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Mapping copy number variation by population-scale genome sequencing

Author

Listed:
  • Ryan E. Mills

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Klaudia Walter

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

  • Chip Stewart

    (Boston College)

  • Robert E. Handsaker

    (Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Ken Chen

    (The Genome Center at Washington University)

  • Can Alkan

    (University of Washington School of Medicine
    Howard Hughes Medical Institute, University of Washington)

  • Alexej Abyzov

    (Program in Computational Biology and Bioinformatics, Yale University)

  • Seungtai Chris Yoon

    (Mount Sinai School of Medicine)

  • Kai Ye

    (Medical Statistics and Bioinformatics, Leiden University Medical Center)

  • R. Keira Cheetham

    (Illumina Cambridge Ltd, Chesterford Research Park, Little Chesterford, Saffron Walden CB10 1XL, UK)

  • Asif Chinwalla

    (The Genome Center at Washington University)

  • Donald F. Conrad

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

  • Yutao Fu

    (Life Technologies)

  • Fabian Grubert

    (Stanford University)

  • Iman Hajirasouliha

    (School of Computing Science, Simon Fraser University)

  • Fereydoun Hormozdiari

    (School of Computing Science, Simon Fraser University)

  • Lilia M. Iakoucheva

    (Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA)

  • Zamin Iqbal

    (Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK)

  • Shuli Kang

    (Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA)

  • Jeffrey M. Kidd

    (University of Washington School of Medicine)

  • Miriam K. Konkel

    (Louisiana State University)

  • Joshua Korn

    (Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Ekta Khurana

    (Program in Computational Biology and Bioinformatics, Yale University
    Yale University)

  • Deniz Kural

    (Boston College)

  • Hugo Y. K. Lam

    (Stanford University)

  • Jing Leng

    (Program in Computational Biology and Bioinformatics, Yale University)

  • Ruiqiang Li

    (BGI-Shenzhen)

  • Yingrui Li

    (BGI-Shenzhen)

  • Chang-Yun Lin

    (Albert Einstein College of Medicine)

  • Ruibang Luo

    (BGI-Shenzhen)

  • Xinmeng Jasmine Mu

    (Program in Computational Biology and Bioinformatics, Yale University)

  • James Nemesh

    (Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Heather E. Peckham

    (Life Technologies)

  • Tobias Rausch

    (Genome Biology Research Unit, European Molecular Biology Laboratory, Heidelberg, Germany)

  • Aylwyn Scally

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

  • Xinghua Shi

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Michael P. Stromberg

    (Boston College)

  • Adrian M. Stütz

    (Genome Biology Research Unit, European Molecular Biology Laboratory, Heidelberg, Germany)

  • Alexander Eckehart Urban

    (Stanford University
    Stanford University)

  • Jerilyn A. Walker

    (Louisiana State University)

  • Jiantao Wu

    (Boston College)

  • Yujun Zhang

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

  • Zhengdong D. Zhang

    (Program in Computational Biology and Bioinformatics, Yale University)

  • Mark A. Batzer

    (Louisiana State University)

  • Li Ding

    (The Genome Center at Washington University
    Washington University)

  • Gabor T. Marth

    (Boston College)

  • Gil McVean

    (University of Oxford)

  • Jonathan Sebat

    (Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA)

  • Michael Snyder

    (Stanford University)

  • Jun Wang

    (BGI-Shenzhen
    University of Copenhagen)

  • Kenny Ye

    (Albert Einstein College of Medicine)

  • Evan E. Eichler

    (University of Washington School of Medicine
    Howard Hughes Medical Institute, University of Washington)

  • Mark B. Gerstein

    (Program in Computational Biology and Bioinformatics, Yale University
    Yale University
    Yale University)

  • Matthew E. Hurles

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

  • Charles Lee

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Steven A. McCarroll

    (Broad Institute of Harvard and Massachusetts Institute of Technology
    Harvard Medical School)

  • Jan O. Korbel

    (Genome Biology Research Unit, European Molecular Biology Laboratory, Heidelberg, Germany)

Abstract

Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.

Suggested Citation

  • Ryan E. Mills & Klaudia Walter & Chip Stewart & Robert E. Handsaker & Ken Chen & Can Alkan & Alexej Abyzov & Seungtai Chris Yoon & Kai Ye & R. Keira Cheetham & Asif Chinwalla & Donald F. Conrad & Yuta, 2011. "Mapping copy number variation by population-scale genome sequencing," Nature, Nature, vol. 470(7332), pages 59-65, February.
    • Handle: RePEc:nat:nature:v:470:y:2011:i:7332:d:10.1038_nature09708
    DOI: 10.1038/nature09708
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    Citations

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    Cited by:

    1. Timofey Prodanov & Vikas Bansal, 2022. "Robust and accurate estimation of paralog-specific copy number for duplicated genes using whole-genome sequencing," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. 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.
    3. Yu Chen & Amy Y. Wang & Courtney A. Barkley & Yixin Zhang & Xinyang Zhao & Min Gao & Mick D. Edmonds & Zechen Chong, 2023. "Deciphering the exact breakpoints of structural variations using long sequencing reads with DeBreak," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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