ser Arg Ser Gln Leu Val Gln Leu Pro Val Ala Asp Cys Met Lys Tyr Arg Ser Cys A1a Asp Cys Val Leu Ala Arg Asp Pro Tyr Cys Ala Trp Ser Val Asn Thr Ser Arg Cys Va1 Ala Va1 Gly Gly His Ser Gly Ser Leu Leu Ile Gln His Val Met Thr Ser Asp Thr Ser Gly Ile Cys Asn Leu Arg Gly Ser Lys Lys Val Arg Pro Thr Pro Lys Asn Ile Thr Val Val Ala Gly Thr Asp Leu Val Leu Pro Cys His Leu Ser Ser Asn Leu Ala His Ala Arg Trp Thr Phe Gly Gly Arg Asp Leu Pro Ala G1u Gln Pro Gly Ser Phe Leu Tyr Asp Ala Arg Leu Gln Ala Leu Val Val Met Ala Ala Gln Pro Arg His Ala Gly Ala Tyr His Cys Phe Ser G1u Glu Gln Gly Ala Arg Leu Ala Ala Glu Gly Tyr Leu Val Ala Val Val Ala Gly Pro Ser Val Thr Leu Glu Ala Arg Ala Pro Leu Glu Asn Leu Gly Leu Val Trp Leu Ala Val Val Ala Leu Gly Ala Val Cys Leu Val Leu Leu Leu Leu Val Leu Ser Leu Arg Arg Arg Leu Arg Glu Glu Leu Glu Lys Gly Ala Lys Ala Thr Glu Arg Thr Leu Val Tyr Pro Leu Glu Leu Pro Lys Glu Pro Thr Ser Pro Pro Phe Arg Pro Cys Pro Glu Pro Asp G1u Lys Leu Trp Asp Pro Val Gly 725 730 ~ 735 Tyr Tyr Tyr Ser Asp Gly Ser Leu Lys Ile Val Pro Gly His Ala Arg Cys Gln Pro Gly Gly Gly Pro Pro Ser Pro Pro Pro Gly Ile Pro Gly Gln Pro Leu Pro Ser Pro Thr Arg Leu His Leu Gly Gly Gly Arg Asn Ser Asn Ala Asn Gly Tyr Val Arg Leu Gln Leu Gly Gly Glu Asp Arg Gly Gly Leu Gly His Pro Leu Pro Glu Leu Ala Asp Glu Leu Arg Arg Lys Leu Gln Gln Arg Gln Pro Leu Pro Asp Ser Asn Pro Glu Glu Ser Ser Val <210> 32 <211> 1291 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 7479484CD1 <400> 32 Met Phe Arg Pro Thr Thr Val Ala Val Asp Glu Asp Gly Gly Glu Glu Asp Lys Asp Glu Ser Ser Thr Asn Ser Gly A1a Ser Ala Val Ser Ser Cys Gly Phe Gly A1a Asp Phe Ser Thr Asp Lys Gly Gly Ser Phe Thr Ser Val G1n Ile Thr Asn Thr Thr Gly Leu Ser Gln A1a Pro Gly Leu Ala Ser Gln Gly Ile Ser Phe Gly Ile Lys Asn Asn Leu Gly Pro Pro Leu GIn Lys Leu Gly Val Ser Phe Ser Phe Ala Lys Lys Ala Pro Val Lys Leu Glu Ser Ile Ala Ser Val Phe Lys Asp His Ala Glu Glu Gly Ser Ser G1u Asp Gly Thr Lys Ala 110 115 l20 Asp Glu Lys Ser Ser Asp Gln Gly Val Gln Lys Val Gly Asp Thr 125 l30 l35 Asp Gly Thr Gly Asn Leu Asp Gly Lys Lys Glu Asp Glu Asp Pro Gln Asp Gly Gly Ser Leu Ala Ser Thr Leu Ser Lys Leu Lys Arg Met Lys Arg Glu Glu Gly Thr Gly Ala Thr Glu Pro Glu Tyr Tyr His Tyr Ile Pro Pro Ala His Cys Lys Val Lys Pro Asn Phe Pro Phe Leu Leu Phe Met Arg Ala Ser Glu Gln Met Glu Gly Asp His Ser Ala His Ser Lys Ser Ala Pro Glu Asn Arg Lys Ser Ser Ser Pro Lys Pro Gln Gly Cys Ser Lys Thr Ala Ala Ser Pro Gly Ala GIu Arg Thr Val Ser Glu Ala Ser Glu Leu Gln Lys Glu Ala Ala Val Ala Gly Pro Ser Glu Pro Gly Gly Lys Thr Glu Thr Lys Lys GIy Ser Gly Gly Gly Glu Asp Glu Gln Ser Val Glu Ser Arg Glu Thr Ser Glu Ser Pro Met Cys Glu Ser Asn Pro Lys Asp Ile Ser Gln Ala Thr Pro Ala Thr Lys Ala Gly Gln Gly Pro Lys His Pro Thr Gly Pro Phe Phe Pro Val Leu Ser Lys Asp Glu Ser Thr Ala Leu Gln Trp Pro Ser Glu Leu Leu Ile Phe Thr Lys Ala Glu Pro Ser Ile Ser Tyr Ser Cys Asn Pro.Leu Tyr Phe Asp Phe Lys Leu Ser Arg Asn Lys Asp Ala Lys AIa Lys Gly Thr GIu Lys Pro Lys Asp Val Ala Gly Ser Ser Lys Asp His Leu Gln Ser Leu Asp Pro Arg Glu Pro Asn Lys Ser Gln Glu Glu Glu Gln Asp Val Val Leu Ser Ser Glu Gly Arg Val Asp Glu Pro Ala Ser G1y Ala Ala Cys Ser Ser Leu Asn Lys G1n Glu Pro Gly Gly Ser His Met Ser Glu Thr Glu Asp Thr Gly Arg Ser His Pro Ser Lys Lys Glu Pro Ser Gly Lys Ser His Arg His Lys Lys Lys Lys Lys His Lys Lys Ser Ser Lys His Lys Arg Lys His Lys Ala Asp Thr Glu Glu Lys Ser Ser Lys Ala Glu Ser Gly Glu Lys Ser Lys Lys Arg Lys Lys Arg Lys Arg Lys Lys Asn Lys Ser Ser Ala Ala Ala Asp Ser Glu Arg Gly Pro Lys Ser G1u Pro Pro Gly Ser Gly Sex Pro Ala Pro Pro Arg Arg Arg Arg Arg Ala Gln Asp Asp Ser Gln Arg Arg Ser Leu Pro Ala Glu Glu Gly Asn Ser Gly Lys Lys Asp Asp Gly Gly Gly Gly Ser Ser Cys Gln Asp His Ser Gly Arg Lys His Lys Gly Glu Pro Pro Thr Ser Ser Cys Gln Arg Arg Ala Asn Thr Lys His Ser Ser Arg Ser Ser His Arg Ser Gln Pro Ser Ser Gly Asp Glu Asp Ser Asp Asp Ala Ser Ser His Arg Leu His Gln Lys Ser Pro Ser Gln Tyr Ser Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Asp Glu Asp Ser Gly Ser Glu His Ser Arg Ser Arg Ser Arg Ser Gly His Arg His Ser Ser His Arg Ser Ser Arg Arg Ser Tyr Ser Ser Ser Ser Asp Ala Ser Ser Asp Gln Ser Cys Tyr Ser Arg Gln His Ser Tyr Ser Asp Asp Ser Tyr Ser Asp Tyr Ser Asp Arg 680 685 ~ 690 Ser Arg Arg His Ser Lys Arg Ser His Asp Ser Asp Asp Ser Asp Tyr Thr Ser Ser Lys His Arg Ser Lys Arg His Lys Tyr Ser Ser Ser Asp Asp Asp Tyr Ser Leu Ser Cys Ser Gln Ser Arg Ser Arg Ser Arg Ser His Thr Arg Glu Arg Ser Arg Ser Arg Gly Arg Ser Arg Ser Ser Ser Cys Ser Arg Ser Arg Ser Lys Arg Arg Ser Arg Ser Thr Thr Ala His Ser Trp Gln Arg Ser Arg Ser Tyr Ser Arg Asp Arg Ser Arg Ser Thr'Arg Ser Pro Ser Gln Arg Ser Gly Ser Arg Lys Gly Ser Trp Gly His Glu Ser Pro Glu Glu Arg Arg Ser Gly Arg Arg Asp Phe Ile Arg Ser Lys Ile Tyr Arg Ser Gln Ser Pro His Tyr Phe Gln Ser Gly Arg Gly Glu Gly Pro Gly Lys Lys Glu Asp Gly Arg Gly Asp Asp Ser Lys Gly Ala Gly Leu Pro Ser Gln Asn Ser Asn Thr Gly Thr Gly Arg Gly Ser Glu Ser Asp Cys Ser Pro Glu Asp Lys Asn Ser Val Thr Ala Arg Leu Leu Leu Glu Lys Ile Gln Ser Arg Lys Val Glu Arg Lys Pro Asn Val Cys Glu Glu Val Leu Ala Thr Pro Asn Lys Ala Gly Leu Lys Tyr Lys Asn Pro Pro Gln Gly Tyr Phe Gly Pro Lys Leu Pro Pro Ser Leu Gly Asn Lys Pro Val Leu Pro Met.Ile Gly Lys Leu Pro Ala Thr Arg Lys Ser Asn Lys Lys Cys Glu Glu Ser Gly Leu Glu Arg Gly G1u Glu Gln Glu His Ser Glu Pro Glu Glu Gly Ser Pro Arg Ser Ser Asp Ala Pro Phe Gly His Gln Phe Ser Glu Glu Ala Ala Gly Pro Leu Ser Asp Pro Pro Pro Glu Glu Pro Lys Ser Glu Glu Ala Thr Ala Asp His Ser Va1 Ala Pro Leu Gly Thr Pro Ala His Thr Asp Cys Tyr Pro Gly Asp Pro Ala Ile Ser His Asn Tyr Leu Pro Asp Pro Ser Asp Gly Asp Thr Leu Glu Ser Leu Asp Ser Gly Ser Gln Pro Gly Pro Val Glu Ser Ser Leu Leu Pro Ile Ala Pro Asp Leu Glu His Phe Pro Asn Tyr Ala Pro Pro Ser Gly Glu Pro Ser Ile Glu Ser Thr Asp Gly Thr Glu Asp Ala Ser Leu Ala Pro Leu Glu Ser Gln Pro Ile Thr Phe Thr Pro Glu Glu Met Glu Lys Tyr Ser Lys Leu Gln Gln Ala Ala Gln Gln His Ile Gln Gln Gln Leu Leu Ala Lys Gln Val Lys Ala Phe Pro Ala Ser Thr Ala Leu Ala Pro . 2130 1135 1140 Ala Thr Pro Ala Leu Gln Pro Ile His Ile Gln Gln Pro Ala Thr Ala Ser Ala Thr Ser Ile Thr Thr Val Gln His Ala Ile Leu Gln His His Ala Ala Ala Ala Ala Ala Ala Ile Gly Ile His Pro His Pro His Pro Gln Pro Leu Ala Gln Val His His Ile Pro Gln Pro His Leu Thr Pro Ile Ser Leu Ser His Leu Thr His Ser Ile Ile 1205 . 1210 1215 Pro Gly His Pro Ala Thr Phe Leu Ala Ser His Pro Ile His TIe Ile Pro Ala Ser Ala Ile His Pro Gly Pro Phe Thr Phe His Pro Val Pro His Ala Ala Leu Tyr Pro Thr Leu Leu Ala Pro Arg Pro Ala Ala Ala Ala Ala Thr Ala Leu His Leu His Pro Leu Leu His Pro IIe Phe Ser Gly Gln Asp Leu Gln His Pro Pro Ser His Gly Thr <210> 33 <211> 736 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 6780147CD1 <400> 33 Met Ala Val Arg Ala Leu Lys Leu Leu Thr Thr Leu Leu Ala Val Val Ala Ala Ala Ser~Gln Ala Glu Val Glu Ser Glu Ala G1y Trp Gly Met Val Thr Pro Asp Leu Leu Phe Ala Glu Gly Thr Ala Ala Tyr Ala Arg Gly Asp Trp Pro Gly Val Val Leu Ser Met Glu Arg Ala Leu Arg Ser Arg Ala Ala Leu Arg A1a Leu Arg Leu Arg Cys Arg Thr Gln Cys Ala Ala Asp Phe Pro Trp Glu Leu Asp Pro Asp Trp Ser Pro Ser Pro A1a Gln Ala Ser Gly Ala Ala Ala Leu Arg Asp Leu Ser Phe Phe Gly Gly Leu Leu Arg Arg Ala Ala Cys Leu l10 115 120 Arg Arg Cys Leu Gly Pro Pro Ala Ala His Ser Leu Ser Glu Glu Met Glu~Leu Glu Phe Arg Lys Arg Ser Pro Tyr Asn Tyr Leu Gln 140 ~ 145 150 Val Ala Tyr Phe Lys Ile Asn Lys Leu Glu Lys Ala Val Ala Ala Ala His Thr Phe Phe Val Gly Asn Pro Glu His Met Glu Met Gln Gln Asn Leu Asp Tyr Tyr Gln Thr Met Ser Gly Val Lys Glu Ala Asp Phe Lys Asp Leu Glu Thr Gln Pro His Met Gln Glu Phe Arg Leu Gly Val Arg Leu Tyr Ser Glu Glu Gln Pro Gln Glu Ala Val Pro His Leu Glu A1a Ala Leu Gln Glu Tyr Phe Val Ala Tyr Glu Glu Cys Arg Ala Leu Cys Glu Gly Pro Tyr Asp Tyr Asp Gly Tyr Asn Tyr Leu Glu Tyr Asn Ala Asp Leu Phe Gln Ala Ile Thr Asp His Tyr Ile Gln Val Leu Asn Cys Lys Gln Asn Cys Val Thr Glu Leu Ala Ser His Pro Ser Arg Glu Lys Pro Phe Glu Asp Phe Leu Pro Ser His Tyr Asn Tyr Leu Gln Phe A1a Tyr Tyr Asn Ile Gly Asn Tyr Thr Gln Ala Val Glu Cys Ala Lys Thr Tyr Leu Leu Phe Phe Pro Asn Asp Glu Val Met Asn Gln Asn Leu Ala Tyr Tyr A1a Ala Met Leu Gly Glu Glu His Thr Arg Ser Ile Gly Pro Arg Glu Ser Ala Lys Glu Tyr Arg Gln Arg Ser Leu Leu Glu Lys Glu Leu Leu Phe Phe Ala Tyr Asp Val Phe Gly I1e Pro Phe Val Asp Pro Asp Ser Trp Thr Pro G1u Glu Val Ile Pro Lys Arg Leu Gln Glu Lys Gln Lys Ser G1u Arg Glu Thr Ala Val Arg Ile Ser Gln Glu I1e Gly Asn Leu Met Lys Glu Ile Glu Thr Leu Val Glu Glu Lys Thr Lys Glu Ser Leu Asp Val Ser Arg Leu Thr Arg Glu Gly Gly 440 445 ~ 450 Pro Leu Leu Tyr Glu Gly Ile Ser Leu Thr Met Asn Sex Lys Leu Leu Asn Gly Ser Gln Arg Val Val Met Asp Gly Val Ile Ser Asp His Glu Cys Gln Glu Leu Gln Arg Leu Thr Asn Val Ala Ala Thr Ser Gly Asp Gly Tyr Arg Gly Gln Thr Ser Pro His Thr Pro Asn Glu Lys Phe Tyr Gly Val Thr Val Phe Lys Ala Leu Lys Leu Gly Gln Glu Gly Lys Val Pro Leu Gln Ser Ala His Leu Tyr Tyr Asn Val Thr Glu Lys Val Arg Arg Ile Met Glu Ser Tyr Phe Arg Leu Asp Thr Pro Leu Tyr Phe Ser Tyr Ser His Leu Val Cys Arg Thr Ala Ile Glu Glu Val Gln Ala Glu Arg Lys Asp Asp Ser His Pro Val His Val Asp Asn Cys Ile Leu Asn Ala Glu Thr Leu Val Cys Val Lys Glu Pro Pro Ala Tyr Thr Phe Arg Asp Tyr Ser Ala Ile Leu Tyr Leu Asn Gly Asp Phe Asp Gly Gly Asn Phe Tyr Phe Thr Glu Leu Asp Ala Lys Thr Val Thr Ala Glu Val Gln Pro Gln Cys Gly Arg Ala Val Gly Phe Ser Ser Gly Thr Glu Asn Pro His Gly Val Lys Ala Val Thr Arg Gly Gln Arg Cys Ala Ile Ala Leu Trp Phe Thr Leu Asp Pro Arg His Ser Glu Arg Asp Arg Val Gln Ala Asp Asp Leu Val Lys Met Leu Phe Ser Pro Glu Glu Met Asp Leu Ser Gln Glu Gln Pro Leu Asp Ala Gln Gln Gly Pro Pro Glu Pro A1a Gln Glu Ser Leu Ser Gly Ser Glu Ser Lys Pro Lys Asp Glu Leu <210> 34 <211> 1896 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7204554CD1 <400> 34 Met Pro Leu Pro Pro Arg Ser Leu Gln Val Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Pro Gly Met Trp Ala Glu Ala Gly Leu Pro Arg Ala Gly Gly Gly Ser Gln Pro Pro Phe Arg Thr Phe Ser Ala Ser Asp Trp Gly Leu Thr His Leu Val Val His Glu Gln Thr Gly Glu Val Tyr Val Gly Ala Val Asn Arg Ile Tyr Lys Leu Ser Gly Asn Leu Thr Leu Leu Arg Ala His Val Thr Gly Pro Val Glu Asp Asn Glu Lys Cys Tyr Pro Pro Pro Ser Val Gln Ser Cys Pro His Gly Leu Gly Ser Thr Asp Asn Val Asn Lys Leu Leu Leu Leu Asp Tyr Ala Ala Asn Arg Leu Leu Ala Cys Gly Ser Ala Ser Gln Gly Ile Cys Gln Phe Leu Arg Leu Asp Asp Leu Phe Lys Leu Gly Glu Pro His His Arg Lys Glu His Tyr Leu Ser Ser Val Gln Glu Ala Gly Ser Met Ala Gly Val Leu Ile Ala Gly Pro Pro Gly Gln 170 175 ~ 180 Gly Gln Ala Lys Leu Phe Val Gly Thr Pro Ile Asp Gly Lys Ser Glu Tyr Phe Pro Thr Leu Ser Ser Arg Arg Leu Met Ala Asn Glu Glu Asp Ala Asp Met Phe Gly Phe Val Tyr Gln Asp Glu Phe Val Ser Ser Gln Leu Lys Ile Pro Ser Asp Thr Leu Ser Lys Phe Pro Ala Phe Asp Ile Tyr Tyr Val Tyr Ser Phe Arg Ser Glu Gln Phe Val Tyr Tyr Leu Thr Leu Gln Leu Asp Thr Gln Leu Thr Ser Pro 260 265 ~ 270 Asp Ala Ala Gly Glu His Phe Phe Thr Ser Lys Ile Val Arg Leu Cys Va1 Asp Asp Pro Lys Phe Tyr Ser Tyr Val Glu Phe Pro Ile Gly Cys Glu Gln Ala Gly Val Glu Tyr Arg Leu Val Gln Asp Ala Tyr Leu Ser Arg Pro Gly Arg Ala Leu Ala His Gln Leu Gly Leu Ala Glu Asp Glu Asp Val Leu Phe Thr Val Phe Ala Gln Gly Gln Lys Asn Arg Val Lys Pro Pro Lys Glu Ser Ala Leu Cys Leu Phe Thr Leu Arg Ala Ile Lys Glu Lys Ile Lys Glu Arg Ile Gln Ser 365 370' 375 Cys Tyr Arg Gly Glu Gly Lys Leu Ser Leu Pro Trp Leu Leu Asn Lys Glu Leu Gly Cys Ile Asn Ser Pro Leu Gln Ile Asp Asp Asp Phe Cys Gly Gln Asp Phe Asn Gln Pro Leu Gly G1y Thr Val Thr Ile Glu Gly Thr Pro Leu Phe Val Asp Lys Asp Asp Gly Leu Thr Ala Val Ala Ala Tyr Asp Tyr Arg Gly Arg Thr Val Val Phe Ala Gly Thr Arg Ser Gly Arg Ile Arg Lys Ile Leu Val Asp Leu Ser Asn Pro Gly Gly Arg Pro Ala Leu Ala Tyr Glu Ser Val Val Ala Gln Glu Gly Ser Pro Ile Leu Arg Asp Leu Val Leu Ser Pro Asn His Gln Tyr Leu Tyr Ala Met Thr G1u Lys Gln Val Thr Arg Val 500 ~ 505 510 Pro Val Glu Ser Cys Val Gln Tyr Thr Ser Cys Glu Leu Cys Leu Gly Ser Arg Asp Pro His Cys Gly Trp Cys Val Leu His Ser Ile Cys Ser Arg Arg Asp Ala Cys Glu Arg Ala Asp Glu Pro Gln Arg Phe Ala A1a Asp Leu Leu Gln Cys Val Gln Leu Thr Val Gln Pro Arg Asn Val Ser Val Thr Met Ser Gln Val Pro Leu Val Leu Gln Ala Trp Asn Val Pro Asp Leu Ser Ala Gly Val Asn Cys Ser Phe Glu Asp Phe Thr Glu Ser Glu Ser Val Leu Glu Asp Gly Arg Ile His Cys Arg Ser Pro Ser Ala Arg Glu Val Ala Pro Ile Thr Arg Gly Gln Gly Asp Gln Arg Val Val Lys Leu Tyr Leu Lys Ser Lys Glu Thr Gly Lys Lys Phe Ala Ser Val Asp Phe Val Phe Tyr Asn Cys Ser Val His Gln Ser Cys Leu Ser Cys Val Asn Gly Ser Phe 665 670 , 675 Pro Cys His Trp Cys Lys Tyr Arg His Val Cys Thr His Asn Val Ala Asp Cys Ala Phe Leu Glu Gly Arg Val Asn Val Ser Glu Asp Cys Pro Gln Ile Leu Pro Ser Thr Gln Ile Tyr Val Pro Val Gly Val Val Lys Pro Ile Thr Leu Ala Ala Arg Asn Leu Pro Gln Pro Gln Ser GIy Gln Arg Gly Tyr Glu Cys Leu Phe His Ile Pro Gly Ser Pro Ala Arg Val Thr Ala Leu Arg Phe Asn Ser Ser Ser Leu Gln Cys Gln Asn Ser Ser Tyr Ser Tyr Glu Gly Asn Asp Val Ser Asp Leu Pro Val Asn Leu Ser Val Val Trp Asn Gly Asn Phe Val Ile Asp Asn Pro Gln Asn Ile Gln Ala His Leu Tyr Lys Cys Pro Ala Leu Arg Glu Ser Cys Gly Leu Cys Leu Lys Ala Asp Pro Arg Phe Glu Cys Gly Trp Cys Val Ala Glu Arg Arg Cys Ser Leu Arg His His Cys Ala Ala Asp Thr Pro A1a Ser Trp Met His Ala Arg His Gly Ser Ser Arg Cys Thr Asp Pro Lys Ile Leu Lys Leu Ser Pro Glu Thr Gly Pro Arg Gln G1y Gly Thr Arg Leu Thr Ile Thr Gly Glu Asn Leu Gly Leu Arg Phe Glu Asp Val Arg Leu Gly Val Arg Val Gly Lys Val Leu Cys Ser Pro Val Glu Ser Glu Tyr Ile Ser Ala Glu Gln Ile Val Cys Glu Tle Gly Asp Ala Ser Ser Val Arg Ala His Asp Ala Leu Val Glu Val Cys Val Arg Asp Cys Ser Pro His Tyr Arg Ala Leu Ser Pro Lys Arg Phe Thr Phe Val Thr Pro Thr Phe Tyr Arg Val Sex Pro Ser Arg Gly Pro Leu Ser Gly Gly Thr Trp Ile Gly Ile Glu Gly Ser His Leu Asn Ala Gly Ser Asp Val Ala Val Ser Val Gly Gly Arg Pro Cys Ser Phe Ser Trp Arg Asn Ser Arg Glu Ile Arg Cys Leu Thr Pro Pro Gly Gln Ser Pro Gly Ser Ala Pro Ile Ile Ile Asn Ile Asn Arg Ala Gln Leu Thr Asn Pro Glu Val Lys Tyr Asn Tyr Thr Glu Asp Pro Thr Tle Leu Arg Ile Asp Pro Glu Trp Ser Ile Asn Ser Gly Gly Thr Leu Leu Thr Val Thr Gly Thr Asn Leu Ala Thr Val Arg Glu Pro Arg Ile Arg Ala Lys Tyr Gly G1y Ile Glu Arg Glu Asn Gly Cys Leu Val Tyr Asn Asp Thr Thr Met Val Cys Arg Ala Pro Ser Val Ala Asn Pro Val Arg Ser Pro Pro Glu Leu Gly Glu Arg Pro Asp Glu Leu Gly Phe Val Met Asp Asn Val Arg Ser Leu Leu Val Leu Asn Ser Thr Ser Phe Leu Tyr Tyr Pro Asp Pro Val Leu Glu Pro Leu Ser Pro Thr Gly Leu Leu Glu Leu Lys Pro Ser Ser Pro Leu Ile Leu Lys Gly Arg Asn Leu Leu Pro Pro Ala Pro Gly Asn Ser Arg Leu Asn Tyr Thr Val Leu Ile G1y Ser Thr Pro Cys Thr Leu Thr Val Ser Glu Thr Gln Leu Leu Cys Glu Ala Pro Asn Leu Thr Gly Gln His Lys Val Thr Val Arg Ala Gly Gly Phe Glu Phe Ser Pro Gly Thr Leu Gln Val Tyr Ser Asp Ser Leu Leu Thr Leu Pro Ala Ile Val Gly Ile Gly Gly Gly Gly Gly Leu Leu Leu Leu Val Ile Val Ala Val Leu Ile Ala Tyr Lys Arg Lys Ser Arg Asp Ala Asp Arg Thr Leu Lys Arg Leu Gln Leu Gln Met Asp Asn Leu Glu Ser 1280 ' 1285 1290 Arg Val Ala Leu Glu Cys Lys Glu Ala Phe Ala Glu Leu G1n Thr Asp Ile His Glu Leu Thr Asn Asp Leu Asp Gly Ala Gly Ile Pro Phe Leu Asp Tyr Arg Thr Tyr Ala Met Arg Val Leu Phe Pro Gly Ile Glu Asp His Pro Val Leu Lys Glu Met Glu Val Gln Ala Asn Val Glu Lys Ser Leu Thr Leu Phe Gly Gln Leu Leu Thr Lys Lys 76'/123 His Phe Leu Leu Thr Phe Ile Arg Thr Leu Glu Ala Gln Arg Ser Phe Ser Met Arg Asp Arg G1y Asn Val A1a Ser Leu Ile Met Thr Ala Leu Gln Gly Glu Met Glu Tyr Ala Thr Gly Val Leu Lys Gln Leu Leu Ser Asp Leu Ile Glu Lys Asn Leu Glu Ser Lys Asn His Pro Lys Leu Leu Leu Arg Arg Thr Glu Ser Val Ala Glu Lys Met Leu Thr Asn Trp Phe Thr Phe Leu Leu Tyr Lys Phe Leu Lys Glu Cys Ala Gly Glu Pro Leu Phe Met Leu Tyr Cys Ala Ile Lys Gln '1460 1465 1470 G1n Met Glu Lys Gly Pro Tle Asp Ala Ile Thr Gly Glu Ala Arg Tyr Ser Leu Ser Glu Asp Lys Leu Ile Arg G1n Gln Ile Asp Tyr Lys Thr Leu Thr Leu Asn Cys Val Asn Pro Glu Asn Glu Asn Ala 1505 1510 ~ 1515 Pro Glu Val Pro Val Lys Gly Leu Asp Cys Asp Thr Val Thr Gln 1520 1525 ~ 1530 Ala Lys Glu Lys Leu Leu Asp Ala Ala Tyr Lys Gly Val Pro Tyr Ser Gln Arg Pro Lys Ala Ala Asp Met Asp Leu Glu Trp Arg Gln Gly Arg Met Ala Arg Ile Ile Leu Gln Asp Glu Asp Val Thr Thr Lys Ile Asp Asn Asp Trp Lys Arg Leu Asn Thr Leu Ala His Tyr G1n Val Thr Asp Gly Ser Ser Val Ala Leu Val Pro Lys Gln Thr Ser Ala Tyr Asn Ile Ser Asn Ser Ser Thr Phe Thr Lys Ser Leu Ser Arg Tyr Glu Ser Met Leu Arg Thr Ala Ser Ser Pro Asp Ser Leu Arg Ser Arg Thr Pro Met Ile Thr Pro Asp Leu Glu Ser Gly Thr Lys Leu Trp His Leu Val Lys Asn His Asp His Leu Asp Gln Arg Glu Gly Asp Arg Gly Ser Lys Met Val Ser Glu Ile Tyr Leu Thr Arg Leu Leu Ala Thr Lys Gly Thr Leu Gln Lys Phe Val Asp 1685 1690 . 1695 Asp Leu Phe Glu Thr Ile Phe Ser Thr Ala His Arg Gly Ser Ala Leu Pro Leu Ala Ile Lys Tyr Met Phe Asp Phe Leu Asp Glu Gln Ala Asp Lys His Gln Ile His Asp Ala Asp Val Arg His Thr Trp Lys Ser Asn Cys Leu Pro Leu Arg Phe Trp Val Asn Val Ile Lys Asn Pro Gln Phe Val Phe Asp Ile His Lys Asn Ser Ile Thr Asp 1760 1765 ~ 1770 Ala Cys Leu Ser Val Val Ala Gln Thr Phe Met Asp Ser Cys Ser Thr Ser Glu His Lys Leu Gly Lys Asp Ser Pro Ser Asn Lys Leu Leu Tyr Ala Lys Asp Ile Pro Asn Tyr Lys Ser Trp Val Glu Arg Tyr Tyr Ala Asp Ile Ala Lys Met Pro Ala Ile Ser Asp Gln Asp Met Ser Ala Tyr Leu Ala Glu Gln Ser Arg Leu His Leu Ser Gln Phe Asn Ser Met Ser Ala Leu His Glu Ile Tyr Ser Tyr Ile Thr Lys Tyr Lys Asp Glu Ile Leu Ala Ala Leu Glu Lys Asp Glu Gln Ala Arg Arg Gln Arg Leu Arg Ser Lys Leu Glu Gln Val Val Asp Thr Met Ala Leu Ser Ser <210> 35 <211> 215 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6833247CD1 <400> 35 Met Gly Leu Glu Lys Pro Gln Ser Lys Leu Glu Gly Gly Met His Pro Gln Leu Ile Pro Ser Val Ile Ala Val Val Phe Ile Leu Leu Leu Ser Val Cys Phe Ile Ala Ser Cys Leu Val Thr His His Asn Phe Ser Arg Cys Lys Arg Gly Thr Gly Val His Lys Leu Glu His His Ala Lys Leu Lys Cys Ile Lys Glu Lys Ser Glu Leu Lys Ser Ala Glu Gly Ser Thr Trp Asn Cys Cys Pro Ile Asp Trp Arg Ala Phe Gln Ser Asn Cys Tyr Phe Pro Leu Thr Asp Asn Lys Thr Trp Ala Glu Ser Glu Arg Asn Cys Ser Gly Met Gly Ala His Leu Met Thr Ile Ser Thr Glu Ala Glu Gln Asn Phe Ile Ile Gln Phe Leu Asp Arg Arg Leu Ser Tyr Phe Leu G1y Leu Arg Asp Glu Asn Ala Lys Gly Gln Trp Arg Trp Val Asp Gln Thr Pro Phe Asn Pro Arg Arg Val Phe Trp His Lys Asn Glu Pro Asp Asn Ser Gln Gly Glu Asn Cys Val Val Leu Val Tyr Asn Gln Asp Lys Trp Ala Trp Asn Asp Val Pro Cys Asn Phe Glu Ala Ser Arg Ile Cys Lys Ile Pro 200 205 ~ 210 Gly Thr Thr Leu Asn <210> 36 <211> 579 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4148119CD1 <400> 36 Met Gly Arg Pro Thr Gln Trp Pro Ser Leu Leu Leu Leu Leu Leu Leu Pro Gly Pro Pro Pro Val Ala Gly Leu Glu Asp Ala Ala Phe Pro His Leu G1y Glu Ser Leu Gln Pro Leu Pro Arg Ala Cys Pro Leu Arg Cys Ser Cys Pro Arg Val Asp Thr Val Asp Cys Asp Gly Leu Asp Leu Arg Val Phe Pro Asp Asn Ile Thr Arg Ala Ala Gln His Leu Ser Leu Gln Asn Asn Gln Leu Gln Glu Leu Pro Tyr Asn Glu Leu Ser Arg Leu Ser Gly Leu Arg Thr Leu Asn Leu His Asn Asn Leu Ile Ser Ser Glu Gly Leu Pro Asp Glu Ala Phe Glu Ser Leu Thr Gln Leu Gln His Leu Cys Val Ala His Asn Lys Leu Ser Val Ala Pro Gln Phe Leu Pro Arg Ser Leu Arg Val Ala Asp Leu Ala Ala Asn Gln Val Met Glu Ile Phe Pro Leu Thr Phe Gly Glu Lys Pro Val Leu Arg Ser Val Tyr Leu His Asn Asn Gln Leu Ser Asn Ala Gly Leu Pro Pro Asp Ala Phe Arg Gly Ser Glu Ala Ile Ala Thr Leu Ser Leu Ser Asn Asn Gln Leu Ser Tyr Leu Pro Pro Ser Leu Pro Pro Ser Leu G1u Arg Leu His Leu Gln Asn Asn Leu Ile Ser Lys Val Pro Arg Gly Ala Leu Ser Arg Gln Thr Gln Leu Arg Glu Leu Tyr Leu Gln His Asn Gln Leu Thr Asp Ser Gly Leu Asp Ala Thr Thr Phe Ser Lys Leu His Ser Leu Glu Tyr Leu Asp Leu Ser His Asn Gln Leu Thr Thr Val Pro Ala Gly Leu Pro Arg Thr Leu Ala Ile Leu His Leu Gly Arg Asn Arg Ile Arg Gln Val Glu Ala Ala Arg Leu His Gly Ala Arg Gly Leu Arg Tyr Leu Leu Leu Gln His Asn Gln Leu Gly Ser Ser Gly Leu Pro Ala Gly Ala Leu Arg Pro Leu Arg Gly Leu His Thr Leu His Leu Tyr Gly Asn Gly Leu Asp Arg Val Pro Pro Ala Leu Pro Arg Arg Leu Arg Ala Leu Val Leu Pro His Asn His Val Ala Ala Leu Gly Ala Arg Asp Leu Val Ala Thr Pro Gly Leu Thr Glu Leu Asn Leu Ala Tyr Asn Arg Leu Ala Ser Ala Arg Val His His Arg Ala Phe Arg Arg Leu Arg Ala Leu Arg Ser Leu Asp Leu Ala Gly Asn Gln Leu Thr Arg Leu Pro Met Gly Leu Pro Thr Gly Leu Arg Thr Leu Gln Leu Gln Arg Asn Gln Leu Arg Met Leu Glu Pro Glu Pro Leu Ala Gly Leu Asp Gln Leu Arg Glu Leu Ser Leu Ala His Asn Arg Leu Arg Val Gly Asp Ile Gly Pro Gly Thr Trp His Glu Leu Gln Ala Leu Gln Met Leu Asp Leu Ser His Asn Glu Leu Ser Phe Val Pro Pro Asp Leu Pro Glu Ala Leu Glu Glu Leu His Leu Glu Gly Asn Arg Ile Gly His Val Gly Pro Glu Ala Phe Leu Ser Thr Pro Arg Leu Arg Ala Leu Phe Leu Arg Ala Asn Arg Leu His Met Thr Ser Ile Ala Ala Glu Ala Phe Leu Gly Leu Pro Asn Leu Arg Val Val Asp Thr Ala Gly Asn Pro Glu Gln Val Leu Ile Arg Leu Pro Pro Thr Thr Pro Arg Gly Pro Arg Ala Gly Gly Pro <210> 37 <211> 1211 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1888682CB1 <400> 37 ccgggacggt cacatcccgc tgcaggggcg ggcggaggcc gccgcactgc ctcccgcacc 60 ggggacccag gccagcgtcc gggcaacgcc ccctgctccc ggacagactc cgtggcccgc 120 tcgagccctg ggggctccgc agacccgcgc ccgctccgcc cgcagctcgg ccccgcgctg 180 cccgcgtcgc cgggcccgcg ccgggatggg gtaggggcag cgccaccgag tcgggcgatg 240 ggccgccctc tgggcaccga gcagcccccc gaggcctgac caaccgcgag gaccggcgga 300 ggagccccgc ctggatgtca agcggatgcc aagcggatgc cacagttccc cccccagcgg 360 actccgtggg gacatggctt cgctggtgcc cctttcccca tatctaagcc ccacggtcct 420 cctgctggtc agctgtgacc tgggcttcgt gcgagcagac cggcctccct ctcctgtgaa 480 tgtgacggtc actcacctca gagccaactc ggccactgtg tcctgggacg tcccagaagg 540 caacatcgtc attggctact ccatttccca gcaacggcag aatggccccg ggcagcgtgt 600 gattcgggag gtgaacacca ccacccgggc ctgtgccctc tggggcctgg ctgaagacag 660 tgactacaca gtgcaggtca ggagcatcgg ccttcgggga gagagtcccc cagggccccg 720 ggtgcacttc cgaactctca agggttctga ccggctacct tcaaacagtt caagcccagg 780 tgacatcaca gtggaaggtc tggatggaga gcggccactg cagactgggg aagtggtcat 840 cattgtggtg gtgttgctca tgtgggctgc tgtaattggg ctgttctgcc gtcagtatga 900 catcatcaag gacaatgact ccaacaacaa tcccaaggag aagggaaagg ggccggaaca 960 gagtcctcag ggaaggccag tggggacaag acagaaaaag tcaccatcta tcaacaccat 1020 cgacgtttga gtgaagaaac acacccagaa gagagatgca ctaacaactg gggataggga 1080 tggggtcagg gggagcccaa gatggtgatc tgcccgagac tcccagaggg tattgccact 1140 cccacaatct caggcctggt acccatcctc tttccactgt gagcagagcc agaaggtagg 1200 tctgttcaga g 1211 <210> 38 <211> 1523 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1794980CB1 <400> 38 ggcggctggc ggcgcgggca ggcaggcggg gaggacaggc tgggggcggc gaccgcgagg 60 ggccgcgcgc ggagggcgcc tggtgcagca tgggcggccc gcgggcttgg gcgctgctct 120 gcctcgggct cctgctcccg ggaggcggcg ctgcgtggag catcggggca gctccgttct 180 ccggacgcag gaactggtgc tcctatgtgg tgacccgcac catctcatgc catgtgcaga 240 atggcaccta ccttcagcga gtgctgcaga actgcccctg gcccatgagc tgtccgggga 300 gcagctacag aactgtggtg agacccacat acaaggtgat gtacaagata gtgaccgccc 360 gtgagtggag gtgctgccct gggcactcag gagtgagctg cgaggaagtt gcagcttcct 420 ctgcctcctt ggagcccatg tggtcgggca gtaccatgcg gcggatggcg cttcggccca 480 cagccttctc aggttgtctc aactgcagca aagtgtcaga gctgacagag cggctgaagg 540 tgctggaggc caagatgacc atgctgactg tcatagagca gccagtacct ccaacaccag 600 ctacccctga ggaccctgcc ccgctctggg gtccccctcc tgcccagggc agccccggag 660 atggaggcct ccaggaccaa gtcggtgctt gggggcttcc cgggcccacc ggccccaagg 720 gagatgccgg cagtcggggc ccaatgggga tgagaggccc accaggtcca cagggccccc 780 cagggagccc tggccgggct ggagctgtgg gcacccctgg agagagggga cctcctgggc 840 caccagggcc tcctggcccc cctgggcccc cagcccctgt tgggccaccc catgcccgga 900 tctcccagca tggagaccca ttgctgtcca acaccttcac tgagaccaac aaccactggc 960 cccagggacc cactgggcct ccaggccctc cagggcccat gggtccccct gggcctcctg 1020 gccccacagg tgtccctggg agtcctggtc acataggacc cccaggcccc actggaccca 1080 aaggaatctc tggccaccca ggagagaagg gcgagagagg actgcgtggg gagcctggcc 1140 cccaaggctc tgctgggcag cggggggaac ctggccctaa gggagaccct ggtgagaaga 1200 gccactgggg ggaggggttg caccagctac gcgaggcttt gaagatttta gctgagaggg 1260 ttttaatctt ggaaacaatg attgggctct atgaaccaga gctggggtct ggggcgggcc 1320 ctgccggcac aggcaccccc agcctccttc ggggcaagag gggcggacat gcaaccaact 1380 accggatcgt ggcccccagg agccgggacg agagaggctg agttggtggc ggcccctgag 1440 gcagaccagg ccaggcttcc cctcctacct ggactcggcc agctgcctcc agggaccgcc 1500 cgtccataat tcaggagcgt ccc 1523 <210> 39 <211> 1368 <212> DNA
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No:°5533958CB1 <400> 39 ctgccgggtg tgccgggtgt ccagcgaacc cctttcccaa accttcgggg agaagggagg 60 tgggaggagg caaagaaact acaggcaggg agctggaagg gggggtgggg ggggcaggag 120 acaagaaatc aagacaccag gcagcaggac acacacacac tcacatacac tcacacacat 180 agagaccaac agatagacag ctacctaaag cctgaaagac tgacagcaac acagaaaaaa 240 agaaacaggc agaaagagag acaaagacag aaatagaaac agactaacac acagagtcaa 300 aaatacagag acagaaagac agggagaaag agaaacagaa aattagacac caaagacata 360 cgaacaggga ggaaggccga ctgaaagaaa gacggagaag aggagagaga agccagggcc 420 gagcgtgcca gcaggcggat ggagggcggc ctggtggagg aggagacgta gtggcctggg 480 ctgagctggg tgggccggga gaagcgggtg cctcagagtg ggggtggggg catgggaggg 540 gcaggcattc tgctgctgct gctggctggg gcgggggtgg tggtggcctg gagaccccca 600 aagggaaagt gtcccctgcg ctgctcctgc tctaaagaca gcgccctgtg tgagggctcc 660 ccggacctgc ccgtcagctt ctctccgacc ctgctgtcac tctcactcgt caggacggga 720 gtcacccagc tgaaggccgg cagcttcctg agaattccgt ctctgcacct gctcctcttc 780 acctccaact ccttctccgt gattgaggac gatgcatttg cgggcctgtc ccacctgcag 840 tacctcttca tcgaggacaa tgagattggc tccatctcta agaatgccct cagaggactt 900 cgctcgctta cacacctaag cctggccaat aaccatctgg agaccctccc cagattcctg 960 ttccgaggcc tggacaccct tactcacgtg gacctccgcg ggaacccgtt ccagtgtgac 1020 tgccgcgtcc tctggctcct gcagtggatg cccaccgtga atgccagcgt ggggaccggc 1080 gcctgtgcgg gccccgcctc cctgagccac atgcagctcc accacctcga ccccaagact 1140 ttcaagtgca gagccatagg tggggggctt tcccgatggg gtgggaggcg ggagatctgg 1200 gggaaaggct gccagggcca agaggctcgt ctcactccct gccctgccat ttcccggagt 1260 gggaagaccc tgagcaagca gcactgcctt cctgagcccc agttttctca tctgtaaagt 1320 gggggtaata aacagtgata taggagtgcc atggaaaaaa aaaaaaaa 1368 <210> 40 <211> 3157 <212> DNA
<213> Homo Sapiens <220>
<221> misc_~eature <223> Incyte ID No: 60210196CB1 <400> 40 tggtcgttcc tcggtttgcc atccattggg cccctgccct ccatccccgt ggaggcccct 60 tgtctgggtg ttcgcactca acgtcgatgt gttgataatg gtgccttttt cgtgaagaaa 120 ctgcctgagt ctcacttcca gaagtttata ggtccacccg ttctctccag cgtccgccag 180 cccagatctc gcatgcgcat ctgtgtctgc ccctctttgc cttctgcctg tccctgggtg 240 cccctcaggg tcagaatcac cctttccgcc cgcactggcc cccacatcac ctgtcttgtc 300 cccactggcc ttccctgagg actctgttcc ggcccctttc ccttctcctt gggattgttg 360 ttggagtcat tgtccttgat gatgtcatac tgacggcaga acagcccaat tacagctgaa 420 acacaataca gtctgagccc agagagccgc ggggaccatg gagccggtgc cgctgcagga 480 cttcgtgcgc gccttggacc ccgcctccct cccgcgcgtg~ctgcgggtct gctcgggggt 540 ctacttcgag ggctccatct atgagatctc tgggaatgag tgctgcctct ccacggggga 600 cctgatcaag gtcacccagg tccgcctcca gaaggtggtc tgtgagaacc cgaagaccag 660 ccagaccatg gagctcgccc ccaacttcca gggctacttc acccccctca acaccccaca 720 gagctatgaa accctggagg agctggtctc tgccacaact cagagctcca agcagctgcc 780 cacttgcttc atgtcgaccc acaggattgt cacagagggc agggtggtga ctgaggacca 840 gctcctcatg cttgaggctg tggtgatgca cctcgggatc cgctctgccc gctgtgtcct 900 gggcatggag ggtcagcagg tcatcctgca cctgccccta tcccagaagg ggcccttctg 960 gacatgggag cctagtgccc ctcgaactct gctccaggtc ctacaggatc cagccctgaa 1020 agacctcgtc ctcacctgcc ccaccctgcc ctggcattcc ctgatcctgc ggccccagta 1080 tgagatccaa gccatcatgc acatgcgcag gaccattgtc aagatccctt ctaccctgga 1140 ggtcgacgtg gaggacgtca ccgcctcctc ccggcacgtc cactttatca aaccgctgct 1200 gctgagcgag gtcctggcct gggaaggccc tttccccctg tccatggaga tcctggaggt 1260 tcctgagggc cgccccatct tcctcagccc gtgggtgggc tccttgcaaa aaggccagag 1320 gctttgcgtc tatggcctag cctcaccacc ctggcgggtc ctggcctcaa gcaagggccg 1380 caaggtgccc aggcacttcc tggtgtcagg gggctaccaa ggcaagctgc ggcggcggcc 1440 aagggagttc cccacggcct atgacctcct aggtgctttc cagccaggcc ggccactccg 1500 ggtggtggcc acaaaggact gtgagggcga gagggaggag aatcccgagt tcacgtccct 1560 ggctgtgggt gaccggctgg aggtgctggg gcctggccag gcccatgggg cccagggcag 1620 tgacgtggat gtcttggttt gtcagcggct gagtgaccag gctggggagg atgaggagga 1680 agagtgcaaa gaggaggcag agagcccaga gcgggtcctg ctgcccttcc acttccctgg 1740 cagtttcgtg gaggagatga gtgacagccg gcgctacagc ctggcagatc tgactgccca 1800 gttttcactg ccttgtgagg tcaaggtggt ggccaaggac accagccacc ccactgaccc 1860 tctgacctcc ttcctgggcc tgcggctgga ggagaagatc acagagccat tcttggtggt 1920 gagcctagac tctgagcctg ggatgtgctt tgagatccct ccccggtggc tggacctgac 1980 tgttgtgaag gccaaggggc agccagactt gccagagggg tctctcccca tagccacagt 2040 ggaggagctg acagacacct tctattatcg tcttcggaag ttaccagcct gtgagatcca 2100 agccccccca cccaggcccc ctaaaaatca gggcctcagc aagcagagga gacacagcag 2160 tgagggaggc gtcaagtctt ctcaagtctt aggattgcag caacacgctc ggctgcccaa 2220 acccaaggcg aagaccttgc cagagttcat caaggatggc tccagtacgt acagcaagat 2280 tcctgcccac aggaagggcc acaggcccgc taagccccaa aggcaggatc tagatgatga 2340 tgaacatgat tatgaagaaa tacttgagca atttcagaaa accatctaag tgctggagga 2400 accacgcttc ctaactgctg cttctcaggg aatccgacac cagccaacca ttttaagcct 2460 ctaaaagacc tcgggcaagt ctcacagaaa ctgagctgca gacggggagt agctttgtgg 2520 aaactgattt gatggacact gcaccagctt ccttcaggtt ctagattctt gctacttagg 2580 gcgggctggt ttggacctaa catctcgcac gtgactccct cagcctcaga gccttgggat 2640 gcagagcagc tggcagggtt cctctcaatc ctgcaacccc agctgtccca ccggtggatg 2700 cagaggggaa tccgaggcca tcaaccttgg tgacagcagc gcagtgccaa tgctgatcac 2760 actgcatggg agattttgtt aacgtctgcc acccccactc tcacccccaa gctctaagcc 2820 cccgggaggc ctggactgtc ttcctcatct ctgtagcacc aagcctgata gatctgtata 2880 tggtaaacag gggtttaacc acatgtggtt aacatggatt aatgtgggaa tttggcttca 2940 agaacacaac cttaggacct tgggccccaa aagctggtgg tgaaatgaga ggagccaatt 3000 taagaagacc cttatggaga cctgaggctg cagaaactgg taggtttcat caggtggtta 3060 aagtcgtcaa agttgtaagt gactaaccaa gattatttca ttttaaaacc acagaataaa 3120 aatgacacct gagcttctct aaaaaaaaaa aaaaaaa 3157 <210> 41 <211> 3264 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 815125CB1 <400> 41 ggagccgggg cagccagaag aggtgggaaa agcggaggag gacgcccagg aggaggcggc 60 ggcggcggcc gggaagtgaa aggtctcgca aagttcagcg gcggctgcgg gcgccgagcc 120 ccgggctagc ggcagacgag cccgcagggc cgctccgcgg ggcagcgcag ccaggccggc 180 tatggtcccg gggctcccgc cgccccccag gtgcccggga cccgccaggc cgggtgcgcg 240 agggtcaccc cacctccccg cgcggtcccg gcccctggct cccagctgcc ggcgaccgct 300 gaccgagccc ggcgccccag gaggaggaag aaaccagggc cccgttccct cccgaggacg 360 gcggcgcttc atcccgcagc ccagaggtct cggctccctc cggcacccgc ccggcccggc 420 tgctcccggc tcctcccggc catggggagc tgcgcgcggc tgctgctgct ctggggctgc 480 acggtggtgg ccgcaggact gagtggagta gctggagtga gttcccgctg tgaaaaagcc 540 tgcaaccctc ggatgggaaa tttggctttg gggcgaaaac tctgggcaga caccacctgc 600 ggtcagaatg ctaccgaact gtactgcttc tacagtgaga acacggatct gacttgtcgg 660 cagcccaaat gtgacaagtg caatgctgcc tatcctcacc tggctcacct gccatctgcc 720 atggcagact catccttccg gtttcctcgc acatggtggc agtctgcgga ggatgtgcac 780 agagaaaagg tccagttaga cctggaagct gaattctact tcactcacct aattgtgatg 840 ttcaagtccc ccaggccagc tgccatggtg ctggaccgct cccaggactt tgggaaaaca 900 tggaagcctt ataagtactt tgcgactaac tgctccgcta catttggcct ggaagatgat 960 gttgtcaaga agggcgctat ttgtacttct aaatactcca gtccttttcc atgcactgga 1020 ggagaggtta ttttcaaagc tttgtcacca ccatacgata cagagaaccc ttacagtgcc 1080 aaagttcagg agcagctgaa gatcaccaac cttcgcgtgc agctgctgaa acgacagtct 1140 tgtccctgtc agagaaatga cctgaacgaa gagcctcaac attttacaca ctatgcaatc 1200 tatgatttca ttgtcaaggg cagctgcttc tgcaatggcc acgctgatca atgcatacct 1260 gttcatggct tcagacctgt caaggcccca ggaacattcc acatggtcca tgggaagtgt 1320 atgtgtaagc acaacacagc aggcagccac tgccagcact gtgccccgtt atacaatgac 1380 cggccatggg aggcagctga tggcaaaacg ggggctccca acgagtgcag aacctgcaag 1440 tgtaatgggc atgctgatac ctgtcacttc gacgttaatg tgtgggaggc atcagggaat 1500 cgtagtggtg gtgtctgtga tgactgtcag cacaacacag aaggacagta ttgccagagg 1560 tgcaagccag gcttctatcg~tgacctgcgg agacccttct cagctccaga tgcttgcaaa 1620 ccgtgttcct gccatccagt aggatcagct gtccttcctg ccaactcagt gaccttctgc 1680 gaccccagca atggtgactg cccttgcaag cctggggtgg cagggcgacg ttgtgacagg 1740 tgcatggtgg gatactgggg cttcggagac tatggctgtc gaccatgtga ctgtgcaggg 1800 agctgtgacc ctatcaccgg agactgcatc agcagccaca cagacataga ctggtatcat 1860 gaagttcctg acttccgtcc cgtgcacaat aagagcgaac cagcctggga gtgggaggat 1920 gcgcaggggt tttctgcact tctacactca ggtaaatgcg aatgtaagga acagacatta 1980 ggaaatgcca aggcattctg tggaatgaaa tattcatatg tgctaaaaat aaagatttta 2040 tcagctcatg ataaaggtac tcatgttgag gtcaatgtga agattaaaaa ggtcttaaaa 2100 tctaccaaac tgaagatttt ccgaggaaag cgaacattat atccagaatc atggacggac 2160 agaggatgca cttgtccaat cctcaatcct ggtttggaat accttgtagc aggacatgag 2220 gatataagaa caggcaaact aattgtgaat atgaaaagct ttgtccagca ctggaaacct 2280 tctcttggaa gaaaagtcat ggatatttta aaaagagagt gcaagtagca ttaagatgga 2340 tagcacataa tggcacttgt ctatgtacaa aacacaaact ttagagcaag aagacctcag 2400 acaggaaact ggaatttttt aaagtgccaa aacatataga aatgtttgaa tgcatgggtc 2460 ttatctaatt tatctcttct ggacccatgt ttaaatacag ttttatttca tgaagagaaa 2520 tgaaaacccc tacactgata tctgttttct atgggactga ttctgaaatt cttaactatt 2580 aagaatattt taatagcagc atgacattta gcagtaatcc attaagggca gtacctctaa 2640 caaggacgcc ttccagcttc agctatgtta cttacgtttg atgctactta aagtaatgaa 2700 tgacgtttta aggaatccct aaccctacta tcagaaaagg tgtttgttaa agagccttct 2760 cttgtgtgtt acgcatgaac tttggtctgt aggtgttaaa tggaacctct ccatgtgtat 2820 atagtatttc cttgtataaa gcactttact acctaccact tgtgttgtga acgtttggtg 2880 actgctgttg aaagaaggaa aagggtgtgt gagaaagcct actgaagcag cagcactgcc 2940 actacatgtg gacaaaagtg aacatataaa agaagttgtg ctatttaact btgaatactt 3000 ggagaaacta ggtgaagatg caaccagaaa ggagaatatg tatgcgtgaa gtctcagctt 3060 tgagctggag gctagattcc aagatgacag ccatgatgaa actttttaaa aaactaaacc 3120 agaagagact ttaaaataag agaaagaaat cataaatgta gacatatgct tggctaaagg 3180 ggaaatggac tttaaatttt aaagagctca tttgcaatgc acttgtatac acttcaaaaa 3240 ttattgtaga cacagcattt gtta 3264 <210> 42 <211> 3383 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1386915CB1 <400> 42 tgcgatctag aacgtccgac ctctcctctc ccagccagtc gtggctggcc tttcaaagtg 60 tgcagttgtc tcctccctgt ccagccccat cgtcgcccag gaccagctgg gccgcggtct 120 gacctgaggc tgctgctcag cgccggggcg ctggcgctct ccattcgagc accttccagc 180 ataccgctcg gctccgggag ccgctctgca aagttgagca gctcagagcg caagctttgc 240 ctctcgactt ctccctcctt gggtccccgg cgcccccgcc tcccacgatc cctttcacta 300 ggagcagcca gtcccagcgg gctggcaact tgcacccctt cctagtcatc ctccctgaaa 360 cgcgaccatg ctgttaaggg gcgtcctcct ggcgttgcaa gccctgcagc tcgccggtgc 420 cctcgacctg cccgctgggt cctgtgcctt tgaagagagc acttgcggct ttgactccgt 480 gttggcctct ctgccgtgga ttttaaatga ggaaggccat tacatttatg tggatacctc 540 ctttggcaag cagggggaga aagctgtgct gctaagtcct gacttacagg ctgaggaatg 600 gagctgcctc cgtttggtct accagataac cacatcttcg gagtctctgt cagatcccag 660 ccagctgaac ctctacatga gatttgaaga tgaaagcttt gatcgcttgc tttggtcagc 720 taaggaacct tcagacagct ggctcatagc cagcttggat ttgcaaaaca gttccaagaa 780 attcaagatt ttaatagaag gtgtactagg acagggaaac acagccagca tcgcactatt 840 tgaaatcaag atgacaaccg gctactgtat tgaatgtgac tttgaagaaa atcatctctg 900 tggctttgtg aaccgctgga atcccaatgt gaactggttt gttggaggag gaagtattcg 960 gaatgtccac tccattctcc cacaggatca caccttcaag agtgaactgg gccactacat 1020 gtacgtggac tcagtttatg tgaagcactt ccaggaggtg gcacagctca tctccccgtt 1080 gaccacggcc cccatggctg gctgcctgtc attttattac cagatccagc aggggaatga 1140 caatgtcttt tccctttaca ctcgggatgt ggctggcctt tacgaggaaa tctggaaagc 1200 agacaggcca gggaatgctg cctggaacct tgcggaggtc gagttcaatg ctccttaccc 1260 catggaggtt atttttgaag ttgctttcaa tggtcccaag ggaggttatg ttgccctgga 1320 tgatatttca ttctctcctg ttcactgcca gaatcagaca gaacttctgt tcagtgccgt 1380 ggaagccagc tgcaattttg agcaagatct ctgcaacttt taccaagata aagaaggtcc 1440 aggttggacc cgagtgaaag taaaaccaaa catgtatcgg gctggagacc acactacagg 1500 cttagggtat tacctgctag ccaacacaaa gttcacatct cagcctggct acattggaag 1560 gctctatggg ccctccctac caggaaactt gcagtattgt ctgcgttttc attatgccat 1620 ctatggattt ttaaaaatga gtgacaccct agcagtttac atctttgaag agaaccatgt 1680 ggttcaagag aagatctggt ctgtgttgga gtccccaagg ggtgtttgga tgcaagctga 1740 aatcaccttt aagaagccca tgcctaccaa ggtggttttc atgagcctat gcaaaagttt 1800 ctgggactgt gggcttgtag ccctggatga cattacaata caattgggaa gctgctcatc 1860 ttcagagaaa cttccacctc cacctggaga gtgtactttc gagcaagatg aatgtacatt 1920 tactcaggag aaaagaaacc ggagcagctg gcacaggagg aggggagaaa ctcccacttc 1980 ctacacagga ccaaagggag atcacactac tggggtaggc tactacatgt acattgaggc 2040 ctcccatatg gtgtatggac aaaaagcacg cctcttgtcc aggcctctgc gaggagtctc 2100 tggaaaacac tgcttgacct ttttctacca catgtatgga gggggcactg gcctgctgag 2160 tgtttatctg aaaaaggaag aagacagtga agagtccctc ttatggagga gaagaggtga 2220 acagagcatt tcctggctac gagcactgat tgaatacagc tgtgagaggc aacaccagat 2280 aatttttgaa gccattcgag gagtatcaat aagaagtgat attgccattg atgatgttaa 2340 atttcaggca ggaccctgtg gagaaatgga agatacaact caacaatcat caggatattc 2400 tgaggactta aatgaaattg agtattaaga aatgatctgc attggattta ctagacgaaa 2460 accatacctc tcttcaatca aaatgaaaac aaagcaaatg aatactggac agtcttaaca 2520 attttataag ttataaaatg actttagagc accctccttc attacttttg caaaaacata 2580 ctgactcagg gctctttttt tctttttgca tatgacaact gttactagaa atacaggcta 2640 ctggttttgc atagatcatt catcttaatt ttggtaccag ttaaaaatac aaatgtacta 2700 tattgtagtc attttaaagt acacaaaggg cacaatcaaa atgagatgca ctcatttaaa 2760 tctgcattca gtgaatgtat tgggagaaaa ataggtcttg caggtttcct tttgaatttt 2820 aagtatcata aatatttttt aagtaaataa tacggggtgt cagtaatatc tgcagaatga 2880 atgcagtctt tcatgctaat gagttagtct ggaaaaataa agtcttattt tctatgtttt 2940 attcatagaa atggagtatt aatttttaat attttcacca tatgtgataa caaaggatct 3000 ttcatgaatg tccaagggta agtcagtatt aattaatgct gtattacaag gcaatgctac 3060 cttctttatt ccccctttga actacctttg aagtcactat gagcacatgg atagaaattt 3120 aacttttttt tgtaaagcaa gcttaaaatg tttatgtata catacccagc aacttttata 3180 aatgtgttaa acaattttac tgatttttat aataaatatt ttggtaagat tttgaataat 3240 atgaattcag gcagatatac taaactgctt ttatttactt gtttagaaaa ttgtatatat 3300 atgtttgtgt atcctaacag ctgctatgaa attataaaat tacctaataa aaataatttg 3360 aaaatcttaa aaaaaaaaaa aaa 3383 <210> 43 <211> 2741 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte TD No: 1344495CB1 <400> 43 ggcagctgcg ggtcgcgggt cgcgggtcgc gagtcgccgg tcgccggtcg cggcggagcc 60 tgggcgctga gtgaagaaaa tgaggcacga ggaattgtta accaagacct tccaaggccc 120 agctgttgtg tgtgggactc cgaccagcca cgtatacatg tttaagaatg gcagtgggga 180 ctcgggggac tcttctgaag aagagtctca ccgtgtggtt ttgcggcccc ggggcaagga 240 gcgccacaag agcggtgtcc accagcctcc ccaggcggga gcaggtgacg tggtgctgct 300 gcagcgggag ctggcccagg aggacagcct caacaagctg gcgctgcagt atggctgcaa 360 agttgcagat atcaagaaag tcaacaactt catcagagaa caagacttat atgctttgaa 420 atctgttaag attccagtga gaaaccatgg gatcctgatg gagacccaca aagaactgaa 480 accccttctg agcccgtctt ccgagaccac agtgaccgtg gaactgccag aggcagacag 540 agcaggcgcg ggcaccggtg cccaggccgg ccaactgatg ggcttcttta aggggattga 600 ccaggatatt gagcgtgcag tgcagtcaga aatctttcta catgaaagtt actgcatgga 6&0 cacctcccat cagccactgc tcccggcacc tccgaagacg'cctatggatg gtgcagattg 720 tggcattcag tggtggaatg ctgttttcat catgctgctg attggtattg tcttgcctgt 780 cttttatttg gtctacttta aaatacaagc tagtggtgag acccctaata gcttgaacac 840 aactgtcatc cccaatggct cgatggcaat gggtacagtt ccagggcaag cccccagact 900 agcagttgca gtgccagccg tcacttctgc agacagccag ttcagtcaga ccacccaagc 960 ggggagctaa gctttgtttt taaagactcg gcccagcttt agcaattggc tgttgatgtg 1020 cctcagctgt cactggcgat gtcctagggg tgctgcattt tgcttccggg gaaggatgga 1080 cacttttcag aagtcactgc agtattccca attgcactgg ccctgggcat ggccttaccc 1140 agtctaagct ggcaggatct aaaacagcag cgacctcggc ccctatccag agaggtgcag 1200 caagagagcc atttccctgt gacatttagt ggactggcca gttcatagca gcactgtgag 1260 gacccccaag ttggacgtgc tcggagggaa agatttatgg cctctgtcga gggacctgca 1320 gcgtgagagc cagtggcatc tgcgcggctt gcctggctct tgctgtatcc tcacttcctg 1380 tggagcgggg attggctctg agaaggagtg ttctctgtct gcctggcaaa ggtgctgtgg 1440 aataggcttg gcatgccacc ctgttttaga gagtgacagt tacagttgta acaagcctac 1500 ttcatattgg ccccctcagt tagccttttt gaggcaatgc catttctaga gttgaaaaag 1560 ccctggaccc aaactgcggc actgttgaat aaagggcagt cctactcctg tccttttaga 1620 gtggcttagt gtgacacaca ggcatctccc aggccaagca cacacaggct gcgcccagtt 1680 ccgcaggagc cgtcccacag cgtggctctc tggattctcc cacttgtcct ccttggaagg 1740 agctcttgct ggccagtgtt tggaggggag gatgagtgcc tgtcactgag gcctcactat 1800 ggttggcgtc tgaagctggg cggtcgtcag gcctgtgctg agagccgcag cccctgtgca 1860 cacctaacac agggcgctcc ccctgctgct tccctggctc agttcttcgg agetccagag 1920 tgagaaggcc gcttcgtcct ttttctctgg gtgatgccct tagaataaca ctatatgcaa 1980 tgtaactcac aatgttccag gaccaaagac ttgatggagg ggctagaggc gacccttgtt 2040 gtaaaaggcg atcagaacac ctgagggagg aaggggcttg cagttttccc agcccttctc 2100 gctgccaagg cagcagtggt gctgtggatg ggctggggac tgcgggacag agcctgctac 2160 tacttgggag ttggtgctgc cctgtggcat ggaggggtgg gaggggctga gatggctgct 2220 ggcccggcct ccaagagttc tggacaggag gcagacactg cccagatgct cggtggaggg 2280 acagtgatgg cctttgactc atgaggcctg gagaaaagta tcaaaggtct caccatgtaa 2340 gagtgatttc cgatttctct cctttcagtt gtgtgaaaaa acagctggcc tgggttccat 2400 tagcaaatta aatcatcttc aatcttaaat tagagaccag aatgatcttc aggataaaaa 2460 gaacttctga atctctgcaa taggaaatgt ttcgatcatg caagtgcttt cccagccaaa 2520 tgtctgtgct ctctgtgtca ctgagggcca caggttcctc taacatctgt cactgtcact 2580 tcaccaggca ggccttggag ttccatgaca aaatcacttt tgtcagacaa agaatgtatc 2640 ctttactttt ctcaaatgga ataaaattat ttcttctgtg gaggaaaatt gattccccct 2700 ttttatttaa tttttttttg gagacagtct cactccttcc c 2741 <210> 44 <211> 2076 <212> DNA
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 1485774CB1 <400> 44 cggggctcca gccaggagcc ctgctgccca gggcatggcc aaacctttct tccgactcca 60 gaagtttctc cgccgaacac agttcctgct gttcttcctc acggctgcct acctgatgac 120 cggcagcctg ctgctgctgc agcgggtccg cgtggctctc ccacagggcc cccgggcacc 180 cggccccctg cagaccttgc cagtggccgc cgtggcgctg ggcgtgggct tgctggacag 240 cagagccctg cacgaccctc gagtcagccc agagctgctg ctgggtgtgg acatgctgca 300 gagccccctg acccggcccc ggcccggccc ccgctggctc cggagccgca actcggagct 3&0 gcgtcagttg cgtcgccgct ggttccacca cttcatgagt gactcccagg gaccgcccgc 420 cctgggcccc gaggctgcca ggcccgccat ccacagccga ggcacctaca ttggatgctt 480 cagtgacgat ggccatgaga ggactctgaa aggagctgtg ttttatgact tgagaaagat 540 gactgtctcc cactgccagg atgcgtgtgc tgagcggtcc tatgtctacg ccggcttgga 600 ggccggggcg gagtgttact gcgggaaccg gctgccagcg gtgagcgtgg ggctggaaga 660 gtgtaaccat gagtgcaaag gcgagaaggg ctctgtgtgc ggggctgtgg accggctctc 720 cgtgtaccgt gtggacgagc tgcagccggg ctccaggaag cggcggaccg ccacctaccg 780 cggatgcttc cgactgccag agaacatcac acatgccttc cccagctccc tgatacaggc 840 caatgtgacc gtggggactt gctcgggctt ttgttcccag aaagagttcc ccttggccat 900 tctcaggggc tgggaatgct actgtgctta ccctaccccc cggttcaacc tgcgggatgc 960 catggacagc tcagtatgtg gccaggaccc tgaggcacag aggctggcag aatactgtga 1020 ggtctaccag acacctgtgc aagacactcg ttgtacagac aggaggttcc tgcctaacaa 1080 atccaaagtg tttgtggctt tgtcaagctt cccaggagcc gggaacacgt gggcacggca 1140 cctcattgag catgccactg gcttctatac agggagctac tactttgatg gaaccctcta 1200 caacaaaggg ttcaagggcg aaaaggacca ctggcggagc cgacgcacca tctgtgtcaa 1260 aacccacgag agtggcagga gggagattga gatgtctgat tcagccatcc tgctaatccg 1320 gaacccatac aggtccctgg tggcagaatt caacagaaaa tgtgccgggc acctgggata 1380 tgcagctgac cgcaactgga agagcaaaga gtggccggac tttgtcaaca gctacgcctc 1440 gtggtggtcc tcgcacgtcc tggactggct caagtacggg aagcggctgc tggtggtgca 1500 ctacgaggag ctgcggcgca gcctggtgcc cacgttacgg gagatggtgg ccttcctcaa 1560 cgtgtctgtg agcgaggagc ggctgctctg cgtggagaac aacaaggagg gcagcttccg 1620 gcggcgcggc cggcgctccc acgaccctga gcccttcacc ccggagatga aagacttgat 1680 caatggctac atccggacgg tggaccaagc cctgcgtgac cacaactgga cggggctgcc 1740 cagggagtat gtgcccagat gataggcctg gcccacgccg ccgcccccgc tgagtgacgc 1800 aatcgcacca cggggctgcg ctccccactc tgatgctcag gcccgtggcc tcactgggac 1860 gaacggtggg tggggggctc accctggtgc tgcctcccgc acaaggagac ctggacacaa 1920 cagacacaca tcacaaggcg aacacaaatg gacacacata cctggccatg aacccacacc 1980 tcctcagaca ctcagacacc actccaggct catagcccgt cttgatgcag agaagccccc 2040 acgtgggtgt gccaggcacc ccagatacaa atgttt 2076 <210> 45 <211> 2957 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7289372CB1 <220>

