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Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome

Nature Genetics volume 43, pages 1074–1081 (2011)Cite this article

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Abstract

We identified complex genomic rearrangements consisting of intermixed duplications and triplications of genomic segments at the MECP2 and PLP1 loci. These complex rearrangements were characterized by a triplicated segment embedded within a duplication in 11 unrelated subjects. Notably, only two breakpoint junctions were generated during each rearrangement formation. All the complex rearrangement products share a common genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which the triplicated segment is inverted and located between directly oriented duplicated genomic segments. We provide evidence that the DUP-TRP/INV-DUP structures are mediated by inverted repeats that can be separated by >300 kb, a genomic architecture that apparently leads to susceptibility to such complex rearrangements. A similar inverted repeat–mediated mechanism may underlie structural variation in many other regions of the human genome. We propose a mechanism that involves both homology-driven events, via inverted repeats, and microhomologous or nonhomologous events.

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Figure 1: General genomic structure of the complex rearrangement triplications embedded in duplications.
Figure 2: Individuals carrying complex triplications of chromosome Xq28.
Figure 3: Southern blot analysis of the region flanked by LCRs K1 and K2 at Xq28.
Figure 4: Rearrangement structure for subjects BAB2772, BAB2796/BAB2980, BAB2797, BAB2805 and BAB2769 based on aCGH, Southern blotting and breakpoint sequencing.
Figure 5: Proposed model for generation of common DUP-TRP/INV-DUP rearrangement product.

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Acknowledgements

We thank all of the families who participated in this study. We acknowledge P. Stankiewicz for helpful discussions. This work was supported in part by US National Institute of Neurological Disorders and Stroke (NINDS) grant R01 NS058529 to J.R.L., NINDS grant R01 HD053862 to H.Y.Z., US National Institute of General Medical Sciences (NIGMS) grant R01 GM064022 to P.J.H. and NINDS grant 5K08NS062711-03 to M.B.R. Lymphoblast cell lines were developed by the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center cell culture core, which is funded by award P30HD024064 from the Eunice Kennedy Shriver US National Institute of Child Health and Human Development (NICHD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NIGMS, NICHD or the US National Institutes of Health. H.Y.Z. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

  1. Claudia M B Carvalho and Melissa B Ramocki: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Claudia M B Carvalho, Davut Pehlivan, Luis M Franco, Claudia Gonzaga-Jauregui, Ping Fang, Daniela del Gaudio, Marjorie Withers, Pengfei Liu, Sau Wai Cheung, John W Belmont, Huda Y Zoghbi, P J Hastings & James R Lupski

  2. Department of Pediatrics, Division of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA

    Melissa B Ramocki & Huda Y Zoghbi

  3. Texas Children's Hospital, Houston, Texas, USA

    Melissa B Ramocki & James R Lupski

  4. Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

    Alanna McCall & James R Lupski

  5. Department of Pediatrics, Division of Clinical Genetics and Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Eniko Karman Pivnick

  6. Division of Medical Genetics LeBonheur Children's Hospital, Nursing Administration, Memphis, Tennessee, USA

    Stacy Hines-Dowell

  7. Kapiolani Medical Specialists, Honolulu, Hawaii, USA

    Laurie H Seaver & Sansan Lee

  8. Children's Medical Associates, Alexandria, Virginia, USA

    Linda Friehling

  9. Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, Maine, USA

    Rosemarie Smith

  10. Department of Pediatrics, Division of Cardiology, Baylor College of Medicine, Houston, Texas, USA

    John W Belmont

  11. Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA

    Huda Y Zoghbi

  12. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA

    Huda Y Zoghbi

  13. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA

    Huda Y Zoghbi

  14. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Luis M Franco

  15. Department of Pediatrics, John A. Burns School of Medicine, Honolulu, Hawaii, USA

    Laurie H Seaver

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  1. Claudia M B Carvalho
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Contributions

C.M.B.C. conducted high-density aCGH, FISH, breakpoint sequencing, Southern-blotting experiments and data analysis. M.B.R. coordinated human studies, recruited subjects and analyzed clinical data. D.P. and P.L. assisted with high-density aCGH and breakpoint sequencing. L.M.F. and J.W.B. conducted SNP genotyping. E.K.P., S.H.-D., L.S., L.F., S.L. and R.S. recruited and clinically characterized subjects. C.G.-J. assisted with data analysis. P.F. conducted the X-chromosome inactivation studies. A.M. and M.W. carried out cell culture. D.d.G. conducted MLPA. S.W.C. was involved in cytogenetic and clinical aCGH studies. J.R.L. and H.Y.Z. were involved in research design and data analyses. P.J.H. was involved in data analyses. C.M.B.C., M.B.R., P.J.H. and J.R.L. prepared the manuscript.

Corresponding authors

Correspondence to Melissa B Ramocki or James R Lupski.

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Competing interests

J.R.L. is on the scientific advisory board of Ion Torrent Systems, is a consultant for Athena Diagnostics and has stock ownership in 23andMe. P.F., D.d.G., S.W.C. and J.R.L. are based in the Department of Molecular and Human Genetics at Baylor College of Medicine, which derives clinical income from the application of high resolution human genome analyses.

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Carvalho, C., Ramocki, M., Pehlivan, D. et al. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet 43, 1074–1081 (2011). https://doi.org/10.1038/ng.944

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