A high-resolution survey of deletion polymorphism in the human genome (original) (raw)

Nature Genetics volume 38, pages 75–81 (2006)Cite this article

Abstract

Recent work has shown that copy number polymorphism is an important class of genetic variation in human genomes1,2,3,4. Here we report a new method that uses SNP genotype data from parent-offspring trios to identify polymorphic deletions. We applied this method to data from the International HapMap Project5 to produce the first high-resolution population surveys of deletion polymorphism. Approximately 100 of these deletions have been experimentally validated using comparative genome hybridization on tiling-resolution oligonucleotide microarrays. Our analysis identifies a total of 586 distinct regions that harbor deletion polymorphisms in one or more of the families. Notably, we estimate that typical individuals are hemizygous for roughly 30–50 deletions larger than 5 kb, totaling around 550–750 kb of euchromatic sequence across their genomes. The detected deletions span a total of 267 known and predicted genes. Overall, however, the deleted regions are relatively gene-poor, consistent with the action of purifying selection against deletions. Deletion polymorphisms may well have an important role in the genetics of complex traits; however, they are not directly observed in most current gene mapping studies. Our new method will permit the identification of deletion polymorphisms in high-density SNP surveys of trio or other family data.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).
    Article CAS Google Scholar
  2. Iafrate, A.J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (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. 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 Google Scholar
  5. The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).
  6. Schmickel, R.D. Contiguous gene syndromes: a component of recognizable syndromes. J. Pediatr. 109, 231–241 (1986).
    Article CAS Google Scholar
  7. 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 Google Scholar
  8. Flint, J. et al. The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat. Genet. 9, 132–140 (1995).
    Article CAS Google Scholar
  9. Gardner, R.J. & Sutherland, G.R. Chromosomes Abnormalities and Genetic Counseling (Oxford Univ. Press, Oxford, 2004).
    Google Scholar
  10. Yu, C.E. et al. Presence of large deletions in kindreds with autism. Am. J. Hum. Genet. 71, 100–115 (2002).
    Article CAS Google Scholar
  11. Petrov, D.A. Mutational equilibrium model of genome size evolution. Theor. Popul. Biol. 61, 531–544 (2002).
    Article Google Scholar
  12. Olson, M.V. When less is more: gene loss as an engine of evolutionary change. Am. J. Hum. Genet. 64, 18–23 (1999).
    Article CAS Google Scholar
  13. Amos, C.I., Shete, S., Chen, J. & Yu, R.K. Positional identification of microdeletions with genetic markers. Hum. Hered. 56, 107–118 (2003).
    Article CAS Google Scholar
  14. Giglio, S. et al. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am. J. Hum. Genet. 68, 874–883 (2001).
    Article CAS Google Scholar
  15. Weber, J.L. et al. Human diallelic insertion/deletion polymorphisms. Am. J. Hum. Genet. 71, 854–862 (2002).
    Article Google Scholar
  16. Bhangale, T.R., Rieder, M.J., Livingston, R.J. & Nickerson, D.A. Comprehensive identification and characterization of diallelic insertion-deletion polymorphisms in 330 human candidate genes. Hum. Mol. Genet. 14, 59–69 (2005).
    Article CAS Google Scholar
  17. Carter, N.P. As normal as normal can be? Nat. Genet. 36, 931–932 (2004).
    Article CAS Google Scholar
  18. Bailey, J.A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).
    Article CAS Google Scholar
  19. Clark, A.G. et al. Inferring nonneutral evolution from human-chimp-mouse orthologous gene trios. Science 302, 1960–1963 (2003).
    Article CAS Google Scholar
  20. Emes, R.D., Goodstadt, L., Winter, E.E. & Ponting, C.P. Comparison of the genomes of human and mouse lays the foundation of genome zoology. Hum. Mol. Genet. 12, 701–709 (2003).
    Article CAS Google Scholar
  21. Hinds, D.A., Kloek, A.P. & Frazer, K.A. Common deletions and SNPs are in linkage disequilibrium in the human genome. Nat. Genet. Advance online publication, 4 December 2005 (10.1038/ng1695).
  22. McCarroll, S.A. et al. Common deletion polymorphisms in the human genome. Nat. Genet. Advance online publication, 4 December 2005 (10.1038/ng1696).
  23. Fredman, D. et al. Complex SNP-related sequence variation in segmental genome duplications. Nat. Genet. 36, 861–866 (2004).
    Article CAS Google Scholar
  24. Selzer, R.R. et al. Analysis of chromosome breakpoints in neuroblastoma at sub-kilobase resolution using fine-tiling oligonucleotide array CGH. Genes Chromosom. Cancer 44, 305–319 (2005).
    Article CAS Google Scholar

Download references

Acknowledgements

We thank G. Coop, D. Cutler, A. DiRienzo, H. Fiegler, M. Przeworski, G. Raca, C. Tyler-Smith and D. Vetrie for comments and discussions; R. Redon for managing the genomic DNA collection; B. Voight for extracting the SNP classifications; S. Das, A. DiRienzo and C. Ober for lab space and equipment and the members of the International HapMap Consortium for their work in creating this dataset. This work was supported by a grant to J.K.P. from the Packard Foundation. D.F.C. was supported in part by US National Institutes of Health/National Institute of General Medical Sciences Genetics and Regulation Training Grant GM07197. Additional funding was provided by the Wellcome Trust.

Author information

Authors and Affiliations

  1. Department of Human Genetics, The University of Chicago, 920 East 58th Street, Chicago, 60637, Illinois, USA
    Donald F Conrad & Jonathan K Pritchard
  2. Genome Dynamics and Evolution Group, The Wellcome Trust, Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
    T Daniel Andrews, Nigel P Carter & Matthew E Hurles

Authors

  1. Donald F Conrad
    You can also search for this author inPubMed Google Scholar
  2. T Daniel Andrews
    You can also search for this author inPubMed Google Scholar
  3. Nigel P Carter
    You can also search for this author inPubMed Google Scholar
  4. Matthew E Hurles
    You can also search for this author inPubMed Google Scholar
  5. Jonathan K Pritchard
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toJonathan K Pritchard.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Conrad, D., Andrews, T., Carter, N. et al. A high-resolution survey of deletion polymorphism in the human genome.Nat Genet 38, 75–81 (2006). https://doi.org/10.1038/ng1697

Download citation

Associated content