<221> unsure <222> 311 <223> a, t, c, g, or other <400> 45 cataagattg ctttacacca gggttcctga aatcaaggaa aatactggcc aaaatcaccg 60 accccattct accttcaatt acctagattc tgcgtccccg gcgctaggta cccaatcctg 120 gctgtccgac cacaggatcc ccggcaggga cgggtcacag tgctctcacc cctcgaccat 180 tttcgaaaaa accttcctct gcaaacgcat tgcgccctcc ccatgggtcc gcgggcgggg 240 actccaggcc cgagcagtcg gtgtgaagtt ctgtgttctg aactggggct gagcaagatg 300 cgatggtctc ntaccgctgg gccgcccgta gcgacggcag gagtaggggt attgatctcc 360 acggaagccc caaaccctcg ccatcgagag acccccatgg cccggggtga tggctgtggg 420 gcttggtgct cccagagagc tcagtggcta cagaatgggt ggggattctg cgtgtctccc 480 ggagcctgaa cccctttcct ggttatggcc ggtagctgtc tccagggact aacgtgggca 540 gcgcaggggg gcggaaaccg ggttttagcc aaatgcctcg acatcgccgc gcctccgcct 600 cctcgtcgct gaaagaaatg tcggggtttc atcagagcta gggagcgaca gtcgggaaca 660 gcgagtctgc cgaagccggc tgttgtgtga gggtgtgaga cggcggggcg gtgaggggcc 720 accgcggctt gggggatagt gcgtgtgggg ttgaccgtgt gtctgcttga gaggctgtga 780 agatatgggg ggcagatatg ggagaaatgc tcgggcctga agtccccagc ccaccgtgct 840 caagagtagc ggacgttttg ccaccatcct tgtctgtgct actgtctgct gcagcttccg 900 tgccccgttc tcctggagca gggcgtaaaa gcggcttgca ttcaattagc agcgaagctc 960 gcgggcgctg gcgggacagg cgcgtgaggc cacaacacat gcgtgtatct tgcttgggct 1020 atcttccctg ctctgccacg ccgggtctgg agaaggggtt tcagccccag gacatttact 1080 gagagtcggc gaatattggg agccgcgatg ttcccccttc gggccctgtg gttggtctgg 1140 gcgcttctag gagtggccgg atcatgcccg gagccgtgcg cctgcgtgga caagtacgct 1200 caccagttcg cggactgcgc ttacaaagag ttgcgtgagg tgccggaagg actgcctgcc 1260 aacgtgacga cgcttagtct gtccgcgaac aagatcactg tgctgcggcg cggggccttc 1320 gccgacgtca cacaggtcac gtcgctgtgg ctggcgcaca atgaggtgcg caccgtggag 1380 ccaggcgcac tggccgtgct gagtcagctc aagaacctcg atctgagcca caacttcata 1440 tccagctttc cgtggagcga cctgcgcaac ctgagcgcgc tgcagctgct caaaatgaac 1500 cacaaccgcc tgggctctct gccccgggac gcactcggtg cgctacccga cctgcgttcc 1560 ctgcgcatca acaacaaccg gctgcgtacg ctggcgcctg gcaccttcga cgcgcttagc 1620 gcgctgtcac acttgcaact ctatcacaat cccttccact gcggctgcgg ccttgtgtgg 1680 ctgcaggcct gggccgcgag cacccgggtg tccttacccg agcccgactc cattgcttgt 1740 gcctcgcctc ccgcgctgca gggggtgccg gtgtaccgcc tgcccgccct gccctgtgca 1800 ccgcccagcg tgcatctgag tgccgagcca ccgcttgaag cacccggcac cccactgcgc 1860 gcaggactgg cgttcgtgtt acactgcatc gccgacggcc accctacgcc tcgcctgcaa 1920 tggcaacttc agatccccgg tggcaccgta gtcttagagc caccggttct gagcggggag 1980 gacgacgggg ttggggcgga ggaaggagag ggagaaggag atggggattt gctgacgcag 2040 acccaagccc aaacgccgac tccagcaccc gcttggccgg cgcccccagc cacaccgcgc 2200 ttcctggccc tcgcaaatgg ctccctgttg gtgcccctcc tgagtgccaa ggaggcgggc 2160 gtctacactt gccgtgcaca caatgagctg ggcgccaact ctacgtcaat acgcgtggcg 2220 gtggcagcaa ccgggccccc aaaacacgcg cctggcgccg ggggagaacc cgacggacag 2280 gccccgacct ctgagcgcaa gtccacagcc aagggccggg gcaacagcgt cctgccttcc 2340 aaacccgagg gcaaaatcaa aggccaaggc ctggccaagg tcagcattct cggggagacc 2400 gagacggagc cggaggagga cacaagtgag ggagaggagg ccgaagacca gatcctcgcg 2460 gacccggcgg aggagcagcg ctgtggcaac ggggacccct ctcggtacgt ttctaaccac 2520 gcgttcaacc agagcgcaga gctcaagccg cacgtcttcg agctgggcgt catcgcgctg 2580 gatgtggcgg agcgcgaggc gcgggtgcag ctgactccgc tggctgcgcg ctggggccct 2640 gggcccggcg gggctggcgg agccccgcga cccgggcggc gacccctgcg cctactctat 2700 ctgtgtccag cggggggcgg cgcggcagtg cagtggtccc gcgtagagga aggcgtcaac 2760 gcctactggt tccgcggcct gcggccgggt accaactact ccgtgtgcct ggcgctggcg 2820 ggcgaagcct gccacgtgca agtggtgttt ccaccaagaa ggagctccca tcgctgctgg 2880 tcatagtggc agtgagcgta tccctcctgg tgctggccac agtgcccctt ctgggcgccg 2940 cctgttgcca tctgctg 2957 <210> 46 <211> 1223 <212> DNA
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID IVo: 1672338CB1 <400> 46 ggcacctgga gggccgcact cccgttccag ccaggctgag ccttctgtcc cctgcctctg 60 gggcctggga accccccttc ttctttctcc tgaatggcac ccccgcccta gaatccagac 120 accgagtttc ccactgtggc tggttcaagg gtatgtgaga gctccctggt~gacagtctgt 180 ggctgagcat ggccctccca gccctgggcc tggacccctg gagcctcctg ggccttttcc 240 tcttccaact gcttcagctg ctgctgccga cgacgaccgc ggggggaggc gggcaggggc 300 ccatgcccag ggtcagatac tatgcagggg atgaacgtag ggcacttagc ttcttccacc 360 agaagggcct ccaggatttt gacactctgc tcctgagtgg tgatggaaat actctctacg 420 tgggggctcg agaagccatt ctggccttgg atatccagga tccaggggtc cccaggctaa 480 agaacatgat accgtggcca gccagtgaca gaaaaaagag tgaatgtgcc tttaagaaga 540 agagcaatga gacacagtgt ttcaacttca tccgtgtcct ggtttcttac aatgtcaccc 600 atctctacac ctgcggcacc ttcgccttca gccctgcttg taccttcatt gtgagttctc 660 tggtgcccag cgctcaggcc cccaagcatc ccttctcaca tctacccacg actttcctct 720 gtagctctgg aaaactctgg ccttccagat gcaggaccct catgaacttc ctggccccag 780 accaatttcc ctctatgtcc ctttcccttc cttcctcaag cccctcattt cccagatgtg 840 agaccttggc gttctggccc cccagcctct ctccccattt aggaacttca agattcctac 900 ctgttgccca tctcggagga caaggtcatg gagggaaaag gccaaagccc ctttgacccc 960 gctcacaagc atacggctgt cttggtgggt gagtatcagg tttcccactt catcccaaca 1020 tctactttct ccagtcacgc tgtgaaatat ggaatattac agagttttcc aaaaggcagg 1080 ggaaactggg tgtggtgatg cgtgcatatg gtcccagtta tttggaagct gaagttgaag 1140 gatgcttgag tttaggggtt tgagtctagc ctgggcaaca cagcgagatc gtctcaaaaa 2200 aaaaaaaaaa aaaaaaaaaa aaa 1223 <210> 47 <211> 2888 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 184661CB1 <400> 47 cgcacgacgt aaatcctgcg gctacatgag cggctcggaa ttcggctcga gcccggcccg 60 ggcagctgcg gctcgggatc cgtcgagggg aggccgagct tgccaagctg gcgcccagcg 120 gggtcatggt gcccggcgcc cgcggcggcg gcgcactggc gcgggctgcc gggcggggcc 180 tcctggcttt gctgctcgcg gtctccgccc cgctccggct gcaggcggag gagctgggtg 240 atggctgtgg acacctagtg acttatcagg atagtggcac aatgacatct aagaattatc 300 ccgggaccta ccccaatcac actgtttgcg aaaagacaat tacagtacca aaggggaaaa 360 gactgattct gaggttggga gatttggata tcgaatccca gacctgtgct tctgactatc 420 ttctcttcac cagctcttca gatcaatatg gtccatactg tggaagtatg actgttccca 480 aagaactctt gttgaacaca agtgaagtaa ccgtccgctt tgagagtgga tcccacattt 540 ctggccgggg ttttttgctg acctatgcga gcagcgacca tccagattta ataacatgtt 600 tggaacgagc tagccattat ttgaagacag aatacagcaa attctgccca gctggttgta 660 gagacgtagc aggagacatt tctgggaata tggtagatgg atatagagat acctctttat 720 tgtgcaaagc tgccatccat gcaggaataa ttgctgatga actaggtggc cagatcagtg 780 tgcttcagcg caaagggatc agtcgatatg aagggattct ggccaatggt gttctttcga 840 gggatggttc cctgtcagac aagcgatttc tgtttacctc caatggttgc agcagatcct 900 tgagttttga acctgacggg caaatcagag cttcttcctc atggcagtcg gtcaatgaga 960 gtggagacca agttcactgg tctcctggcc aagcccgact tcaggaccaa ggcccatcat 1020 gggcttcggg cgacagtagc aacaaccaca aaccacgaga gtggctggag atcgatttgg 1080 gggagaaaaa gaaaataaca ggaattagga ccacaggatc tacacagtcg aacttcaact 1140 tttatgttaa gagttttgtg atgaacttca aaaacaataa ttctaagtgg aagacctata 1200 aaggaattgt gaataatgaa gaaaaggtgt ttcagggtaa ctctaacttt cgggacccag 1260 tgcaaaacaa tttcatccct cccatcgtgg ccagatatgt gcgggttgtc ccccagacat 1320 ggcaccagag gatagccttg aaggtggagc tcattggttg ccagattaca caaggtaatg 1380 attcattggt gtggcgcaag acaagtcaaa gcaccagtgt ttcaactaag aaagaagatg 1440 agacaatcac aaggcccatc ccctcggaag aaacatccac aggaataaac attacaacgg 1500 tggctattcc attggtgctc cttgttgtcc tggtgtttgc tggaatgggg atctttgcag 1560 cctttagaaa gaagaagaag aaaggaagtc cgtatggatc agcagaggct cagaaaacag 1620 actgttggaa gcagattaaa tatccctttg ccagacatca gtcagctgag tttaccatca 1680 gctatgataa tgagaaggag atgacacaaa agttagatct catcacaagt gatatggcag 1740 attaccagca gcccctcatg attggcaccg ggacagtcac gaggaagggc tccaccttcc 1800 ggcccatgga cacggatgcc gaggaggcag gggtgagcac cgatgccggc ggccactatg 1860 actgcccgca gcgggccggc cgccacgagt acgcgctgcc ctggcgcccc cggagcccga 1920 gtacgccacg cccatcgtgg agcggcacgt gctgcgcgcc cacacgttct ctgcgcagag 1980 cggctaccgc gtcccagggc cccagcccgg ccacaaacac tccctctcct cgggcggctt 2040 ctcccccgta gcgggtgtgg gcgcccagga cggagactat caaaggccac acagcgcaca 2100 gcctgcgggc aggggctacg accggcccaa agctgtcagc gccctcgcca ccgaaagcgg 2160 acaccctgac tctcagaagc ccccaacgca tcccgggacg agtgacagct attctgcccc 2220 cagagactgc ctcacacccc tcaaccagac ggccatgact gcccttttgt gaacacaatg 2280 tgaaagaagc ctgctgtggt actgagcgtc gggctgtcac aaggcactgg aagaagggag 2340 cctgctggtc cagagtgtgc gtgtgtatcg gtgtgtgtgt acacttgcat gtgtgtgtgt 2400 gatccagtag gatcctagag acaacctgtc atactgttta caaaattgtg cagctggttt 2460 cgtgctgacc cttagggtgc gtctgttggg ttttgttggg ctagaaaaat gaaaattttt 2520 agatggcgtt ttcattcctc tgactgatat tgagctgctt tggtgttaaa ggtgtaatgt 2580 gtacagagtt gtatttaaca ataataaaag taacttaagt ttgctctatc agattttagt 2640 tctgcacaga ggttaagtgg gaaaatgcag ctgttgcaaa atgtatataa atagtatgtt 2700 catttttttc agtatattat ctgatactgt gttagcagca ggtctgtctt aaacctagtc 2760 ttgttgttat ttgagtcatt tcctctcctt tgataactag aactgaaagc atttttaaca 2820 ttcttctcct ggaagaaatg aattacttga agcatgaaaa gcacaccagg gtggttgttt 2880 atttagca 2888 <210> 48 <211> 3142 <212> DNA
<213> Homo sapiens <220>
<221> misc feature <223> Incyte ID No: 3719737CB1 <400> 48.
tgcgcgcagg ctcacaggcc ctgggagtga gctggtgccc ggcgacctgg cacccgcgcc 60 tggatatggg gcgtctacat cgtcccagga gcagcaccag ctacaggaac ctgccgcatc 120 tgtttctgtt tttcctcttc gtgggaccct tcagetgcct cgggagttac agccgggcca 180 ccgagcttct gtacagccta aacgagggac tacccgcggg ggtgctcatc ggcagcctgg 240 ccgaggacct gcggctgctg cccaggtctg cagggaggcc ggacccgcag tcgcagctgc 300 cagagcgcac cggtgctgag tggaaccccc ctctctcctt cagcctggcc tcccggggac 360 tgagtggcca gtacgtgacc ctagacaacc gctctgggga gctgcacact tcagctcagg 420 agatcgacag ggaggccctg tgtgttgaag ggggtggagg gactgcgtgg agcggcagcg 480 tttccatctc ctcctctcct tctgactctt gtcttttgct gctggatgtg cttgtcctgc 540 ctcaggaata cttcaggttt gtgaaggtga agatcgccat cagagacatc aatgacaacg 600 ccccgcagtt ccctgtttcc cagatctcgg tgtgggtccc ggaaaatgca cctgtaaaca 660 cccgactggc catagagcat cctgctgtgg acccagatgt aggcattaat ggggtacaga 720 cctatcgctt actggactac catggtatgt tcaccctgga cgtggaggag aatgagaatg 780 gggagcgcac cccctaccta attgtcatgg gtgctttgga cagggaaacc caggaccagt 840 atgtgagcat catcatagct gaggatggtg ggtctccacc acttttgggc agtgccactc 900 tcaccattgg catcagtgac attaatgaca attgccctct cttcacagac tcacaaatca 960 atgtcactgt gtatgggaat gctacagtgg gcaccccaat tgcagctgtc caggctgtgg 1020 ataaagactt ggggaccaat gctcaaatta cttattctta cagtcagaaa gttccacaag 1080 catctaagga tttatttcac ctggatgaaa acactggagt cattaaactt ttcagtaaga 1140 ttggaggaag tgttctggag tcccacaagc tcaccatcct tgctaatgga ccaggctgca 1200 tccctgctgt aatcactgct cttgtgtcca ttattaaagt tattttcaga ccccctgaaa 1260 ttgtccctcg ttacatagca aacgagatag atggtgttgt ttatctgaaa gaactggaac 1320 ccgttaacac tcccattgcg tttttcacca taagagatcc agaaggtaaa tacaaggtta 1380 actgctacct ggatggtgaa gggccgttta ggttatcacc ttacaaacca tacaataatg 1440 aatatttact agagaccaca aaacctatgg actatgagct acagcagttc tatgaagtag 1500 ctgtggtggc ttggaactct gagggatttc atgtcaaaag ggtcattaaa gtgcaacttt 1560 tagatgacaa tgataatgct ccaattttcc ttcaaccctt aatagaacta accatcgaag 1620 agaacaactc acccaatgcc tttttgacta agctgtatgc tacagatgcc gacagcgagg 1680 agagaggcca agtttcatat tttctgggac ctgatgctcc atcatatttt tccttagaca 1740 gtgtcacagg aattctgaca gtttctactc agctggaccg agaagagaaa gaaaagtaca 1800 gatacactgt cagagctgtt gactgtggga agccacccag agaatcagta gccactgtgg 1860 ccctcacagt gttggataaa aatgacaaca gtcctcggtt tatcaacaag gacttcagct 1920 tttttgtgcc tgaaaacttt ccaggctatg gtgagattgg agtaattagt gtaacagatg 1980 ctgacgctgg acgaaatgga tgggtcgccc tctctgtggt gaaccagagt gatatttttg 2040 tcatagatac aggaaagggt atgctgaggg ctaaagtctc tttggacaga gagcagcaaa 2100 gctcctatac tttgtgggtt gaagctgttg atgggggtga gcctgccctc tcctctacag 2260 caaaaatcac aattctcctt ctagatatca atgacaaccc tcctcttgtt ttgtttcctc 2220 agtctaatat gtcttatctg ttagtactgc cttctactct gccaggctcc ccggttacag 2280 aagtctatgc tgtcgacaaa gacacaggca tgaatgctgt catagcttac agcatcatag 2340 ggagaagagg tcctaggcct gagtccttca ggattgaccc taaaactggc aacattactt 2400 tggaagaggc attgctgcag acagattatg ggctccatcg cttactggtg aaagtgagtg 2460 atcatggtta tcccgagcct ctccactcca cagtcatggt gaacctattt gtcaatgaca 2520 ctgtcagtaa tgagagttac attgagagtc ttttaagaaa agaaccagag attaatatag 2580 aggagaaaga accacaaatc tcaatagaac cgactcatag gaaggtagaa tctgtgtctt 2640 gtatgcccac cttagtagct ctgtctgtaa taagcttggg ttccatcaca ctggtcacag 2700 ggatgggcat atacatctgt ttaaggaaag gggaaaagca tcccagggaa gatgaaaatt 2760 tggaagtaca gattccactg aaaggaaaaa ttgacttgca tatgcgagag agaaagccaa 2820 tggatatttc taatatttga tatttcatgg tggaataaca cagagaaatg ttttaactga 2880 ctttggatct tcatcaccta aaaaagagtg tgttgatggc agttccaatg aaggacaact 2940 aatttataac ttgttctata ttgtaaatag ctgtttacag gtttttaaat ttaaattcag 3000 aggttataaa atgtgtacag catttttaag tgaaaattag tactaacagc tataggactt 3060 gtatttaaaa aaaaaaaaaa aaagcttgga catggtttgc agctttcata caccaagcag 3120 atgtttgata aaacctgggg gt 3142 <210> 49 <211> 4749 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 5773251CB1 <400> 49 gtgcttgcag tggtggaatt cctagagcgt taaatattca gtgataagtg ggcagggttg 60 aggctgaaaa gatagatagg ggccaggtca aagtgggtta atttatgtgc tgtttgtacc 120 aacaagcttg gactttggta ttgtgacagg cagttaggag gcattcaaga cttaagcaga 180 gtgacatggt aaaattactc cagaaaacgt tcaaattata tttgatgatc cactaccaat 240 ttcatacagt cagccagaga aggtgaatgg agagtccaag agcagcagta ccagcgagag 300 tggggacagt gataacatga ggatttccag ctgcagcgat gaaagtagta acagcaacag 360 cagtcgtaag agtgacaatc attcaccagc tgtggtcact accactgtga gcagcaaaaa 420 gcagccatca gttcttgtta catttccaaa ggaagagaga aaatctgttt ctggcaaggc 480 ttcaataaaa ttgtcagaaa ctatcagtga agggaccagt aattctctat ctacttgtac 540 aaaatctggt ccatctcccc tttcttctcc aaatgggaag ttaacagtag caagtcctaa 600 gcgtgggcaa aagagggaag aaggatggaa agaagttgta agaaggtcaa agaaagtcgg 660 aggctggctt tggctgcgaa aagagaaaaa agaaaagaga agagaaggaa gaaaaaggaa 720 gaacaaagaa ggaaactaga agaaattgaa gccaaaaata aaagagaact ttgaactcca 780 agctgctcaa gaaaaagaaa agcttaaagt tgaagatgag cctgaagtct tgacagaacc 840 tccaagtgcc acaaccacta ctaccatagg tatatctgca acctggacaa ctttggcagg 900 ttctcatggt aaaagaaata ataccataac tacaaccagt tcaaagagga aaaacaggaa 960 aaataaaatt actccagaaa acgttcaaat tatatttgat gatccactac caatttcata 1020 cagtcagcca gagaaggtga atggagagtc caagagcagc agtaccagcg agagtgggga 1080 cagtgataac atgaggattt ccagctgcag cgatgaaagt agtaacagca acagcagtcg 1140 taagagtgac aatcattcac cagctgtggt cactaccact gtgagcagca aaaagcagcc 1200 atcagttctt gttacatttc caaaggaaga gagaaaatct gtttctggca aggcttcaat 1260 aaaattgtca gaaactatca gtgaagggac cagtaattct ctatctactt gtacaaaatc 1320 tggtccatct cccctttctt ctccaaatgg gaagttaaca gtagcaagtc ctaagcgtgg 1380 gcaaaagagg gaagaaggat ggaaagaagt tgtaagaagg tcaaagaaag tatctgttcc 1440 atcaactgtg atatccagag tgattggaag aggaggctgt aatatcaatg ctattcggga 1500 gtttactggt gcacacatag atattgataa acagaaagac aagactggag accggataat 1560 cactataagg ggtggcactg aatcaacaag acaagcaact caattgatta atgctttgat 1620 caaggatcca gacaaagaaa ttgatgaact tattccaaag aatcgtttga aaagctcctc 1680 agcaaattcc aaaatagggt catcagcacc taccaccact gctgctaaca cttccttaat 1740 gggaattaaa atgacaactg tagctctgtc atcaacatct caaactgcca cagcactcac 1800 tgtgcctgca atttcttctg catccactca caaaaccatt aagaacccag tgaataatgt 1860 gaggcctggt tttccagttt ctcttccatt agcatatcct cctccacagt ttgcacatgc 1920 tttgcttgct gctcagactt tccagcagat ccgtccacca aggttgccca tgacccactt 1980 tggaggtact tttccaccag ctcaatccac ttggggtccg tttcctgtca ggcctttgag 2040 ccctgccaga gctactaact cgcctaagcc tcacatggtg cctcgccata gcaatcagaa 2100 tagcagtggt tctcaggtga attcagcagg ttctttaact tcaagcccaa caactacaac 2160 cagttcatca gcttcaacgg tgcctggtac atctacaaat ggcagtccaa gttcaccttc 2220 tgtccgaagg cagctttttg tcacagttgt gaagacatcc aatgccacca caacaacagt 2280 cacaaccacg gcaagcaaca acaacactgc acccacaaat gccacatatc ctatgcctac 2340 tgccaaagaa cactatccag tatcatcccc atcttcccca tcaccaccag cccagccagg 2400 aggggtttct agaaacagcc ctttggattg tggatcagca tctccaaata aagtggcatc 2460 ttcctccgaa caggaagcag gtagtccacc agtagtagaa acaacaaaca ctagacctcc 2520 aaacagcagc agttcttctg ggagttcatc agctcattct aatcagcaac aacctccggg 2580 atctgtttct caggaaccaa gaccacctct tcagcagtct caggttcctc ccccggaagt 2640 tagaatgact gttcctcctt tagcaacaag ttctgctcca gtggcggtgc cttctactgc 2700 cccagtgact taccctatgc ctcagacacc aatgggatgc ccccagccta ctcctaaaat 2760 ggaaacccct gctattagac caccccctca tggcacaact gcccctcaca agaattcagc 2820 ttcagtgcaa aattcatctg ttgcagtcct tagtgtcaat cacattaaaa gacctcacag 2880 tgttccctct tctgtccagc taccttcgac cttaagtaca caaagtgctt gtcagaattc 2940 agtacatcca gcaaataagc ctattgctcc caatttcagt gcccccttac catttgggcc 3000 ctttagcaca ttgtttgaaa acagccctac ttctgctcat gccttctggg gaggatctgt 3060 tgtttcatct cagtcaacac cagaatctat gctatcagga aaatcctcat atttgccaaa 3120 ttcagatcct ttacatcagt ctgatacttc caaagctcca ggttttagac caccattaca 3180 gagacctgct ccaagtccct caggtattgt caatatggac tcgccatatg gttctgtaac 3240 accttcttca acacatttgg gaaactttgc ttcaaacatt tcaggaggtc agatgtacgg 3300 acctggggca ccccttggag gagcacccgc agctgctaac tttaacagac aacatttttc 3360 cccgcttagt ttgttgactc cgtgttcatc agcatcaaat gattcttctg cacagtcagt 3420 atcctcggga gttcgtgcac catctcctgc cccatcatca gtaccgttag ggtcagaaaa 3480 gcccagcaat gtgtctcagg acaggaaagt tccagtccct attgggactg aacgttctgc 3540 acgtatcagg caaactggaa cgtcagctcc atctgttatt gggagcaatt tgtctacatc 3600 agtaggacat agtggcatct ggtcctttga agggattggt ggcaatcaag acaaagtaga 3660 ctggtgtaac cctgggatgg gaaatcctat gatccacaga ccgatgtctg acccaggagt 3720 attttcacaa catcaagcaa tggagcgaga tagtacagga attgtaactc cttctggtac 3780 attccatcag catgttcctg caggctacat ggactttcct aaagttgggg gtatgccttt 3840 ttctgtgtat gggaatgcaa tgattcctcc agtagcacct atccctgatg gtgctggagg 3900 acccatattt aatggccctc atgctgcaga cccttcttgg aactcactga taaagatggt 3960 ttccagctcc acggaaaata atggccctca aacggtgtgg actggaccct gggcacctca 4020 catgaacagt gtgcatatga accagcttgg ctgatgagga tcagcttgtt agcctgcaga 4080 ttccttttca tttggaggaa atcacaagtg gccgaaaaaa aaaattatgc tcccaaatca 4140 ttctactgat gtgcttgact gaagtgtgta ggctttttgc agaagatctt actaactgac 4200 ctattttctg tgaacatttg tgactgccca ttccccatca tcatccgttt taccttagtt 4260 agcatttttc ttatcatttt tctttttttc tttccctctt cccctttgga cataactttc 4320 tgttgaagct gttctttggc tggttggttt tagtactgta aactgcttct gagcaaacac 4380 ggaaatttag caaaattatg taaacttgat cctgaagttt tagaatggca aataaatgta 4440 caattgttta cataacagaa aaggctaagc agaaagtaaa tttcaatatg tcagtataga 4500 ggctctactt tatgtagact taaattaatg tgagatatgt accttcatat tcagaaatct 4560 ggatgtttcc ttcatacatt aaactattaa taagcataac ttttctactg gtgtaattta 4620 agtataaagt aaaataatgg gcattatcat tggatgtttc cccacattgg cttttaaaat 4680 acccatcttg ctttcttttt ggtttatttg tagcaaggca catatagaag aagaaatttc 4740 tggcttttc 4749 <210> 50 <211> 4155 <212> DNA
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 5426470CB1 <400> 50 gccgtcgggg cgggcgtctg gcgagctgca gagaccagat taaaggattt acctgaagag 60 aaagcattct attcatcaga gactggacaa gagttactct tgcatttggc aattaaagat 120 gatgtttcca tggaaacagt tgatcctgct ttcattcatt ggctgcttag gaggtgagct 180 tctcttacaa ggccctgtat ttatcaaaga acccagcaac agcattttcc ctgttggttc 240 agaagataaa aaaataactt tgcattgtga agcaagaggc aatccatcac ctcattacag 300 atggcagctg aatggaagtg atattgatat gagtatggaa catcgttata agttgaatgg 360 aggaaatctt gtggttatta atcccaacag aaattgggat acaggaactt accaatgttt 420 tgcaacaaat tcacttggaa caattgtcag cagagaagcc aaacttcagt ttgcctatct 480 tgaaaatttt aaaaccaaaa tgaggagtac agtgtctgtg cgtgaaggcc agggagttgt 540 gctgctctgc ggccccccac cacactctgg agaactgtca tatgcttgga tcttcaatga 600 atacccatcg tttgttgaag aagatagtcg gagatttgtc tcccaggaga cagggcacct 660 ctacatatct aaggtggagc cgtctgatgt gggaaattac acatgtgtgg tgacaagtat 720 ggtgacaaat gcccgagtgc tgggctctcc aactcctttg gtgctacgtt ctgatggtgt 780 gatgggtgaa tatgaaccta aaatagaagt tcagtttcca gaaactcttc cagcagctaa 840 aggttcgact gtgaaattgg aatgttttgc ccttggaaat cccatacctc agattaattg 900 gagaagaagt gatgggctgc cattttccag caaaattaaa ttaaggaagt tcagtggtgt 960 gcttgaaatc cccaacttcc aacaggaaga tgcaggttcc tatgaatgca ttgctgagaa 1020 ttcacgagga aaaaatgttg ccagagggcg tctcacttac tatgcaaagc cccattgggt 1080 tcaactcata aaggatgtgg aaatagccgt ggaggacagt ctttattggg aatgcagggc 1140 aagcggcaag cccaagcctt cctaccgatg gctgaaaaat ggagcagccc tggtgctaga 1200 ggagagaaca cagatagaaa atggtgccct tacaatatca aacctaagtg tgactgattc 1260 tggcatgttc caatgcatag cagaaaacaa acatggcctt gtttattcca gtgctgagct 1320 caaagttgtt gcttctgctc cagatttttc aaagaatcca atgaagaagt tggttcaggt 1380 gcaggtgggc agcctggtca gcttggattg taaacccaga gcctccccaa gggcactctc 1440 ttcctggaag aagggggatg tgagcgtgca ggagcatgaa agaatttctt tgttaaacga 1500 tggaggactc aaaatagcca atgtgactaa agctgatgct ggaacttaca cctgcatggc 1560 agaaaaccag tttgggaaag caaatggcac aacacatttg gttgttacgg aaccaacaag 1620 aataactttg gcaccatcta acatggatgt ttctgttggt gaaagcgtca tattgccctg 1680 ccaggtacaa catgacccgc tgttagacat catctttacc tggtatttca atggggccct 1740 tgcagatttt aagaaagatg gatctcactt tgagaaagtt ggtgggagtt catctggtga 1800 tttaatgatc agaaacattc agctgaaaca cagtgggaaa tatgtttgta tggtgcaaac 1860 gggggtggac agtgtttcat ctgctgctga cctcatagta agaggttcac ctggaccacc 1920 agaaaatgtg aaggtagatg aaattacaga cacaacagcc caactctctt ggaaagaagg 1980 taaagacaac catagcccag ttatatccta ttctatccag gctcggacac ctttctccgt 2040 gggttggcaa accgtcacaa cagtgcctga ggtcatcgat gggaagacgc acacagccac 2100 tgtagttgag ttaaacccat gggtggaata tgaatttcgg gttgtagcca gtaacaaaat 2160 tggaggtgga gaaccaagtt taccctcaga aaaagtaaga actgaagagg cagttccaga 2220 agtgcctcct tctgaagtca atggaggagg cggaagccgg tctgaacttg tgataacctg 2280 ggatccagtc cctgaagaac tacagaatgg tgaaggtttt gggtatgttg ttgctttccg 2340 ccctcttggg gttaccacct ggatccagac agtggtgaca tcccctgaca ccccaagata 2400 tgtctttagg aatgaaagca tcgtgccata ttcaccatat gaagttaaag tgggtgttta 2460 taataacaaa ggtgaaggac catttagccc agtgacaaca gtgttctctg cagaagaaga 2520 gcctacagtg gccccatctc aagtctctgc aaatagccta tcttcctcag aaattgaggt 2580 ttcatggaac accattcctt ggaagttgag caatggacat ttactgggct atgaggtgcg 2640 gtactggaat gggggtggaa aggaggaatc atccagtaag atgaaagtgg caggaaatga 2700 gacatcagcc agactacggg gcctgaagag caacctggcc tattacacgg ctgtccgggc 2760 ttacaacagt gccggcgctg ggccttttag cgccacagtt aatgtaacca ccaagaaaac 2820 gcctcccagt cagccaccag gaaatgttgt ttggaatgcc acagacacta aagtgttact 2880 taattgggag caagttaaag ccatggagaa tgagtcagaa gtaacaggat ataaagtttt 2940 ctataggact agcagtcaaa ataacgtaca agtactgaac acaaataaaa cttcagctga 3000 acttgtgctg cccattaaag aggactacat tattgaagtc aaggccacaa cagatggagg 3060 ggatgggacc agtagtgaac agatcaggat tccacgaata accagtatgg atgcaagagg 3120 atccacttca gccatctcga atgtccaccc tatgtcaagt tatatgccta tagtactgtt 3180 cttaattgta tatgtcctgt ggtgatatta actccttttt attatttatt ggaaagttat 3240 ttggttacca aaaaaagtgc tttcatgaaa tgcagtgatt atgcatgttt ttttcaactc 3300 ttatttttaa ctttctactt cattataggt aaatatgaat ataattaaaa aaacagtaaa 3360 tccttttagg ggaatctgaa atgccttaat attaacttga taaaccaaag gaatttacat 3420 attacatact tcagactttt gatataaatg ttcttaaact atgagtttaa gcactgccta 3480 tggataaaga ctcacacact ctcacatgta cacacacacg catgagaatt tctttttaca 3540 ttgaaaaact ctttcattta attcaaatgc tattttccca ttataatagc attatttgga 3600 agacttaacc agtatcaatt tgaaatgctg atttaagtcc ccaaggatga aaaatacatt 3660 ttaaaaatta ttttgttgga gaggagtggc atgtgattca aaagagcatt gttggaaaat 3720 gctactgtgg ggcttagaag aatgatgttt ggtttggtat gctgctaact agttgtaaga 3780 ctttacaaat cactttgcca tctgtacctc tcaattattc ctctataaaa tatggagata 3840 ataataccta tctgatcaga ctttgcccca tgaattagtt tttaaaagat aaagactgaa 3900 gtatgaaagt gcttttgtca ccccaaatgc aattgaccca tgcaaaatat tagcatgaat 3960 ttatttaatc acataaaagt catgaagacc agccagattt tcaagcttca ttctgtttca 4020 ttcagttata ttccaaaatt caaatgatca cattttattc tttctcaaaa aaaaaaaagt 4080 ttttttaaat taaaaaagga attgtttcct tcacagctat gaataagctt tcaggtttta 4140 ttaaaaccta gagga 4155 <210> 51 <211> 1327 <212> DNA
<213> Homo sapiens <220>
