Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Genomic rearrangements and sporadic disease

Abstract

Many clinical phenotypes occur sporadically despite genetics contributing partly or entirely to their cause. To what extent are de novo mutations the cause of sporadic traits? Locus-specific mutation rates for genomic rearrangements appear to be two to four orders of magnitude greater than nucleotide-specific rates for base substitutions. Widespread implementation of high-resolution genome analyses to detect de novo copy-number variation may identify the cause of traits previously intractable to conventional genetic analyses.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genome analysis and locus-specific mutation rates (μ).
Figure 2: Breakpoint mapping in 17p11.2: the SMS deletion and PLS duplication region of proximal 17p.

Similar content being viewed by others

References

  1. Kalter, H. & Warkany, J. Medical progress. Congenital malformations: etiologic factors and their role in prevention (first of two parts). N. Engl. J. Med. 308, 424–431 (1983).

    Article  CAS  PubMed  Google Scholar 

  2. Kalter, H. & Warkany, J. Congenital malformations (second of two parts). N. Engl. J. Med. 308, 491–497 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. Baird, P.A., Anderson, T.W., Newcombe, H.B. & Lowry, R.B. Genetic disorders in children and young adults: a population study. Am. J. Hum. Genet. 42, 677–693 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kondrashov, A.S. Direct estimates of human per nucleotide mutation rates at 20 loci causing mendelian diseases. Hum. Mutat. 21, 12–27 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Nachman, M.W. & Crowell, S.L. Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297–304 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Crow, J.F. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Crow, J.F. Age and sex effects on human mutation rates: an old problem with new complexities. J. Radiat. Res. 47 (suppl. B), B75–B82 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Goriely, A., McVean, G.A., Rojmyr, M., Ingemarsson, B. & Wilkie, A.O. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science 301, 643–646 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Szigeti, K., Garcia, C.A. & Lupski, J.R. Charcot-Marie-Tooth disease and related hereditary polyneuropathies: molecular diagnostics determine aspects of medical management. Genet. Med. 8, 86–92 (2006).

    Article  PubMed  Google Scholar 

  11. Wise, C.A. et al. Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMT1A duplication. Am. J. Hum. Genet. 53, 853–863 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Nelis, E. et al. Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur. J. Hum. Genet. 4, 25–33 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Potocki, L. et al. DNA rearrangements on both homologues of chromosome 17 in a mildly delayed individual with a family history of autosomal dominant carpal tunnel syndrome. Am. J. Hum. Genet. 64, 471–478 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lupski, J.R. 2002 Curt Stern Award address. Genomic disorders recombination-based disease resulting from genomic architecture. Am. J. Hum. Genet. 72, 246–252 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Newman, T.L. et al. A genome-wide survey of structural variation between human and chimpanzee. Genome Res. 15, 1344–1356 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Khaja, R. et al. Genome assembly comparison identifies structural variants in the human genome. Nat. Genet. 38, 1413–1418 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wong, K.K. et al. A comprehensive analysis of common copy-number variations in the human genome. Am. J. Hum. Genet. 80, 91–104 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Fiegler, H. et al. Accurate and reliable high-throughput detection of copy number variation in the human genome. Genome Res. 16, 1566–1574 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Komura, D. et al. Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays. Genome Res. 16, 1575–1584 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lupski, J.R. Structural variation in the human genome. N. Engl. J. Med. 356, 1169–1171 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. Stankiewicz, P. & Lupski, J.R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Shaffer, L.G. & Lupski, J.R. Molecular mechanisms for constitutional chromosomal rearrangements in humans. Annu. Rev. Genet. 34, 297–329 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Coulondre, C., Miller, J.H., Farabaugh, P.J. & Gilbert, W. Molecular basis of base substitution hotspots in Escherichia coli. Nature 274, 775–780 (1978).

    Article  CAS  PubMed  Google Scholar 

  30. Cooper, D.N. & Youssoufian, H. The CpG dinucleotide and human genetic disease. Hum. Genet. 78, 151–155 (1988).

    Article  CAS  PubMed  Google Scholar 

  31. Lupski, J.R. & Chance, P.F. Hereditary motor and sensory neuropathies involving altered dosage or mutation of PMP22: the CMT1A duplication and HNPP deletion. In Peripheral Neuropathy (eds. Dyck, P.J. & Thomas, P.K.) Ch. 70 1659–1680 (Elsevier, Philadelphia, 2005).

    Chapter  Google Scholar 

  32. Lupski, J.R. & Garcia, A. Charcot-Marie-Tooth peripheral neuropathies and related disorders. in The Metabolic and Molecular Bases of Inherited Diseases (eds. Scriver, C.R. et al.) Ch. 227, 5759–5788 (McGraw-Hill, New York, 2001).

    Google Scholar 

  33. Skre, H. Genetic and clinical aspects of Charcot-Marie-Tooth's disease. Clin. Genet. 6, 98–118 (1974).

    Article  CAS  PubMed  Google Scholar 

  34. Shy, M.E., Lupski, J.R., Chance, P.F., Klein, C.J. & Dyck, P.J. Hereditary motor and sensory neuropathies. in Peripheral Neuropathy Vol. I (eds. Dyck, P.J. & Thomas, P.K.) Ch. 69, 1623–1658 (Elsevier, Philadelphia, 2005).

