Integrated detection and population-genetic analysis of SNPs and copy number variation |
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Authors: | McCarroll Steven A Kuruvilla Finny G Korn Joshua M Cawley Simon Nemesh James Wysoker Alec Shapero Michael H de Bakker Paul I W Maller Julian B Kirby Andrew Elliott Amanda L Parkin Melissa Hubbell Earl Webster Teresa Mei Rui Veitch James Collins Patrick J Handsaker Robert Lincoln Steve Nizzari Marcia Blume John Jones Keith W Rava Rich Daly Mark J Gabriel Stacey B Altshuler David |
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Institution: | Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. |
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Abstract: | 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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