<221> misc_~eature <223> Incyte ID No: 7087904CB1 <400> 51 gcgagctgaa agctgctgga gagtgagcag ccctagcagg gatggacatg atgctgttgg 60 tgcagggtgc ttgttgctcg aaccagtggc tggcggcggt gctcctcagc ctgtgctgcc 120 tgctaccctc ctgcctcccg gctggacaga gtgtggactt cccctgggcg gccgtggaca 180 acatgatggt cagaaaaggg gacacggcgg tgcttaggtg ttatttggaa gatggagctt 240 caaagggtgc ctggctgaac cggtcaagta ttatttttgc gggaggtgat aagtggtcag 300 tggatcctcg agtttcaatt tcaacattga ataaaaggga ctacagcctc cagatacaga 360 atgtagatgt gacagatgat ggcccataca cgtgttctgt tcagactcaa catacaccca 420 gaacaatgca ggtgcatcta actgtgcaag ttcctcctaa gatatatgac atctcaaatg 480 atatgaccgt caatgaagga accaacgtca ctcttacttg tttggccact gggaaaccag 540 agccttccat ttcttggcga cacatctccc catcagcaaa accatttgaa aatggacaat 600 atttggacat ttatggaatt acaagggacc aggctgggga atatgaatgc agtgcggaaa 660 atgatgtgtc attcccagat gtgaggaaag taaaagttgt tgtcaacttt gctcctacta 720 ttcaggaaat taaatctggc accgtgaccc ccggacgcag tggcctgata agatgtgaag 780 gtgcaggtgt gccgcctcca gcctttgaat ggtacaaagg agagaagaag ctcttcaatg 840 gccaacaagg aattattatt caaaatttta gcacaagatc cattctcact gttaccaacg 900 tgacacagga gcacttcggc aattatactt gtgtggctgc caacaagcta ggcacaacca 960 atgcgagcct gcctcttaac cctccaagta cagcccagta tggaattacc gggagcgctg 1020 atgttctttt ctcctgctgg taccttgtgt tgacactgtc ctctttcacc agcatattct 1080 acctgaagaa tgccattcta caataaattc aaagacccat aaaaggcttt taaggattct 1140 ctgaaagtgc tgatggctgg atccaatctg gtacagttgt taaaagcgcg tgggatttat 1200 cagcagtgct acctgggatg accgctttgg aaaatgccct tatttatcct tatccaccct 1260 tttgaaagaa ctccttgagg cgacattgcc tttaaacgac gcgaatctaa gatacggccg 1320 ttgcacc 1327 <210> 52 <211> 5529 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477312CB1 <400> 52 atgcagctga gccgcgccgc cgccgccgcc gccgccgccc ctgcggagcc cccggagccg 60 ctgtcccccg cgccggcccc ggccccggcc ccccccggcc ccctcccgcg cagcgcggcc 120 gacggggctc cggcgggggg gaaggggggg ccggggcgcc gcgcgcggag tccccgggcg 180 ctccgttccc cggcgcgagc ggccccggcc cgggccccgg cgcggggatg gacggccccg 240 gggccagggg ccagcgccgt ggtcgtgcgc gtcggcatcc cggacctgca gcagacgaag 300 tgcctgcgcc tggacccggc cgcgcccgtg tgggccgcca agcagcgcgt gctctgcgcc 360 ctcaaccaca gcctccagga cgcgctcaac tatgggcttt tccagccgcc ctcccggggc 420 cgcgccggca agttcctgga tgaggagcgg ctcctgcagg agtacccgcc caacctggac 480 acgcccctgc cctacctgga gtttcgatac aagcggcgag tttatgccca gaacctcatc 540 gatgataagc agtttgcaaa gcttcacaca aaggcgaacc tgaagaagtt catggactac 600 gtccagctgc atagcacgga caaggtggca cgcctgttgg acaaggggct ggaccccaac 660 ttccatgacc ctgactcagg agagtgcccc ctgagcctcg cagcccagct ggacaacgcc 720 acggacctgc taaaggtgct gaagaatggt ggtgcccacc tggacttccg cactcgcgat 780 gggctcactg ccgtgcactg tgccacacgc cagcggaatg cggcagcact gacgaccctg 840 ctggacctgg gggcttcacc tgactacaag gacagccgcg gcttgacacc cctctaccac 900 agcgccctgg ggggtgggga tgccctctgc tgtgagctgc ttctccacga ccacgctcag 960 ctggggacca ccgacgagaa tggctggcag gagatccacc aggcctgccg ctttgggcac 1020 gtgcagcatc tggagcacct gctgttctat ggggcagaca tgggggccca gaacgcctcg 1080 gggaacacag ccctgcacat ctgtgccctc tacaaccagg agagctgtgc tcgtgtcctg 1140 ctcttccgtg gagctaacag ggatgtccgc aactacaaca gccagacagc cttccaggtg 1200 gccatcatcg cagggaactt tgagcttgca gaggttatca agacccacaa agactcggat ~~1260 gttggacagg acagtcatga cttgctacat cctatgccca ctggggtccc agagtggggc 1320 ctgtacacag aagaggaact ggaaggaggt gccgccttct ctgtaccatt cagggaaacc 1380 cccagctatg cgaagcggcg gcgactggct ggccccagtg gcttggcatc ccctcggcct 1440 ctgcagcgct cagccagcga tatcaacctg aagggggagg cacagccagc agcttctcct 1500 ggaccctcgc tgagaagcct cccccaccag ctgctgctcc agcggctgca agaggagaaa 1560 gatcgtgacc gggatgccga ccaggagage aacatcagtg gccctttagc aggcagggcc 1620 ggccaaagca agatcaggag ctgtattcga attcgagctc ggttccccgc gccccctgcg 1680 ccccccgcac cgccgccccg gggcccgaag cggaaacttt acagcgccgt ccccggccgc 1740 aagttcatcg ccgtgaaggc gcacagcccg cagggtgaag gcgagatccc gctgcaccgc 1800 ggcgaggccg tgaaggtgct cagcattggg gagggcggtt tctgggaggg aaccgtgaaa 1860 ggccgcacgg gctggttccc ggccgactgc gtggaggaag tgcagatgag gcagcatgac 1920 acacggcctg aaacgcggga ggaccggacg aagcggctct ttcggcacta cacagtgggc 1980 tcctacgaca gcctcacctc acacagcgat tatgtcattg atgacaaagt ggctgtcctg 2040 cagaaacggg accacgaggg ctttggtttt gtgctccggg gagccaaagc agagaccccc 2100 atcgaggagt tcacgcccac gccagccttc ccggcgctgc agtatctcga gtcggtggac 2160 gtggagggtg tggcctggag ggccgggctg cgcacgggag acttcctcat cgaggtgaac 2220 ggggtgaacg tggtgaaggt cggacacaag caggtggtgg ctctgattcg ccagggtggc 2280 aaccgcctcg tcatgaaggt tgtgtctgtg acaaggaagc cagaagagga cggggctcgg 2340 cgcagagccc caccgccccc caagagggcc cccagcacca cactgaccct gcgctccaag 2400 tccatgacag ctgagctcga ggaacttgag aagctggacg agatgctggc agccgccgca 2460 gagccaacgc tgcggccaga catcgcagac gcagactcca gagccgccac cgtcaaacag 2520 aggcccacca gtcggaggat cacacccgcc gagattagct cattgtttga acgccagggc 2580 ctcccaggcc cagagaagct gccgggctcc ttgcggaagg ggattccacg gaccaagtct 2640 gtaggggagg acgagaagct ggcgtccctg ctggaagggc gcttcccgcg gagcacctcg 2700 atgcaagacc cggtgcgcga gggtcgcggc atcccgcccc cgccgcagac cgcgccgcct 2760 cccccgcccg cgccctacta cttcgactcg gggccgcccc cggccttctc gccgccgccc 2820 ccgccgggcc gcgcctacga cacggtgcgc tccagcttca agcccggcct ggaggcgcgc 2880 ctgggcgcgg gcgctgccgg cctgtacgag ccgggcgcgg ccctcggccc gctgccgtat 2940 cccgagcggc agaagcgcgc gcgctccatg atcatcctgc aggactcggc gcccgagtcg 3000 ggcgacgccc ctcgaccccc gcccgcggcc accccgcccg agcgacccaa gcgccggccg 3060 cggccgcccg gccccgacag cccctacgcc aacctgggcg ccttcagcgc cagcctcttc 3120 gctccgtcca agccgcagcg ccgcaagagc cccctggtga agcagctgca ggtggaggac 3180 gcgcaggagc gcgcggccct ggccgtgggc agccccggtc ccggcggcgg cagcttcgcc 3240 cgcgagccct ccccgaccca ccgcggtccg cgcccgggtg gcctcgacta cggcgcgggc 3300 gatggcccgg ggctcgcgtt cggcggcccg ggcccggcca aggaccggcg gctggaggag 3360 cggcgccgct ccactgtgtt cctgtccgtg ggggccatcg agggcagcgc ccccggcgcg 3420 gatctgccat ccctacagcc ctcccgctcc atcgacgagc gcctcctggg gaccggcccc 3480 accgccggcc gcgacctgct gctgccctcc ccggtgtctg ccctgaagcc gttggtcagc 3540 ggcccgagcc tggggccctc gggttccacc ttcatccacc cactcaccgg caaacccctg 3600 gaccccagct cacccctggc ccttgccctg gctgcccgag agcgagctct ggcctcccag 3660 gcgccctccc ggtcccccac acccgtgcac agtcccgacg ccgaccgccc cggacccctg 3720 tttgtggatg tacaggcccg ggacccagag cgagggtccc tggcttcccc ggctttctcc 3780 ccacggagcc cagcctggat tcctgtgcct gctcgcaggg aggcagagaa ggtcccccgg 3840 gaggagcgga agtcacccga ggacaagaag tccatgatcc tcagcgtcct ggacacatcc 3900 ctgcagcggc cagctggcct catcgttgtg cacgccacca gcaacgggca ggagcccagc 3960 aggctggggg gggccgaaga ggagcgcccg ggcaccccgg agttggcccc ggcccccatg 4020 cagtcagcgg ctgtggcaga gcccctgccc agcccccggg cccagccccc tggtggcacc 4080 ccggcagacg ccgggccagg ccagggcagc tcagaggaag agccagagct ggtgtttgct 4140 gtgaacctgc cacctgccca gctgtcgtcc agcgatgagg agaccaggga ggagctggcc 4200 cgaattgggt tggtgccacc ccctgaagag tttgccaacg gggtcctgct ggccacccca 4260 ctcgctggcc cgggcccctc gcccaccacg gtgcccagcc cggcctcagg gaagcccagc 4320 agtgagccac cccctgcccc tgagtctgca gccgactctg gggtggagga ggctgacaca 4380 cgcagctcca gcgaccccca cctggagacc acaagcacca tctccacggt gtccagcatg 4440 tccaccttga gctcggagag cggggaactc actgacaccc acacctcctt cgctgacgga 4500 cacacttttc tactcgagaa gccaccagtg cctcccaagc ccaagctcaa gtccccgctg 4560 gggaaggggc cggtgacctt cagggacccg ctgctgaagc agtcctcgga cagcgagctc 4620 atggcccagc agcaccacgc cgcctctgcc gggctggcct ctgccgccgg gcctgcccgc 4680 cctcgctacc tcttccagag aaggtccaag ctatgggggg accccgtgga gagccggggg 4740 ctccctgggc ctgaagacga caaaccaact gtgatcagtg agctcagctc ccgcctgcag 4800 cagctgaaca aggacacgcg ttccctgggg gaggaaccag ttggtggcct gggcagcctg 4860 ctggaccctg ccaagaagtc gcccatcgca gcagctcggc tcttcagcag cctcggtgag 4920 ctgagctcca tttcagcgca gcgcagcccc gggggcccgg gcggcggggc ctcgtactcg 4980 gtgaggccca gtggccgcta ccccgtggcg agacgcgccc cgagcccggt gaagcccgcg 5040 tcgctggagc gggtggaggg gctgggggcg ggcgcggggg gcgcagggcg gcccttcggc 5100 ctcacgcccc ccaccatcct caagtcgtcc agcctctcca tcccgcacga gcccaaggag 5160 gtgcgcttcg tggtgcgcag cgtgagcgcg cgcagtcgct ccccctcgcc gtcgccgctg 5220 ccctcgcccg cgtccggccc cggccccggc gcccccggcc cacgccgacc cttccagcag 5280 aagccgctgc agctctggag caagttcgac gtgggcgact ggctggagag catccaccta 5340 ggcgagcacc gcgaccgctt cgaggaccat gagatagaag gcgcgcacct acccgcgctt 5400 accaaggacg acttcgtgga gctgggcgtc acgcgcgtgg gccaccgcat gaacatcgag 5460 cgcgcgctca ggcagctgga cggcagctga cgccccaccc ccactcccgc cccaggccga 5520 gcccgcggc <210> 53 <211> 1623 <212> DNA
<213> Homo sapiens <220>
<221> mist feature <223> Incyte ID No: 2739431CB1 <400> 53 tgatatttga agaagtgttt tcatctatcc aagaaaaata tgatgtctcc atcccaagcc 60 tcactcttat tcttaaatgt atgtattttt atttgtggag aagctgtaca aggtaactgt 120 gtacatcatt ctacggactc ttcagtagtt aacattgtag aagatggatc taatgcaaaa 180 gatgaaagta aaagtaatga tactgtttgt aaggaagact gtgaggaatc atgtgatgtt 240 aaaactaaaa ttacacgaga agaaaaacat ttcatgtgta gaaatttgca aaattctatt 300 gtttcctaca caagaagtac caaaaaacta ctaaggaata tgatggatga gcaacaagct 360 tccttggatt atttatctaa tcaggtaatg tgtgacatgg attacagagg aggtggatgg 420 actgtgatac agaaaagaat tgatgggata attgatttcc agag.gttgtg gtgtgattat 480 ctggatggat ttggagatct tctaggagaa ttttggctag gactgaaaaa gattttttat 540 atagtaaatc agaaaaatac cagttttatg ctgtatgtgg ctttggaatc tgaagatgac 600 actcttgctt atgcatcata tgataatttt tggctagagg atgaaacgag attttttaaa 660 atgcacttag gacggtattc aggaaatgct ggtgatgcat tccggggtct caaaaaagaa 720 gataatcaaa atgcaatgcc ttttagcaca tcagatgttg ataatgatgg gtgtcgccct 780 gcatgcctgg tcaatggtca gtctgtgaag agctgcagtc acctccataa caagaccggc 840 tggtggttta acgagtgtgg tctagcaaat ctaaatggca ttcatcactt ctctggaaaa 900 ttgcttgcaa ctggaattca atggggcacg tggaccaaaa acaactcacc tgtcaagatt 960 aaatctgttt caatgaaaat tagaagaatg tacaatccat attttaaata atctcattta 1020 acattgtaat gcaagttcta caatgataat atattaaaga tttttaaaag tttatctttt 1080 cacttagtgt ttcaaacata ttaggcaaaa tttaactgta gatggcattt agatgttatg 1140 agtttaatta gaaaacttca attttgtagt attctataaa agaaaacatg gcttattgta 1200 tgtttttact tctgactata ttaacaatat acaatgaaat ttgtttcaag tgaactacaa 1260 cttgtcttcc taaaatttat agtgatttta aaggattttg ccttttcttt gaagcatttt 1320 taaaccataa tatgttgtaa ggaaaattga agggaatatt ttacttattt ttatacttta 1380 tatgattata taatctacag ataatttcta ctgaagacag ttacaataaa taactttatg 1440 cagattaata tataagctac acatgatgta aaaaccttac tatttctagg tgatgccata 1500 ccattttaaa agtagtaaga gtttgctgcc caaatagttt ttcttgtttt catatctaat 1560 catggttaac tattttgtta ttgtttgtaa taaatatatg tacttttata tcctgaaaaa 1620 aaa 1623 <210> 54 <211> 2242 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473606CB1 <400> 54 ccacaagggc ctgactgagc gagcgagcat ggacggccgc ggggctttct ggacagtggc 60 cattcccaga gccaggcagg aaggcctcgg gaggctgggg ctcccgttcc cggtgaagcg 120 gacgccgcca gcgccccaga acccaggagg aagcacacag gccccacaga gagtggttgg 180 caagagtcac tcggggatta ggatgccggc caaatcgcgg aatttgaggc tggaatccaa 240 gctcaacagg aaagtagtga aatacaaatg gggaaaacag ggctctggag cggggaggga 300 gctggtgccg gcatttccca ccas.cgccgg tttaggaaga cgggaccgat gccggccgcc 360 ccctgctgga ggggatgtgg catctcacgg gctgccaggg agcggggttg gctactcctg 420 caaccagcgt gaagagggtc tcaggggagg ctgtggtggg~ atcccccacg tgcccttgtt 480 cctctcaccg ttacctctgg atgcctcggg gcaaaggcct tcttccacct atagacagag 540 tctacgcagg ggtcttggaa cccgggcaca ccagtcccca gctaacgaaa tccccgagtt 600 gggggatttg agagggtcac gtttggccca agaacccgca gtcctctttg gtcttcggcc 660 ctctatttct aagcgtgggc ttctggcacg gcggctctgg gcacagccca tgctgctttc 720 gggctgggtg gtttcaacga cgacaacaat tatcacagtg acggtgacct tcaccccaac.780 aggactgctg tgtgtgaagc actcaagagg gcccctacaa ccaacctgcc aggagtcggc 840 tcctgaaaac agggtcggaa aagcgctaat tactttttcc aaaggctgga gggcttcact 900 ccggctggcg ccgccgccta gcgcgctcct gcttcgccgc cacggtccgg gggggctgcc 960 ggtcccgggt accatgtgtg acggcgccct gctgcctccg ctcgtcctgc ccgtgctgct 1020 gctgctggtt tggggactgg acccgggcac aggtagcgcc ccctcccaca gccctcttca 1080 ccccgcgtcc tgcggctacc ttccctctgc gttctcgcgg cgtcctggcg gcccgggggc 1140 ggcggcggga ccgctgacgg cgcccgagcg gaggaggcgc gggccgcggc cggagtacgg 1200 gaatcgggtg gctccgtggc aggcgcgccg ccgccgggtc tccgctcgcc gatgcgcggc 1260 gccgttccgg gaggtgctcg cgcggctgcg ccggagaccc tccccgggtg gcgcgggcca 1320 gcgtggagct gtcggcgacg cggcggccga cgtggaggtg gtgctcccgt ggcgggtgcg 1380 ccccgacgac gtgcacctgc cgccgctgcc cgcagccccc gggccccgac ggcggcgacg 1440 cccccgcacg cccccagccg ccccgcgcgc ccggcccgga gagcgcgccc tgctgctgca 1500 cctgccggcc ttcgggcgcg acctgtacct tcagctgcgc cgcgacctgc gcttcctgtc 1560 ccgaggcttc gaggtggagg aggcgggcgc ggcccggcgc cgcggccgcc ccgccgagct 1620 gtgcttctac tcgggccgtg tgctcggcca ccccggctcc ctcgtctcgc tcagcgcctg 1680 cggcgccgcc ggcggcctgg ttggcctcat tcagcttggg caggagcagg tgctaatcca 1740 gcccctcaac aactcccagg gcccattcag tggacgagaa catctgatca ggcgcaaatg 1800 gtccttgacc cccagccctt ctgctgaggc ccagagacct gagcagctct gcaaggttct 1860 aacagttcca cagtgtctgg gcctcacctg ggaggacttg aaatctggag gctggagtga 1920 tctggaggtg cctcattcat gtgtctggcc tggaggtgga tgacttgaag acaaggacaa 1980 caacgtggag cgtctacctg tggcctctgc agcttggcgt ccataccttg gtggcagaca 2040 tacttcttct atggccacca gggctcccaa tgcaagagtt cccgcaagcc cagcaggagc 2100 tgtgctgcct ttgaggatca gcctcagaaa tcctagagca tcactctgaa ggtactctgt 2160 tggctgaagc ggttagaaac ctacccaggt tcaagggcag agagatagac cccaccgctc 2220 aatgtcaaag aatttggggg gc 2242 <210> 55 <211> 3751 <212> DNA
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 3534918CB1 <400> 55 ttcatggagc atggagcgct tggcagcctt ggggaacatg cagcgaaagt tgtgggaaag 60 gtactcagac aagagcaaga ctttgtaata acccaccacc agcgtttggt gggtcctact 120 gtgatggagc agaaacacag atgcaagttt gcaatgaaag aaattgtcca attcatggca 180 agtgggcgac ttgggccagt tggagtgcct gttctgtgtc atgtggagga ggtgccagac 240 agagaacaag gggctgctcc gaccctgtgc cccagtatgg aggaaggaaa tgcgaaggga 300 gtgatgtcca gagtgatttt tgcaacagtg acccttgccc aagtgagtgt tggaaatacc 360 catggtaact ggagtccttg gagtggctgg ggaacatgca gccggacgtg taacggaggg 420 cagatgcggc ggtaccgcac atgtgataac cctcctccct ccaatggggg aagagcttgt 480 gggggaccag actcccagat ccagaggtgc aacactgaca tgtgtcctgt ggatggaagt 540 tggggaagct ggcatagttg gagccagtgc tctgcctcct gtggaggagg tgaaaagact 600 cggaagcggc tgtgcgacca tcctgtgcca gttaaaggtg gccgtccctg tcccggagac 660 actactcagg tgaccaggtg caatgtacaa gcatgtccag gtgggcccca gcgagccaga 720 ggaagtgtta ttggaaatat taatgatgtt gaatttggaa ttgctttcct taatgccaca 780 ataactgata gccctaactc tgatactaga ataatacgtg ccaaaattac caatgtacct 840 cgtagtcttg gttcagcaat gagaaagata gtttctattc taaatcccat ttattggaca 900 acagcaaagg aaataggaga agcagtcaat ggctttaccc tcaccaatgc agtcttcaaa 960 agagaaactc aagtggaatt tgcaactgga gaaatcttgc agatgagtca tattgcccgg 1020 ggcttggatt ccgatggttc tttgctgcta gatatcgttg tgagtggcta tgtcctacag 1080 cttcagtcac ctgctgaagt cactgtaaag gattacacag aggactacat tcaaacaggt 1140 cctgggcagc tgtacgccta ctcaacccgg ctgttcacca ttgatggcat cagcatccca 1200 tacacatgga accacaccgt tttctatgat caggcacagg gaagaatgcc tttcttggtt 1260 gaaacacttc atgcatcctc tgtggaatct gactataacc agatagaaga gacactgggt 1320 tttaaaattc atgcttcaat atccaaagga gatcgcagta atcagtgccc ctccgggttt 1380 accttagact cagttggacc tttttgtgct gatgaggatg aatgtgcagc agggaatccc 1440 tgctcccata gctgccacaa tgccatgggg acttactact gctcctgccc taaaggcctc 1500 accatagctg cagatggaag aacttgtcaa gatattgatg agtgtgcttt gggtaggcat 1560 acctgccacg ctggtcagga ctgtgacaat acgattggat cttatcgctg tgtggtccgt 1620 tgtggaagtg gctttcgaag aacctctgat gggctgagtt gtcaagatat taatgaatgt 1680 caagaatcca gcccctgtca ccagcgctgt ttcaatgcca taggaagttt ccattgtgga 1740 tgtgaacctg ggtatcagct caaaggcaga aaatgcatgg atgtgaacga gtgtagacaa 1800 aatgtatgca gaccagatca gcactgtaag aacacccgtg gtggctataa gtgcattgat 1860 ctttgtccaa atggaatgac caaggcagaa aatggaacct gtattgatat tgatgaatgt 1920 aaagatggga cccatcagtg cagatataac cagatatgtg agaatacaag aggcagctat 1980 cgttgtgtat gcccaagagg ttatcggtct,caaggagttg gaagaccctg catggatatt 2040 gatgaatgtg aaaatacaga tgcctgccag catgagtgta agaatacctt tggaagttat 2100 cagtgcatct gcccacctgg ctatcaactc acacacaatg gaaagacatg ccaagatatc 2160 gatgaatgtc tggagcagaa tgtgcactgt ggacccaatc gcatgtgctt caacatgaga 2220 ggaagctacc agtgcatcga tacaccctgt ccacccaact accaacggga tcctgtttca 2280 gggttctgcc tcaagaactg tccacccaat gatttggaat gtgccttgag cccatatgcc 2340 ttggaataca aactcgtctc cctcccattt ggaatagcca ccaatcaaga tttaatccgg 2400 ctggttgcat acacacagga tggagtgatg catcccagga caactttcct catggtagat 2460 gaggaacaga ctgttccttt tgccttgagg gatgaaaacc tgaaaggagt ggtgtataca 2520 acacgaccac tacgagaagc agagacctac cgcatgaggg tccgagcctc atcctacagt 2580 gccaatggga ccattgaata tcagaccaca ttcatagttt atatagctgt gtccgcctat 2640 ccatactaag gaactctcca aagcctattc cacatattta aaccgcatta atcatggcaa 2700 tcaagccccc ttccagatta ctgtctcttg aacagttgca atcttggcag cttgaaaatg 2760 gtgctacact ctgttttgtg tgccttcctt ggtacttctg aggtattttc atgatcccac 2820 catggtcata tcttgaagta tggtctagaa aagtccctta ttattttatt tattacactg 2880 gagcagttac ttcccaaaga ttattctgaa catctaacag gacatatcag tgatggttta 2940 cagtagtgta gtacctaaga tcattttcct gaaagccaaa ccaaacaacg aaaaacaaga 3000 acaactaatt cagaatcaaa tagagttttt gagcatttga ctatttttag aatcataaaa 3060 ttagttacta agtattttga tcaaagctta taaaataact tacggagatt tttgtaagta 3120 ttgatacatt ataataggac ttgcctattt tcatttttaa gaagaaaaac accactcatt 3180 ttataaaata tagtacagct actataaggc ttgtttgatc ccaaatggtg cttatcttga 3240 ttgaacattc agaacaagga tattattttc agtgattttg tgagatcagc tgaaccactt 3300 atgataataa taataaaaaa gactgctttg ccctcacgtc agttgtacat ggcatggaac 3360 tttaaaaatt ttaatataaa ctttcatcca gttagcttca taacttttac gttccagaat 3420 tttgtttatt ttcctgtcaa tgaaagcaat ttttaaagat accagtggga caggtttggt 3480 tttttaaaaa tctcatgtgt tcaaattaac ataaatatta cacgtcaata cactgtacat 3540 ggtggtaata gactctaagc aattgccaag atgtattcta tttttatgaa gtgtatatat 3600 attaccttag tgtgcatttt ctatataata tcttgatgga ctcttttata aaattatttt 3660 ataaaaaaca atgttacact aaaatcagcc taaataaatt ttcacaactt tttttcataa 3720 ccaaaaacaa caaacaacaa aaccggggcc g 3751 <210> 56 <211> 3579 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2428715CB1 <400> 56 gggtcgacca cgcgtcgggg caggtggcga gcagcgagca gcgcctgcgg gagcggcc,gg 60 tcggtcgggt ccccgcgccc cgcacgcccg cacgcccagc ggggcccgca ttgagcatgg 120 gcgcggcggc cgtgcgctgg cacttgtgcg tgctgctggc cctgggcaca cgcgggcggc 180 tggccggggg cagcgggctc ccagggtcag tcgacgtgga tgagtgctca gagggcacag 240 atgactgcca catcgatgcc atctgtcaga acacgcccaa gtcctacaaa tgcctctgca 300 agccaggcta caagggggaa ggcaagcagt gtgaagacat tgacgagtgt gagaatgact 360 actacaatgg gggctgtgtc cacgagtgca tcaacatccc ggggaactac aggtgtacct 420 gctttgatgg cttcatgctg gcacacgatg gacacaactg cctggatgtg gacgagtgtc 480 aggacaataa tggtggctgc cagcagatct gcgtcaatgc catgggcagc tacgagtgtc 540 agtgccacag tggcttcttc cttagtgaca accagcatac ctgcatccac cgctccaatg 600 agggtatgaa ctgcatgaac aaagaccatg gctgtgccca catctgccgg gagacgccca 660 aaggtggggt ggcctgcgac tgcaggcccg gctttgacct tgcccaaaac cagaaggact 720 gcacactaac ctgtaattat ggaaacggag gctgccagca cagctgtgag gacacagaca 780 caggccccac gtgtggttgc caccagaagt acgccctcca ctcagacggt cgcacgtgca 840 tcgagaagga tgaggctgca attgagcgct ctcagttcaa tgccacgtca gtagctgatg 900 tggacaagcg ggtgaaacgg cggctactca tggagacgtg cgcagtcaat aacggaggct 960 gcgaccggac atgcaaggac acagccactg gcgtgcgatg cagctgcccc gttggattca 1020 cactgcagcc ggacgggaag acatgcaaag acatcaacga gtgcctggtc aacaacggag 1080 gctgcgacca cttctgccgc aacaccgtgg gcagcttcga gtgcggctgc cggaagggct 1140 acaagctgct caccgacgag cgcacctgcc aggacatcga cgagtgctcc ttcgagcgga 1200 cctgtgacca catctgcatc aactccccgg gcagcttcca gtgcctgtgt caccgcggct 1260 acatcctcta cgggacaacc cactgcggag atgtggacga gtgcagcatg agcaacggga 1320 gctgtgacca gggctgcgtc aacaccaagg gcagctacga gtgcgtctgt cccccgggga 1380 ggcggctcca ctggaaccgg aaggattgcg tggagacagg caagtgtctt tctcgtgcca 1440 agacctcccc ccgggcccag ctgtcctgca gcaaggcagg cggtgtggag agctgcttcc 2500 tttcctgccc ggctcacaca ctcttcgtgc cagatgcccc caccaccccc atcaaacaga 1560 aggcccgctt caagatccga gatgccaagt gccacctccg gccccacagc caggcacgag 1620 caaaggagac cgccaggcag ccgctgctgg accactgcca tgtgactttc gtgaccctca 1680 agtgtgactc ctccaagaag aggcgccgtg gccgcaagtc cccatccaag gaggtgtccc 1740 acatcacagc agagtttgag atcgagacaa agatggaaga ggcctcagac acatgcgaag 1800 cggactgctt gcggaagcga gcagaacaga gcctgcaggc cgccatcaag accctgcgca.1860 agtccatcgg ccggcagcag ttctatgtcc aggtctcagg cactgagtac gaggtagccc 1920 agaggccagc caaggcgctg gaggggcagg gggcatgtgg cgcaggccag gtgctacagg 1980 acagcaaatg cgttgcctgt gggcctggca cccacttcgg tggtgagctc ggccagtgtg 2040 tgccatgtat gccaggaaca taccaggaca tggaaggcca gctcagttgc acaccgtgcc 2100 ccagcagcga cgggcttggt ctgcctggtg cccgcaacgt gtcggaatgt ggaggccagt 2160 gttctccagg cttcttctcg gccgatggct tcaagccctg ccaggcctgc cccgtgggca 2220 cgtaccagcc tgagcccggg cgcaccggct gcttcccctg tggagggggt ttgctcacca 2280 aacacgaagg caccacctcc ttccaggact gcgaggctaa agtgcactgc tcccccggcc 2340 accactacaa caccaccacc caccgctgca tccgctgccc cgtcggcacc taccagcccg 2400 agtttggcca gaaccactgc atcacctgtc cgggcaacac cagcacagac ttcgatggct 2460 ccaccaacgt cacacactgc aaaaaccagc actgcggcgg cgagcttggt gactacaccg 2520 gctacatcga gtcccccaac taccctggcg actacccagc caacgctgaa tgcgtctggc 2580 acatcgcacc tcccccaaag cgcaggatcc tcatcgtggt ccctgagatc ttcctgccca 2640 tcgaggatga gtgcggcgat gttctggtca tgaggaagag tgcctctccc acgtccatca 2700 ccacctatga gacctgccag acctacgaga ggcccatcgc cttcacctcc cgctcccgca 2760 agctctggat ccagttcaaa tccaatgaag gcaacagcgg caaaggcttc caagtgccct 2820 atgtcaccta cgatgaggac taccagcaac tcatagagga catcgtgcgc gatgggcgcc 2880 tgtacgcctc ggagaaccac caggaaattt tgaaagacaa gaagctgatc aaggccctct 2940 tcgacgtgct ggcgcatccc cagaaccgcg gcttagtttc ctcatgttaa aagaaaatac 3000 ttatcctccc tgtggcacag ggttttgttt aaaagattag acaagatgat acaaccattt 3060 tggaaataat ttggcagctt cttataaaca tatactttac aggtaagcca gcaattgcac 3120 tcctagctgc acccacgaga aatgaaaata tgtccataca aagatttata cacaaatgtt 3180 tatagcagct ttattcataa taatcaaaaa ctgaaaacaa ctcaaacatc catcaacagg 3240 cagatggata aacaaattat ggtatgtcca tgcaacggaa tacaactcac tgatgaaaag 3300 gaataaacca caaatgcctg caacgccatg atgaatctca aaacatgctg agtgtagaga 3360 agccagacac aagagtagat actcctatac aattccactt acatggaaat ctagaaaaga 3420 caattcgaat atatagtggc aaaaagcaga agagtggttg cctggaacca gggtgggaat 3480 gaagattaac tgcccagagg cataaaaaat ggggtggtgg gggcggtgat ggaaaagtgc 3540 tatgccttca ctgtaccttt gtcaaaactt gttgaactg 3579 <210> 57 <211> 5178 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3351332CB1 <400> 57 gggaacccag aaccagcccg agccgcctgc cccgtcgccc ggccgccggc ttagggcgca 60 gcgcggttgg tcctcgcccc ctcccgcccg ccggcctacc aggccatggg ggcgtcccgg 120 gaccgcgggc tggccgcgct ctggtgcctt gggctcctgg ggggcctggc gcgcgtcgcg 180 ggcacgcact accgctacct ctggaggggc tgctacccat gtcacctggg ccaggccggc 240 taccccgtga gcgccggtga ccagaggcca gatgtggacg aatgccgaac ccacaacggt 300 ggctgccagc accggtgcgt gaacacccca ggctcctacc tctgtgagtg caagcccggc 360 ttccggctcc acactgacag caggacctgc ctggccatta actcctgcgc cctgggcaat 420 ggcggctgcc agcaccactg tgtccagctc acaatcactc ggcatcgctg ccagtgccgg 480 cccgggttcc agctccagga ggacggcagg cattgtgtcc gtagaagccc gtgtgccaac 540 aggaacggca gctgcatgca caggtgccag gtggtccggg gcctcgcccg ctgtgagtgc 600 cacgtgggct atcagctagc agcggacggc aaggcctgtc cagatgtgga cgaatgtgcc 660 gcagggctgg cccagtgtgc ccatggctgc ctcaacaccc aggggtcctt caagtgcgtg 720 tgtcacgcgg gctatgagct gggcgccgat ggccggcagt gctaccggat tgagatggaa 780 atcgtgaaca gctgtgaggc caacaacggc ggctgctccc atggctgcag ccacaccagt 840 gctgggcccc tgtgcacatg tccccgcggc tacgagctgg acacagatca gaggacctgc 900 atcgatgtcg acgactgtgc agacagcccg tgctgccagc aggtgtgcac caacaaccct 960 ggcgggtacg agtgcggctg ctacgccggc taccggctca gtgccgatgg ctgcggctgt 1020 gaggatgtgg atgagtgcgc ctccagccgt ggcggctgcg agcaccactg caccaacctg 1080 gccggctcct tccagtgctc ctgcgaggcc ggctaccggc tgcacgagga ccgtaggggc 1140 tgcagccccc tggaggagcc gatggtggac ctggacggcg agctgccttt cgtgcggccc 1200 ctgccccaca ttgccgtgct ccaggacgag ctgccgcaac tcttccagga tgacgacgtc 1260 ggggccgatg aggaagaggc agagttgcgg ggcgaacaca cgctcacaga gaagtttgtc 1320 tgcctggatg actcctttgg ccatgactgc agcttgacct gtgatgactg caggaacgga 1380 gggacctgcc tcctgggcct ggatggctgt gattgccccg agggctggac tgggctcatc 1440 tgcaatgaga cttgtcctcc ggacaccttt gggaagaact gcagcttctc ctgcagctgt 1500 cagaatggtg ggacctgcga ctctgtcacg ggggcctgcc gctgcccccc gggtgtcagt 1560 ggaactaact gtgaggatgg ctgccccaag ggctactatg'gcaagcactg tcgcaagaaa 1620 tgcaactgtg ccaaccgggg ccggtgccac cgcctctacg gggcctgcct ctgcgaccca 1680 gggctctacg gccgcttctg ccacctcacc tgcccgccgt gggcctttgg gccgggctgc 1740 tcggaggagt gccagtgtgt gcagccccac acgcagtcct gtgacaagag ggatggcagc 1800 tgctcctgca aggctggctt ccggggcgag cgctgtcagg cagagtgtga gctgggctac 1860 tttgggccgg ggtgctggca ggcatgcacc tgcccagtgg gcgtggcctg tgactccgtg 1920 agcggcgagt gtgggaagcg gtgtcctgct ggcttccagg gagaggactg tggccaagag 1980 tgcccggtgg ggacgtttgg cgtgaactgc tcgagctcct gctcctgtgg gggggccccc 2040 tgccacgggg tcacggggca gtgccggtgt ccgccgggga ggactgggga agactgtgag 2100 gcagattgtc ccgagggccg ctgggggctg ggctgccagg agatctgccc agcatgccag 2160 cacgctgccc gctgcgaccc tgagaccgga gcctgcctgt gcctccctgg cttcgtcggc 2220 agccgctgcc aggacgtgtg cccagcaggc tggtatggtc ccagctgcca gacaaggtgc 2280 tcttgtgcca atgatgggca ctgccaccca gccaccggac actgcagctg tgcccccggg 2340 tggaccggct ttagctgcca gagagcctgt gatactgggc actggggacc tgactgcagc 2400 cacccctgca actgcagcgc tggccacggg agctgtgatg ccatcagcgg cctgtgtctg 2460 tgtgaggctg gctacgtggg cccgcggtgc gagcagcagt gtccccaggg ccactttggg 2520 cccggctgtg agcagctgtg ccagtgtcag catggagcag cctgtgacca cgtcagcggg 2580 gcctgcacct gcccggccgg ctggaggggc accttctgcg agcatgcctg cccggccggc 2640 ttctttggat tggactgtcg cagtgcctgc aactgcaccg ccggagctgc ctgtgatgcc 2700 gtgaatggct cctgcctctg ccccgctggc cgccggggcc cccgctgtgc cgagacctgc 2760 ccagcccaca cctacgggca caattgcagc caggcctgtg cctgctttaa cggggcctcc 2820 tgtgaccctg tccacgggca gtgccactgt gcccctggct ggatggggcc ctcctgcctg 2880 caggagtgcc tcccccggga cgtcagagct ggctgccggc acagcggcgg ttgcctcaac 2940 gggggcctgt gtgacccgca cacgggccgc tgcctctgcc cagccggctg gactggggac 3000 aagtgtcaga gcccctgcct gcggggctgg tttggagagg cctgtgccca gcgctgcagc 3060 tgcccgcctg gcgctgcctg ccaccacgtc actggggcct gccgctgtcc ccctggcttc 3120 actggctccg gctgcgagca ggcctgccca cccggcagct ttggggagga ctgtgcgcag 3180 atgtgccagt gtcccggtga gaacccggcc tgccaccctg ccaccgggac ctgctcatgt 3240 gctgctggct accacggccc cagctgccag caacgatgtc cgcccgggcg gtatgggcca 3300 ggctgtgaac agctgtgtgg gtgtctcaac gggggctcct gtgatgcggc cacgggggcc 3360 tgccgctgcc ccactgggtt cctcgggacg gactgcaacc tcacctgtcc gcagggccgc 3420 ttcggcccca actgcaccca cgtgtgtggg tgtgggcagg gggcggcctg cgaccctgtg 3480 accggcacct gcctctgccc cccggggaga gccggcgtcc gctgtgagcg aggctgcccc 3540 cagaaccggt ttggcgtggg ctgcgagcac acctgctcct gcagaaatgg gggcctgtgc 3600 cacgccagca acggcagctg ctcctgtggc ctgggctgga cggggcggca ctgcgagctg 3660 gcctgtcccc ctgggcgcta cggagccgcc tgccatctgg agtgctcctg ccacaacaac 3720 agcacgtgtg agcctgccac gggcacctgc cgctgcggcc