A structural variation reference for medical and population genetics
Authors: Collins Ryan L. , Brand Harrison , Karczewski Konrad J. , Zhao Xuefang , Alföldi Jessica , Francioli Laurent C. , Khera Amit V. , Lowther Chelsea , Gauthier Laura D. , Wang Harold , Watts Nicholas A. , Solomonson Matthew , O’Donnell-Luria Anne , Baumann Alexander , Munshi Ruchi , Walker Mark , Whelan Christopher W. , Huang Yongqing , Brookings Ted , Sharpe Ted , Stone Matthew R. , Valkanas Elise , Fu Jack , Tiao Grace , Laricchia Kristen M. , Ruano-Rubio Valentin , Stevens Christine , Gupta Namrata , Cusick Caroline , Margolin Lauren ,   Genome Aggregation Database Production Team, Alföldi Jessica , Armean Irina M. , Banks Eric , Bergelson Louis , Cibulskis Kristian , Collins Ryan L. , Connolly Kristen M. , Covarrubias Miguel , Cummings Beryl , Daly Mark J. , Donnelly Stacey , Farjoun Yossi , Ferriera Steven , Francioli Laurent , Gabriel Stacey , Gauthier Laura D. , Gentry Jeff , Gupta Namrata , Jeandet Thibault , Kaplan Diane , Karczewski Konrad J. , Laricchia Kristen M. , Llanwarne Christopher , Minikel Eric V. , Munshi Ruchi , Neale Benjamin M. , Novod Sam , O’Donnell-Luria Anne H. , Petrillo Nikelle , Poterba Timothy , Roazen David , Ruano-Rubio Valentin , Saltzman Andrea , Samocha Kaitlin E. , Schleicher Molly , Seed Cotton , Solomonson Matthew , Soto Jose , Tiao Grace , Tibbetts Kathleen , Tolonen Charlotte , Vittal Christopher , Wade Gordon , Wang Arcturus , Wang Qingbo , Ware James S. , Watts Nicholas A. , Weisburd Ben , Whiffin Nicola ,   Genome Aggregation Database Consortium, Salinas Carlos A. Aguilar , Ahmad Tariq , Albert Christine M. , Ardissino Diego , Atzmon Gil , Barnard John , Beaugerie Laurent , Benjamin Emelia J. , Boehnke Michael , Bonnycastle Lori L. , Bottinger Erwin P. , Bowden Donald W. , Bown Matthew J. , Chambers John C. , Chan Juliana C. , Chasman Daniel , Cho Judy , Chung Mina K. , Cohen Bruce , Correa Adolfo , Dabelea Dana , Daly Mark J. , Darbar Dawood , Duggirala Ravindranath , Dupuis Josée , Ellinor Patrick T. , Elosua Roberto , Erdmann Jeanette , Esko Tõnu , Färkkilä Martti , Florez Jose , Franke Andre , Getz Gad , Glaser Benjamin , Glatt Stephen J. , Goldstein David , Gonzalez Clicerio , Groop Leif , Haiman Christopher , Hanis Craig , Harms Matthew , Hiltunen Mikko , Holi Matti M. , Hultman Christina M. , Kallela Mikko , Kaprio Jaakko , Kathiresan Sekar , Kim Bong-Jo , Kim Young Jin , Kirov George , Kooner Jaspal , Koskinen Seppo , Krumholz Harlan M. , Kugathasan Subra , Kwak Soo Heon , Laakso Markku , Lehtimäki Terho , Loos Ruth J. F. , Lubitz Steven A. , Ma Ronald C. W. , MacArthur Daniel G. , Marrugat Jaume , Mattila Kari M. , McCarroll Steven , McCarthy Mark I. , McGovern Dermot , McPherson Ruth , Meigs James B. , Melander Olle , Metspalu Andres , Neale Benjamin M. , Nilsson Peter M. , O’Donovan Michael C. , Ongur Dost , Orozco Lorena , Owen Michael J. , Palmer Colin N. A. , Palotie Aarno , Park Kyong Soo , Pato Carlos , Pulver Ann E. , Rahman Nazneen , Remes Anne M. , Rioux John D. , Ripatti Samuli , Roden Dan M. , Saleheen Danish , Salomaa Veikko , Samani Nilesh J. , Scharf Jeremiah , Schunkert Heribert , Shoemaker Moore B. , Sklar Pamela , Soininen Hilkka , Sokol Harry , Spector Tim , Sullivan Patrick F. , Suvisaari Jaana , Tai E. Shyong , Teo Yik Ying , Tiinamaija Tuomi , Tsuang Ming , Turner Dan , Tusie-Luna Teresa , Vartiainen Erkki , Vawter Marquis P. , Ware James S. , Watkins Hugh , Weersma Rinse K. , Wessman Maija , Wilson James G. , Xavier Ramnik J. , Taylor Kent D. , Lin Henry J. , Rich Stephen S. , Post Wendy S. , Chen Yii-Der Ida , Rotter Jerome I. , Nusbaum Chad , Philippakis Anthony , Lander Eric , Gabriel Stacey , Neale Benjamin M. , Kathiresan Sekar , Daly Mark J. , Banks Eric , MacArthur Daniel G. , Talkowski Michael E. 
Published: May 2020

AbstractStructural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide variants (SNVs)5. However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25–29% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage6. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9% of samples, and estimate that 0.13% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings7. This SV resource is freely distributed via the gnomAD browser8 and will have broad utility in population genetics, disease-association studies, and diagnostic screening.