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Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs


Accurate and complete measurement of single nucleotide (SNP) and copy number (CNV) variants, both common and rare, will be required to understand the role of genetic variation in disease. We present Birdsuite, a four-stage analytical framework instantiated in software for deriving integrated and mutually consistent copy number and SNP genotypes. The method sequentially assigns copy number across regions of common copy number polymorphisms (CNPs), calls genotypes of SNPs, identifies rare CNVs via a hidden Markov model (HMM), and generates an integrated sequence and copy number genotype at every locus (for example, including genotypes such as A-null, AAB and BBB in addition to AA, AB and BB calls). Such genotypes more accurately depict the underlying sequence of each individual, reducing the rate of apparent mendelian inconsistencies. The Birdsuite software is applied here to data from the Affymetrix SNP 6.0 array. Additionally, we describe a method, implemented in PLINK, to utilize these combined SNP and CNV genotypes for association testing with a phenotype.

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Figure 1: Overview of Birdsuite.
Figure 2: Schematic of how a CNP is processed through Canary illustrated with data from chromosome 4.
Figure 3: Schematic of how a single SNP is processed through Birdsuite and evaluation of mendelian inconsistencies.
Figure 4: Discovery of unknown or de novo copy number variation using Birdseye.


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We wish to thank G. Getz for discussions on algorithms and comments regarding the supplemental methods. We also thank E. Lander and J. Hirschhorn for their readings and feedback. Finally, we are indebted to the testing labs that provided us with many replicates of HapMap samples run on the Affymetrix SNP 6.0 array. S.A.M. was supported by a Lilly Life Sciences Research Fellowship.

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Authors and Affiliations



J.M.K., F.G.K., S.A.M., M.J.D. and D.A. conceived of and refined the four-stage structure of Birdsuite. S.A.M., F.G.K. and J.N. developed and implemented Canary. J.N., S.A.M. and J.M.K. validated Canary calls, using data provided by P.J.C., J.V. and S.C. J.M.K., F.G.K., A.W., S.C. and E.H. developed, implemented, tested and validated Birdseed. J.M.K. developed, implemented and validated Birdseye. A.W. implemented Fawkes, which J.N., A.W. and J.M.K. validated. J.N., A.W., M.M.N. and S.B.G. were responsible for integration of the components and supporting software. K.D., C.L., J.M.K. and S.A.M. compared Birdsuite to Nexus and Partek. S.P. implemented the association tools. J.M.K., F.G.K., S.A.M., S.P., M.J.D. and D.A. wrote the manuscript. Discussion among all authors led to improvements in the algorithms and their implementations.

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Correspondence to Joshua M Korn or David Altshuler.

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Competing interests

S.C., E.H., J.V. and P.J.C. are employees of Affymetrix. The remaining authors (J.M.K., F.G.K., S.A.M., A.W., J.N., K.D., C.L., M.M.N., S.B.G., S.P., M.J.D. 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.

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Supplementary Figures 1 and 2, Supplementary Tables 1 and 2, Supplementary Note and Supplementary Methods (PDF 350 kb)

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Korn, J., Kuruvilla, F., McCarroll, S. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 40, 1253–1260 (2008).

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