Non-Mendelian Inheritance

 Mitochondria

 Chloroplasts

 Examples of non-Mendelian inheritance

 Human mtDNA defects

Other forms of non-Mendelian Inheritance:

 Infectious cytoplasmic inheritance

 Maternal effect

 Genomic (parental) imprinting

Extranuclear Genomes:

Mitochondria (animals and plants)

Chloroplasts (plants)

1. Mitochondria and chloroplasts occur outside the nucleus, in the

cytoplasm of the cell.

2. Contain genomes (mtDNA/cpDNA) and genes, i.e.,

extrachromosomal genes, cytoplasmic genes, organelle genes, or
extranuclear genes.

3. Inheritance is non-Mendelian (e.g., cytoplasm typically is inherited

from the mother).
Origin of mitochondria and chloroplasts:

Both mitochondria and chloroplasts are believed to be derived from:

Endosymbiotic bacteria = free-living prokaryotes that invaded ancestral

eukaryotic cells and established a mutually beneficial relationship.

1. Mitochondria - derived from a photosynthetic purple bacterium that

entered a eukaryotic cell >billion years ago.

2. Chloroplasts - derived from a photosynthetic cyanobacterium.

Organization of the mtDNA genome:

• mtDNAs occur in all aerobic eukaryotic cells and generate energy for
cell function by oxidative phosphorylation (OXPHOS) producing ATP.

• Most mtDNA genomes are circular and supercoiled (linear mtDNAs

occur in some protozoa and some fungi).

• In some species %GC is high, allowing easy separation of pure

mtDNA from nuclear DNA by gradient centrifugation.

• mtDNAs lack histone-like proteins (like bacteria).

• Copy number is high, multiple genomes per mitochondria and many

mitochondria per cell (1000-2000 in a liver cell; makes mtDNA easy
to isolate and PCR).

• Size of mtDNA varies widely.

• Humans and other vertebrates ~16 kb

(all of the mtDNA codes gene products)

• Yeast ~80 kb
• Plants ~100 kb to 2 Mb
(lots of non-coding mtDNA)
Replication of the mtDNA genome:

• Replication is semi-conservative (like nuclear DNA replication) and

uses DNA polymerases specific to the mitochondria.

• Occurs throughout the cell-cycle (not just S phase); mitochondria

are constantly created.

• Control region (non-coding) similar to Ori sequence in E. coli forms a

displacement loop (d-loop) that functions in mtDNA replication.

• Mitochondria (organelle) are not synthesized de novo, but grow and

divide like other cells (e.g., mitosis).
Fig. 23.3, mtDNA replication
Contents of the mtDNA genome:

• mtDNA contains genes for:

• tRNAs
• rRNAs
• cytochrome oxidase, NADH-dehydrogenase, & ATPase subunits.
• mtDNA genes occur on both strands.
• Functions of all human mtDNA ORFs are assigned.

• Mitochondria’s genetic information also occurs in the nuclear DNA:

• DNA polymerase, replication factors

• RNA polymerase, transcription factors
• ribosomal proteins, translation factors, aa-tRNA synthetase
• Additional cytochrome oxidase, NADH, ATPase subunits.

• Most required mitochondrial (and chloroplast) proteins are coded by

nuclear genes in the nuclear genome.

• Five mtDNA complexes with 13 mtDNA subunit genes are paired with
76 nuclear subunit genes to make the same proteins.

I – NADH; II - Succinate dehydrogenase; III - Cytochrome bc

IV - Cytochrome c oxidase; V - ATP synthase
Fig. 23.4, Physical map of the human mtDNA
 Copies of mtDNA and chloroplast genes can be transposed to the
nuclear genome and vice versa.

chloroplast

mitochondrion

numtDNA (numt) =
mtDNA gene in the nucleus,
transposition can cause
heritable disease

nucleus
Transcription of the mtDNA genome:

• mRNAs from the mtDNA are synthesized and translated in the

mitochondria.

• Gene products encoded by nuclear genes are transported from the

cytoplasm to the mitochondria.