ccggcttcta tggccaggcc 3780 tgcgagcacc cctgtccccc tggcttccac ggggctggct gccaggggtt gtgctggtgt 3840 caacatggag ccccctgcga ccccatcagt ggccgatgcc tctgccctgc cggcttccac 3900 ggccacttct gtgagagggg gtgtgagcca ggttcatttg gagagggctg ccaccagcgc 3960 tgtgactgtg acgggggggc accctgtgac cctgtcaccg gtctctgcct ttgcccacca 4020 gggcgctcag gagccacctg taacctggat tgcagaaggg gccagtttgg gcccagctgc 4080 accctgcact gtgactgcgg gggtggggct gactgcgacc ctgtcagtgg gcagtgtcac 4140 tgtgtggatg gctacatggg gcccacgtgc cgggaaggtg ggcccctccg gctccccgag 4200 aacccgtcct tagcccaggg ctcagcgggc acactgcccg cctccagcag acccacatcc 4260 cggagcggtg gaccagcgag gcactagtag aggcagtccc gtggagcccg cctctccagt 4320 cccagccaga ggggaccctg gcctttggtg accactgaga aggacacttc acgggcccag 4380 agctcctggt actgcccttc ctttgagggc cgtggagggc tgtggacagc ccagcaacct 4440 gtcgctcttg gaggctggtg tggccttgag gagggaagcc tcgcatggcc gctggaagag 4500 aggcgcctcc tggcctggct ctgcagaacc caggggcacg ctctgggcct gggctgagga 4560 agtcccgctc tccccgcggc tctgagttgg actgaggaca ggtgtgggcg ccagtgtggg 4620 tgcaggcgca ggtgcaggca cagggccact gtcctccagg caggcttttt ggtgctaggc 4680 cctgggactg gaagtcgccc agcccgtatt tatgtaaagg tatttatggg ccactgcaca 4740 tgcccgctgc agccctggga tcagctggaa gctgcctgtc atctcctgcc caatccccag 4800 aaaccctgat tcaggtctgc aggctcctgc gggctcacca ggctgctggc tccggtacca 4860 tgtaaaccta ggaaggtaaa ggagcaggca acctcctcgt ggcctgtgtg tttgctgtgt 4920 tacgtggact ctgtgtgggc tcctccctgg ggcccggcca gcataacggt gcacccaggg 4980 acctcccagt gcacccgggg ccctttgcag gggtgggggt gccacacaag tgaagaagtt 5040 gggactcatc tcagttccca gtgctattga ggagaacgct ggggctgcat tcattaccgc 5100 tgagacccag agactggctg ttcccagaga atggcccagg gggaggaggg ctggtgtgga 5160 agggcaactt ggactgag 5178 <210> 58 <211> 11367 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 6382722CB1 <400> 58 atggcgaagc ggctctgcgc ggggagcgca ctgtgtgttc gcggcccccg gggccccgcg 60 ccgctgctgc tggtcgggct ggcgctgctg ggcgcggcgc gggcgcggga ggaggcgggc 120 ggcggcttca gcctgcaccc gccctacttc aacctggccg agggcgcccg catcgccgcc 180 tccgcgacct gcggagagga ggccccggcg cgcggctccc cgcgccccac cgaggacctt 240 tactgcaagc tggtaggggg ccccgtggcc ggcggcgacc ccaaccagac catccggggc 300 cagtactgcg acatctgcac ggctgccaac agcaacaagg cacaccccgc gagcaatgcc 360 atcgatggca cggagcgctg gtggcagagt ccaccgctgt cccgcggcct ggagtacaac 420 gaggtcaacg tcaccctgga cctgggccag gtcttccacg tggcctacgt cctcatcaag 480 tttgccaact caccccggcc ggacctctgg gtgctggagc ggtccatgga cttcggccgc 540 acctaccagc cctggcagtt ctttgcctcc tctaagaggg actgtctgga gcggttcggg 600 ccacagacgc tggagcgcat cacacgggac gacgcggcca tctgcaccac cgagtactca 660 cgcatcgtgc ccctggagaa cggagagatc gtggtgtccc tggtgaacgg acgtccgggc 720 gccatgaatt tctcctactc gccgctgcta cgtgagttca ccaaggccac caacgtccgc 780 ctgcgcttcc tgcgtaccaa cacgctgctg ggccatctca tggggaaggc gctgcgggac 840 cccacggtca cccgccggta ttattacagc atcaaggata tcagcatcgg aggccgctgt 900 gtctgccacg gccacgcgga tgcctgcgat gccaaagacc ccacggaccc gttcaggctg 960 cagtgcacct gccagcacaa cacctgcggg ggcacctgcg accgctgctg ccccggcttc 1020 aatcagcagc cgtggaagcc tgcgactgcc aacagtgcca acgagtgcca gtcctgtaac 1080 tgctacggcc atgccaccga ctgttactac gaccctgagg tggaccggcg ccgcgccagc 1140 cagagcctgg atggcaccta tcagggtggg ggtgtctgta tcgactgcca gcaccacacc 1200 gccggcgtca actgtgagcg ctgcctgccc ggcttctacc gctctcccaa ccaccctctc 1260 gactcgcccc acgtctgccg ccgctgcaac tgcgagtccg acttcacgga tggcacctgc 1320 gaggacctga cgggtcgatg ctactgccgg cccaacttct ctggggagcg gtgtgacgtg 1380 tgtgccgagg gcttcacggg cttcccaagc tgctacccga cgccctcgtc ctccaatgac 1440 accagggagc aggtgctgcc agctggccag attgtgaatt gtgactgcag cgcggcaggg 1500 acccagggca acgcctgccg gaaggaccca agggtgggac gctgtctgtg caaacccaac 1560 ttccaaggca cccattgtga gctctgcgcg ccagggttct acggccccgg ctgccagccc 1620 tgccagtgtt ccagccctgg agtggccgat gaccgctgtg accctgacac aggccagtgc 1680 aggtgccgag tgggcttcga gggggccaca tgtgatcgct gtgcccccgg ctactttcac 1740 ttccctctct gccagttgtg tggctgcagc cctgcaggaa ccttgcccga gggctgcgat 1800 gaggccggcc gctgcctatg ccagcctgag tttgctggac ctcattgtga ccggtgccgc 1860 cctggctacc atggtttccc caactgccaa gcatgcacct gcgaccctcg gggagccctg 1920 gaccagctct gtggggcggg aggtttgtgc cgctgccgcc ccggctacac aggcactgcc 1980 tgccaggaat gcagccccgg ctttcacggc ttccccagct gtgtcccctg ccactgctct 2040 gctgaaggct ccctgcacgc agcctgtgac ccccggagtg ggcagtgcag ctgccggccc 2100 cgtgtgacgg ggctgcggtg tgacacgtgt gtgcccggtg cctacaactt cccctactgc 2160 gaagctggct cttgccaccc tgccggtctg gccccagtgg atcctgccct tcctgaggca 2220 caggttccct gtatgtgccg ggctcacgtg gaggggccga gctgtgaccg ctgcaaacct 2280 gggttctggg gactgagccc cagcaacccc gagggctgta cccgctgcag ctgcgacctc 2340 aggggcacac tgggtggagt tgctgagtgc cagccgggca ccggccagtg cttctgcaag 2400 ccccacgtgt gcggccaggc ctgcgcgtcc tgcaaggatg gcttctttgg actggatcag 2460 gctgactatt ttggctgccg cagctgccgg tgtgacattg gcggtgcact gggccagagc 25.20 tgtgaaccga ggacgggcgt ctgccggtgc cgccccaaca cccagggccc cacctgcagc 2580 gagcctgcga gggaccacta cctcccggac ctgcaccacc tgcgcctgga gctggaggag 2640 gctgccacac ctgagggtca cgccgtgcgc tttggcttca accccctcga gttcgagaac 2700 ttcagctgga ggggctacgc gcagatggca cctgtccagc ccaggatcgt ggccaggctg 2760 aacctgacct cccccgacct tttctggctc gtcttccgat acgtcaaccg gggggccatg 2820 agtgtgagcg ggcgggtctc tgtgcgagag gagggcaggt cggccgcctg tgccaactgc 2880 acagcacaga gtcagcccgt ggccttccca cccagcacgg agcctgcctt catcaccgtg 2940 ccccagaggg gcttcggaga gccctttgtg ctgaaccctg gcacctgggc cctgcgtgtg 3000 gaggccgaag gggtgctcct ggactacgtg gttctgctgc ctagcgcata ctacgaggcg 3060 gcgctcctgc agctgcgggt gactgaggcc tgcacatacc gtccctctgc ccagcagtct 3120 ggcgacaact gcctcctcta cacacacctc cccctggatg gcttcccctc ggccgc.cggg 3180 ctggaggccc tgtgtcgcca ggacaacagc ctgccccggc cctgccccac ggagcagctc 3240 agcccgtcgc acccgccact gatcacctgc acgggcagtg atgtggacgt ccagcttcaa 3300 gtggcagtgc cacagccagg ccgctatgcc ctagtggtgg agtacgccaa tgaggatgcc 3360 cgccaggagg tgggcgtggc tgtgcacacc ccacagcggg ccccccagca ggggctgctc 3420 tccctgcacc cctgcctgta cagcaccctg tgccggggca ctgcccggga tacccaggac 348,0 cacctggctg tcttccacct ggactcggag gccagcgtga ggctcacagc cgagcaggca 3540 cgcttcttcc tgcacggggt cactctggtg cccattgagg agttcagccc ggagttcgtg 3600 gagccccggg tcagctgcat cagcagccac ggcgcctttg gccccaacag tgccgcctgt 3660 ctgccctcgc gcttcccaaa gccgccccag cccatcatcc tcagggactg ccaggtgatc 3720 ccgctgccgc ccggcctccc gctgacccac gcgcaggatc tcactccagc cacgtcccca 3780 gctggacccc gacctcggcc ccccaccgct gtggaccctg atgcagagcc caccctgctg 3840 cgtgagcccc aggccaccgt ggtcttcacc acccatgtgc ccacgctggg ccgctatgcc 3900 ttcctgctgc acggctacca gccagcccac cccaccttcc ccgtggaagt cctcatcaac 3960 gccggccgcg tgtggcaggg ccacgccaac gccagcttct gtccacatgg ctacggctgc 4020 cgcaccctgg tggtgtgtga gggccaggcc ctgctggacg tgacccacag cgagctcact 4080 gtgaccgtgc gtgtgcccga gggccggtgg ctctggctgg attatgtact cgtggtccct 4140 gagaacgtct acagctttgg ctacctccgg gaggagcccc tggataaatc ctatgacttc 4200 atcagccact gcgcagccca gggctaccac atcagcccca gcagctcatc cctgttctgc 4260 cgaaacgctg ctgcttccct ctccctcttc tataacaacg gagcccgtcc atgtggctgc 4320 cacgaagtag gtgctacagg ccccacgtgt gagcccttcg ggggccagtg tccctgccat 4380 gcccatgtca ttggccgtga ctgctcccgc tgtgccaccg gatactgggg cttccccaac 4440 tgcaggccct gtgactgcgg tgcccgcctc tgtgacgagc tcacgggcca gtgcatctgc 4500 ccgccacgca ccatcccgcc cgactgcctg ctgtgccagc cccagacctt tggctgccac 4560 cccctggtcg gctgtgagga gtgtaactgc tcagggcccg gcatccagga gctcacagac 4620 cctacctgtg acacagacag cggccagtgc aagtgcagac ccaacgtgac tgggcgccgc 4680 tgtgatacct gctctccggg cttccatggc tacccccgct gccgcccctg tgactgtcac 4740 gaggcgggca ctgcgcctgg cgtgtgtgac cccctcacag ggcagtgcta ctgtaaggag 4800 aacgtgcagg gccccaaatg tgaccagtgc agccttggga ccttctcact ggatgctgcc 4860 aaccccaaag gttgcacccg ctgcttctgc tttggggcca cggagcgctg ccggagctcg 4920 tcctacaccc gccaggagtt cgtggatatg gagggatggg tgctgctgag cactgaccgg 4980 caggtggtgc cccacgagcg gcagccaggg acggagatgc tccgtgcaga cctgcggcac 5040 gtgcctgagg ctgtgcccga ggctttcccc gagctgtact ggcaggcccc accctcctac 5100 ctgggggacc gggtgtcatc ctacggtggg accctccgtt atgaactgca ctcagagacc 5160 cagcggggag atgtctttgt ccccatggag agcaggccgg atgtggtgct gcagggcaac 5220 cagatgagca tcacattcct ggagccggca taccccacgc ctggccacgt tcaccgtggg 5280 cagctgcagc tggtggaggg gaacttccgg catacggaga ctcgcaacac tgtgtcccgc 5340 gaggagctca tgatggtgct ggccagcctg gagcagctgc agatccgtgc cctcttctca 5400 cagatctcct cggctgtctc cctgcgcagg gtggcactgg aggtggccag cccagcaggc 5460 cagggggccc tggccagcaa tgtggagctg tgcctgtgcc ccgccagcta ccggggggac 5520 tcatgccagg aatgtgcccc cggcttctat cgggacgtca aaggtctctt cctgggccga 5580 tgtgtccctt gtcagtgcca tggacactca gaccgctgcc tccctggctc tggcgtctgt 5640 gtggactgcc agcacaacac cgaaggggcc cactgtgagc gctgccaggc tggcttcatg 5700 agcagcaggg acgaccccag cgccccctgt gtcagctgcc cctgccccct ctcagtgcct 5760 tccaacaact tcgccgaggg ctgtgtcctg cgaggcggcc gcacccagtg cctctgcaaa 5820 cctggttatg caggtgcctc ctgcgagcgg tgtgcgcccg gattctttgg gaacccactg 5880 gtgctgggca gctcctgcca gccatgcgac tgcagcggca acggtgaccc caacttgctc 5940 ttcagcgact gcgaccccct gacgggcgcc tgccgtggct gcctgcgcca caccactggg 6000 ccccgctgcg agatctgtgc ccccggcttc tacggcaacg ccctgctgcc cggcaactgc 6060 acccggtgcg actgtacccc atgtgggaca gaggcctgcg acccccacag cgggcactgc 6120 ctgtgcaagg cgggcgtgac tgggcggcgc tgtgaccgct gccaggaggg acattttggt 6180 ttcaatggct gcgggggctg ccgcccgtgt gcttgtggac cggccgccga gggctccgag 6240 tgccaccccc agagcggaca gtgccactgc cgaccaggga ccatgggacc ccagtgccgc 6300 gagtgtgccc ctggctactg ggggctccct gagcagggct gcaggcgctg ccagtgccct 6360 gggggccgct gtgaccctca cacgggccgc tgcaactgcc ccccggggct cagcggggag 6420 cgctgcgaca cctgcagcca gcagcatcag gtgcctgttc caggcgggcc tgtgggccac 6480 agcatccact gtgaagtgtg tgaccactgt gtggtcctgc tcctggatga cctggaacgg 6540 gccggcgccc tcctccccgc cattcacgag caactgcgtg gcatcaatgc cagctccatg 6600 gcctgggccc gtctgcacag gctgaacgcc tccatcgctg acctgcagag ccagctccgg 6660 agccccctgg gcccccgcca tgagacggca cagcagctgg aggtgctgga gcagcagagc 6720 acaagcctcg ggcaggacgc acggcggcta ggcggccagg ccgtggggac ccgagaccag 6780 gcgagccaat tgctggccgg caccgaggcc acactgggcc atgcgaagac gctgttggcg 6840 gccatccggg ctgtggaccg caccctgagc gagctcatgt cccagacggg ccacctgggg 6900 ctggccaatg cctcggctcc atcaggtgag cagctgctcc ggacactggc cgaggtggag 6960 cggctgctct gggagatgcg ggcccgggac ctgggggccc cgcaggcagc agctgaggct 7020 gagttggctg cagcacagag attgctggcc cgggtgcagg agcagctgag cagcctctgg 7080 gaggagaacc aggcactggc cacacaaacg~cgcgaccggc tggcccagca cgaggccggc 7140 ctcatggacc tgcgagaggc tttgaaccgg gcagtggacg ccacacggga ggcccaggag 7200 ctcaacagcc gcaaccagga gcgcctggag gaagccctgc aaaggaagca ggagctgtcc 7260 cgggacaatg ccaccctgca ggccactctg catgcggcta gggacaccct ggccagcgtc 7320 ttcagattgc tgcacagcct ggaccaggct aaggaggagc tggagcgcct cgccgccagc 7380 ctggacgggg ctcggacccc actgctgcag aggatgcaga ccttctcccc ggcgggcagc 7440 aagctgcgtc tagtggaggc cgccgaggcc cacgcacagc agctgggcca gctggcactc 7500 aatctgtcca gcatcatcct ggacgtcaac caggaccgcc tcacccagag ggccatcgag 7560 gcctccaacg cctacagccg catcctgcag gccgtgcagg ctgccgagga tgctgctggc 7620 caggccctgc agcaggcgga ccacacgtgg gcgacggtgg tgcggcaggg cctggtggac 7680 cgagcccagc agctcctggc caacagcact gcactagaag aggccatgct ccaggaacag 7740 cagaggctgg gccttgtgtg ggctgccctc cagggtgcca ggacccagct ccgagatgtc 7800 cgggccaaga aggaccagct ggaggcgcac atccaggcgg cgcaggccat gcttgccatg 7860 gacacagacg agacaagcaa gaagatcgca catgccaagg ctgtggctgc tgaagcccag 7920 gacaccgcca cccgtgtgca gtcccagctg caggccatgc aggagaatgt ggagcggtgg 7980 cagggccagt acgagggcct gcggggccag gacctgggcc aggcagtgct tgacgcaggc 8040 cactcagtgt ecaccctgga gaagacgctg ccccagctgc tggccaagct gagcatcctg 8100 gagaaccgtg gggtgcacaa cgccagcctg gccctgtccg ccagcattgg ccgcgtgcga 8160 gagctcattg cccaggcccg gggggctgcc agtaaggtca aggtgcccat gaagttcaac 8220 gggcgctcag gggtgcagct gcgcacccca cgggatcttg ccgaccttgc tgcctacact 8280 gccctcaagt tctacctgca gggcccagag cctgagcctg ggcagggtac cgaggatcgc 8340 tttgtgatgt acatgggcag ccgccaggcc actggggact acatgggtgt gtctctgcgt 8400 gacaagaagg tgcactgggt gtatcagctg ggtgaggcgg gccctgcagt cctaagcatc 8460 gatgaggaca ttggggagca gttcgcagct gtcagcctgg acaggactct ccagtttggc 8520 cacatgtccg tcacagtgga gagacagatg atccaggaaa ccaagggtga cacggtggcc 8580 cctggggcag aggggctgct caacctgcgg ccagacgact tcgtcttcta cgtcgggggg 8640 taccccagta ccttcacgcc ccctcccctg cttcgcttcc ccggctaccg gggctgcatc 8700 gagatggaca cgctgaatga ggaggtggtc agcctctaca acttcgagag gaccttccag 8760 ctggacacgg ctgtggacag gccttgtgcc cgctccaagt cgaccgggga cccgtggctc 8820 acggacggct cctacctgga cggcaccggc ttcgcccgca tcagcttcga cagtcagatc 8880 agcaccacca agcgcttcga gcaggagctg cggctcgtgt cctacagcgg ggtgctcttc 8940 ttcctgaagc agcagagcca gttcctgtgc ttggccgtgc aagaaggcag cctcgtgctg 9000 ttgtatgact ttggggctgg cctgaaaaag gccgtcccac tgcagccccc accgcccctg 9060 acctcggcca gcaaggcgat ccaggtgttc ctgctggggg gcagccgcaa gcgtgtgctg 9120 gtgcgtgtgg agcgggccac ggtgtacagc gtggagcagg acaatgatct ggagctggcc 9180 gacgcctact acctgggggg cgtgccgccc gaccagctgc ccccgagcct gcgacggctc 9240 ttccccaccg gaggctcagt ccgtggctgc gtcaaaggca tcaaggccct gggcaagtat 9300 gtggacctca agcggctgaa cacgacaggc gtgagcgccg gctgcaccgc cgacctgctg 9360 gtggggcgcg ccatgacttt ccatggccac ggcttccttc gcctggcgct ctcgaacgtg 9420 gcaccgctca ctggcaacgt ctactccggc ttcggcttcc acagcgccca ggacagtgcc 9480 ctgctctact accgggcgtc cccggatggg ctatgccagg tgtccctgca gcagggccgt 9540 gtgagcctac agctcctgag gactgaagtg aaaactcaag cgggcttcgc cgatggtgcc 9600 ccccattacg tcgccttcta cagcaatgcc acgggagtct ggctgtatgt cgatgaccag 9660 ctccagcaga tgaagcccca ccggggacca ccccccgagc tccagccgca gcctgagggg 9720 cccccgaggc tcctcctggg agg.cctgcct gagtctggca ccatttacaa cttcagtggc 9780 tgcatcagca acgtcttcgt gcagcggctc ctgggcccac agcgcgtatt tgatctgcag 9840 cagaacctgg gcagcgtcaa tgtgagcacg ggctgtgcac ccgccctgca agcccagacc 9900 ccgggcctgg ggcctagagg actgcaggcc accgcccgga aggcctcccg ccgcagccgt 9960 cagcccgccc ggcatcctgc ctgcatgctg cccccacacc tcaggaccac ccgagactcc 10020 taccagtttg ggggttccct gtccagtcac ctggagtttg tgggcatcct ggcccgacat 10080 aggaactggc ccagtctctc catgcacgtc ctcccgcgaa gctcccgagg cctcctcctc 20140 ttcactgccc gtctgaggcc cggcagcccc tccctggcgc tcttcctgag caatggccac 10200 ttcgttgcac agatggaagg cctcgggact cggctccgcg cccagagccg ccagcgctcc 10260 cggcctggcc gctggcacaa ggtctccgtg cgctgggaga agaaccggat cctgctggtg 10320 acggacgggg cccgggcctg gagccaggag gggccgcacc ggcagcacca gggggcagag 10380 cacccccagc cccacaccct ctttgtgggc ggcctcccgg ccagcagcca cagctccaaa 10440 cttccggtga ccgtcgggtt cagcggctgt gtgaagagac tgaggctgca cgggaggccc 10500 ctgggggccc ccacacggat ggcaggggtc acaccctgca tcttgggccc cctggaggcg 10560 ggcctgttct tcccaggcag cgggggagtt atcactttag acctcccagg agctacactg 10620 cctgatgtgg gcctggaact ggaggtgcgg cccctggcag tcaccggact gatcttccac 10680 ttgggccagg cccggacgcc cccctacttg cagttgcagg tgaccgagaa gcaagtcctg 10740 ctgcgggcgg atgacggagc aggggagttc tccacgtcag tgacccgccc ctcagtgctg 10800 tgtgatggcc agtggcaccg gctagcggtg atgaaaagcg ggaatgtgct ccggctggag 10860 gtggacgcgc agagcaacca caccgtgggc cccttgctgg cggctgcagc tggtgcccca 10920 gcccctctgt acctcggggg cctgcctgag cccatggccg tgcagccctg gccccccgcc 10980 tactgcggct gcatgaggag gctggcggtg aaccggtccc ccgtcgccat gactcgctct 11040 gtggaggtcc acggggcagt gggggccagt ggctgcccag ccgcctagga cacagccaac 11100 cccggcccct ggtcaggccc ctgcagctgc ctcacaccgc cccttgtgct cgcctcatag 11160 gtgtctattt ggactctaag ctctacgggt gacagatctt gtttctgaag atggtttaag 11220 ttatagcttc ttaaacgaaa gaataaaata ctgcaaaatg tttttatatt tggcccttcc 11280 acccattttt aattgtgaga gatttgtcac caatcatcac tggttcctcc ttaaaaatta 11340 aaaagtaact tctgtgtaaa aaaaaaa 11367 <210> 59 <211> 4255 <212> DNA
<213> Homo Sapiens <220>
<221> misc feature <223> Incyte ID No: 55022490CB1 <400> 59 gcggcacaga cccagctctg aattctgggt caaccatgga ccaactgtga cccttcggac 60 aagtcccttc gcctctctgg agctggccta taagagggaa aaggaacccc tgtggagagg 120 gtctatttat cctggcgaag atcgcctgaa gtgatcttct aacaggagtg tttccagagg 180 aggggctggg ccgggagagg tgtggacagc tggggaccgc tctgagcagc gcagccccgg 240 gcgccccaca ccaccacatg gtccggggag gaaggtggga gcaggcacac aagaaggaac 300 ctctgggggt ctgggggccc ctgccatgtg tgaggggtgc ccaggggacc cttggggaca 360 ggaacggggg cacgggtggg tggcggcact ggggagggtg tgagggtatg cccatgccct 420 cctcctcgca gaatgtctgc acaaactctg gtgcatctgt ggggaccacc tgtcactcca 480 agetggatgc agctgtggac ggcacccggt gtggggagaa taagtggtgt ctcagtgggg 540 agtgcgtacc cgtgggcttc cggcccgagg ccgtggatgg tggctggtct ggctggagcg 600 cctggtccat ctgctcacgg agctgtggca tgggcgtaca gagcgccgag cggcagtgca 660 cgcagcctac gcccaaatac aaaggcagat actgtgtggg tgagcgcaag cgcttccgcc 720 tctgcaacct gcaggcctgc cctgctggcc acccctcctt ccgccacgtc cagtgcagcc 780 actttgacgc tatgctctac aagggccagc tgcacacatg ggtgcccgtg gtcaatgacg 840 tgaacccctg cgagctgcac tgccggcccg cgaatgagta ctttgccgag aagctgcggg 900 acgccgtggt cgatggcacc ccctgctacc aggtccgagc cagccgggac ctctgcatca 960 acggcatctg taagaacgtg ggctgtgact tcgagattga ctccggtgct atggaggacc 1020 gctgtggtgt gtgccacggc aacggctcca cctgccacac cgtgagcggg accttcgagg 1080 aggccgaggg cctggggtat gtggatgtgg ggctgatccc agccggcgca cgcgagatcc 1140 gcatccaaga ggttgccgag gctgccaact tcctggcact gcggagtgag gacccggaga 1200 agtacttcct caatggtggc tggaccatcc agtggaacgg ggactaccag gtggcaggga 1260 ccaccttcac atacgcacgc aggggcaact gggagaacct cacgtccccg ggtcccacca 1320 aggagcctgt ctggatccag ctgctgttcc aggagagcaa ccctggggtg cactacgagt 1380 acaccatcca cagggaggca ggtggccacg acgaggtccc gccgcccgtg ttctcctggc 1440 attatgggcc ctggaccaag tgcacagtca cctgcggcag aggtgtgcag aggcagaatg 1500 tgtactgctt ggagcggcag gcagggcccg tggacgagga gcactgtgac cccctgggcc 1560 ggcctgatga ccaacagagg aagtgcagcg agcagccctg ccctgccagg tggtgggcag 1620 gtgagtggca gctgtgctcc agctcctgcg ggcctggggg cctctcccgc cgggccgtgc 1680 tctgcatccg cagcgtgggg ctggatgagc agagcgccct ggagccaccc gcctgtgaac 1740 accttccccg gccccctact gaaacccctt gcaaccgcca tgtaccctgt ccggccacct 1800 gggctgtggg gaactggtct cagtgctcag tgacatgtgg ggagggcact cagcgccgaa 1860 atgtcctctg caccaatgac accggtgtcc cctgtgacga ggcccagcag ccagccagcg 1920 aagtcacctg ctctctgcca ctctgtcggt ggcccctggg cacactgggc cctgaaggct 1980 caggcagcgg ctcctccagc cacgagctct tcaacgaggc tgacttcatc ccgcaccacc 2040 tggccccacg cccttcaccc gcctcatcac ccaagccagg caccatgggc aacgccattg 2100 aggaggaggc tccagagctg gacctgccgg ggcccgtgtt tgtggacgac ttctactacg 2160 actacaattt catcaatttc cacgaggatc tgtcctacgg gccctctgag gagcccgatc 2220 tagacctggc ggggacaggg gaccggacac ccccaccaca cagccgtcct gctgcgccct 2280e ccacgggtag ccctgtgcct gccacagagc ctcctgcagc caaggaggag ggggtactgg 2340 gaccttggtc cccgagccct tggcctagcc aggccggccg ctccccaccc ccaccctcag 2400 agcagacccc tgggaaccct ttgatcaatt tcctgcctga ggaagacacc cccatagggg 2460 ccccagatct tgggctcccc agcctgtcct ggcccagggt ttccactgat ggcctgcaga 2520 cacctgccac ccctgagagc caaaatgatt tcccagttgg caaggacagc cagagccagc 2580 tgccccctcc atggcgggac aggaccaatg aggttttcaa ggatgatgag gaacccaagg 2640 gccgcggagc accccacctg cccccgagac ccagctccac gctgccccct ttgtcccctg 2700 ttggcagcac ccactcctct cctagtcctg acgtggcgga gctgtggaca ggaggcacag 2760 tggcctggga gccagctctg gagggtggcc tggggcctgt ggacagtgaa ctgtggccca 2820 ctgttggggt ggcttctctc cttcctcctc ccatagcccc tctgccagag atgaaggtca 2880 gggacagttc cctggagccg gggactccct ccttcccaac cccaggacca ggctcatggg 2940 acctgcagac tgtggcagtg tgggggacct tcctccccac aaccctgact ggcctcgggc 3000 acatgcctga gcctgccctg aacccaggac ccaagggtca gcctgagtcc ctcagccctg 3060 aggtgcccct gagctctagg ctgctgtcca caccagcttg ggacagcccc gccaacagcc 3120 acagagtccc tgagacccag ccgctggctc ccagcctggc tgaagcgggg ccccccgcgg 3180 acccgttggt tgtcaggaac gccagctggc aagcgggaaa ctggagcgag tgctctacca 3240 cctgtggcct gggtgcggtc tggaggccgg tgcgctgtag ctccggccgg gatgaggact 3300 gcgcccccgc tggccggccc cagcctgccc gccgctgcca cctgcggccc tgtgccacct 3360 ggcactcagg caactggagt aagtgctccc gcagctgcgg cggaggttcc tcagtgcggg 3420 acgtgcagtg tgtggacaca cgggacctcc ggccactgcg gcccttccat tgtcagcccg 3480 ggcctgccaa gccgcctgcg caccggccct gcggggccca gccctgcctc agctggtaca 3540 catcttcctg gagggagtgc tccgaggcct gtggcggtgg tgagcagcag cgtctagtga 3600 cctgcccgga gccaggcctc tgcgaggagg cgctgagacc caacaccacc cggccctgca 3660 acacccaccc ctgcacgcag tgggtggtgg ggccctgggg ccagtgctca gccccctgtg 3720 gtggtggtgt ccagcggcgc ctggtcaagt gtgtcaacac ccagacaggg ctgcccgagg 3780 aagacagtga ccagtgtggc cacgaggcct ggcctgagag ctcccggccg tgtggcaccg 3840 aggattgtga gcccgtcgag cctccccgct gtgagcggga ccgcctgtcc ttcgggttct 3900 gcgagacgct gcgcctactg ggccgctgcc agctgcccac catccgcacc cagtgctgcc 3960 gctcgtgctc tccgcccagc cacggcgccc cctcccgagg ccatcagcgg gttgcccgcc 4020 gctgactgtg ccaggatgca cagaccgacc gacagacctc agtgcccacc acgggctgtg 4080 gcggagctcc cgccccctgc gccctaatgg tgctaacccc ctctcactac ccagcagcag 4140 gctggggacc tcctccccct caaaaaaggt atttttttat tctaacagtt tgtgtaacat 4200 ttattatgat tttacataaa tgagcatcta ccattccaaa aaaaaaaaaa aaaaa 4255 <210> 60 <211> 3438 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6755002CB1 <400> 60 tgtgcgccgg gagggccggc gccctcttcc gaatgtcctg cggccccagc ctctcctcac 60 gctcgcgcag tctccgccgc agtctcagct gcagctgcag gactgagccg tgcacccgga 120 ggagaccccc ggaggaggcg acaaacttcg cagtgccgcg acccaacccc agccctgggt 180 agcctgcagc atggcccagc tgttcctgcc cctgctggca gccctggtcc tggcccaggc 240 tcctgcagct ttagcagatg ttctggaagg agacagctca gaggaccgcg cttttcgcgt 300 gcgcatcgcg ggcgacgcgc cactgcaggg cgtgctcggc ggcgccctca ccatcccttg 360 ccacgtccac tacctgcggc caccgccgag ccgccgggct gtgctgggct ctccgcgggt 420 caagtggact ttcctgtccc ggggccggga ggcagaggtg ctggtggcgc ggggagtgcg 480 cgtcaaggtg aacgaggcct accggttccg cgtggcactg cctgcgtacc cagcgtcgct 540 caccgacgtc tccctggcgc tgagcgagct.gcgccccaac gactcaggta tctatcgctg 600 tgaggtccag cacggcatcg atgacagcag cgacgctgtg gaggtcaagg tcaaaggggt 660 cgtctttctc taccgagagg gctctgcccg ctatgctttc tccttttctg gggcccagga 720 ggcctgtgcc cgcattggag cccacatcgc caccccggag cagctctatg ccgcctacct 780 tgggggctat gagcaatgtg atgctggctg gctgtcggat cagaccgtga ggtatcccat 840 ccagacccca cgagaggcct gttacggaga catggatggc ttccccgggg tccggaacta 900 tggtgtggtg gacccggatg acctctatga tgtgtactgt tatgctgaag acctaaatgg 960 agaactgttc ctgggtgacc ctccagagaa gctgacattg gaggaagcac gggcgtactg 1020 ccaggagcgg ggtgcagaga ttgccaccac gggccaactg tatgcagcct gggatggtgg 1080 cctggaccac tgcagcccag ggtggctagc tgatggcagt gtgcgctacc ccatcgtcac 1140 acccagccag cgctgtggtg ggggcttgcc tggtgtcaag actctcttcc tcttccccaa 1200 ccagactggc ttccccaata agcacagccg cttcaacgtc tactgcttcc gagactcggc 1260 ccagccttct gccatccctg aggcctccaa cccagcctcc aacccagcct ctgatggact 1320 agaggctatc gtcacagtga cagagaccct ggaggaactg cagctgcctc aggaagccac 1380 agagagtgaa tcccgtgggg ccatctactc catccccatc atggaggacg gaggaggtgg 1440 aagctccact ccagaagacc cagcagaggc ccctaggacg ctcctagaat ttgaaacaca 1500 atccatggta ccgcccacgg ggttctcaga agaggaaggt aaggcattgg aggaagaaga 1560 gaaatatgaa gatgaagaag agaaagagga ggaagaagaa gaggaggagg tggaggatga 1620 ggctctgtgg gcatggccca gcgagctcag cagcccgggc cctgaggcct ctctccccac 1680 tgagccagca gcccaggaga agtcactctc ccaggcgcca gcaagggcag tcctgcagcc 1740 tggtgcatca ccacttcctg atggagagtc agaagcttcc aggcctccaa gggtccatgg 1800 accacctact gagactctgc ccactcccag ggagaggaac ctagcatccc catcaccttc 1860 cactctggtt gaggcaagag aggtggggga ggcaactggt ggtcctgagc tatctggggt 1920 ccctcgagga gagagcgagg agacaggaag ctccgagggt gccccttccc tgcttccagc 1980 cacacgggcc cctgagggta ccagggagct ggaggccccc tctgaagata attctggaag 2040 aactgcccca gcagggacct cagtgcaggc ccagccagtg ctgcccactg acagcgccag 2100 ccgaggtgga gtggccgtgg tccccgcatc aggtgactgt gtccccagcc cctgccacaa 2160 tggtgggaca tgcttggagg aggaggaagg ggtccgctgc ctatgtctgc ctggctatgg 2220 gggggacctg tgcgatgttg gcctccgctt ctgcaacccc ggctgggacg ccttccaggg.2280 cgcctgctac aagcactttt ccacacgaag gagctgggag gaggcagaga cccagtgccg 2340 gatgtacggc gcgcatctgg ccagcatcag cacacccgag gaacaggact tcatcaacaa 2400 ccggtaccgg gagtaccagt ggatcggact caacgacagg accatcgaag gcgacttctt 2460 gtggtcggat ggcgtccccc tgctctatga gaactggaac cctgggcagc ctgacagcta 2520 cttcctgtct ggagagaact gcgtggtcat ggtgtggcat gatcagggac aatggagtga 2580 cgtgccctgc aactaccacc tgtcctacac ctgcaagatg gggctggtgt cctgtgggcc 2640 gccaccggag ctgcccctgg ctcaagtgtt cggccgccca cggctgcgct atgaggtgga 2700 cactgtgctt cgctaccggt gccgggaagg actggcccag cgcaatctgc cgctgatccg 2760 atgccaagag aacggtcgtt gggaggcccc ccagatctcc tgtgtgccca gaagacctgc 2820 ccgagctctg cacccagagg aggacccaga aggacgtcag gggaggctac tgggacgctg 2880 gaaggcgctg ttgatccccc cttccagccc catgccaggt ccctaggggg caaggccttg 2940 aacactgccg gccacagcac tgccctgtca cccaaatttt ccctcacacc ctgcgctccc 3000 gccaccacag gaagtgacaa catgacgagg ggtggtgctg gagtccaggt gacagttcct 3060 gaaggggctt ctgggaaata cctaggaggc tccagcccag cccaggccct ctccccctac 3120 cctgggcacc agatcttcca tcagggccgg agtaaatccc taagtgcctc aactgccctc 3180 tccctggcag ccatcttgtc ccctctattc ctctagggag cactgtgccc actctttctg 3240 ggttttccaa gggaatgggc ttgcaggatg gagtgtctgt aaaatcaaca ggaaataaaa 3300 ctgtgtatga gcccagggta gggggagagg gcctgggctg ggctggagcc tcctaggtat 3360 ttcccagaag ccccttcagg aactgtcacc tggactccag caccacccct cgtcatgttg 3420 tcacttcctg tggtggcg 3438 <210> 61 <221> 1683 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7350907CB1 <400> 61 ggcgtgggga cacgagccag gcgccgccgc cggagccagc ggagccgggg ccagagccgg 60 agcgcgtccg cgtccacgca gccgccggcc ggccagcacc cagggccctg catgccaggt 120 cgttggaggt