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


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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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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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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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).

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