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Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability

Abstract

Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (0.5–0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons—a 14-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15.

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Figure 1: Structural variation at 15q13.
Figure 2: Sequence refinement of β inversion breakpoints.
Figure 3: Sequence refinement of γ inversion breakpoints.
Figure 4: Comparative sequence analysis of the 15q13.3 region among apes.
Figure 5: Model of chromosomal evolution at 15q13.3.
Figure 6: Analysis of 15q13.3 microdeletion breakpoints.
Figure 7: Summary of the 15q13.3 rearrangements mediated by GOLGA8 repeats.

References

  1. Cooper, G.M. et al. A copy number variation morbidity map of developmental delay. Nat. Genet. 43, 838–846 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Kaminsky, E.B. et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet. Med. 13, 777–784 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. Sharp, A.J. et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat. Genet. 40, 322–328 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Helbig, I. et al. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat. Genet. 41, 160–162 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008).

  6. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Miller, D.T. et al. Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J. Med. Genet. 46, 242–248 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Shinawi, M. et al. A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nat. Genet. 41, 1269–1271 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Williams, N.M. et al. Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3. Am. J. Psychiatry 169, 195–204 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kidd, J.M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Antonacci, F. et al. Characterization of six human disease-associated inversion polymorphisms. Hum. Mol. Genet. 18, 2555–2566 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pujana, M.A. et al. Additional complexity on human chromosome 15q: identification of a set of newly recognized duplicons (LCR15) on 15q11-q13, 15q24, and 15q26. Genome Res. 11, 98–111 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pujana, M.A. et al. Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons. Eur. J. Hum. Genet. 10, 26–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Zody, M.C. et al. Analysis of the DNA sequence and duplication history of human chromosome 15. Nature 440, 671–675 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Jiang, Z. et al. Ancestral reconstruction of segmental duplications reveals punctuated cores of human genome evolution. Nat. Genet. 39, 1361–1368 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Sudmant, P.H. et al. Evolution and diversity of copy number variation in the great ape lineage. Genome Res. 23, 1373–1382 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huddleston, J. et al. Reconstructing complex regions of genomes using long-read sequencing technology. Genome Res. 24, 688–696 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sudmant, P.H. et al. Diversity of human copy number variation and multicopy genes. Science 330, 641–646 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dennis, M.Y. et al. Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication. Cell 149, 912–922 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Itsara, A. et al. Resolving the breakpoints of the 17q21.31 microdeletion syndrome with next-generation sequencing. Am. J. Hum. Genet. 90, 599–613 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. She, X. et al. Shotgun sequence assembly and recent segmental duplications within the human genome. Nature 431, 927–930 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Antonacci, F. et al. A large and complex structural polymorphism at 16p12.1 underlies microdeletion disease risk. Nat. Genet. 42, 745–750 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

  25. Hardenbol, P. et al. Multiplexed genotyping with sequence-tagged molecular inversion probes. Nat. Biotechnol. 21, 673–678 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. O'Roak, B.J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zody, M.C. et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat. Genet. 40, 1076–1083 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Girirajan, S. et al. Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am. J. Hum. Genet. 92, 221–237 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Steinberg, K.M. et al. Structural diversity and African origin of the 17q21.31 inversion polymorphism. Nat. Genet. 44, 872–880 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sharp, A.J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38, 1038–1042 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Meyer, M. et al. A mitochondrial genome sequence of a hominin from Sima de los Huesos. Nature 505, 403–406 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014).

    Article  PubMed  CAS  Google Scholar 

  33. Mefford, H.C. et al. Further clinical and molecular delineation of the 15q24 microdeletion syndrome. J. Med. Genet. 49, 110–118 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Wat, M.J. et al. Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond-Blackfan anaemia. J. Med. Genet. 47, 777–781 (2010).

    Article  PubMed  Google Scholar 

  35. Amos-Landgraf, J.M. et al. Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. Am. J. Hum. Genet. 65, 370–386 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. El-Hattab, A.W. et al. Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping. Hum. Genet. 126, 589–602 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Marques-Bonet, T. et al. A burst of segmental duplications in the genome of the African great ape ancestor. Nature 457, 877–881 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Locke, D.P. et al. Refinement of a chimpanzee pericentric inversion breakpoint to a segmental duplication cluster. Genome Biol. 4, R50 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Giannuzzi, G. et al. Hominoid fission of chromosome 14/15 and the role of segmental duplications. Genome Res. 23, 1763–1773 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sharp, A.J. et al. Characterization of a recurrent 15q24 microdeletion syndrome. Hum. Mol. Genet. 16, 567–572 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Lupski, J.R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Bengesser, K. et al. A novel third type of recurrent NF1 microdeletion mediated by nonallelic homologous recombination between LRRC37B-containing low-copy repeats in 17q11.2. Hum. Mutat. 31, 742–751 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Gordenin, D.A. et al. Inverted DNA repeats: a source of eukaryotic genomic instability. Mol. Cell. Biol. 13, 5315–5322 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Leach, D.R. Long DNA palindromes, cruciform structures, genetic instability and secondary structure repair. Bioessays 16, 893–900 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Collick, A. et al. Instability of long inverted repeats within mouse transgenes. EMBO J. 15, 1163–1171 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Akgün, E. et al. Palindrome resolution and recombination in the mammalian germ line. Mol. Cell. Biol. 17, 5559–5570 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ruskin, B. & Fink, G.R. Mutations in POL1 increase the mitotic instability of tandem inverted repeats in Saccharomyces cerevisiae. Genetics 134, 43–56 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lemoine, F.J., Degtyareva, N.P., Lobachev, K. & Petes, T.D. Chromosomal translocations in yeast induced by low levels of DNA polymerase a model for chromosome fragile sites. Cell 120, 587–598 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Inagaki, H. et al. Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations. Nat. Commun. 4, 1592 (2013).

