An integrated map of structural variation in 2,504 human genomes

Peter H. Sudmant, Tobias Rausch, Eugene J. Gardner, Robert E. Handsaker, Alexej Abyzov, John Huddleston, Yan Zhang, Kai Ye, Goo Jun, Markus His Yang Fritz, Miriam K. Konkel, Ankit Malhotra, Adrian M. Stütz, Xinghua Shi, Francesco Paolo Casale, Jieming Chen, Fereydoun Hormozdiari, Gargi Dayama, Ken Chen, Maika MaligMark J.P. Chaisson, Klaudia Walter, Sascha Meiers, Seva Kashin, Erik Garrison, Adam Auton, Hugo Y.K. Lam, Xinmeng Jasmine Mu, Can Alkan, Danny Antaki, Taejeong Bae, Eliza Cerveira, Peter Chines, Zechen Chong, Laura Clarke, Elif Dal, Li Ding, Sarah Emery, Xian Fan, Madhusudan Gujral, Fatma Kahveci, Jeffrey M. Kidd, Yu Kong, Eric Wubbo Lameijer, Shane McCarthy, Paul Flicek, Richard A. Gibbs, Gabor Marth, Christopher E. Mason, Androniki Menelaou

Research output: Contribution to journalArticlepeer-review

1119 Scopus citations


Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.

Original languageEnglish (US)
Pages (from-to)75-81
Number of pages7
Issue number7571
StatePublished - Sep 30 2015

Bibliographical note

Funding Information:
Acknowledgements We thank M. Hurles, R. Durbin and D. Reich for valuable comments during the preparation of this work, S. Scherer for providing PCR-based inversion genotyping data for the initial calibration of our inversion caller, B. Nelson and V. Benes for technical assistance, and T. Brown and N. Habermann for critical review of the manuscript. The following people are acknowledged for contributing to PacBio sequencing or analysis: E. Patel, S. Lee, H. Doddapaneni, L. Lewis, R. Ruth, Q. Meng, V. Vee, Y. Han, J. Jayaseelan, A. English, J. Korlach, M. Hunkapiller, B. Hüttel and R. Reinhardt. We acknowledge the Yale University Biomedical High-Performance Computing Center and high-performance compute infrastructure made available through the EMBL and EMBL-EBI IT facilities. We thank the people generously contributing samples to the 1000 Genomes Project. Funding for this research project came from the following grants: NIH U41HG007497 (to C.L., E.E.E., J.O.K., M.A.B., M.G., S.A.M., R.E.M. and J.S.), RO1GM59290 (M.A.B.), R01HG002898 (S.E.D.) and R01CA166661 (S.E.D.), P01HG007497 (to E.E.E.), R01HG007068 (to R.E.M.), RR19895 and RR029676-01 (to M.B.G.), Wellcome Trust WT085532/Z/08/Z and WT104947/Z/14/Z (to P.F.), an Emmy Noether Grant from the German Research Foundation (KO4037/1-1, to J.O.K.) and the European Molecular Biology Laboratory. C.L. is on the scientific advisory board (SAB) of BioNano Genomics. E.E.E. is.on the scientific advisory board (SAB) of DNAnexus, Inc. and is a consultant for Kunming University of Science and Technology (KUST) as part of the 1000 China Talent Program. P.F. is on the SAB of Omicia, Inc. C.L. is an Ewha Womans University Distinguished Professor. E.E.E. is an investigator of the Howard Hughes Medical Institute. J.O.K. is a European Research Council investigator.

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.


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