• Mammalian and other vertebrate mtDNAs are transcribed as a single

large RNA molecule (polycistronic) and cleaved to produce mRNAs,
tRNAs, and rRNAs before they are processed.

• Most mtDNA genes are separated by tRNAs that signal transcription

termination.

• In plants and yeast (mtDNA is much larger):

• tRNAs do not separate genes

• Gaps between genes are large
• Transcription is signaled by non-tRNA sequences
• Introns occur (do not occur in animal mtDNA)
• Some lack a complete stop codon (3’ end is U or UA; poly (A) tail
completes the stop codon)
• Transcription is monocistronic
Translation of the mtDNA genome:

• Mitochondrial mRNAs do not have a 5’ cap (yeast and plant mt

mRNAs have a leader).

• mtDNA-specific initiation factors (IFs), elongation factors (EFs), and

release factors (RFs) are used for translation.

• AUG is the start codon (binds with fMet-tRNA like bacteria).

• Only plants use the “universal” genetic code. Codes for mammals,
birds, and other organisms differ slightly.

• Extended wobble also occurs in tRNA-mRNA base-pairing (22 tRNAs

are sufficient rather than 32 tRNA needed for standard wobble in the
nuclear genome).
Useful applications of mtDNA:

• Easy to isolate and PCR (high copy #).

• Most mtDNA is inherited maternally. Can be used to assess maternal

population structure (to the exclusion of male-mediated gene flow)

• Because it is “haploid” effective population size of mtDNA is 1/4 that

of a nuclear gene.

• We refer to mtDNA sequences as “haplotypes” not “alleles”

• As a result of drift, mtDNA substitutions “fix” rapidly (due to genetic

drift) and typically show higher levels of genetic differentiation
between populations.

Useful for:

• Maternity & forensics (maternal ID)

• Phylogenetic systematics
• Population &conservation genetics)
 A parapatric propensity for breeding precludes the completion of speciation in common teal (Anas
crecca, sensu lato)

Molecular Ecology
Volume 21, Issue 18, pages 4563-4577, 31 JUL 2012 DOI: 10.1111/j.1365-
294X.2012.05711.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-294X.2012.05711.x/full#f4
Chloroplast genomes (cpDNA):

• Chloroplast organelles are the site of photosynthesis and occur only

in green plants and photosynthetic protists,

• Like mtDNA, chloroplast genome is:

• Circular, double-stranded
• Lacks structural proteins
• %GC content differs

• Chloroplast genome is much larger than animal mtDNA, ~80-600 kb.

• Chloroplast genomes occur in multiple copies and carry lots of non-

coding DNA.

• Complete chloroplast sequences have been determined for several

organisms (tobacco 155,844 bp; rice 134,525 bp).
cpDNA organization:

• Nuclear genome encodes some chloroplast components, and cpDNA

codes the rest, including:

• 2 copies of each chloroplast rRNA (16S, 23S, 4.5s, 5S)

• tRNAs (30 in tobacco and rice, 32 in liverwort)
• 100 highly conserved ORFs (~60 code for proteins required for
transcription, translation, and photosynthesis).

• Genes are coded on both strands (like mtDNA).

cpDNA translation- similar to prokaryotes:

• Initiation uses fMet-tRNA.

• Chloroplast specific IFs, EFs, and RFs.

• Universal genetic code.

Fig. 23.7

cpDNA of rice
Rules of non-Mendelian inheritance for mtDNA and cpDNA:

• Ratios typical of Mendelian segregation do not occur because meiotic

segregation is not involved.

• Reciprocal crosses usually show uniparental inheritance because

zygotes typically receive cytoplasm only from the mother.

• Genotype and phenotype of offspring is same as mother.

Examples of non-Mendelian inheritance:

• Mutant [poky] Neurospora possess altered mtDNA cytochrome

complements that lead to slow growth, inherited from female.

• [poky] phenotype is inherited with the cytoplasm.

protoperitheca (sexual mating type)

conidia
(asexual mating type)

Fig. 23.10, Reciprocal crosses of poky and wild-type Neurospora.