    Article  PubMed  CAS  Google Scholar 

  50. Tanaka, H., Bergstrom, D.A., Yao, M.C. & Tapscott, S.J. Widespread and nonrandom distribution of DNA palindromes in cancer cells provides a structural platform for subsequent gene amplification. Nat. Genet. 37, 320–327 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Carvalho, C.M. et al. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat. Genet. 43, 1074–1081 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee, J.A., Carvalho, C.M. & Lupski, J.R.A. DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Hastings, P.J., Ira, G. & Lupski, J.R. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 5, e1000327 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Payen, C., Koszul, R., Dujon, B. & Fischer, G. Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms. PLoS Genet. 4, e1000175 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Parsons, J.D. Miropeats: graphical DNA sequence comparisons. Comput. Appl. Biosci. 11, 615–619 (1995).

    CAS  PubMed  Google Scholar 

  56. Smith, J.J., Stuart, A.B., Sauka-Spengler, T., Clifton, S.W. & Amemiya, C.T. Development and analysis of a germline BAC resource for the sea lamprey, a vertebrate that undergoes substantial chromatin diminution. Chromosoma 119, 381–389 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Alkan, C. et al. Personalized copy number and segmental duplication maps using next-generation sequencing. Nat. Genet. 41, 1061–1067 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  PubMed  Google Scholar 

  59. Larkin, M.A. et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Tamura, K., Dudley, J., Nei, M. & Kumar, S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol. Biol. Evol. 24, 1596–1599 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Igartua, C. et al. Targeted enrichment of specific regions in the human genome by array hybridization. Curr. Protoc. Hum. Genet. Chapter 18 Unit 18.3 (2010).

  62. Nuttle, X. et al. Rapid and accurate large-scale genotyping of duplicated genes and discovery of interlocus gene conversions. Nat. Methods 10, 903–909 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M. Ventura, C. Campbell and H.C. Mefford for useful discussions and T. Brown for critical review of the manuscript. We also thank S. Diede, H. Tanaka, B. Brewer, C. Payen, L. Harshman and K. Penewit for experimental advice and support for the palindromic snapback assay. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base. This work was supported, in part, by US National Institutes of Health grants HG002385 and HG004120 to E.E.E. M.Y.D. is supported by the National Institute of Neurological Disorder and Stroke of the US National Institutes of Health (award K99NS083627). E.E.E. is an investigator of the Howard Hughes Medical Institute.

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Contributions

F.A., M.Y.D. and E.E.E. designed the study. F.A. performed FISH experiments, library construction for Illumina sequencing, array CGH experiments and sequence analysis. M.Y.D. performed MIP experiments, library construction for Illumina sequencing, array CGH experiments and sequence analysis. J.H. performed SMRT sequence analysis and haplotype reconstruction. P.H.S. and K.M.S. performed sequencing data analysis. T.A.G. and R.K.W. performed capillary sequencing and analysis of CH17 and nonhuman primate BAC clones. L.V. and M. Malig performed FISH experiments. M. Miroballo performed array CGH experiments. B.M. performed library construction for SMRT sequencing. L.D. performed MIP experiments and library construction for SMRT sequencing. A.R. performed SMRT sequence analysis. C.T.A., A.S. and J.T. performed library construction for the VMRC53, VMRC54 and VMRC57 BACs. J.A.R. and L.G.S. contributed to 15q13.3 microdeletion data collection. F.A., M.Y.D. and E.E.E. contributed to data interpretation. F.A., M.Y.D. and E.E.E. wrote the manuscript.

Corresponding author

Correspondence to Evan E Eichler.

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Competing interests

E.E.E. is on the scientific advisory board (SAB) of DNAnexus, Inc., and was an SAB member of Pacific Biosciences, Inc. (2009–2013) and SynapDx Corp. (2011–2013). J.A.R. is an employee of Signature Genomic Laboratories, a subsidiary of PerkinElmer, Inc. L.G.S. was an employee of Signature Genomic Laboratories and is now an employee of Genetic Veterinary Sciences, Inc.

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Antonacci, F., Dennis, M., Huddleston, J. et al. Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability. Nat Genet 46, 1293–1302 (2014). https://doi.org/10.1038/ng.3120

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