ggcagcgaga catgcacccg gcccggaagc tcctcagcct cctcttcctc 180 atcctgatgg gcactgaact cactcaagtg ctgcccacca accctgagga gagctggcag 240 gtgtacagct ctgcccagga cagcgagggc aggtgtatct gcacagtggt cgccccacag 300 cagaccatgt gttcacggga tgcccgcaca aaacagctga ggcagctact.ggagaaggtg 360 cagaacatgt ctcaatccat agaggtcttg gacaggcgga cccagagaga cttgcagtac 420 gtggagaaga tggagaacca aatgaaagga ctggagtcca agttcaaaca ggtggaggag 480 agtcataagc aacacctggc caggcagttt aaggcgataa aagcgaaaat ggatgaactt 540 aggcctttga tacctgtgtt ggaagagtac aaggccgatg ccaaattggt attgcagttt 600 aaagaggagg tccagaatct gacgtcagtg cttaacgagc tgcaagagga aattggcgcc 660 tatgactacg atgaacttca gagcagagtg tccaatcttg aagaaaggct ccgtgcatgc 720 atgcaaaaac tagcttgcgg gaagttgacg ggcatcagtg accccgtgac tgtcaagacc 7'80 tccggctcga ggttcggatc ctggatgaca gaccctctcg cccctgaagg cgataaccgg 840 gtgtggtaca tggacggcta tcacaacaac cgcttcgtac gtgagtacaa gtccatggtt 900 gacttcatga acacggacaa tttcacctcc caccgtctcc cccacccctg gtcgggcacg 960 gggcaggtgg tctacaacgg ttctatctac ttcaacaagt tccagagcca catcatcatc 1020 aggtttgacc tgaagacaga gaccatcctc aagacccgca gcctggacta tgccggttac 1080 aacaacatgt accactacgc ctggggtggc cactcggaca tcgacctcat ggtggacgag 1140 agcgggctgt gggccgtgta cgccaccaac cagaacgctg gcaacatcgt ggtcagtagg 1200 ctggaccccg tgtccctgca gaccctgcag acctggaaca cgagctaccc caagcgcagc 1260 gccggggagg ccttcatcat ctgcggcacg ctgtacgtca ccaacggcta ctcagggggt 1320 accaaggtcc actatgcata ccagaccaat gcctccacct atgaatacat cgacatccca 1380 ttccagaaca aatactccca catctccatg ctggactaca accccaagga ccgggccctg 1440 tatgcctgga acaacggcca ccagatcctc tacaacgtga ccctcttcca cgtcatccgc 1500 tccgacgagt tgtagctccc tcctcctgga agccaagggc ccacgtcctc accacaaagg 1560 gactcctgtg aaactgctgc caaaaagata ccaataacac taacaatacc gatcttgaaa 1620 aatcatcagc agtgcggatt ctgacatcga gggatggcat tacctccgtg tttctccctt 1680 tcg 1683 <210> 62 <211> 6886 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7474411CB1 <400> 62 cggggcacag cgggagcccg tgcaggcggg cgcggggcgg ctgggcggcg gtggcggccg 60 tccatgcggc ggcgctcggg gctgcccggc gccgggaacc acgcgggggc gaggcgaggc 120 gaggcggccg ccggtcgctc cgggacgcgg accgccagga cttgaacgca actcccaatt 180 gcagaaaatt ggcaacgtct ctgaagagcc cttgcttttg cctggacccc cagcatcatg 240 gtttcccatt tcatggggtc tctcagtgtc ctgtgtttcc ttctgctgct tggattccag 300 ttcgtctgcc cacagccctc cactcaacac aggaaggtcc cgcagcggat ggcggcggag 360 ggcgcccccg aggacgacgg cggcggcggc gccccgggag tgtggggcgc ctggggcccc 420 tggtcggcct gctcgcgtag ctgcagcggc ggcgtgatgg agcagacgcg gccctgcctg 480 ccccgctcct accgcctgcg cggcggccag cggcctggcg cccctgcgcg cgccttcgcg 540 gaccacgtgg tgtcggcggt gcgcacgtcg gtgccactgc accggagccg cgacgagacg 600 ccagcgctgg ccggtacgga cgccagccgc cagggcccca cggtgctgcg aggcagccgg 660 cacccacagc cccagggcct cgaagtcact ggggacagaa ggagcaggac ccgtggtacc 720 attggccctg gcaagtatgg ctatggtaag gccccatata tcttaccact gcagacagac 780 actgcacaca cgccacagag gctccggaga cagaagctct catcccgcca ttccaggtcc 840 cagggagcat cttctgctag gcatggctac agttcaccag cccaccaggt cccccaacat 900 gggcctttgt accaaagtga cagtggccct cgctctggac tgcaggctgc ggaggccccc 960 atctaccagc tacctttgac ccatgatcaa ggctaccctg cagcttcaag tctctttcac 1020 agcccagaaa caagcaacaa ccacggtgtg gggacccatg gggcaactca gagcttctct 1080 cagcctgccc gatctacagc aatctcatgc atcggggcct atcggcagta caagctgtgc 1140 aacaccaacg tatgtccaga aagcagtaga agtatccggg aggtacagtg tgcatcctac 1200 aacaacaagc cattcatggg ccggttttat gagtgggaac catttgcaga agtaaaaggc 1260 aatcgcaaat gtgagttgaa ctgccaggca atgggctacc gcttctatgt acggcaagct 1320 gagaaagtca tcgatggcac cccctgtgac cagaacggca cggccatctg tgtgtctggg 1380 cagtgcaaga gcattggctg tgatgactac ttaggctccg acaaagtcgt ggacaaatgt 1440 ggggtgtgtg gaggagacaa cacgggctgt caggttgtgt cgggcgtgtt taagcatgcc 1500 ctcaccagcc tgggctacca ccgcgtcgtg gagattcccg agggagccac gaaaatcaac 1560 atcacggaga tgtacaagag caacaactat ttggccctga gaagtcgttc tggacgctcc 1620 atcatcaatg ggaactgggc aattgatcga ccaggaaaat acgagggcgg agggaccatg 1680 ttcacctaca agcgtccaaa tgagatttcg agcactgccg gagagtcctt tttggcggaa 1740 ggtcccacca acgagatctt ggatgtctac atgatacacc agcagccaaa cccaggcgtg 1800 cactacgagt acgtgatcat ggggaccaac gccatcagcc cccaggtgcc accccacagg 1860 agaccagggg aacccttcaa tggccagatg gtgacagaag gcaggagcca ggaggaggga 1920 gaacagaaag ggaggaacga ggagaaggaa gacttgcgtg gggaggcccc tgagatgttc 1980 acctcagaat cggcacagac cttcccagtc aggcatccag acagattttc tccccatcga 2040 ccggacaact tggtgccacc agcaccgcag cccccacggc gcagccggga tcacaactgg 2100 aagcagcttg ggacaacaga atgttccacg acctgtggga aaggatcgca gtaccctatt 2160 ttccgctgtg tgcacagaag cactcatgaa gaggctcctg agagttactg tgactccagc 2220 atgaagccga cccccgagga ggagccctgc aacatcttcc cttgcccagc cttctgggac 2280 atcggggagt ggtctgagtg cagcaagacc tgtggcctgg gcatgcagca ccgccaggtt 2340 ctgtgccgcc aggtgtacgc caaccgcagc ctgacggtgc agccctaccg ctgccagcac 2400 ctggagaaac ctgagaccac cagcacctgc caactcaaga tctgcagcga gtggcagatc 2460 cggaccgact ggacctcgtg ctcggtgccc tgtggcgtgg gacagaggac ccgtgatgtg 2520 aagtgtgtga gcaacattgg ggatgtggtt gacgatgagg aatgcaacat gaagctccgg 2580 ccgaatgaca ttgagaactg cgacatggga ccctgtgcca agagctggtt cctcaccgag 2640 tggagcgaaa ggtgctcagc ggagtgtggg gccggagtgc ggacacgctc ggtggtgtgc 2700 atgaccaacc atgtcagcag cctgcccctg gagggctgtg ggaacaaccg gccggcagag 2760 gccaccccat gtgacaacgg accctgcacg ggcaaggtgg agtggtttgc cgggagctgg 2820 agtcagtgtt ccatcgagtg tgggagcggg acgcaacaga gggaggtgat ttgtgttaga 2880 aagaatgcag acacctttga agtgttggac ccctctgaat gttctttcct ggagaaaccc 2940 cccagccagc aatcctgcca cctcaagcct tgcggagcca aatggtttag caccgaatgg 3000 agcatgtgtt ccaagagctg ccagggtggc tttcgggtcc gggaagtgcg gtgtctgtct 3060 gatgacatga ctctaagtaa cctctgtgac cctcagttga aaccagaaga gagagaatct 3120 tgtaaccctc aggactgtgt ccctgaagtt gatgaaaact gcaaggacaa gtactacaac 3180 tgcaacgtgg tggtccaggc aagactctgt gtctacaact actacaagac cgcctgctgt 3240 gcctcctgca cccgtgtggc caacaggcag acgggcttcc tggggagcag ataacactcc 3300 tgcaccccca tcagtagggc agcatcactg ccttcccggg ggcttcagca gtgcgcctgg 3360 ctggctgctg ctccaccacg ggccccctgg cccaggcgct gccaaccaac ttagtcacca 3420 cccctgcctc cggtgaatgc accccgtggt acccaggggc tttttacaca agatgtttga 3480 aagccacagt cagtccttta agcatcacca tgtactgatg atcccctcct tggacctggc 3540 atctgctaat ggtgcccttt gaaagtcaag cagtgggaag tacatggagc tctcagccct 3600 gctcccatct ggcaccttca agtcagcaga tgggccactg actgagcact gccccgtccc 3660 tggtgctact ggtctttcta aacttagcac cctggagagt ccaaggaggc agcgccccca 3720 acccagcgcc ccactaagcc ttgctgacac gcgtgcatcc ctctgtgacc tcagcccaga 3780 tgtgcctgtt ttcattctca aagacattag actgttttcc tgccctatga cacagatagc 3840 tcacatgaat attgtgcttt atttagcagg tgtactcaca gatactagct ccttagcagc 3900 tcacaacatc ccagaatggg aggcaggggg tgactcatta tccccatttt actgacaggg 3960 aaactgaggc tcaacttaag taattgacct gccaggtata ttcaeccatc cagtggaaga 4020 gctgagtccc cgccccagtc atctaccagt atccagcctg gggcctgtac ttagatgtga 4080 aaggtgctgc ttcatttctg accaagagac tgagaagttt cccagaatgc aaacaaagcc 4140 caggcccctg aaatctttcc ggtcaagcct ttatcccagc actcagttgt tttggatgtc 4200 tgttcctact tgcccttacc cccaaagtta cagatcctag ttacaggact ctgccagctt 4260 tgttaaactg tccgtgagac aagaaagcca ttggggaaac caggtgattg cctgaaattc 4320 ttactccgtt ccaagtgctg ttcctcccag gaaatcaaag gccagggtcc ttatggccgt 4380 ggagccttcc cgaccacaga gccaacttgt gaagcacaca gctctgcagc ctgggctctg 4440 ccctgcctca gccgcctccc ccacgctctt caccacgttc ctggagagtc cggccaacct 4500 gtcccagcca aaacactgct gtattagaaa aagtctcttt ctggtctttc tggttttgtt 4560 tatgaatttc cctctgtggc cacaaattcc tcccctcccc catgactcac agtccatatg 4620 gcccaccccc agacttgagc accaagctct gcattaatgc agttggcctg cgacaaggag 4680 ctgtggaccc ttccccatct cttccaattc actttcccca actatccagt tccagaggcc 4740 gcaggcctgg aaggatgcag tgcatattga aaggtggacc ctctgaaaac agttaagagg 4800 aatatatgta tgttttgccc attaagaaaa aatggcaagc taaacaaatg ttaaacttac 4860 agaaaatttg tcttatggtc ctgagcatat ttccctttta gagcaagcct ggattcttag 4920 caaagtgttt cccccatttg ctcttttagc tgacaaatct gccactgtga tgatggtttg 4980 cagcttttgg aagcagtatg gcaacctggc ctgacatgct ctttaggctt ccactaacct 5040 ggggctttca gaaattctat ttggcctttc tgtgggtagc tttccagctt ctcttctagg 5100 gagccccagg catcatttcc caaaagcatc cccatctcct gattctcttg gaactcctac 5160 agataagcat cctggcagag gcccaggctc ccaaaccgac aaagtgaaaa gagaccagag 5220 aggccaagca tattgactgg tgctgttcag ggcctgctct tttccactca ccacttgttt 5280 tgctgcttgt cacgaggaga gttgttcctg tatgtggctg ctctcagatc tttccaagca 5340 agccagtcat ttgaagaggt tttcttttca tgctggaggg caggctaaga tcaatgagtg 5400 gaagagagaa aggctgtttt agctcaagtt aaaggaacac cttctagcca tcaaagccgc 5460 ccaacagagg caagggccac cacacatgag agagcgctct gtccttaaag ggaattctct 5520 gttgagtggg aggtgaacac cctggttctt ccaactcagg aattctcgtg gctgggctgg 5580 gtcagtgatg gctttgtctc tttatgtcta aagtgcccta tggctgctga aggttaccta 5640 accattcttt aaaaggagaa tgaccctcca tgggaatggc cagcctgcca actgtgcaat 5700 tgaagaagac ccgatggatc aaccccatgt ctcccttggg gagaaagtgc ataaaccagg 5760 ggtctctttt tttttttttt caacaaacca ttgagctgtt cttggagttc atctctggag 5820 aggttataca ttattagaag tttgattatt attatagttt gatcaattta tttgtcttag 5880 agatccaatt tttactaatt ccctagtttt ttatttcagc atctgaatgt ctttctccct 5940 agcacagtgc atacaatcag ggccttgggt atttccagtg ataactttcc ttggagagga 6000 tctaagaaaa gcccagattt cggtagccat ctccctccaa atatgtctct ttctgctttc 6060 ttagtgccca ttatttcccc ttctcctttc ttctgtcact gccatctcct tcttggtctt 6120 cccattgttc tttaactggc tgtaatgtgg aattgatatt tacattttga tacggttttt 6180 ttcttggcct gtgtacggga ttgcctcatt tcctgctctg aattttaaaa ttagatatta 6240 aagctgtcat atggtttcct cacaaaagtc aacaaagtcc aaacaaaaat agtttgccgt 6300 tttactttca tccattgaaa aaggaaattg tgcctcttgc agcctaggca aaggacattt 6360 agtactatcg attctttcca ccctcacgat gacttgcggt tctctctgta gaaaagggat 6420 ggcctaagaa atacaactaa aaaaacaaac aaaaacacca aaagaaaaaa aaaagccatt 6480 taaagccagc cactagaggg agtcagttca gttccgtaaa ggtatgctca gtgcccgctg 6540 cctgcaagct gttggggacc ccagggaggg caaggcagcc tgtccccgcc cccagggaac 6600 tagaacatga caagaattct ccgcactgtg cctacctgtc cctttaactt acctctctgg 6660 cccagagttc ttggagggta aaccttctat ttctcttatg tactcatcta cttattctca 6720 aagtatttag cattcaacac tcttttggct ttaaaaagaa tgggccttac aaagggacag 6780 aacacgagaa gacacgagct aggtgtattt catcaagtat gtggcacgag aaatccagat 6840 attaccagga cctgtctaac caatgtgggg ttactttcat cggatg 6886 <210> 63 <211> 4457 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4755911CB1 <400> 63 atggggaagg agcaggagct ggtgcaggcg gtgaaggcgg aggacgtagg gaccg'cgcag 60 aggctgctgc agaggccgcg gcccgggaag gccacgcgta gcctccctgg gggccgccgg 120 agatggatgg atgggcgtgt ggaccagccg cgtgtgcggc tgcgcacgta tagccgtgtc 180 agtgtgtcag ggcacctgtg cgggcacgga cagggctctg cagagctcct gggttccacc 240 aagaagatca atgtcaactt ccaggacccg gatggggttg ggtttggggt caagggtcag 300 ctcccagcat cccctcgccc cccaggcatg cggccgctgc actatgcggc ctggcagggc 360 cggaaggagc ccatgaagct ggtgctgaag gcgggctcgg ccgtgaacat cccgtctgat 420 gagggccaca tccccctgca cctggcggcc cagcatggtc actatgatgt gtctgagatg 480 ctgctacagc accagtctaa cccgtgcatg gtggacaact cggggaagac gcccctggac 540 ctggcctgcg agttcggccg cgttggggtg gtccagctgc tcctcagcag caatatgtgt 600 gcggcgctgc tggagccccg gccgggagac gccaccgacc ccaacggcac cagccctttg 660 cacctcgcag ctaaaaacgg ccacatcgac atcatcaggc tcctcctcca agccggcatc 720 gacattaacc gccagaccaa gtccggcacg gccctgcacg aggctgcgct ctgcggaaag 780 acagaggtgg tgcggctgct gctggatagc gggatcaatg cccacgtgag gaacacctac 840 agccagacag ccctggacat cgtgcaccag ttcaccacgt cccaggccag cagggagatc 900 aagcagctgt tgcgagaggc ctcagcggcc ctgcaggtcc gggcgaccaa ggattattgc 960 aacaattacg acctgaccag cctcaacgtg aaggcagggg acatcatcac agtcctcgag 1020 cagcatccgg atggccggtg gaagggctgc atccatgaca accggacggg caatgaccgg 1080 gtgggctact tcccgtcctc cctgggcgag gccattgtca agcgagcagg ttcccgagca 1140 ggcactgaac caagcctgcc ccagggaagc agctcatcgg gaccctctgc acccccagag 1200 gagatctggg tgctgaggaa gccttttgca ggtggggacc gaagcggcag cattagcggc 1260 atggctggcg gccggggcag cgggggtcac gccctacacg cgggctctga aggcgtcaag 1320 ctcctggcaa cggtgctttc ccagaagtcc gtctctgagt ccggcccggg ggacagcccc 1380 gccaagcctc cggaaggctc tgcaggtgtg gcccggtccc agcctccagt ggcccacgcc 1440 gggcaggtct atggggagca gccgcccaag aagctggagc cagcatcgga gggcaagagc 1500 tctgaggccg tgagccagtg gctcaccgcg ttccagctgc agctctacgc ccccaacttc 1560 atcagcgccg gctacgacct gcccaccatc agccgcatga ctcccgagga cctcacggcc 1620 attggtgtca ccaagccggg ccaccggaag aagatcgcgg cagagatcag cggcctaagc 1680 atccctgact ggctgcctga gcacaaaccc gctaacctgg ccgtgtggct gtccatgatc 1740 ggcctggccc agtactacaa ggtgttggtg gacaatggct acgagaacat tgatttcatc 2800 accgacatca cctgggagga cctgcaggag atcggcatca ccaagctggg gcaccagaag 1860 aagctgatgc tcgctgtgag gaagctggca gagctgcaga aggctgaata cgccaagtat 1920 gaggggggcc ccctgcgccg gaaggcgccc cagtctcttg aagtgatggc catcgagtcg 1980 ccgcccccgc ctgagcccac accggccgac tgccagtccc ctaaaatgac caccttccag 2040 gacagcgagc tcagtgacga gctgcaggct gccatgactg gcccggctga ggtggggccc 2100 accactgaga agccctccag ccacctgcca cccaccccga gggccaccac gcggcaggac 2160 tccagcctgg gtggtcgggc acggcacatg agcagctcgc aggagctgct gggagatggg 2220 ccccctgggc ccagcagccc catgtctcga agccaggagt acctcctgga tgagggcccc 2280 gcccccggca ccccgcccag ggaggcccgg cccggccgcc acggccacag catcaagagg 2340 gccagcgtgc cccccgtgcc tggcaagcca cggcaggtcc tcccaccagg cactagccac 2400 ttcacgcccc cccagacgcc caccaaaacc cgaccaggct ctccccaggc ccttggggga 2460 cctcatggtc cagccccagc tacggccaag gtgaagccca ccccgcagct gctgccgccg 2520 acagagcgcc ccatgtcacc ccgctccctg cctcagtcac cgacgcaccg cggctttgcc 2580 tacgtgctgc cccagcccgt ggagggcgag gtggggccgg ctgccccggg gcctgcgccc 2640 ccacccgtgc cgacggctgt gcccacactg tgcctgcccc ctgaggccga cgcggagccg 2700 gggcggccca agaagcgggc ccacagcctg aatcgctatg cggcgtccga cagcgagccg 2760 gagcgggacg agctgctggt gcctgcggct gccggcccct atgccacggt ccagcggcgc 2820 gtgggccgca gccactcagt gagggcgccc gcaggtgccg acaagaacgt caaccgcagc 2880 cagtcctttg ccgtgcggcc ccgaaagaag gggcccccgc cgcccccacc caagcgctcc 2940 agctcggccc tggctagtgc caacctggcg gatgagccgg tgcctgacgc cgagcctgag 3000 gatggcctgc tgggggtccg ggcacagtgc cggcgggcca gtgacctggc cggcagcgtg 3060 gacacgggta gtgccggcag tgtgaagagc atcgcggcca tgctggagct gtcctccatt 3120 gggggtgggg gccgggctgc ccgcaggcct cctgagggec accccactcc ccgccctgcc 3180 agcccagagc cgggccgggt ggccaccgtg ctggcctcag tgaaacacaa agaggccatc 3240 gggcctggcg gggaggtggt gaaccggcgc cgcacgctca gcgggccagt caccggactt 3300 ctggccactg cccgccgggg gcctggggag tcggcagacc caggcccctt tgtggaggat 3360 ggcactggcc ggcagcggcc tcggggtccc tccaagggcg aggcgggtgt cgaaggcccg 3420 cccttggcca aggtggaagc cagcgccaca ctcaagaggc gcatccgggc caagcagaac 3480 cagcaggaga acgtcaagtt catcctgacc gagtctgaca cggtcaagcg caggcccaag 3540 gccaaggagc gggaggccgg gcctgagcca ccaccgccac tgtccgtgta ccataatggc 3600 actggcaccg tgcgccgccg accggcctcg gagcaggctg ggcctccgga gctgcctcca 3660 ccgcccccgc ctgccgaacc cccgcccacc gacctggcgc acctaccccc attgcccccg 3720 cccgagggcg aagcccggaa gccggccaag ccgcctgtct ctcccaagcc cgtcctgacg 3780 cagcctgtgc ccaagctcca gggctcgccc acacccacct ccaagaaggt gccgctgcca 3840 ggccctggca gcccagaggt gaagcgcgcc cacggcacgc caccgcccgt gtctcccaag 3900 ccgccgccgc cgcccacagc gcccaagccc gtcaaggcgg tcgcggggct gccttcgggc 3960 agcgccggcc cttcacccgc accctcgccc gcgcgacagc cgcccgccgc cctcgccaag 4020 ccgcccggta cgccgccctc gctgggcgcc agccccgcca agcccccgtc ccccggcgcg 4080 cccgcgctgc acgtgcccgc caagcccccg cgagccgccg ccgccgccgc cgccgccgcc 4140 gccgcgcccc ccgccccgcc cgaaggcgcc tcgccagggg acagcgcccg gcagaaactg 4200 gaggagacaa gcgcgtgcct ggccgcggcg ctgcaggcgg tggaggagaa gatccggcag 4260 gaggacgcgc agggcccgcg cgactcggcg gcggaaaaga gcactggcag catcctggac 4320 gacatcggca gcatgttcga cgacctggcc gaccagctgg atgccatgct ggagtgaacg 4380 ccgcctggcc gggccctccc gcgccgcccg ggccctcccc gcacactgac ctatacctca 4440 ggatgggcgc gtctggg 4457 <210> 64 <211> 1943 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 379766CB1 <400> 64 ggcggcggcg actgcggcgc cgcgggctgg aggccggcgt cggggaaggt cctggtgccg 60 gattccgcac gaggtgttga cgggcggctt ctgccaactt ctccccagcg cgcgccgagc 120 ccgcgcggcc ccggggctgc acgtcccaga tacttctgcg gcgcaaggct acaactgaga 180 cccggaggag actagacccc atggcttcct ggacgagccc ctggtgggtg ctgataggga 240 tggtcttcat gcactctccc ctcccgcaga ccacagctga gaaatctcct ggagcctatt 300 tccttcccga gtttgcactt tctcctcagg gaagttttct ggaagacaca acaggggagc 360 agttcctcac ttatcgctat gatgaccaga cctcaagaaa cactcgttca gatgaagaca 420 aagatggcaa ctgggatgct tggggcgact ggagtgactg ctcccggacc tgtgggggag 480 gagcatcata ttctctgcgg agatgtttga ctggaaggaa ttgtgaaggg cagaacattc 540 ggtacaagac atgcagcaat catgactgcc ctccagatgc agaagatttc agagcccagc 600 agtgctcagc ctacaatgat gtccagtatc aggggcgtta ctatgaatgg cttccacgat 660 ataatgatcc tgctgccccg tgtgcactca agtgtcatgc acaaggacaa aacttggtgg 720 tggagctggc acctaaggta ctggatggaa ctcgttgcaa cacggactcc ttggacatgt 780 gtatcagtgg catctgtcag gcagtgggct gcgatcggca actgggaagc aatgccaagg 840 aggacaactg tggagtctgt gccggcgatg gctccacctg caggcttgta cggggacaat 900 caaagtcaca cgtttctcct gaaaaaagag aagaaaatgt aattgctgtt cctttgggaa 960 gtcgaagtgt gagaattaca gtgaaaggac ctgcttatcc tgtggcctgg gctttagcca 1020 tctcttccaa taccaattgc ctagtgttat tatgtaaagc taatttggcc agctctggtc 1080 cttattttgc actcattcca gtaaacccaa ccactatggc acttaatact gccattgtca 1140 gtcagtctgc agtattgatt gactgccttt agagctctct tttgtgtgcc ttgtccactc 1200 ttcagtcact gagagagaga ccaaagaaca gagaccaaca ccctgtactt ggcatggcca 1260 ttagtcactg gagttagatg aatcacactg tatctaagag agaagactca gggagaaggg 1320 cttagcacaa cacagaaaag ctttaaacac tcttaccttt gactggaatt acacacacac 1380 acacacacac acacacatac acacacacac atacacacac acacactaag gctttcccac 1440 aaagccatga tgcatcctta aaaataacac acagctctga aaagtgaatg tcgggggtga 1500 agagagccct cctacactccattttcctagt gatgacaagg ttgtgggggc atggctgact 1560 gtgaggagca gaagatgaga gggagatatc attttacttc tttgtactgc aataataaaa 1620 agaacagata gaatggaagg aagaggccag gggcagtggc tcatacctgt aatcccagca 1680 ctttgggagg ctgaggcagg tggatcacct gaggtcagga gttcgagacc agcctggcca 1740 acatggagaa actccgtctc tattaagaat acaaaaatta gccaggcgtg gtggtgggca 1800 cctataatca cagctacccg ggaggttgag gcaggagaat cacttgaact tgtggggcgg 1860 aggtcgcagt gagccaagat tgcaccactt cactccagcc tgggcgagaa agtgaactct 1920 gtctcaaaaa aaaaaaaaaa aaa 1943 <210> 65 <211> 4111 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 553744CB1 <400> 65 gcgatctagg gcggggcaac tgtacagatg aacaatctgg aatattaaat tcaactcaca 60 gagtggcaac aaacaatact ggagagctgg gcatgaatcc tggaaagcct tgtatggccc 120 tgcaagggaa gccatgttct gaaagctcct atgaggggga ctgactgact ctagataagt 180 agattgaaag aattagaggt aaagtcagtg cagcagcact aatcacaatt aaaataaatg 240 ctttaatttt taaaaagcgg aaaaacatga aaggacactt cgcaagcttc tcaaaacttc 300 ctgtgatttg gagggctatt ttgagcagag tctagacgaa aactggatct gactggctcc 360 agagtaaaga tctgagaaat ggaacccagc aatttagata ttacaagagc ctgttatact 420 tgtcattttt tatttggtat ttgttaaata ttacaaaaat ggttatgctt tttaattcaa 480 aatttgacgt ttcagcatga tgatacattc ttgccttttt tcccccttcc atatagcatt 540 ttccacccca gcaagtcaac tcttttctcc tcatggttct aatccttcaa cacctgctgc 600 aactcctgtt cctactgcat ccccagtcaa ggcaattaat catccatcag catcagcagc 660 tgccaccgtt tctggaatga acctgctgaa tactgtcctt cctgtgttcc cagggcaggt 720 ctcctcagcc gttcacacac ctcagccatc aataccaaac ccaacagtta tcagaacccc 780 ttcattgccc actgcacctg ttacatccat ccacagtaca accaccactc ctgttccttc 840 cattttttct ggcctagtgt cactgccagg tccttctgcc actcctaccg cagccactcc 900 taccccagga cctacaccac ggtccactct tggttccagt gaagcatttg cttctacttc 960 tgcacctttc actagcctcc ccttttccac cagctcttct gctgcttcta ccagcaaccc 1020 aaattctgct tcattgtcat cagtttttgc agggctccct ttgcccttac caccaacatc 1080 ccaaggccta tccaacccga ctcctgtaat tgctggtggc tctactccca gcgttgccgg 1140 tccacttggt gtgaacagtc catcttttgt ctgcgttaaa aggttttctg acatccaatg 1200 acaccaattt aatcaactcc tctgctttat cctctgctgt cacaagtggg ctggcttcac 1260 tatcttctct tactcttcag aactctgact cttctgcttc agcccctaac aagtgctatg 1320 ccccatcagc catccctacc ccacagagga cttccactcc agggttggcc ctgttcccag 1380 gcctgccgtc tcccgtggct aactcaactt ccactcccct gacattgcct gtacagtctc 1440 ctttagccac tgctgcatca gcttccacgt cagtgccagt tagctgtggc tcctcagcct 1500 cccttttgcg tggcccccac ccaggtacct cagatctgca tatttcatct acccctgctg 1560 caacaactct tcctgttatg atcaaaactg agcccacaag tcctactccc tcggccttca 1620 aaggtccatc tcattctggg aatccctctc atggcacttt aggtttgtca gggacattgg 1680 gccgtgcata tacttcaaca tccgtgccca tcagtttatc tgcttgcctt aatcctgcat 1740 tgtcaggtct ctccagcttg agtactcctt taaatggttc aaatcctctt tcctctattt 1800 cccttccacc acatggttcc tccactccca ttgcaccagt attcactgct cttccttctt 1860 ttacttcttt gaccaacaat tttcctttaa ctggcaaccc atctcttaat ccgtcagtat 1920 ctctcccagg gtcattaata gccacctcat ctaccgctgc cacctccaca tctctccctc 1980 atcctagctc aacggcagct gttctctcag ggctttctgc ttcagcacca gtctcagcag 2040 cacctttccc cctcaacctg tccactgctg ttccctcact tttctctgtt actcaaggac 2100 ctctgtcatc ttcaaatccc tcctatccag gcttttctgt ctctaatacc ccaagcgtta 2160 cccctgctct tccctcattc ccggggctgc aggcgccctc tacagtcgca gctgtcacac 2220 cactacctgt ggctgccaca gccccatccc cagctccagt cctcccagga ttcgcctcag 2280 cattcagttc caatttcaac tccgctcttg ttgcacaagc cggtttatca tctggacttc 2340 aagctgcagg cagttctgtt tttccaggcc ttttgtccct cccgggtatc cctgggtttc 2400 ctcagaatcc ttcacaatca tccttgcaag aattacagca taatgcggct gcgcagtcag 2460 cattgttaca gcaggtccat tcagcttcgg ctctggaaag ctatccagct cagcctgatg 2520 ggtttcctag ttatccttca gcgccaggaa caccattttc tttgcaacca agcctgtccc 2580 agagtgggtg gcagtgaata cttttaactt ttattctcct tcagagcaac atcagaattg 2640 cctgagaact gcaatgaaca atctgacaaa tgtgaagctg gccaaaagtc ggaaaatgag 2700 aatgagggta atcctggaga aattgtgaca acaatttgaa aattgtggtt gcattttaaa 2760 gtgtgaacac tcccctatgt aaatatgctg acaataaatt gtatggagaa tggtatttaa 2820 aaagtgtttg gagacttttc acctgtccta taaaattttg aattgtgtat gtgatctaca 2880 tagaaagaat attaaagagt aggttgaact ctttatagcc gaatacagcc ttaaatatgc 2940 ttgtatagca tccactggca gaagtaatag ttgtgcctca gacttggggg ttgcatgtgg 3000 ccctggggga gttactaccc ttggtatgca tgagcggttc ctattagcat cagtgggaac 3060 tcagtactct gtatgtatcc acaaaaggga acttgagacc cacagttatt cttaatttct 3120 gatattaaca accgtacata ctgctgaatt taactcaaaa tatttcaggt aagtgaaagt 3180 ggtgcttaat gtagactata gaatgacttt caggtgtttt caactgaaag tatatatcca 3240 gaactgcatc cttatagaaa tacaagtaag acttaggata atttgecttc aaaacagttt 3300 tcctaatctc agcagtatcc agtgagtgaa gaacacttga ctgactcttg ggccacctct 3360 gttacttact gtactatgga agctcctggt gaatgtttac aattatggga tgtagtattt 3420 ctatttgtac tttaagtcaa atgcttatat gaaatatgtg acaacaaata gagaagactg 3480 gctctgttag taattatgca gtatgtactc tatttaagga tctgtggtag tataacatga 3540 gtgaatgtca ttaattttga agtaataact gccacatgtg ggaagtaggg gagtaaggag 3600 aatgaattcc aatctgtgat taaaagtgta aactatagac tctactgtag tacatttcag 3660 gatctagaag ttttactttt ataaagatgg tgtccggaag atgttgctaa tgtattttac 3720 ttcaacatag ggaacaaact ttttaagtat attaataaac ctgtatggtt agtttttaac 3780 agttttttaa aataaactat ggatatgaca aatattctgt gttttactaa gtgcttggat 3840 aggctttcta attttgtata cgtgctagag ttaattattg aacattttta tccaaattta 3900 gttgtaactc tgtttatact actgattgct cattcgttta aatgatattt taatgtaaaa 3960 gtcataacca acatatgaac agacagattt atgtctttaa acacagaatg taagctatag 4020 tttaatctga taccagttgc tggaagttgc catttgtttt tcttaaatct atacccataa 4080 aacttctttt aagattaaaa aaaaaaaaaa a 4111 <210> 66 <211> 1604 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1825473CB1 <400> 66 gatcttaaat ctaatagatt tcctatttcc aaaaagctcg actggagtgt tataaaacct 60 gaaaattctc ttgtgctttc tcttcttttg cttctagtta ccatcctcaa aggattggct 120 aaaagcaagc aactggattg aacaccctaa gaagaaagat tcacactgca ccaggagaca 180 tcagaaagaa tgaaaactct gccgctgttt gtgtgcatct gtgcactgag tgcttgcttc 240 tcgttcagtg aaggtcgaga aagggatcat gaactacgtc acagaaggca tcatcaccaa 300 tcacccaaat ctcactttga attaccacat tatcctggac tgctagctca ccagaagccg 360 ttcattagaa agtcctataa atgtctgcac aaacgctgta ggcctaagct tccaccttca 420 cctaataacc cccccaaatt cccaaatcct caccagccac ctaaacatcc agataaaaat 480 agcagtgtgg tcaaccctac cttagtggct acaacccaaa ttccatctgt gactttccca 540 tcagcttcca ccaaaattac tacccttcca aatgtgactt ttcttcccca gaatgccacc 600 accatatctt caagagaaaa tgttaacaca agctcttctg tagctacatt agcaccagtg 660 aattccccag ctccacaaga caccacagct gccccaccca caccttctgc aactacacca 720 gctccaccat cttcctcagc tccaccagag accacagctg ccccacccac accttctgca 780 actacacaag ctccaccatc ttcctcagct ccaccagaga ccacagctgc cccacccaca 840 cctcctgcaa ctacaccagc tccaccatct tcctcagctc caccagagac cacagctgcc 900 ccacccacac cttctgcaac tacaccagct ccactatctt cctcagctcc accagagacc 960 acagctgtcc cacccacacc ttctgcaact accctagacc catcatccgc ctcagctcca 1020 ccagagacca cagctgcccc acccacacct tctgcaacta caccagctcc accgtcttcc 1080 ccagctccac aagagaccac agctgcccca attaccacac ctaattcttc cccaactact 1140 cttgcacctg acacttctga aacttcagct gcacccacac accagactac tacttcggtc 1200 actactcaaa ctactactac taaacaacca acttcagctc ctggccaaaa taaaatttct 1260 cgatttcttt tatatatgaa gaatctacta aacagaatta ttgacgacat ggtggagcaa 1320 tagtatattg tatgttgtaa agtgttctgt catttacaag atgtgattca tgagtgcaga 1380 actaccacct ttcttttagc accaatccca acatgaaatt atattactca gatttaaagc 1440 actatcatta atctttcaat ctaattattc accaccacaa gacctattaa caagacaaaa 1500 tgcctctatc ccacaagcca gatgcaggtc tggggttcaa aataactctt tggatcctac 1560 agagatagcc tactgagggc agagaaagtc cttagataaa gaga 1604 <210> 67 <211> 2646 <212> DNA
<213> Homo sapiens <220>

