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Common deletion polymorphisms in the human genome

Nature Genetics 38, 86–92 (2006) | Download Citation

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Abstract

The locations and properties of common deletion variants in the human genome are largely unknown. We describe a systematic method for using dense SNP genotype data to discover deletions and its application to data from the International HapMap Consortium to characterize and catalogue segregating deletion variants across the human genome. We identified 541 deletion variants (94% novel) ranging from 1 kb to 745 kb in size; 278 of these variants were observed in multiple, unrelated individuals, 120 in the homozygous state. The coding exons of ten expressed genes were found to be commonly deleted, including multiple genes with roles in sex steroid metabolism, olfaction and drug response. These common deletion polymorphisms typically represent ancestral mutations that are in linkage disequilibrium with nearby SNPs, meaning that their association to disease can often be evaluated in the course of SNP-based whole-genome association studies.

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References

  1. 1.

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

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

    International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  6. 6.

    & Deletion mapping of polymorphic loci by apparent parental exclusion. Am. J. Med. Genet. 14, 43–48 (1983).

  7. 7.

    et al. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72, 143–151 (1993).

  8. 8.

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

  9. 9.

    , , & Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc. Natl. Acad. Sci. USA 85, 7293–7297 (1988).

  10. 10.

    et al. A new deleted allele in the human cytochrome P450 2A6 (CYP2A6) gene found in individuals showing poor metabolic capacity to coumarin and (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502). Pharmacogenetics 8, 239–249 (1998).

  11. 11.

    et al. Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem. J. 300, 271–276 (1994).

  12. 12.

    et al. Characterization of a common deletion polymorphism of the UGT2B17 gene linked to UGT2B15. Genomics 84, 707–714 (2005).

  13. 13.

    et al. Genetic inheritance of gene expression in human cell lines. Am. J. Hum. Genet. 75, 1094–1105 (2004).

  14. 14.

    et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).

  15. 15.

    et al. Efficiency and power in genetic association studies. Nat. Genet. (in the press).

  16. 16.

    , , , & A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet., advance online publication 4 December 2005 (10.1038/ng1697).

  17. 17.

    , & Common deletions and SNPs are in linkage disequilibrium in the human genome. Nat. Genet., advance online publication 4 December 2005 (10.1038/ng1695).

  18. 18.

    et al. Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

  19. 19.

    Computational Information Design. Thesis, Massachusetts Institute of Technology (2005).

Download references

Acknowledgements

The authors wish to thank J. Moore and L. Ziaugra for contributing their expertise on the behavior of genotyping platforms and C. Patil, J. Melo and E. Lander for commenting on manuscript drafts. We thank G. Thorisson and A. Vernon-Smith for extensive help with data coordination, and D. Conrad, J. Pritchard and K. Frazer for exchanging manuscripts before publication.

Author information

Affiliations

  1. Department of Molecular Biology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Steven A McCarroll
    • , Tracy N Hadnott
    •  & David M Altshuler

  2. Center for Human Genetic Research, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Steven A McCarroll
    • , Mark J Daly
    •  & David M Altshuler

  3. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02141, USA.

    • Steven A McCarroll
    • , Pardis C Sabeti
    • , Michael C Zody
    • , Jeffrey C Barrett
    • , Stacey B Gabriel
    • , Mark J Daly
    •  & David M Altshuler

  4. Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.

    • George H Perry
    • , Stephanie Dallaire
    •  & Charles Lee

  5. Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Charles Lee
    • , Mark J Daly
    •  & David M Altshuler

  6. Department of Medicine, Massachusetts General Hospital, Simches Research Center, 185 Cambridge St., Boston, Massachusetts 02114, USA.

    • Mark J Daly
    •  & David M Altshuler

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David M Altshuler.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Physical clustering of patterns of apparent mendelian inconsistency and null genotypes in the HapMap data.

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    Supplementary Fig. 2

    Distinct patterns of aberrant SNP genotypes caused by the same deletion polymorphisms in multiple populations.

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    Supplementary Fig. 3

    Confirmation of segregating deletion variants by fluorescent in situ hybridization (FISH).

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    Supplementary Fig. 4

    Deletion variants flanked by segmental duplications.

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    Supplementary Fig. 5

    Linkage disequilibrium between gene deletion polymorphisms and nearby SNPs.

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    Supplementary Table 1

    Predicted deletion variants and supporting SNP evidence.

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    Supplementary Table 2

    Validation of candidate deletion variants.

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    Supplementary Table 3

    Gene deletion genotypes obtained by quantitative PCR for ten loci in 269 individuals.

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    Supplementary Table 4

    SNP alleles that tag common gene deletion alleles, for potential use in medical genetic studies.

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    Supplementary Table 5

    Primer and probe sequences used.

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    Supplementary Note

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DOI

https://doi.org/10.1038/ng1696

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