Article

Nature 464, 704-712 (1 April 2010) | doi:10.1038/nature08516; Received 14 August 2009; Accepted 21 September 2009; Published online 7 October 2009

Origins and functional impact of copy number variation in the human genome

Donald F. Conrad1,7, Dalila Pinto2,7, Richard Redon1,3, Lars Feuk2,4, Omer Gokcumen5, Yujun Zhang1, Jan Aerts1, T. Daniel Andrews1, Chris Barnes1, Peter Campbell1, Tomas Fitzgerald1, Min Hu1, Chun Hwa Ihm5, Kati Kristiansson1, Daniel G. MacArthur1, Jeffrey R. MacDonald2, Ifejinelo Onyiah1, Andy Wing Chun Pang2, Sam Robson1, Kathy Stirrups1, Armand Valsesia1, Klaudia Walter1, John Wei2, The Wellcome Trust Case Control Consortium, Chris Tyler-Smith1, Nigel P. Carter1, Charles Lee5, Stephen W. Scherer2,6 & Matthew E. Hurles1

  1. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
  2. The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, MaRS Centre–East Tower, 101 College Street, Room 14-701, Toronto, Ontario M5G 1L7, Canada
  3. Inserm UMR915, L’institut du thorax, Nantes 44035, France
  4. Uppsala: Department of Genetics and Pathology, Rudbeck Laboratory Uppsala University, Uppsala 751 85, Sweden
  5. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
  6. Department of Molecular Genetics, University of Toronto, Toronto M5S 1A8, Canada
  7. These authors contributed equally to this work.
  8. Lists of participants and affiliations appear in Supplementary Information.

Correspondence to: Stephen W. Scherer2,6Matthew E. Hurles1 Correspondence and requests for materials should be addressed to M.E.H. (Email: meh@sanger.ac.uk) or S.W.S. (Email: steve@genet.sickkids.on.ca).

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Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.

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