<221> misc_feature <223> Incyte ID No: 7950094CB1 <400> 67 gcgagcgcgg gcaggcggcg acgcgggggc aggggtggac ggcggtcaga gccgaacgcg 60 agggcggcgc ccggggactg gagctgcgcg caataggaca gctggcctga agctcagagc 120 cggggcgtgc gccatggccc cacactgggc tgtctggctg ctggcagcaa ggctgtgggg 180 cctgggcatt ggggctgagg tgtggtggaa ccttgtgccg cgtaagacag tgtcttctgg 240 ggagctggcc acggtagtac ggcggttctc ccagaccggc atccaggact tcctgacact 300 gacgctgacg gagcccactg ggcttctgta cgtgggcgcc cgagaggccc tgtttgcctt 360 cagcatggag gccctggagc tgcaaggagc gatctcctgg gaggcccccg tggagaagaa 420 gactgagtgt atccagaaag ggaagaacaa ccagaccgag tgcttcaact tcatccgctt 480 cctgcagccc tacaatgcct cccacctgta cgtctgtggc acctacgcct tccagcccaa 540 gtgcacctac gtcaacatgc tcaccttcac tttggagcat ggagagtttg aagatgggaa 600 gggcaagtgt ccctatgacc cagctaaggg ccatgctggc cttcttgtgg atggtgagct 660 gtactcggcc acactcaaca acttcctggg cacggaaccc attatcctgc gtaacatggg 720 gccccaccac tccatgaaga cagagtacct ggccttttgg ctcaacgaac ctcactttgt 780 aggctctgcc tatgtacctg agagtgtggg cagcttcacg ggggacgacg acaaggtcta 840 cttcttcttc agggagcggg cagtggagtc cgactgctat gccgagcagg tggtggctcg 900 tgtggcccgt gtctgcaagg gcgatatggg gggcgcacgg accctgcaga ggaagtggac 960 cacgttcctg aaggcgcggc tggcatgctc tgccccgaac tggcagctct acttcaacca 1020 gctgcaggcg atgcacaccc tgcaggacac ctcctggcac aacaccacct tctttggggt 1080 ttttcaagca cagtggggtg acatgtacct gtcggccatc tgtgagtacc agttggaaga 1140 gatccagcgg gtgtttgagg gcccctataa ggagtaccat gaggaagccc agaagtggga 1200 ccgctacact gaccctgtac ccagccctcg gcctggctcg tgcattaaca actggcatcg 1260 gcgccacggc tacaccagct ccctggagct acccgacaac atcctcaact tcgtcaagaa 1320 gcacccgctg atggaggagc aggtggggcc tcggtggagc cgccccctgc tcgtgaagaa 1380 gggcaccaac ttcacccacc tggtggccga ccgggttaca ggacttgatg gagccaccta 1440 tacagtgctg ttcattggca caggagacgg ctggctgctc aaggctgtga gcctggggcc 1500 ctgggttcac ctgattgagg agctgcagct gtttgaccag gagcccatga gaagcctggt 1560 gctatctcag agcaagaagc tgctctttgc cggctcccgc tctcagctgg tgcagctgcc 1620 cgtggccgac tgcatgaagt atcgctcctg tgcagactgt gtcctcgccc gggaccccta 1680 ttgcgcctgg agcgtcaaca ccagccgctg tgtggccgtg ggtggccact ctggatctct 1740 actgatccag catgtgatga cctcggacac ttcaggcatc tgcaacctcc gtggcagtaa 1800 gaaagtcagg cccactccca aaaacatcac ggtggtggcg ggcacagacc tggtgctgcc 1860 ctgccacctc tcctccaact tggcccatgc ccgctggacc tttgggggcc gggacctgcc 1920 tgcggaacag cccgggtcct tcctctacga tgcccggctc caggccctgg ttgtgatggc 1980 tgcccagccc cgccatgccg gggcctacca ctgcttttca gaggagcagg gggcgcggct 2040 ggctgctgaa ggctaccttg tggctgtcgt ggcaggcccg tcggtgacct tggaggcccg 2100 ggcccccctg gaaaacctgg ggctggtgtg gctggcggtg gtggccctgg gggctgtgtg 2160 cctggtgctg ctgctgctgg tgctgtcatt gcgccggcgg ctgcgggaag agctggagaa 2220 aggggccaag gctactgaga ggaccttggt gtaccccctg gagctgccca aggagcccac 2280 cagtcccccc ttccggccct gtcctgaacc agatgagaaa ctttgggatc ctgtcggtta 2340 ctactattca gatggctccc ttaagatagt acctgggcat gcccggtgcc agcccggtgg 2400 ggggccccct tcgccacctc caggcatccc aggccagcct ctgccttctc caactcggct 2460 tcacctgggg ggtgggcgga actcaaatgc caatggttac gtgcgcttac aactaggagg 2520 ggaggaccgg ggagggctcg ggcaccccct gcctgagctc gcggatgaac tgagacgcaa 2580 actgcagcaa cgccagccac tgcccgactc caaccccgag gagtcatcag tatgagggga 2640 accccc 2646 <210> 68 <211> 3876 <222> DNA
<213> Homo sapiens <220>

