%0 Journal Article %1 karczewski2020mutational %A Karczewski, Konrad J. %A Francioli, Laurent C. %A Tiao, Grace %A Cummings, Beryl B. %A Alföldi, Jessica %A Wang, Qingbo %A Collins, Ryan L. %A Laricchia, Kristen M. %A Ganna, Andrea %A Birnbaum, Daniel P. %A Gauthier, Laura D. %A Brand, Harrison %A Solomonson, Matthew %A Watts, Nicholas A. %A Rhodes, Daniel %A Singer-Berk, Moriel %A England, Eleina M. %A Seaby, Eleanor G. %A Kosmicki, Jack A. %A Walters, Raymond K. %A Tashman, Katherine %A Farjoun, Yossi %A Banks, Eric %A Poterba, Timothy %A Wang, Arcturus %A Seed, Cotton %A Whiffin, Nicola %A Chong, Jessica X. %A Samocha, Kaitlin E. %A Pierce-Hoffman, Emma %A Zappala, Zachary %A O’Donnell-Luria, Anne H. %A Minikel, Eric Vallabh %A Weisburd, Ben %A Lek, Monkol %A Ware, James S. %A Vittal, Christopher %A Armean, Irina M. %A Bergelson, Louis %A Cibulskis, Kristian %A Connolly, Kristen M. %A Covarrubias, Miguel %A Donnelly, Stacey %A Ferriera, Steven %A Gabriel, Stacey %A Gentry, Jeff %A Gupta, Namrata %A Jeandet, Thibault %A Kaplan, Diane %A Llanwarne, Christopher %A Munshi, Ruchi %A Novod, Sam %A Petrillo, Nikelle %A Roazen, David %A Ruano-Rubio, Valentin %A Saltzman, Andrea %A Schleicher, Molly %A Soto, Jose %A Tibbetts, Kathleen %A Tolonen, Charlotte %A Wade, Gordon %A Talkowski, Michael E. %A Aguilar Salinas, Carlos A. %A Ahmad, Tariq %A Albert, Christine M. %A Ardissino, Diego %A Atzmon, Gil %A Barnard, John %A Beaugerie, Laurent %A Benjamin, Emelia J. %A Boehnke, Michael %A Bonnycastle, Lori L. %A Bottinger, Erwin P. %A Bowden, Donald W. %A Bown, Matthew J. %A Chambers, John C. %A Chan, Juliana C. %A Chasman, Daniel %A Cho, Judy %A Chung, Mina K. %A Cohen, Bruce %A Correa, Adolfo %A Dabelea, Dana %A Daly, Mark J. %A Darbar, Dawood %A Duggirala, Ravindranath %A Dupuis, Josée %A Ellinor, Patrick T. %A Elosua, Roberto %A Erdmann, Jeanette %A Esko, Tõnu %A Färkkilä, Martti %A Florez, Jose %A Franke, Andre %A Getz, Gad %A Glaser, Benjamin %A Glatt, Stephen J. %A Goldstein, David %A Gonzalez, Clicerio %A Groop, Leif %A Haiman, Christopher %A Hanis, Craig %A Harms, Matthew %A Hiltunen, Mikko %A Holi, Matti M. %A Hultman, Christina M. %A Kallela, Mikko %A Kaprio, Jaakko %A Kathiresan, Sekar %A Kim, Bong-Jo %A Kim, Young Jin %A Kirov, George %A Kooner, Jaspal %A Koskinen, Seppo %A Krumholz, Harlan M. %A Kugathasan, Subra %A Kwak, Soo Heon %A Laakso, Markku %A Lehtimäki, Terho %A Loos, Ruth J. F. %A Lubitz, Steven A. %A Ma, Ronald C. W. %A MacArthur, Daniel G. %A Marrugat, Jaume %A Mattila, Kari M. %A McCarroll, Steven %A McCarthy, Mark I. %A McGovern, Dermot %A McPherson, Ruth %A Meigs, James B. %A Melander, Olle %A Metspalu, Andres %A Neale, Benjamin M. %A Nilsson, Peter M. %A O’Donovan, Michael C. %A Ongur, Dost %A Orozco, Lorena %A Owen, Michael J. %A Palmer, Colin N. A. %A Palotie, Aarno %A Park, Kyong Soo %A Pato, Carlos %A Pulver, Ann E. %A Rahman, Nazneen %A Remes, Anne M. %A Rioux, John D. %A Ripatti, Samuli %A Roden, Dan M. %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J. %A Scharf, Jeremiah %A Schunkert, Heribert %A Shoemaker, Moore B. %A Sklar, Pamela %A Soininen, Hilkka %A Sokol, Harry %A Spector, Tim %A Sullivan, Patrick F. %A Suvisaari, Jaana %A Tai, E. Shyong %A Teo, Yik Ying %A Tiinamaija, Tuomi %A Tsuang, Ming %A Turner, Dan %A Tusie-Luna, Teresa %A Vartiainen, Erkki %A Ware, James S. %A Watkins, Hugh %A Weersma, Rinse K. %A Wessman, Maija %A Wilson, James G. %A Xavier, Ramnik J. %A Neale, Benjamin M. %A Daly, Mark J. %A MacArthur, Daniel G. %A Consortium, Genome Aggregation Database %D 2020 %J Nature %K gnomAD human_genome mutation_rate mutation_spectrum %N 7809 %P 434--443 %R 10.1038/s41586-020-2308-7 %T The mutational constraint spectrum quantified from variation in 141,456 humans %U https://doi.org/10.1038/s41586-020-2308-7 %V 581 %X Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

