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

Donald F. Conrad, Dalila Pinto, Richard Redon, Lars Feuk, Omer Gokcumen, Yujun Zhang, Jan Aerts, T. Daniel Andrews, Chris Barnes, Peter Campbell, Tomas Fitzgerald, Min Hu, Chun Hwa Ihm, Kati Kristiansson, Daniel G. MacArthur, Jeffrey R. MacDonald, Ifejinelo Onyiah, Andy Wing Chun Pang, Sam Robson, Kathy Stirrups, Armand Valsesia, Klaudia Walter, John Wei, Chris Tyler-Smith, Nigel P. Carter, Charles Lee, Stephen W. Scherer () and Matthew E. Hurles ()
Additional contact information
Donald F. Conrad: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Dalila Pinto: 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
Richard Redon: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Lars Feuk: 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
Omer Gokcumen: Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
Yujun Zhang: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Jan Aerts: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
T. Daniel Andrews: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Chris Barnes: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Peter Campbell: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Tomas Fitzgerald: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Min Hu: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Chun Hwa Ihm: Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
Kati Kristiansson: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Daniel G. MacArthur: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Jeffrey R. MacDonald: 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
Ifejinelo Onyiah: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Andy Wing Chun Pang: 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
Sam Robson: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Kathy Stirrups: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Armand Valsesia: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Klaudia Walter: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
John Wei: 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
Chris Tyler-Smith: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Nigel P. Carter: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
Charles Lee: Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
Stephen W. Scherer: 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
Matthew E. Hurles: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK

Nature, 2010, vol. 464, issue 7289, 704-712

Abstract: Abstract 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 42 million 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.

Date: 2010
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DOI: 10.1038/nature08516

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