Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes
Authors: Wang Qingbo , Pierce-Hoffman Emma , Cummings Beryl B. , Alföldi Jessica , Francioli Laurent C. , Gauthier Laura D. , Hill Andrew J. , O’Donnell-Luria Anne H. ,   Genome Aggregation Database Production Team, Armean Irina M. , Banks Eric , Bergelson Louis , Cibulskis Kristian , Collins Ryan L. , Connolly Kristen M. , Covarrubias Miguel , Daly Mark J. , Donnelly Stacey , Farjoun Yossi , Ferriera Steven , Gabriel Stacey , Gentry Jeff , Gupta Namrata , Jeandet Thibault , Kaplan Diane , Laricchia Kristen M. , Llanwarne Christopher , Minikel Eric V. , Munshi Ruchi , Neale Benjamin M. , Novod Sam , 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 , Ware James S. , Watts Nicholas A. , Weisburd Ben , Whiffin Nicola ,   Genome Aggregation Database Consortium, Aguilar Salinas Carlos A. , 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 , 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. , Marrugat Jaume , Mattila Kari M. , McCarroll Steven , McCarthy Mark I. , McGovern Dermot , McPherson Ruth , Meigs James B. , Melander Olle , Metspalu Andres , 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 , Watkins Hugh , Weersma Rinse K. , Wessman Maija , Wilson James G. , Xavier Ramnik J. , Vawter Marquis P. , Karczewski Konrad J. , MacArthur Daniel G. 
Published: May 2020

AbstractMulti-nucleotide variants (MNVs), defined as two or more nearby variants existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, existing tools typically do not accurately classify MNVs, and understanding of their mutational origins remains limited. Here, we systematically survey MNVs in 125,748 whole exomes and 15,708 whole genomes from the Genome Aggregation Database (gnomAD). We identify 1,792,248 MNVs across the genome with constituent variants falling within 2 bp distance of one another, including 18,756 variants with a novel combined effect on protein sequence. Finally, we estimate the relative impact of known mutational mechanisms - CpG deamination, replication error by polymerase zeta, and polymerase slippage at repeat junctions - on the generation of MNVs. Our results demonstrate the value of haplotype-aware variant annotation, and refine our understanding of genome-wide mutational mechanisms of MNVs.