Article abstract

Nature Genetics 40, 1166 - 1174 (2008)
Published online: 7 September 2008 | doi:10.1038/ng.238

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

Steven A McCarroll1,2,3,4,10, Finny G Kuruvilla1,2,3,4,10, Joshua M Korn1,2,3,4,5,6, Simon Cawley7, James Nemesh1, Alec Wysoker1, Michael H Shapero7, Paul I W de Bakker1,4,8, Julian B Maller3, Andrew Kirby3, Amanda L Elliott1, Melissa Parkin1, Earl Hubbell7, Teresa Webster7, Rui Mei7, James Veitch7, Patrick J Collins7, Robert Handsaker1, Steve Lincoln7, Marcia Nizzari1, John Blume7, Keith W Jones7, Rich Rava7, Mark J Daly1,3,4,9, Stacey B Gabriel1 & David Altshuler1,2,3,4,9

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.

  1. Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
  2. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  4. Harvard Medical School, Boston, Massachusetts 02115, USA.
  5. Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts 02139, USA.
  6. Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts 02138, USA.
  7. Affymetrix Inc., Santa Clara, California 95051, USA.
  8. Division of Genetics, Brigham and Women's Hospital, and Harvard Medical School-Partners HealthCare Systems Center for Genetics and Genomics, Boston, Massachusetts 02115, USA.
  9. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  10. These authors contributed equally to this work.

Correspondence to: Steven A McCarroll1,2,3,4,10 e-mail:

Correspondence to: David Altshuler1,2,3,4,9 e-mail:


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