@article{karczewski2020mutational, abstract = {Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.}, added-at = {2020-05-28T20:01:16.000+0200}, author = {Karczewski, Konrad J. and Francioli, Laurent C. and Tiao, Grace and Cummings, Beryl B. and Alföldi, Jessica and Wang, Qingbo and Collins, Ryan L. and Laricchia, Kristen M. and Ganna, Andrea and Birnbaum, Daniel P. and Gauthier, Laura D. and Brand, Harrison and Solomonson, Matthew and Watts, Nicholas A. and Rhodes, Daniel and Singer-Berk, Moriel and England, Eleina M. and Seaby, Eleanor G. and Kosmicki, Jack A. and Walters, Raymond K. and Tashman, Katherine and Farjoun, Yossi and Banks, Eric and Poterba, Timothy and Wang, Arcturus and Seed, Cotton and Whiffin, Nicola and Chong, Jessica X. and Samocha, Kaitlin E. and Pierce-Hoffman, Emma and Zappala, Zachary and O’Donnell-Luria, Anne H. and Minikel, Eric Vallabh and Weisburd, Ben and Lek, Monkol and Ware, James S. and Vittal, Christopher and Armean, Irina M. and Bergelson, Louis and Cibulskis, Kristian and Connolly, Kristen M. and Covarrubias, Miguel and Donnelly, Stacey and Ferriera, Steven and Gabriel, Stacey and Gentry, Jeff and Gupta, Namrata and Jeandet, Thibault and Kaplan, Diane and Llanwarne, Christopher and Munshi, Ruchi and Novod, Sam and Petrillo, Nikelle and Roazen, David and Ruano-Rubio, Valentin and Saltzman, Andrea and Schleicher, Molly and Soto, Jose and Tibbetts, Kathleen and Tolonen, Charlotte and Wade, Gordon and Talkowski, Michael E. and Aguilar Salinas, Carlos A. and Ahmad, Tariq and Albert, Christine M. and Ardissino, Diego and Atzmon, Gil and Barnard, John and Beaugerie, Laurent and Benjamin, Emelia J. and Boehnke, Michael and Bonnycastle, Lori L. and Bottinger, Erwin P. and Bowden, Donald W. and Bown, Matthew J. and Chambers, John C. and Chan, Juliana C. and Chasman, Daniel and Cho, Judy and Chung, Mina K. and Cohen, Bruce and Correa, Adolfo and Dabelea, Dana and Daly, Mark J. and Darbar, Dawood and Duggirala, Ravindranath and Dupuis, Josée and Ellinor, Patrick T. and Elosua, Roberto and Erdmann, Jeanette and Esko, Tõnu and Färkkilä, Martti and Florez, Jose and Franke, Andre and Getz, Gad and Glaser, Benjamin and Glatt, Stephen J. and Goldstein, David and Gonzalez, Clicerio and Groop, Leif and Haiman, Christopher and Hanis, Craig and Harms, Matthew and Hiltunen, Mikko and Holi, Matti M. and Hultman, Christina M. and Kallela, Mikko and Kaprio, Jaakko and Kathiresan, Sekar and Kim, Bong-Jo and Kim, Young Jin and Kirov, George and Kooner, Jaspal and Koskinen, Seppo and Krumholz, Harlan M. and Kugathasan, Subra and Kwak, Soo Heon and Laakso, Markku and Lehtimäki, Terho and Loos, Ruth J. F. and Lubitz, Steven A. and Ma, Ronald C. W. and MacArthur, Daniel G. and Marrugat, Jaume and Mattila, Kari M. and McCarroll, Steven and McCarthy, Mark I. and McGovern, Dermot and McPherson, Ruth and Meigs, James B. and Melander, Olle and Metspalu, Andres and Neale, Benjamin M. and Nilsson, Peter M. and O’Donovan, Michael C. and Ongur, Dost and Orozco, Lorena and Owen, Michael J. and Palmer, Colin N. A. and Palotie, Aarno and Park, Kyong Soo and Pato, Carlos and Pulver, Ann E. and Rahman, Nazneen and Remes, Anne M. and Rioux, John D. and Ripatti, Samuli and Roden, Dan M. and Saleheen, Danish and Salomaa, Veikko and Samani, Nilesh J. and Scharf, Jeremiah and Schunkert, Heribert and Shoemaker, Moore B. and Sklar, Pamela and Soininen, Hilkka and Sokol, Harry and Spector, Tim and Sullivan, Patrick F. and Suvisaari, Jaana and Tai, E. Shyong and Teo, Yik Ying and Tiinamaija, Tuomi and Tsuang, Ming and Turner, Dan and Tusie-Luna, Teresa and Vartiainen, Erkki and Ware, James S. and Watkins, Hugh and Weersma, Rinse K. and Wessman, Maija and Wilson, James G. and Xavier, Ramnik J. and Neale, Benjamin M. and Daly, Mark J. and MacArthur, Daniel G. and Consortium, Genome Aggregation Database}, biburl = {https://www.bibsonomy.org/bibtex/234b45a6a5fcb4f980319f04e20d44b02/peter.ralph}, doi = {10.1038/s41586-020-2308-7}, interhash = {780c28bde04400eb9bc6f7c80598f40b}, intrahash = {34b45a6a5fcb4f980319f04e20d44b02}, issn = {14764687}, journal = {Nature}, keywords = {gnomAD human_genome mutation_rate mutation_spectrum}, number = 7809, pages = {434--443}, refid = {Karczewski2020}, timestamp = {2020-05-28T21:01:25.000+0200}, title = {The mutational constraint spectrum quantified from variation in 141,456 humans}, url = {https://doi.org/10.1038/s41586-020-2308-7}, volume = 581, year = 2020 }