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Major changes in our DNA lead to major changes in our thinking

Abstract

Variability in the human genome has far exceeded expectations. In the course of the past three years, we have learned that much of our naturally occurring genetic variation consists of large-scale differences in genome structure, including copy-number variants (CNVs) and balanced rearrangements such as inversions. Recent studies have begun to reveal that structural variants are an important contributor to disease risk; however, structural variants as a class may not conform well to expectations of current methods for gene mapping. New approaches are needed to understand the contribution of structural variants to disease.

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References

  1. Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).

    Article  CAS  Google Scholar 

  2. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).

    Article  CAS  Google Scholar 

  3. Tuzun, E. et al. Fine-scale structural variation of the human genome. Nat. Genet. 37, 727–732 (2005).

    Article  CAS  Google Scholar 

  4. McCarroll, S.A. et al. Common deletion polymorphisms in the human genome. Nat. Genet. 38, 86–92 (2006).

    Article  CAS  Google Scholar 

  5. Conrad, D.F., Andrews, T.D., Carter, N.P., Hurles, M.E. & Pritchard, J.K. A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet. 38, 75–81 (2006).

    Article  CAS  Google Scholar 

  6. Eichler, E.E. et al. Completing the map of human genetic variation. Nature 447, 161–165 (2007).

    Article  CAS  Google Scholar 

  7. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    Article  CAS  Google Scholar 

  8. Altshuler, D. et al. An SNP map of the human genome generated by reduced representation shotgun sequencing. Nature 407, 513–516 (2000).

    Article  CAS  Google Scholar 

  9. Wang, D.G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).

    Article  CAS  Google Scholar 

  10. Sachidanandam, R. et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001).

    Article  CAS  Google Scholar 

  11. McClintock, B. The origin and behavior of mutable loci in maize. Proc. Natl. Acad. Sci. USA 36, 344–355 (1950).

    Article  CAS  Google Scholar 

  12. Jacobs, P.A. Human chromosome heteromorphisms (variants). Prog. Med. Genet. 2, 251–274 (1977).

    CAS  PubMed  Google Scholar 

  13. 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  Google Scholar 

  14. Ledbetter, D.H. et al. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N. Engl. J. Med. 304, 325–329 (1981).

    Article  CAS  Google Scholar 

  15. Ewart, A.K. et al. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat. Genet. 5, 11–16 (1993).

    Article  CAS  Google Scholar 

  16. Lupski, J.R. et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219–232 (1991).

    Article  CAS  Google Scholar 

  17. Higgs, D.R. et al. A review of the molecular genetics of the human α-globin gene cluster. Blood 73, 1081–1104 (1989).

    CAS  PubMed  Google Scholar 

  18. Shaw-Smith, C. et al. Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J. Med. Genet. 41, 241–248 (2004).

    Article  CAS  Google Scholar 

  19. Koolen, D.A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 (2006).

    Article  CAS  Google Scholar 

  20. Shaw-Smith, C. et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat. Genet. 38, 1032–1037 (2006).

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Centers for Disease Control and Prevention. Prevalence of autism spectrum disorders–autism and developmental disabilities monitoring network, 14 sites, United States, 2002. MMWR Surveill. Summ. 56, 12–28 (2007).

  23. Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).

    Article  CAS  Google Scholar 

  24. Jacquemont, M.L. et al. Array-based comparative genomic hybridization identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J. Med. Genet. 43, 843–849 (2006).

    Article  CAS  Google Scholar 

  25. Risch, N. et al. A genomic screen of autism: evidence for a multilocus etiology. Am. J. Hum. Genet. 65, 493–507 (1999).

    Article  CAS  Google Scholar 

  26. Pickles, A. et al. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am. J. Hum. Genet. 57, 717–726 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bassett, A.S., Bury, A., Hodgkinson, K.A. & Honer, W.G. Reproductive fitness in familial schizophrenia. Schizophr. Res. 21, 151–160 (1996).

    Article  CAS  Google Scholar 

  28. Lee, J.A. & Lupski, J.R. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52, 103–121 (2006).

    Article  CAS  Google Scholar 

  29. Hoogendijk, J.E. et al. De-novo mutation in hereditary motor and sensory neuropathy type I. Lancet 339, 1081–1082 (1992).

    Article  CAS  Google Scholar 

  30. Lam, K.W. & Jeffreys, A.J. Processes of copy-number change in human DNA: the dynamics of α-globin gene deletion. Proc. Natl. Acad. Sci. USA 103, 8921–8927 (2006).

    Article  CAS  Google Scholar 

  31. Blunt, T., Steers, F., Daniels, G. & Carritt, B. Lack of RH C/E expression in the Rhesus D–phenotype is the result of a gene deletion. Ann. Hum. Genet. 58, 19–24 (1994).

    Article  CAS  Google Scholar 

  32. Vollrath, D., Nathans, J. & Davis, R.W. Tandem array of human visual pigment genes at Xq28. Science 240, 1669–1672 (1988).

    Article  CAS  Google Scholar 

  33. Nathans, J., Piantanida, T.P., Eddy, R.L., Shows, T.B. & Hogness, D.S. Molecular genetics of inherited variation in human color vision. Science 232, 203–210 (1986).

    Article  CAS  Google Scholar 

  34. Gonzalez, E. et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434–1440 (2005).

    Article  CAS  Google Scholar 

  35. Aitman, T.J. et al. Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851–855 (2006).

    Article  CAS  Google Scholar 

  36. Fanciulli, M. et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat. Genet. 39, 721–723 (2007).

    Article  CAS  Google Scholar 

  37. Lupski, J.R. Genomic rearrangements and sporadic disease. Nat. Genet. 39, S43–S47 (2007).

    Article  CAS  Google Scholar 

  38. McCarroll, S.A. & Altshuler, D. M. Copy-number variation and association studies of human disease. Nat. Genet. 39, S37–S42 (2007).

    Article  CAS  Google Scholar 

  39. Pritchard, J.K. Are rare variants responsible for susceptibility to complex diseases? Am. J. Hum. Genet. 69, 124–137 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

Special thanks to M. Wigler, M.-C. King and D. Levy for helpful discussions and to J. Lupski for his critical reading of the manuscript. My laboratory is funded by the Simons Foundation, Lattner Foundation, Stanley Foundation, the US National Institutes of Health (National Institute of Mental Health, National Human Genome Research Institute), Autism Speaks and the Southwest Autism Research and Resource Center.

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Sebat, J. Major changes in our DNA lead to major changes in our thinking. Nat Genet 39 (Suppl 7), S3–S5 (2007). https://doi.org/10.1038/ng2095

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