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Integrated detection and population-genetic analysis of SNPs and copy number variation


Dissecting the genetic basis of disease risk requires measuring all forms of genetic variation, including SNPs and copy number variants (CNVs), and is enabled by accurate maps of their locations, frequencies and population-genetic properties. We designed a hybrid genotyping array (Affymetrix SNP 6.0) to simultaneously measure 906,600 SNPs and copy number at 1.8 million genomic locations. By characterizing 270 HapMap samples, we developed a map of human CNV (at 2-kb breakpoint resolution) informed by integer genotypes for 1,320 copy number polymorphisms (CNPs) that segregate at an allele frequency >1%. More than 80% of the sequence in previously reported CNV regions fell outside our estimated CNV boundaries, indicating that large (>100 kb) CNVs affect much less of the genome than initially reported. Approximately 80% of observed copy number differences between pairs of individuals were due to common CNPs with an allele frequency >5%, and more than 99% derived from inheritance rather than new mutation. Most common, diallelic CNPs were in strong linkage disequilibrium with SNPs, and most low-frequency CNVs segregated on specific SNP haplotypes.

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Figure 1: Design of new microarrays.
Figure 2: Discovery and sizes of CNV regions.
Figure 3: Classes of copy number variants and reproducibility and discrete quality of copy-number measurements.
Figure 4: Linkage disequilibrium properties of CNPs.
Figure 5: Dissection of complex CNVs.
Figure 6: Capture of CNPs in genome-wide association studies via direct interrogation and linkage disequilibrium.


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We thank J. Kidd, G. Cooper and E. Eichler for sharing data on high-resolution breakpoints of select CNVs prior to its publication; E. Lander, J. Hirschhorn and S. Kathiresan for thoughtful readings of the manuscript; the Affymetrix team of the Broad Institute Genetic Analysis Platform: W. Brodeur, N. Chia, M. DaSilva, J. Gibbons, N. Houde, M. McConnell, R. Barry, K. Nguyen, J. Camarata, M. Fava and T. Nyinjee under the supervision of C. Gates, B. Blumenstiel, D. Gage and M. Parkin; members of the Affymetrix informatics team: X. Di, H. Gorrell, G. Liu, M. Mittmann, M. Shen, C. Sugnet, A. Willams and G. Yang; members of the Affymetrix arrays and assays team: T. Berntsen, M. Chadha, J. Law, H. Matsuzaki, B. Nguyen, K. Travers, N. Vissa and S. Walsh. S.A.M. was supported by a Lilly Life Sciences Research Fellowship.

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Authors and Affiliations



F.G.K. conceived a strategy for empirical probe reduction of SNP probe sets. S.A.M. conceived of hybrid arrays consisting of polymorphic (SNP) and nonpolymorphic (copy number) probes. F.G.K., S.A.M. and D.A. proposed to Affymetrix a specific redesign of the 500K SNP array based on these concepts. The idea was further developed with input from R.R., J.B., S.C., S.L., K.W.J., S.B.G. and M.J.D., and a pilot initiated. For the pilot (which became the SNP 5.0 array), F.G.K. and J.B.M. selected SNP probe sets, and S.A.M. and J.M.K. selected copy number probes. For the development of the SNP 6.0 array, R.M. directed laboratory SNP screening experiments which were analyzed by S.C., E.H. and T.W. P.I.W.d.B., J.B.M. and S.C. selected SNPs from those which passed the screening effort, using a linkage-disequilibrium tagging strategy. S.A.M. and M.H.S. designed and M.H.S. directed laboratory work for the titration experiment that guided empirical selection of copy number probes; on the basis of these results, together with informatic analyses which A.K. performed, S.A.M. and J.M.K. selected copy number probes. Laboratory experiments at Broad Institute were led by M.P. and S.B.G. A.W., J.N., R.H. and E.H. developed supporting software. S.A.M., J.M.K. and J.N. analyzed the data to identify CNVs. S.A.M., J.N., F.G.K. and J.M.K. developed CNP genotyping analysis. P.J.C. conducted and J.V. analyzed experiments to validate CNP genotypes experimentally. S.A.M. analyzed the population-genetic and linkage-disequilibrium properties of CNVs. J.M.K. analyzed the data for evidence of de novo CNVs. A.L.E. analyzed platforms' coverage of CNVs. S.A.M., F.G.K., J.M.K., M.J.D. and D.A. wrote the manuscript. Discussions among all authors informed the array design, the development of algorithms for analysis and the interpretation of results.

Corresponding authors

Correspondence to Steven A McCarroll or David Altshuler.

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Competing interests

S.C., M.H.S., E.H., T.W., R.M., S.L., J.B., K.J. and R.R. are employees of Affymetrix. The remaining authors (S.A.M., F.G.K., J.M.K., J.N., A.W., P.I.W.dB., J.M., A.K., A.L.E., M.P., R.H., M.J.B., S.B.G. and D.A.) neither personally nor institutionally receive financial support from Affymetrix, and neither the authors nor their employers receive compensation or royalties from the work described in this article.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1, 4 and Supplementary Figures 1 and 2 (PDF 1559 kb)

Supplementary Table 2

Genomic locations of copy-number polymorphisms (XLS 147 kb)

Supplementary Table 3

Sample-level determinations of integer copy number for each CNP (XLS 2419 kb)

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McCarroll, S., Kuruvilla, F., Korn, J. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40, 1166–1174 (2008).

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