A structural variation reference for medical and population genetics

作者：Ryan L. Collins, Harrison Brand, Konrad J. Karczewski, Xuefang Zhao, Jessica Alföldi, Laurent C. Francioli, Amit Khera, Chelsea Lowther, Laura Doyle Gauthier, Harold Wang, Nicholas A. Watts, Matthew Solomonson, Anne O’Donnell‐Luria, Alexander Baumann, Ruchi Munshi, Mark A Walker, Christopher W. Whelan, Yongqing Huang, Ted Brookings, Ted Sharpe, Matthew R. Stone, Elise Valkanas, Jack M. Fu, Grace Tiao, Kristen M. Laricchia, Valentín Ruano-Rubio, Christine R. Stevens, Namrata Gupta, Caroline M. Cusick, Lauren Margolin, Genome Aggregation Database Production Team, Jessica Alföldi, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Ryan L. Collins, Kristen M. Connolly, Miguel Covarrubias, Beryl B. Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Laurent C. Francioli, Stacey L. Gabriel, Laura Doyle Gauthier, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Konrad J. Karczewski, Kristen M. Laricchia, Christopher Llanwarne, Eric Vallabh Minikel, Ruchi Munshi, Benjamin M. Neale, Sam Novod, Anne O’Donnell‐Luria, Nikelle Petrillo, Timothy Poterba, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Kaitlin E. Samocha, Molly M. Schleicher, Cotton Seed, Matthew Solomonson, José Soto, Grace Tiao, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo S. Wang, James S. Ware, Nicholas A. Watts, Ben Weisburd, Nicola Whiffin, Carlos Alberto Aguilar-Salinas, Tariq Ahmad, Christine M. Albert, Diego Ardissino, Gil Atzmon, John A. Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Böttinger, Donald W. Bowden, Matthew J. Bown, John Campbell Chambers, Juliana C.N. Chan, Daniel I. Chasman, Judy H. Cho, Mina K. Chung, Bruce M. Cohen, Adolfo Correa, Dana Dabelea, Mark J. Daly, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosúa, Jeanette Erdmann, Tõnu Esko, Martti A. Färkkilä, José C. Florez, André Franke, Gad A. Getz, Benjamin Gläser, Stephen J. Glatt, David B. Goldstein, Clicerio González, Leif Groop, Christopher A. Haiman, Craig L. Hanis, Matthew B. Harms, Mikko O. Hiltunen, Matti Mikael Holi, Christina M. Hultman, Mikko Kallela, Jaakko A. Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Singh Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho J. Lehtimäki, Ruth J. F. Loos, Steven A. Lubitz, Ronald C.W., Daniel G. MacArthur, Jaume Marrugat, Kari M. Mattila, Steven A. McCarroll, Mark I. McCarthy, Dermot P.B. McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Benjamin M. Neale, Peter M. Nilsson, Michael C. O’Donovan, Döst Öngür, Lorena Orozco, Michael J. Owen, Colin N. A. Palmer, Aarno V. Palotie, Kyong Soo Park, Carlos N. Pato, Ann E. Pulver, Nazneen Rahman, Anne Marja Remes, John David Rioux, Samuli Ripatti, Dan M. Roden, Danish Saleheen, Veikko V Salomaa, Nilesh J. Samani, Jeremiah M. Scharf, Heribert Schunkert, Moore Benjamin Shoemaker, Pamela B. Sklar, Hilkka S. Soininen, Harry Sokol, Tim D. Spector, Patrick F. Sullivan, Jaana Suvisaari, E Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming T. Tsuang, Dan Turner, Teresa Tusié‐Luna, Erkki A Vartiainen, Marquis P. Vawter, James S. Ware, Hugh C Watkins, Rinse Karel Weersma, Maija Wessman, James Graham Wilson, Ramnik J. Xavier, Kent D. Taylor, Henry J. Lin, Stephen S. Rich, Wendy S. Post, Yii‐Der Ida Chen, Jerome I. Rotter, Chad Nusbaum, Anthony Philippakis, Eric S. Lander, Stacey L. Gabriel, Benjamin M. Neale, Sekar Kathiresan, Mark J. Daly, Eric Banks, Daniel G. MacArthur, Michael E. Talkowski · 发表于：Nature · 年份：2020 · DOI：10.1038/s41586-020-2287-8 · 被引用次数：1207 · 研究领域：Genomics and Rare Diseases、Genetic Associations and Epidemiology、Genomic variations and chromosomal abnormalities

Abstract Structural variants (SVs) rearrange large segments of DNA 1 and can have profound consequences in evolution and human disease 2,3 . 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 dosage 6 . 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 incidenta...