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

Author

Listed:
  • 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
    Inserm UMR915, L’institut du thorax, Nantes 44035, France)

  • 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
    Rudbeck Laboratory Uppsala University)

  • 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
    University of Toronto)

  • Matthew E. Hurles

    (The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK)

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.

Suggested Citation

  • 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 & K, 2010. "Origins and functional impact of copy number variation in the human genome," Nature, Nature, vol. 464(7289), pages 704-712, April.
    • Handle: RePEc:nat:nature:v:464:y:2010:i:7289:d:10.1038_nature08516
    DOI: 10.1038/nature08516
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    Cited by:

    1. Jakub Kopal & Kuldeep Kumar & Kimia Shafighi & Karin Saltoun & Claudia Modenato & Clara A. Moreau & Guillaume Huguet & Martineau Jean-Louis & Charles-Olivier Martin & Zohra Saci & Nadine Younis & Elis, 2024. "Using rare genetic mutations to revisit structural brain asymmetry," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Lin Chang-Yun & Lo Yungtai & Ye Kenny Q., 2012. "Genotype Copy Number Variations using Gaussian Mixture Models: Theory and Algorithms," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 11(5), pages 1-26, October.
    3. Zhuoran Xu & Quan Li & Luigi Marchionni & Kai Wang, 2023. "PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Thomas E. Wilson & Samreen Ahmed & Amanda Winningham & Thomas W. Glover, 2024. "Replication stress induces POLQ-mediated structural variant formation throughout common fragile sites after entry into mitosis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Jingfen Lan & Ziheng Liao & A. K. Alvi Haque & Qiang Yu & Kun Xie & Yang Guo, 2024. "CNVbd: A Method for Copy Number Variation Detection and Boundary Search," Mathematics, MDPI, vol. 12(3), pages 1-15, January.
    6. Lucia Ruojia Wu & Peng Dai & Michael Xiangjiang Wang & Sherry Xi Chen & Evan N. Cohen & Gitanjali Jayachandran & Jinny Xuemeng Zhang & Angela V. Serrano & Nina Guanyi Xie & Naoto T. Ueno & James M. Re, 2022. "Ensemble of nucleic acid absolute quantitation modules for copy number variation detection and RNA profiling," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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