Mapping copy number variation by population-scale genome sequencing

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, Yutao Fu, Fabian Grubert, Iman Hajirasouliha, Fereydoun Hormozdiari, Lilia M. Iakoucheva, Zamin Iqbal, Shuli Kang, Jeffrey M. Kidd, Miriam K. Konkel, Joshua Korn, Ekta Khurana, Deniz Kural, Hugo Y. K. Lam, Jing Leng, Ruiqiang Li, Yingrui Li, Chang-Yun Lin, Ruibang Luo, Xinmeng Jasmine Mu, James Nemesh, Heather E. Peckham, Tobias Rausch, Aylwyn Scally, Xinghua Shi, Michael P. Stromberg, Adrian M. Stütz, Alexander Eckehart Urban, Jerilyn A. Walker, Jiantao Wu, Yujun Zhang, Zhengdong D. Zhang, Mark A. Batzer, Li Ding, Gabor T. Marth, Gil McVean, Jonathan Sebat, Michael Snyder, Jun Wang, Kenny Ye, Evan E. Eichler, Mark B. Gerstein, Matthew E. Hurles, Charles Lee, Steven A. McCarroll and Jan O. Korbel ()
Additional contact information
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
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
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
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
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
Kenny Ye: Albert Einstein College of Medicine
Evan E. Eichler: University of Washington School of Medicine
Mark B. Gerstein: Program in Computational Biology and Bioinformatics, 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
Jan O. Korbel: Genome Biology Research Unit, European Molecular Biology Laboratory, Heidelberg, Germany

Nature, 2011, vol. 470, issue 7332, 59-65

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature09708

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