<221> misc_feature <223> Incyte ID No: 7479484CB1 <400> 68 atgttccgac caaccacggt ggctgtagac gaggatggtg gagaagagga taaagatgag 60 tcatcaacca acagtggtgc aagtgctgtt tcttcttgtg gctttggagc cgacttctcc 120 acagataaag ggggctcctt cacgtcagta cagatcacta ataccactgg actgtcacag 180 gctcctggct tagcctccca aggtattagc tttggcatta agaataatct gggaccccca 240 ctgcagaaat tgggagtatc attttccttt gccaagaaag ctcccgtcaa acttgaatca 300 atagcatccg ttttcaagga ccatgcagag gaagggagct cagaagatgg aacgaaggct 360 gatgagaaga gctctgacca aggggtgcag aaggtgggag atactgatgg cactggtaat 420 cttgatggaa agaaagaaga tgaagaccct caggatggag ggtcccttgc ctcaacactg 480 tccaagttga aaaggatgaa acgggaagaa ggaacagggg ctacagagcc agaatattac 540 cactacatcc ccccagcaca ctgcaaggtc aaacctaatt tccccttctt actctttatg 600 agagccagtg aacagatgga aggggatcat agtgcacact caaagagtgc ccccgagaac 660 agaaaaagca gctctcccaa gccgcaaggc tgtagtaaga cagcagcaag cccaggggca 720 gaaagaacag tgagtgaagc ttctgagctg caaaaggaag ccgctgtggc tgggccttca 780 gagcctggag gtaaaactga aacaaagaaa ggctccggag gaggggaaga tgagcagagt 840 gtagagagta gggagacgtc agagagcccg atgtgtgagt ccaatcctaa agacatttct 900 caggccaccc cagcaacaaa agcaggccag ggacccaagc atcctactgg tccattcttt 960 ccagttttaa gcaaggatga aagcactgcc ctccagtggc catcagaact actcattttc 2020 accaaagcag agccttccat ctcctacagt tgtaatcctt tatactttga ctttaaactt 1080 tcaagaaaca aagatgctaa agctaaaggg acagaaaagc caaaagatgt cgcaggctcc 1140 tcaaaggatc atctccagag ccttgatcct agagaaccga ataaaagcca ggaagaggag 1200 caggatgtag tgctctcttc agaaggcaga gtggatgaac ctgcatcagg ggctgcctgt 1260 agcagcctga acaagcagga gcctgggggt agccatatgt cagaaactga agacactggg 1320 agaagccatc ctagcaagaa agaaccatca ggcaagtctc acagacacaa gaagaaaaag 1380 aaacacaaaa aatccagcaa gcacaaacgt aaacacaagg ctgacacgga agagaagagt 1440 tctaaggcag agtctgggga gaaatctaag aagcgcaaga aacgaaaacg gaagaagaac 1500 aaatcatcag ccgcagctga ttctgaacgc ggacccaaat cagaacctcc tggaagcggc 1560 agcccggcac caccgagaag gcggcgccga gctcaagatg attcccagcg gagatccctt 1620 cctgctgaag aaggaaacag tggcaagaag gatgatggtg ggggtggtag cagttgccaa 1680 gatcacagtg ggaggaaaca caaaggtgaa ccaccaactt cctcctgcca gcggagagct 1740 aacaccaaac atagcagccg gtccagccat cggagccaac ccagtagtgg tgatgaggat 1800 agtgatgatg cttcctcaca ccgactgcac cagaagtctc catcccagta cagtgaggag 1860 gaggaagagg aggaggagga agaagaggag gaagatgaag actccggtag tgagcattct 1920 cgtagccgct ctcggtctgg ccatcgccat tcctcacatc gttcctcccg gcgctcttat 1980 tctagcagct ctgatgcctc ttcagaccag agctgctata gtagacagca cagttactct 2040 gatgatagct atagtgacta tagcgaccga tcacgaaggc actctaagcg ctctcacgat 2100 tcagatgatt cagactatac cagctccaaa cacaggtcta aacgacacaa atactcatca 2160 tctgatgatg actatagcct cagttgcagc cagtcccgaa gccgatctcg gagtcataca 2220 agggagcgat caagatcccg gggtcgaagc cgcagtagca gctgtagtcg cagtcgaagc 2280 aagaggagaa gtcgcagcac cacagcccac agctggcagc gaagccgaag ctatagccgg 2340 gaccggagcc gcagcaccag gagcccttct cagagatcag gctccagaaa gggctcatgg 2400 ggtcatgaga gcccagagga aaggcgctct ggccgccggg atttcattcg ttcaaagatc 2460 taccgctctc aatcccccca ctatttccaa tcaggtcggg gagaaggtcc tggaaagaaa 2520 gaagatggca gaggagatga cagtaaagga gcaggcctgc cctcccagaa tagcaatact 2580 ggcacaggaa gggggtcaga aagtgactgc agtcctgaag ataagaattc tgttactgcc 2640 agactgctgc tagagaagat ccagtccagg aaagtggaga ggaaacccaa tgtgtgcgag 2700 gaggtgctgg ccacccctaa taaggctggg ctcaagtaca agaacccccc acaaggttac 2760 tttgggccta agctcccccc gtctcttggt aataagcctg ttcttccaat gatagggaag 2820 cttccagcta cccggaagtc caataagaaa tgtgaagagt ctggcttaga aaggggagaa 2880 gagcaggaac attcagagcc agaagaaggg tccccaagga gtagtgatgc tccatttggg 2940 catcagttct cagaggaagc agctggtccc ttatcagacc ctcccccaga agagccaaag 3000 tctgaagaag ctactgctga tcactctgtg gctccgctag gcaccccagc ccacactgac 3060 tgctaccctg gggatccagc catctcccat aactacctcc cggaccccag tgatggggat 3120 actctggagt ctctggatag tggcagtcaa ccaggccctg tggaatccag cttgctgcct 3180 atagccccag accttgagca cttccccaat tatgcacctc ccagtgggga acctagtatt 3240 gaatcaacag atgggactga ggatgcctcc ttggctcctc tcgagagcca gcccatcacc 3300 ttcacccctg aggagatgga gaagtacagc aagctccagc aggctgcaca gcagcacatc 3360 cagcagcagc ttctggccaa acaagtgaag gcctttccag cctccaccgc cctagctcca 3420 gccacaccag ccctgcagcc catccacatt cagcagccag ccacagcctc tgccacctcc 3480 atcaccactg ttcagcatgc catcctacag catcatgctg cagccgctgc tgccgccatt 3540 ggcattcacc ctcaccccca ccctcagccg cttgctcaag tacatcatat tccccagccc 3600 catctaaccc ctatttcttt gtcccatctc actcactcaa ttatccctgg ccaccctgcc 3660 acctttcttg ctagccaccc tatccatata attcctgcct cagccatcca tcctgggccc 3720 ttcacctttc atcccgtccc acacgctgcc ctctacccca ccctgcttgc cccacggcct 3780 gctgcagcag ctgccacagc cctccatctt cacccactgc ttcaccccat cttctcaggt 3840 caggacctgc agcaccctcc cagccatggg acttga 3876 <210> 69 <211> 2583 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6780147CB1 <400> 69 ggtggcgggt ggctggcggt tccgttaggt ctgagggagc gatggcggta cgcgcgttga 60 agctgctgac cacactgctg gctgtcgtgg ccgctgcctc ccaagccgag gtcgagtccg 120 aggcaggatg gggcatggtg acgcctgatc tgctcttcgc cgaggggacc gcagcctacg 180 cgcgcgggga ctggcccggg gtggtcctga gcatggaacg ggcgctgcgc tcccgggcag 240 ccctccgcgc ccttcgcctg cgctgccgca cccagtgtgc cgccgacttc ccgtgggagc 300 tggaccccga ctggtccccc agcccggccc aggcctcggg cgccgccgcc ctgcgcgacc 360 tgagcttctt cgggggcctt ctgcgtcgcg ctgcctgcct gcgccgctgc ctcgggccgc 420 cggccgccca ctcgctcagc gaagagatgg agctggagtt ccgcaagcgg agcccctaca 480 actacctgca ggtcgcctac ttcaagatca acaagttgga gaaagctgtt gctgcagcac 540 acaccttctt cgtgggcaat cctgagcaca tggaaatgca gcagaaccta gactattacc 600 aaaccatgtc tggagtgaag gaggccgact tcaaggatct tgagactcaa ccccatatgc 660 aagaatttcg actgggagtg cgactctact cagaggaaca'gccacaggaa gctgtgcccc 720 acctagaggc ggcgctgcaa gaatactttg~tggcctatga ggagtgccgt gccctctgcg 780 aagggcccta tgactacgat ggctacaact accttgagta caacgctgac ctcttccagg 840 ccatcacaga tcattacatc caggtcctca actgtaagca gaactgtgtc acggagcttg 900 cttcccaccc aagtcgagag aagccctttg aagacttcct cccatcgcat tataattatc 960 tgcagtttgc ctactataac attgggaatt atacacaggc tgttgaatgt gccaagacct 1020 atcttctctt cttccccaat gacgaggtga tgaaccaaaa tttggcctat tatgcagcta 1080 tgcttggaga agaacacacc agatccatcg gcccccgtga gagtgccaag gagtaccgac 1140 agcgaagcct actggaaaaa gaactgcttt tcttcgctta tgatgttttt ggaattccct 1200 ttgtggatcc ggattcatgg actccagaag aagtgattcc caagagattg caagagaaac 1260 agaagtcaga acgggaaaca gccgtacgca tctcccagga gattgggaac cttatgaagg 1320 aaatcgagac ccttgtggaa gagaagacca aggagtcact ggatgtgagc agactgaccc 1380 gggaaggtgg ccccctgctg tatgaaggca tcagtctcac catgaactcc aaactcctga 1440 atggttccca gcgggtggtg atggacggcg taatctctga ccacgagtgt caggagctgc 1500 agagactgac caatgtggca gcaacctcag gagatggcta ccggggtcag acctccccac 1560 atactcccaa tgaaaagttc tatggtgtca ctgtcttcaa agccctcaag ctggggcaag 1620 aaggcaaagt tcctctgcag agtgcccacc tgtactacaa cgtgacggag aaggtgcggc 1680 gcatcatgga gtcctacttc cgcctggata cgcccctcta cttttcctac tctcatctgg 1740 tgtgccgcac tgccatcgaa gaggtccagg cagagaggaa ggatgatagt catccagtcc 1800 acgtggacaa ctgcatcctg aatgccgaga ccctcgtgtg tgtcaaagag cccccagcct 1860 acaccttccg cgactacagc gccatccttt acctaaatgg ggacttcgat ggcggaaact 1920 tttatttcac tgaactggat gccaagaccg tgacggcaga ggtgcagcct cagtgtggaa 1980 gagccgtggg attctcttca ggcactgaaa acccacatgg agtgaaggct gtcaccaggg 2040 ggcagcgctg tgccatcgcc ctgtggttca ccctggaccc tcgacacagc gagcgggaca 2100 gggtgcaggc agatgacctg gtgaagatgc tcttcagccc agaagagatg gacctctccc 2160 aggagcagcc cctggatgcc cagcagggcc cccccgaacc tgcacaagag tctctctcag 2220 gcagtgaatc gaagcccaag gatgagctat gacagcgtcc aggtcagacg gatgggtgac 2280 tagacccatg gagaggaact cttctgcact ctgagctggc cagcccctcg gggctgcaga 2340 gcagtgagcc tacatctgcc actcagccga ggggaccctg ctcacagcct tctacatggt 2400 gctactgctc ttggagtgga catgaccaga caccgcaccc cctggatctg gctgagggct 2460 caggacacag gcccagccac ccccaggggc ctccacaggc cgctgcataa cagcgataca 2520 gtacttaagt gtctgtgtag acaaccaaag aataaatgat tcatggtttt ttttaaaaaa 2580 aaa 2583 <210> 70 <211> 6147 <212> DNA
<213> Homo sapiens <220>
<221> misc_~eature <223> Incyte ID No: 7204554CB1.
<400> 70 tgatatatag ggccatgctt atctagcatg catgctcgag acgcgcgcat atgtgctgga 60 aagggcgggg cgcgccccgg ggcggcgggg ctgaagctcc tggcaccatg atgctcaccc 120 cagcaggacc agagcaccga ggcccaaggc cccagcctgc catgccgctg ccaccgcgga 180 gcctgcaggt gctcctgctg ctgctgctgt tgctgctgct gctgccgggc atgtgggctg 240 aggcaggctt gcccagggca ggcgggggtt cacagccccc cttccgcacc ttctcggcca 300 gcgactgggg cctcacccac ctagtggtgc atgagcagac aggcgaggtg tatgtgggcg 360 cagtgaaccg catctataag ctgtcgggga acctgacact gctgcgggcc cacgtcacgg 420 gccctgtgga ggacaacgag aagtgctacc cgccgcccag cgtgcagtcc tgcccccacg 480 gcctgggcag tactgacaac gtcaacaagc tgctgctgct ggactatgcc gctaaccgcc 540 tgctggcctg tggcagcgcc tcccagggca tctgccagtt cctgcgtctg gacgatctct 600 tcaaactggg tgagccacac caccgtaagg agcactacct gtccagcgtg caggaggcag 660 gcagcatggc gggcgtgctc attgccgggc caccgggcca gggccaggcc aagctcttcg 720 tgggcacacc catcgatggc aagtccgagt acttccccac actgtccagc cgtcggctca 780 tggccaacga ggaggatgcc gacatgttcg gcttcgtgta ccaggatgag tttgtgtcat 840 cacagctcaa gatcccttcg gacacgctgt ccaagttccc ggcctttgac atctactatg 900 tgtacagctt ccgcagcgag cagtttgtct actacctcac gctgcagcta gacacacagc 960 tgacctcgcc tgatgccgcc ggcgagcact tcttcacgtc caagatcgtg cggctctgtg 1020 tggacgaccc caaattctac tcgtacgttg agttccccat tggctgcgag caggcgggtg 1080 tggagtaccg cctggtgcag gatgcctacc tgagccggcc cggccgtgcc ctggcccacc 1140 agctgggcct ggctgaggac gaggacgtgc tgttcactgt gttcgcccag ggccagaaga 1200 accgcgtgaa gccaccaaag gagtcagcac tgtgcctgtt cacgctcagg gccatcaagg 1260 agaagattaa ggagcgcatc cagtcctgct accgtggtga gggcaagctc tccctgccgt 1320 ggctgctcaa caaggagctg ggctgcatca actcgcccct gcagatcgat gacgacttct 1380 gcgggcagga cttcaaccag cccctggggg gcacagtcac cattgagggg acgcccctgt 1440 tcgtggacaa ggatgatggc ctgaccgccg tggctgccta tgactatcgg ggccgcactg 1500 tggtattcgc cggcacgcga agtggccgca tccgcaagat cctggtggac ctctcaaacc 1560 ccggtggccg gcctgccctg gcctacgaga gcgtcgtggc ccaggagggc agccccatcc 1620 tgcgagacct cgtcctcagc cccaaccacc agtacctcta cgccatgacc gagaagcagg 1680 tgacgcgggt gcctgtggag agctgtgtgc agtacacgtc ctgtgagctg tgtctggggt 1740 cacgggaccc ccactgtggc tggtgtgtcc tgcacagcat ctgctcgcgg cgggacgcct 1800 gtgagcgagc agacgagccc cagcgctttg ctgcggacct gctgcagtgt gtgcagctga 1860 ctgtgcagcc ccgcaatgtg tctgtcacca tgtcccaggt eccacttgtg ctgcaggcct 1920 ggaacgtgcc tgacctctca gctggcgtca actgctcctt egaggacttc acggaatctg 1980 agagcgtcct ggaggatggc cggatccact gccgctcacc ctccgcccgg gaggtggcgc 2040 ccatcacgcg gggccaggga gaccagcggg tggtgaaact ctacctaaag tccaaggaga 2100 cagggaagaa gtttgcgtct gtggacttcg tcttctacaa ctgcagcgtc caccagtcct 2160 gcctgtcctg tgtcaacggc tcctttccct gccactggtg caaataccgc cacgtgtgca 2220 cacacaacgt ggctgactgc gccttcctgg agggccgtgt caacgtgtct gaggactgcc 2280 cacagatcct gccctccacg cagatctacg tgccagtggg agtggtaaaa cccatcaccc 2340 tggccgcacg gaacctgcca cagccacagt caggccagcg tggatatgag tgcctcttcc 2400 acatcccggg cagcccggcc cgtgtcaccg ccctgcgctt caacagctcc agcctgcagt 2460 gccagaattc ctcgtactcc tacgagggga acgatgtcag cgacctgcca gtgaacctgt 2520 cagtcgtgtg gaacggcaac tttgtcattg acaacccaca gaacatccag gcgcacctct 2580 acaagtgccc ggccctgcgc gagagctgcg gcctctgcct caaggccgac ccgcgcttcg 2640 agtgcggatg gtgcgtggcc gagcgccgct gctccctgcg acaccactgc gctgccgaca 2700 cacctgcatc gtggatgcac gcgcgtcacg gcagcagtcg ctgcaccgac cccaagatcc 2760 tcaagctgtc ccccgagacg ggcccgaggc agggcggcac gcggctcact atcacaggcg 2820 agaacctggg cctgcgattc gaagacgtgc gtctgggcgt gcgcgtgggc aaggtgctgt 2880 gcagccctgt ggagagcgag tacatcagtg cggagcagat cgtctgtgag atcggggacg 2940 ecagctccgt gcgtgcccat gacgccctgg tggaggtgtg tgtgcgggac tgctcaccac 3000 actaccgcgc cctgtcaccc aagcgcttca ccttcgtgac accaaccttc taccgtgtga 3060 gcccctcccg tgggcctctg tcagggggca cctggattgg catcgaggga agccacctga 3120 acgcaggcag tgatgtggct gtgtcggtcg gtggccggcc ctgctccttc tcctggagga 3180 actcccgtga gatccggtgc ctgacacccc ccgggcagag ccctggcagc gctcccatca 3240 tcatcaacat caaccgcgcc cagctcacca accctgaggt gaagtacaac tacaccgagg 3300 accccaccat cctgaggatc gaccccgagt ggagcatcaa cagcggtggg accctcctga 3360 cggtcacagg caccaacctg gccactgtcc gtgaaccccg aatccgggcc aagtatggag 3420 gcattgagag ggagaacggc tgcctggtgt acaatgacac caccatggta tgccgcgccc 3480 cgtctgtggc caaccctgtg cgcagcccac cagagctggg ggagcggccg gatgagctgg 3540 gcttcgtcat ggacaacgtg cgctccctgc ttgtgctcaa ctccacctcc ttcctctact 3600 accctgaccc cgtactggag ccactcagcc ccactggcct gctggagctg aagcccagct 3660 ccccactcat cctcaagggc cggaacctct tgccacctgc acccggcaac tcccgactca 3720 actacacggt gctcatcggc tccacaccct gtaccctcac cgtgtcggag acgcaactgc 3780 tgtgcgaggc gcccaacctc actgggcagc acaaggtcac ggtgcgggca ggtggcttcg 3840 agttctcgcc agggacactg caggtgtact cggacagcct gctgacgctg cctgccattg 3900 tgggcattgg cggaggcggg ggtctcctgc tgctggtcat cgtggctgtg ctcatcgcct 3960 acaagcgcaa gtcacgagat gctgaccgca cactcaagcg gctgcagctc cagatggaca 4020 acctggagtc ccgcgtggcc ctcgaatgca aggaagcctt tgcagagctg cagacagaca 4080 tccacgagct gaccaatgac ctggacggtg ccggcatccc cttccttgac taccggacat 4140 atgccatgcg ggtgctcttt cctgggatcg aggaccaccc tgtgctcaag gagatggagg 4200 tgcaggccaa tgtggagaag tcgctgacac tgttcgggca gctgctgacc aagaagcact 4260 tcctgctgac cttcatccgc acgctggagg cacagcgcag cttctccatg cgcgaccgcg 4320 ggaatgtggc ctcgctcatc atgacggccc tgcagggcga gatggaatac gccacaggcg 4380 tgctcaagca gctgctttcc gacctcatcg agaagaacct ggagagcaag aaccacecca 4440 agctgctact gcgccggact gagtcggtgg cagagaagat gctaactaac tggttcacct 4500 tcctcttgta taagttcctc aaggagtgcg ctggggagcc gctgttcatg ctgtactgcg 4560 ccatcaagca gcagatggag aagggcccca ttgacgccat cacgggtgag gcacgctact 4620 ccctgagtga ggacaagctc atccggcagc agattgacta caagacactg accctgaact 4680 gtgtgaaccc tgagaatgag aatgcacctg aggtgccggt gaaggggctg gactgtgaca 4740 cggtcaccca ggccaaggag aagctgctgg acgctgccta caagggcgtg ccctactccc 4800 agcggcccaa ggccgcggac atggacctgg agtggcgcca gggccgcatg gcgcgcatca 4860 tcctgcagga cgaggacgtc accaccaaga ttgacaacga ttggaagagg ctgaacacac 4920 tggctcacta ccaggtgaca gacgggtcct cggtggcact ggtgcccaag cagacgtccg 4980 cctacaacat ctccaactcc tccaccttca ccaagtccct cagcagatac gagagcatgc 5040 tgcgcacggc cagcagcccc gacagcctgc gctcgcgcac gcccatgatc acgcccgacc 5100 tggagagcgg caccaagctg tggcacctgg tgaagaacca cgaccacctg gaecagcgtg 5160 agggtgaccg cggcagcaag atggtctcgg agatctactt gacacggcta ctggccacca 5220 agggcacact gcagaagttt gtggacgacc tgtttgagac catcttcagc acggcacacc 5280 ggggctcagc cctgccgctg gccatcaagt acatgttcga cttcctggat gagcaggccg 5340 acaagcacca gatccacgat gctgacgtgc gccacacctg gaagagcaac tgcctgcccc 5400 tgcgcttctg ggtgaacgtg atcaagaacc cacagtttgt gttcgacatt cacaagaaca 5460 gcatcacgga cgcctgcttg tcggtggtgg cccagacctt catggactcc tgctccacct 5520 ctgagcacaa gctgggcaag gactcaccct ccaacaagct gctctacgcc aaggacatcc 5580 ccaactacaa gagctgggtg gagaggtact atgcagacat cgccaagatg ccagccatca 5640 gcgaccagga catgagtgcg tatctggctg agcagtcccg cctgcacctg agccagttca 5700 acagcatgag cgccttgcac gagatctact cctacatcac caagtacaag gatgagatcc 5760 tggcagccct ggagaaggat gagcaggcgc ggcggcagcg gctgcggagc aagctggagc 5820 aggtggtgga cacgatggcc ctgagcagct gagccccagc tgtgatcatc cagcatgatg 5880 cagcgtgagg acagctgagc agggaccggg acagccctca ccgcatgcgt gtggagtgtc 5940 cggtggtgct cgggccgccg cagtgcagcg actgcccggc cctccctccc ctgcctcacc 6000 cggtcgggtc ccggctcttc ctgtgtggag gtgatggtac ctgccacacc acagctgcgc 6060 acacagctgc ttgctcaggg gccgggacag cactgggtgc tcaggctggc vaaggacctt 6120 cattgcctgg gcaagagctg cccagtg 6147 <210> 71 <211> 888 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6833247CB1 <400> 71 cgagcttact tatactggta cctttctaat ctcactacaa tatgtaacat tggtgttcga 60 tctcaagtat ttctgaatat attcccctat ccacagaaat atactctggg ggaaaaaaaa 120 tagaacaaat tcttgccgtc ctgaccattg aacaagagac taattagaca atggggctag 180 aaaaacctca aagtaaactg gaaggaggca tgcatcccca gctgatacct tcggttattg 240 ctgtagtttt catcttactt ctcagtgtct gttttattgc aagttgtttg gtgactcatc 300 acaacttttc acgctgtaag agaggcacag gagtgcacaa gttagagcac catgcaaagc 360 tcaaatgcat caaagagaaa tcagaactga aaagtgctga agggagcacc tggaactgtt 420 gtcctattga ctggagagcc ttccagtcca actgctattt tcctcttact gacaacaaga 480 cgtgggctga gagtgaaagg aactgttcag ggatgggggc ccatctgatg accatcagca 540 cggaagctga gcagaacttt attattcagt ttctggatag acggctttcc tatttccttg 600 gacttagaga tgagaatgcc aaaggtcagt ggcgttgggt ggaccagacg ccatttaacc 660 cacgcagagt attctggcat aagaatgaac ccgacaactc tcagggagaa aactgtgttg 720 ttcttgttta taaccaagat aaatgggcct ggaatgatgt tccttgtaac tttgaagcaa 780 gtaggatttg taaaatacct ggaacaacat tgaactagaa actcagaaag tggtccttgt 840 gatggaaaga gaaaagaaaa accaattaga ataaggcaga atgtacgt 888 <210> 72 <211> 3582 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4148119CB1 <400> 72 ctggccacac cgaaagagag cccacccaag tctgaggaac cacacccgga gcagttccga 60 aaagcgaggg agacttcccc tgatctggaa agggtgccag gcacttcagc accatcggca 120 gccccagccc ctcacccacg gca~gagagg cagagcggct ctcaccgggt ccagaccggc 180 ccagcccacc ataatggtca aaagaaggcc aagctctgga aggtgggaac aactgaggca 240 gatggggaca gtaaagccag atggaccgcg cttgagcctt catctccacc agggacccag 300 gccaccttcc cagttccata cctcttcagc ctcaggtccc~tcttgactga gcccagcgtc 360 accgccccca agaaagttcc ccaatcaccc tgtcccacgc tgggccacct gcttccctcc 420 ctgaaggctg tccctaagct gtgggtattt atcctactaa ggaggctggg acagagtcct 480 gacctgcacc catctgttcc caacccacca gccttcaaac aagggggctc ctcctccccg 540 gggcagctct ggcctctgct gggggccagt cgaggcagat agaagggtga gcctaaccaa 600 tgacccaacg cccccttccc aattaactac cgccttccaa cggaatccaa gggaatccct 660 catccccaaa acttcaccgc ggaaggatct gcggggactg acaggcagaa gccaggcaca 720 gggatatccg aacagcctca gtcttgctac ccaactctgc cttcaagaca ttccaatctg 780 atgggaagag tcctgtctgg gaagctccct gtctgatggg agacagccct gtccacatgg 840 ~aggtctcagt ctgacggagg aaacagcctg gccagccagg cccaggccga caggggagac 900 acagtccctg cccaaggagc ttccaagcta agggcggaac cacagccaag cccagggagc 960 tcccaggcta agggcggaga ctgtcccagc ccagggagct cccagtcaaa agggggagac 1020 acagcactgc ccttacaaag ctaccagcct cacggagaag gcgcagtccc tgtccacaga 1080 gacacagcct tgccccagtt actgcccacc tgcaagagat ccacatttct gccctccaga 1140 gctcccaaac tgatggggga gagagacatc atcccccagc tctgggagtt tccagtctga 1200 tggaggagac agagcctgct tcggtaactc tcactctgcg ggggaagact cagccctatc 1260 cagggagctc ccacactttc aatggggagg cccacccagt ggccgagcct gctgctgctc 1320 ctgctgttgc cggggccccc gcccgtcgcc ggcttggaag acgctgcctt cccccacctg 1380 ggggagagct tgcagcccct gccccgggcc tgtcccctgc gctgctcctg cccccgagtc 1440 gacactgtgg actgtgatgg cttggacctt cgagtgttcc cggacaacat caccagagcc 1500 gctcagcacc tctccctgca gaacaaccag ctccaggaac tcccctacaa tgagctgtcc 1560 cgcctcagtg gcctgcgaac cctcaacctc cacaacaacc tcatctcctc cgaaggcctg 1620 cctgacgagg ccttcgagtc cctcacccag ctgcagcacc tctgcgtggc tcacaacaag 1680 ctctcagtgg cccctcagtt tctgccccgg tccctccgtg tcgcggatct ggctgccaac 1740 caagtgatgg agatcttccc cctcaccttt ggggagaagc cggtactcag gtccgtgtac 1800 ctccacaaca accagctgag caacgctggc ctgccccccg acgccttccg cggctccgag 1860 gccatcgcca'ccctcagcct ctccaacaac cagctcagct acctgc,cgcc cagcctgccg 1920 ccctcactcg agcggctcca cctgcagaac aatctcatct ccaaggtgcc ccgaggagcc 1980 ctgagccgcc agactcaact ccgtgagctc tacctccagc acaaccagct gacagacagt 2040 ggcctggatg ccaccacctt cagcaagctg catagccttg aatacctgga tctctcccac 2100 aaccagctga ccacagtgcc cgccggcctg ccccggaccc tggctatcct gcacctgggc 2160 cgcaaccgca tccggcaggt ggaggcggct cggctgcacg gggcgcgtgg tctgcgctat 2220 ttgttgctgc agcacaacca gctggggagc tcagggctgc ccgccggggc tctgcggccg 2280 ctgcggggcc tgcacacgct gcacctctat ggcaatgggc tggaccgcgt gcctccagcc 2340 ctgccccgcc gcctgcgtgc cctggtgctg ccccacaacc acgtggccgc gctgggtgcc 2400 cgtgacctgg tcgccacacc gggcctgacg gagcttaacc tggcctataa ccgcctggcc 2460 agcgcccgtg tgcaccaccg ggccttccgc cggttgcgtg ccctgcgcag cctcgacctg 2520 gcagggaatc agctaacccg gctgcccatg ggcctgccca ctggcctgcg caccctgcag 2580 ctgcaacgca accagctgcg gatgctcgag cccgagcctc tggccggcct ggaccaactg 2640 cgggagctca gcctggcgca caaccggctc cgggtcggcg acatcgggcc aggcacctgg 2700 catgagctcc aagccctcca gatgctggac ctcagccaca atgagctgtc ctttgtgccc 2760 ccggacctgc ctgaggccct agaggagctg cacctcgagg gcaaccgcat cggccacgtg 2820 ggccccgagg ccttcctcag cacaccccgc ctgcgtgccc tcttcctcag ggccaacagg 2880 cttcacatga cgagcatcgc ggctgaggcc ttcctggggc tcccaaacct gcgtgtggtg 2940 gacacggcag ggaatccgga gcaggtcctg atccggctgc ctcccaccac cccacgtggg 3000 ccacgggcag ggggcccctg atcctagaga ggcccagcag agcagctcag actcctggga 3060 ctccgctggg ccgtggactg aggagacaac gcccaccagg ggcccttggt ctggctctcc 3120 tgggcctcca gggctgggcc tgctctgcct gccactggcc gagacacaga ggcacacagc 3180 tggcatactc caggctcaca gaccacgccg gcctggcggg acacacccta ccccaaactc 3240 ccaacacaga tggaggcagc aacaataaag ccaaaccctt ccagcactca gcacggacca 3300 ggcacccttc gggggctctg tccacggact cctccccaca accagtccag ctggggaaac 3360 tgaggctctg ggatgctaag tgggtcagga ctgaattttg aggtcttgag gcacacactg 3420 gggtcaccaa acagcaccct gtgcgaccta gccacgtgtg attgcaggga cgcccaaggc 3480 cacccactga aaaaacactg ggtgacagat atagggaccc tcacatgtat ccccccccac 3540 agcaagcatg ggaatgaaat gcatccttca aaaaaaaaaa as 3582

