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Systematic assessment of copy number variant detection via genome-wide SNP genotyping

Nature Genetics volume 40, pages 1199–1203 (2008)Cite this article

Abstract

SNP genotyping has emerged as a technology to incorporate copy number variants (CNVs) into genetic analyses of human traits. However, the extent to which SNP platforms accurately capture CNVs remains unclear. Using independent, sequence-based CNV maps, we find that commonly used SNP platforms have limited or no probe coverage for a large fraction of CNVs. Despite this, in 9 samples we inferred 368 CNVs using Illumina SNP genotyping data and experimentally validated over two-thirds of these. We also developed a method (SNP-Conditional Mixture Modeling, SCIMM) to robustly genotype deletions using as few as two SNP probes. We find that HapMap SNPs are strongly correlated with 82% of common deletions, but the newest SNP platforms effectively tag about 50%. We conclude that currently available genome-wide SNP assays can capture CNVs accurately, but improvements in array designs, particularly in duplicated sequences, are necessary to facilitate more comprehensive analyses of genomic variation.

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Figure 1: Probe-coverage histogram for 500 nonredundant deletion events greater than 1 kb in size identified in nine human samples by fosmid ESP placements and refined using oligonucleotide array-CGH experiments4.
Figure 2: Deletion predictions validated by fosmid ESP placement data.
Figure 3: Amplification events validated by clusters of 'everted' fosmid ESP placements.
Figure 4: Example of fluorescence intensity measurements for each of 126 samples for a single SNP probe (rs10076425).

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Cooper, G.M., Nickerson, D.A. & Eichler, E.E. Mutational and selective effects on copy-number variants in the human genome. Nat. Genet. 39, S22–S29 (2007).

    Article  CAS  Google Scholar 

  6. Singleton, A.B. et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).

    Article  CAS  Google Scholar 

  7. 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 

  8. 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 

  9. Perry, G.H. et al. Diet and the evolution of human amylase gene copy number variation. Nat. Genet. 39, 1256–1260 (2007).

    Article  CAS  Google Scholar 

  10. Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008).

    Article  CAS  Google Scholar 

  11. Estivill, X. & Armengol, L. Copy number variants and common disorders: filling the gaps and exploring complexity in genome-wide association studies. PLoS Genet. 3, 1787–1799 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  14. 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 

  15. Locke, D.P. et al. Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome. Am. J. Hum. Genet. 79, 275–290 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Peiffer, D.A. et al. High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping. Genome Res. 16, 1136–1148 (2006).

    Article  CAS  Google Scholar 

  18. 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  Google Scholar 

  19. Colella, S. et al. QuantiSNP: an objective Bayes hidden-Markov model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res. 35, 2013–2025 (2007).

    Article  CAS  Google Scholar 

  20. Wang, K. et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 17, 1665–1674 (2007).

    Article  CAS  Google Scholar 

  21. Day, N., Hemmaplardh, A., Thurman, R.E., Stamatoyannopoulos, J.A. & Noble, W.S. Unsupervised segmentation of continuous genomic data. Bioinformatics 23, 1424–1426 (2007).

    Article  CAS  Google Scholar 

  22. 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 

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

    Article  CAS  Google Scholar 

  24. Dempster, A.P., Laird, N.M. & Rubin, D.B. Maximum likelihood from incomplete data via the EM algorithm. J. Roy. Statist. Soc. Ser. B. Methodological 39, 1–38 (1977).

    Google Scholar 

  25. Newman, T.L. et al. High-throughput genotyping of intermediate-size structural variation. Hum. Mol. Genet. 15, 1159–1167 (2006).

    Article  CAS  Google Scholar 

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

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

    Article  CAS  Google Scholar 

  28. Korbel, J.O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).

    Article  CAS  Google Scholar 

  29. de Smith, A.J. et al. Array CGH analysis of copy number variation identifies 1284 new genes variant in healthy white males: implications for association studies of complex diseases. Hum. Mol. Genet. 16, 2783–2794 (2007).

    Article  CAS  Google Scholar 

  30. Schwarz, G. Estimating the dimension of a model. Annals of Statistics 6, 461–464 (1978).

    Article  Google Scholar 

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Acknowledgements

We thank D. Peiffer and colleagues at Illumina for sharing Human 1M and HumanHap 550K genotyping data. We apologize to all colleagues whose work we could not cite because of space constraints. G.M.C. is supported by a Merck, Jane Coffin Childs Memorial Fund Postdoctoral Fellowship. T.Z. acknowledges support from the National Human Genome Research Institute (NHGRI) Interdisciplinary Training in Genomic Sciences grant T32 HG00035. J.M.K. is supported by a National Science Foundation graduate fellowship. This work was supported by the National Heart, Lung, and Blood Institute Programs for Genomic Applications grant HL066682 to D.A.N. and NHGRI grant HG004120 to E.E.E. E.E.E. is an investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Gregory M Cooper and Troy Zerr: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genome Sciences, University of Washington, Seattle, 98195, Washington, USA

    Gregory M Cooper, Troy Zerr, Jeffrey M Kidd, Evan E Eichler & Deborah A Nickerson

  2. Howard Hughes Medical Institute.,

    Evan E Eichler

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  1. Gregory M Cooper
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  2. Troy Zerr
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Corresponding author

Correspondence to Gregory M Cooper.

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Supplementary Methods, Supplementary Tables 1, 3–6, 9, 10 and Supplementary Figures 1–4 (PDF 1667 kb)

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Supplementary Table 7 (XLS 97 kb)

Supplementary Table 8 (XLS 297 kb)

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Cooper, G., Zerr, T., Kidd, J. et al. Systematic assessment of copy number variant detection via genome-wide SNP genotyping. Nat Genet 40, 1199–1203 (2008). https://doi.org/10.1038/ng.236

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