    Chapter  Google Scholar 

  35. Bort, S., Martinez, F. & Palau, F. Prevalence and parental origin of de novo 1.5-Mb duplication in Charcot-Marie-Tooth disease type 1A. Am. J. Hum. Genet. 60, 230–233 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Marques, W., Jr. et al. 17p duplicated Charcot-Marie-Tooth 1A: characteristics of a new population. J. Neurol. 252, 972–979 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. van Ommen, G.J. Frequency of new copy number variation in humans. Nat. Genet. 37, 333–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Haldane, J.B.S. The rate of spontaneous mutation of a human gene. J. Genet. 31, 317–326 (1935).

    Article  Google Scholar 

  39. Den Dunnen, J.T. et al. Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. Am. J. Hum. Genet. 45, 835–847 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. White, S. et al. Comprehensive detection of genomic duplications and deletions in the DMD gene, by use of multiplex amplifiable probe hybridization. Am. J. Hum. Genet. 71, 365–374 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sharp, A.J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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 

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

    Article  CAS  PubMed  Google Scholar 

  44. Lupski, J.R. & Stankiewicz, P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 1, E49 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Shaw, C.J. & Lupski, J.R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum. Mol. Genet. 13 (review issue 1), R57–R64 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Potocki, L. et al. Characterization of the Potocki-Lupski syndrome [dup(17)(p11.2p11.2)] and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am. J. Hum. Genet. 80, 633–649 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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  PubMed  PubMed Central  Google Scholar 

  48. Brewer, C., Holloway, S., Zawalnyski, P., Schinzel, A. & FitzPatrick, D. A chromosomal deletion map of human malformations. Am. J. Hum. Genet. 63, 1153–1159 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Brewer, C., Holloway, S., Zawalnyski, P., Schinzel, A. & FitzPatrick, D. A chromosomal duplication map of malformations: regions of suspected haplo- and triplolethality—and tolerance of segmental aneuploidy—in humans. Am. J. Hum. Genet. 64, 1702–1708 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kurahashi, H. et al. Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22). Hum. Mol. Genet. 9, 1665–1670 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Edelmann, L. et al. AT-rich palindromes mediate the constitutional t(11;22) translocation. Am. J. Hum. Genet. 68, 1–13 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Kurahashi, H. & Emanuel, B.S. Unexpectedly high rate of de novo constitutional t(11;22) translocations in sperm from normal males. Nat. Genet. 29, 139–140 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Lupski, J.R. Genome structural variation and sporadic disease traits. Nat. Genet. 38, 974–976 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Kato, T. et al. Genetic variation affects de novo translocation frequency. Science 311, 971 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Eichler, E.E. Segmental duplications: what's missing, misassigned, and misassembled–and should we care? Genome Res. 11, 653–656 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Vorstman, J.A. et al. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol. Psychiatry 11, 18–28 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cheung, S.W. et al. Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet. Med. 7, 422–432 (2005).

    Article  PubMed  Google Scholar 

  60. Bejjani, B.A. et al. Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: is less more? Am. J. Med. Genet. A. 134, 259–267 (2005).

    Article  PubMed  Google Scholar 

  61. Shaffer, L.G. et al. Targeted genomic microarray analysis for identification of chromosome abnormalities in 1500 consecutive clinical cases. J. Pediatr. 149, 98–102 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Lu, X. et al. Clinical implementation of chromosomal microarray analysis: summary of 2513 consecutive postnatal cases. PLoS ONE 3, E327 (2007).

    Article  Google Scholar 

  63. Chen, K.-S. et al. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat. Genet. 17, 154–163 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Potocki, L. et al. Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat. Genet. 24, 84–87 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Stankiewicz, P. et al. Genome architecture catalyzes nonrecurrent chromosomal rearrangements. Am. J. Hum. Genet. 72, 1101–1116 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bi, W. et al. Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2. Am. J. Hum. Genet. 73, 1302–1315 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Shaw, C.J., Withers, M.A. & Lupski, J.R. Uncommon deletion of the Smith-Magenis syndrome region can be recurrent when alternate low-copy repeats act as homologous recombination substrates. Am. J. Hum. Genet. 75, 75–81 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Stankiewicz, P., Bi, W. & Lupski, J.R. Smith-Magenis syndrome deletion, reciprocal duplication dup(17)(p11.2p11.2), and other proximal 17p rearrangements. in Genomic Disorders (eds. Lupski, J.R. & Stankiewicz, P.) 179–191 (Humana, Totowa, New Jersey, USA, 2006).

    Chapter  Google Scholar 

  69. Lee, J.A. et al. Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Hum. Mol. Genet. 15, 2250–2265 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I thank M. Hurles, P. Stankiewicz, A. Beaudet and members of my laboratory for thoughtful reviews. I apologize to colleagues and authors of relevant papers that could not be cited due to space limitations. My laboratory has been generously supported by the US National Institutes of Health (National Institute of Neurological Disorders and Stroke, National Eye Institute, National Institute of Dental and Craniofacial Research, National Cancer Institute and National Institute of Child Health and Human Development), the Muscular Dystrophy Association, the Charcot-Marie-Tooth Association and the March of Dimes.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lupski, J. Genomic rearrangements and sporadic disease. Nat Genet 39 (Suppl 7), S43–S47 (2007). https://doi.org/10.1038/ng2084

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng2084

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing