8 An extremely complex SV involving 49 breakpoints and seven chromosomes. These results demonstrate the value of imputing SVs into GWAS, and for the eventual unification of short variants and SVs in all trait association studies. Given that short-read WGS is blind to a disproportionate fraction of repeat-mediated SVs and small insertions by comparison to long-read methods, this study certainly underestimates the true mutation rates within such hypermutable regions. Hurles, M. E., Dermitzakis, E. T. & Tyler-Smith, C. The functional impact of structural variation in humans. Pendleton, M. et al. As short-read WGS is rapidly becoming the predominant technology in large-scale human disease studies, and will probably displace conventional methods for diagnostic screening, there is a mounting need for comparable references of SVs across global populations. Structural variation has been defined as genomic alteration involving segments of DNA longer than 1 kb 1. A structural variation reference for medical and population genetics | Nature Article Open Access Published: 27 May 2020 A structural variation reference for medical and population genetics. J. Colour codes are consistent between a, c, eh, and between b and d. Although SVs alter more nucleotides per genome than SNVs and short insertion/deletion variants (indels; <50 bp)1, surprisingly little is known about their mutational spectra on a global scale. Furthermore, these SVs have been integrated directly into the gnomAD browser8. 1d, Supplementary Fig. Nonetheless, 92.7% of all known autosomal protein-coding nucleotides are not localized to simple- or low-copy repeats, and therefore we expect that the catalogues of SVs accessible to short-read WGS across large populations like gnomAD-SV will capture a majority of the most interpretable gene-disrupting SVs in humans. Reference variants - Reference variants (analogous to rs identifiers in dbSNP - e.g., rs1872633) do not currently exist for structural variants. M.J.D. Components of variation. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Genet. Given the potential value of this resource, we have released these linkage disequilibrium maps in Supplementary Table 7. INTRODUCTION. 4eh). Association between titin loss-of-function variants and early-onset atrial fibrillation. Opin. Dev. As national biobanks, disease-association studie was supported by NIDCR K99DE026824. Correction to: Nature 10.1038/s41586-020-2287-8Published online 27 May 2020 In this Article, author Marquis P. Vawter was missing from the Genome Aggregation Database Consortium list. N. Engl. a, Functional enrichments of 2,307 common SVs in strong linkage disequilibrium (R20.8) with an SNV associated with a trait or disease in the GWAS catalogue or the UK Biobank33,34. A structural variation reference for medical and population genetics 48, 11071111 (2016). Methods 12, 780786 (2015). Theor. Individual points are outlier samples at least three standard deviations away from the cohort-wide mean. Nat. All code is made available under the MIT license, unless stated otherwise. distributed via the gnomAD browser 8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening. Sudlow, C. et al. Extended Data Fig. Bars reflect 95% confidence intervals from 100-fold bootstrapping. PGG.SV: a whole-genome-sequencing-based structural variant resource and Science 360, 327331 (2018). Present address: Cellarity Inc., Cambridge, MA, USA, Present address: Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, Australia, Present address: Centre for Population Genomics, Murdoch Childrens Research Institute, Melbourne, Australia, These authors contributed equally: Ryan L. Collins, Harrison Brand, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Ryan L. Collins,Harrison Brand,Konrad J. Karczewski,Xuefang Zhao,Jessica Alfldi,Laurent C. Francioli,Amit V. Khera,Chelsea Lowther,Laura D. Gauthier,Harold Wang,Nicholas A. Watts,Matthew Solomonson,Anne ODonnell-Luria,Mark Walker,Matthew R. Stone,Elise Valkanas,Jack Fu,Grace Tiao,Kristen M. Laricchia,Christine Stevens,Namrata Gupta,Caroline Cusick,Lauren Margolin,Jessica Alfldi,Irina M. Armean,Ryan L. Collins,Beryl Cummings,Mark J. Daly,Stacey Donnelly,Laurent Francioli,Namrata Gupta,Konrad J. Karczewski,Kristen M. Laricchia,Eric V. Minikel,Benjamin M. Neale,Anne H. ODonnell-Luria,Timothy Poterba,Andrea Saltzman,Molly Schleicher,Matthew Solomonson,Grace Tiao,Arcturus Wang,Qingbo Wang,James S. Ware,Nicholas A. Watts,Nicola Whiffin,Mark J. Daly,Patrick T. Ellinor,Tnu Esko,Jose Florez,Sekar Kathiresan,Steven A. Lubitz,Daniel G. MacArthur,James B. Meigs,Benjamin M. Neale,Samuli Ripatti,Jeremiah Scharf,James S. Ware,Chad Nusbaum,Eric Lander,Stacey Gabriel,Benjamin M. Neale,Sekar Kathiresan,Mark J. Daly,Daniel G. MacArthur&Michael E. Talkowski, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA, Ryan L. Collins,Harrison Brand,Xuefang Zhao,Amit V. Khera,Chelsea Lowther,Harold Wang,Matthew R. Stone,Elise Valkanas,Jack Fu,Ryan L. Collins,Sekar Kathiresan,Jeremiah Scharf,Benjamin M. Neale,Sekar Kathiresan,Mark J. Daly,Daniel G. MacArthur&Michael E. Talkowski, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA, Ryan L. Collins,Elise Valkanas,Ryan L. Collins,Beryl Cummings&Qingbo Wang, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, Harrison Brand,Xuefang Zhao,Chelsea Lowther,Jack Fu&Michael E. Talkowski, Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA, Konrad J. Karczewski,Jessica Alfldi,Laurent C. Francioli,Nicholas A. Watts,Matthew Solomonson,Anne ODonnell-Luria,Grace Tiao,Kristen M. Laricchia,Benjamin M. Neale,Mark J. Daly&Daniel G. MacArthur, Department of Medicine, Harvard Medical School, Boston, MA, USA, Laurent C. Francioli,Daniel Chasman,Bruce Cohen,Gad Getz,Sekar Kathiresan,James B. Meigs,Dost Ongur,Sekar Kathiresan&Daniel G. MacArthur, Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Laura D. Gauthier,Alexander Baumann,Ruchi Munshi,Mark Walker,Christopher W. 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Rotter, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Department of Systems Biology, Harvard Medical School, Boston, MA, USA, Department of Biology, MIT, Cambridge, MA, USA, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Mark J. Daly,Timothy Poterba,Cotton Seed,Christopher Vittal,Arcturus Wang,Mark J. Daly,Steven McCarroll,Aarno Palotie,Jeremiah Scharf,Benjamin M. Neale,Mark J. Daly&Michael E. Talkowski, Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA, Jessica Alfldi,Irina M. Armean,Beryl Cummings,Mark J. Daly,Laurent Francioli,Konrad J. Karczewski,Kristen M. Laricchia,Benjamin M. Neale,Timothy Poterba,Cotton Seed,Matthew Solomonson,Grace Tiao,Christopher Vittal,Arcturus Wang,Qingbo Wang,Nicholas A. Watts,Mark J. Daly,Daniel G. MacArthur,Benjamin M. Neale&Aarno Palotie, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK, Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA, Steven Ferriera,Stacey Gabriel&Namrata Gupta, Division of Genetics and Genomics, Boston Childrens Hospital, Boston, MA, USA, Department of Pediatrics, Harvard Medical School, Boston, MA, USA, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK, National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK, James S. Ware,Nicola Whiffin,Jaspal Kooner&James S. Ware, Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK, James S. Ware,Nicola Whiffin&James S. 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