Exceptions to maternal inheritance:

• Paternal leakage & heteroplasmy  mice have paternal mtDNA

present at 1/10,000 the level of maternal DNA

• Usually is transient, but occurs when mtDNA from sperm leak into
maternal egg cytoplasm at the time of fertilization and is not
degraded.

• In these cases, maternal and paternal mtDNA are both present and
can recombine!

• Paternal inheritance of chloroplasts common in some plants (e.g.,

gymnosperms).

www.researchgate.net/figure/221936836

www.sciencemusings.com/
http://bmj-sti.highwire.org/content/77/3/158.full
Examples of maternally inherited human mtDNA defects:

• Leber’s hereditary optic neuropathy (LHON), OMIM-535000

• Mid-life adult blindness from optic nerve degeneration.

• Mutations in ND1, ND2, ND4, ND5, ND6, cyt b, CO I, CO II, and
ATPase 6 inhibit electron transport chain.

• Kearns-Sayre Syndrome, OMIM-530000

• Paralysis of eye muscles, accumulation of pigment and

degeneration of the retina, and heart disease.
• Deletion of mtDNA tRNAs.

• Myoclonic epilepsy & ragged-red fiber disease (MERRF), OMIM-

545000

• Spasms and abnormal tissues, accumulation of lactic acid in the

blood, and uncoordinated movement.
• Nucleotide substitution in the mtDNA lysine tRNA.

Most individuals with mtDNA disorders possess a mix of normal and

mutant mtDNA, therefore severity of diseases varies depending on
the level of normal mtDNA.
Examples of non-Mendelian inheritance:

• Variegated-shoot phenotypes in four o’clocks

Mixed chloroplasts
White/green

Mutant chloroplast
White
non-photosynthetic

Normal chloroplast
Green
photosynthetic

Fig. 23.8b
Fig. 23.9

Chloroplasts are inherited

via the seed cytoplasm

3 types of eggs (female):

Normal
Mutant
Mixed

Assumption:

Pollen (male) contributes

no information
Maternal effect:

Some maternal phenotypes are produced by the nuclear genome rather

than the mtDNA/cpDNA genomes.

• Proteins or mRNA (maternal factors) deposited in the oocyte prior

to fertilization; these are important for development.

• Genes for maternal factors occur on nuclear chromosomes; no

mtDNA is involved (not epigenetic).

• e.g., shell coiling in the snail Limnaea peregra.

• Determined by a pair of nuclear alleles; D produces dextral

(right-handed) coiling, d produces sinistral (left-handed)
coiling.

• Shell coiling always is determined by the maternal genotype,

not the alleles that the progeny carry or maternal phenotype.

• If coiling were controlled by extranuclear gene (e.g., mtDNA),

progeny would always have the same phenotype as mother.

• Cause-female snail deposits products in the egg that regulate

orientation of mitotic spindle and direction of cell cleavage.
Fig. 23.17

dextral sinistral

*****dextral ***** *****dextral *****

Maternal effect:

• mRNAs coded by maternal genes (not offspring) are essential for

normal structural development and axis orientation.

• Placement of bicoid mRNA determines anterior end of developing

Drosophila embryo.

http://scienceblogs.com/pharyngula/2006/06/maternal_effect_genes.php
Genomic (parental) imprinting:

• Expression of genes (or alleles) is determined by whether the gene

is inherited from the father or mother.

• Occurs when there is expression of only a single allele (either from

father or mother).

• Mechanism is entirely different from maternal effect (e.g.,

dextral/sinistral coiling of snail shells).

• One allele frequently suppressed by methylation.

• Prader-Willi syndrome, OMIM-176270

• Common in various cancers

Transovarial disease transmission - a type of maternal inheritance:

• Infected cytoplasm infects the egg and is transmitted to offspring.

• Many insect-vectored diseases show transovarial transmission.

• Example - eggs and larvae of mosquitoes infected with West Nile

Virus also are infected.

http://gsbs.utmb.edu/microbook/ch056.htm