Claims (116)

What is claimed is:

1. An isolated polypeptide selected from the group consisting of:

a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, b) a naturally occurring polypeptide comprising an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-36.

2. An isolated polypeptide of claim 1 selected from the group consisting of SEQ 1D NO:1-36.

3. An isolated polynucleotide encoding a polypeptide of claim 1.

4. An isolated polynucleotide encoding a polypeptide of claim 2.

5. An isolated polynucleotide of claim 4 selected from the group consisting of SEQ ID
NO:37-72.

6. A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim 3.

7. A cell transformed with a recombinant polynucleotide of claim 6.

8. A transgenic organism comprising a recombinant polynucleotide of claim 6.

9. A method for producing a polypeptide of claim 1, the method comprising:

a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide, and said recombinant polynucleotide comprises a promoter sequence operably linked to a polynucleotide encoding the polypeptide of claim 1, and b) recovering the polypeptide so expressed.

10. An isolated antibody which specifically binds to a polypeptide of claim 1.

11. An isolated polynucleotide selected from the group consisting of:

a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:37-72, b) a naturally occurring polynucleotide comprising a polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:37-72, c) a polynucleotide complementary to a polynucleotide of a), d) a polynucleotide complementary to a polynucleotide of b), and e) an RNA equivalent of a)-d).

12. An isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide of claim 11.

13. A method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 11, the method comprising:

a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof.

14. A method of claim 13, wherein the probe comprises at least 60 contiguous nucleotides.

15. A method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 11, the method comprising:

a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.

16. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.

17. A composition of claim 16, wherein the polypeptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1-36.

18. A method for treating a disease or condition associated with decreased expression of functional ECMCAD, comprising administering to a patient in need of such treatment the composition of claim 16.

19. A method for screening a compound for effectiveness as an agonist of a polypeptide of claim 1, the method comprising:

a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting agonist activity in the sample.

20. A composition comprising an agonist compound identified by a method of claim 19 and a pharmaceutically acceptable excipient.

21. A method for treating a disease or condition associated with decreased expression of functional ECMCAD, comprising administering to a patient in need of such treatment a composition of claim 20.

22. A method for screening a compound for effectiveness as an antagonist of a polypeptide of claim 1, the method comprising:

a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting antagonist activity in the sample.

23. A composition comprising an antagonist compound identified by a method of claim 22 and a pharmaceutically acceptable excipient.

24. A method for treating a disease or condition associated with overexpression of functional ECMCAD, comprising administering to a patient in need of such treatment a composition of claim 23.

25. A method of screening for a compound that specifically binds to the polypeptide of claim 1, said method comprising the steps of:

a) combining the polypeptide of claim 1 with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide of claim 1 to the test compound, thereby identifying a compound that specifically binds to the polypeptide of claim 1.

26. A method of screening for a compound that modulates the activity of the polypeptide of claim 1, said method comprising:

a) combining the polypeptide of claim 1 with at least one test compound under conditions permissive for the activity of the polypeptide of claim 1, b) assessing the activity of the polypeptide of claim 1 in the presence of the test compound, and c) comparing the activity of the polypeptide of claim 1 in the presence of the test compound with the activity of the polypeptide of claim 1 in the absence of the test compound, wherein a change in the activity of the polypeptide of claim 1 in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide of claim 1.

27. A method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence of claim 5, the method comprising:

a) exposing a sample comprising the target polynucleotide to a compound, under conditions suitable for the expression of the target polynucleotide, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.

28. A method for assessing toxicity of a test compound, said method comprising:

a) treating a biological sample containing nucleic acids with the test compound;
b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide of claim 11 under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence of a polynucleotide of claim 11 or fragment thereof;

c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

29. A diagnostic test for a condition or disease associated with the expression of ECMCAD
in a biological sample comprising the steps of:

a) combining the biological sample with an antibody of claim 10, under conditions suitable for the antibody to bind the polypeptide and form an antibody polypeptide complex;
and b) detecting the complex, wherein the presence of the complex correlates with the presence of the polypeptide in the biological sample.

30. The antibody of claim 10, wherein the antibody is:

a) a chimeric antibody, b) a single chain antibody, c) a Fab fragment, d) a F(ab')2 fragment, or e) a humanized antibody.

31. A composition comprising an antibody of claim 10 and an acceptable excipient.

32. A method of diagnosing a condition or disease associated with the expression of ECMCAD in a subject, comprising administering to said subject an effective amount of the composition of claim 31.

33. A composition of claim 31, wherein the antibody is labeled.

34. A method of diagnosing a condition or disease associated with the expression of ECMCAD in a subject, comprising administering to said subject an effective amount of the composition of claim 33.

35. A method of preparing a polyclonal antibody with the specificity of the antibody of claim comprising:

a) immunizing an animal with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, or an immunogenic fragment thereof, under conditions to elicit an antibody response;
b) isolating antibodies from said animal; and c) screening the isolated antibodies with the polypeptide, thereby identifying a polyclonal antibody which binds specifically to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-36.

36. An antibody produced by a method of claim 35.

37. A composition comprising the antibody of claim 36 and a suitable carrier.

38. A method of making a monoclonal antibody with the specificity of the antibody of claim comprising:

a) immunizing an animal with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-36, or an immunogenic fragment thereof, under conditions to elicit an antibody response;
b) isolating antibody producing cells from the animal;
c) fusing the antibody producing cells with immortalized cells to form monoclonal antibody-producing hybridoma cells;
d) culturing the hybridoma cells; and e) isolating from the culture monoclonal antibody which binds specifically to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-36.

39. A monoclonal antibody produced by a method of claim 38.

40. A composition comprising the antibody of claim 39 and a suitable carrier.

41. The antibody of claim 10, wherein the antibody is produced by screening a Fab expression library.

42. The antibody of claim 10, wherein the antibody is produced by screening a recombinant immunoglobulin library.

43. A method for detecting a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-36 in a sample, comprising the steps of:

a) incubating the antibody of claim 10 with a sample under conditions to allow specific binding of the antibody and the polypeptide; and b) detecting specific binding, wherein specific binding indicates the presence of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
N0:1-36 in the sample.

44. A method of purifying a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-36 from a sample, the method comprising:

a) incubating the antibody of claim 10 with a sample under conditions to allow specific binding of the antibody and the polypeptide; and b) separating the antibody from the sample and obtaining the purified polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-36.

45. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:1.

46. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:2.

47. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:3.

48. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:4.

49. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:5.

50. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:6.

51. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:7.

52. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:8.

53. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:9.

54. A polypeptide of claim 1, comprising the amino acid sequence of SEQ 177 NO:10.

55. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:11.

56. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:12.

57. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:13.

58. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:14.

59. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:15.

60. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:16.

61. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:17.

62. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N018.

63. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N019.

64. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:20.

65. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:21.

66. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:22.

67. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:23.

68. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:24.

69. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:25.

70. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:26.

71. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:27.

72. A polypeptide of claim 1, comprising the amino acid sequence of SEQ 1D
N0:28.

73. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:29.

74. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:30.

75. A polypeptide of claim 1, comprising the amino acid sequence of SEQ 1D
N0:31.

76. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:32.

77. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:33.

78. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:34.

79. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:35.

80. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
N0:36.

81. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID N0:37.

82. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID N0:38.

83. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID N0:39.

84. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID N0:40.

85. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID N0:41.

86. A polypeptide of claim 11, comprising the polynucleotide sequence of SEQ
ID N0:42.

87. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID N0:43.

88. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID N0:44.

89. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:45.

90. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:46.

91. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:47.

92. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:48.

93. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:49.

94. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:50.

95. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:51.

96. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:52.

97. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:53.

98. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:54.

99. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID NO:55.

100. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:56.

101. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:57.

102. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:58.

103. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:59.

104. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:60.

105. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:61.

106. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:62.

107. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:63.

108. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:64.

109. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:65.

110. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:66.

111. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:67.

112. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:68.

113. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:69.

114. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:70.

115. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
N0:71.

116. A polynucleotide of claim 1l, comprising the polynucleotide sequence of SEQ ID
N0:72.