Abstract
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 285-291 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 536 |
| Issue number | 7616 |
| DOIs | |
| State | Published - Aug 17 2016 |
ASJC Scopus subject areas
- General
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Analysis of protein-coding genetic variation in 60,706 humans. / Lek, Monkol; Karczewski, Konrad J.; Minikel, Eric V.; Samocha, Kaitlin E.; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H.; Ware, James S.; Hill, Andrew J.; Cummings, Beryl B.; Tukiainen, Taru; Birnbaum, Daniel P.; Kosmicki, Jack A.; Duncan, Laramie E.; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hoffman, Emma; Berghout, Joanne; Cooper, David N.; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja I.; Moonshine, Ami Levy; Natarajan, Pradeep; Orozco, Lorena; Peloso, Gina M.; Poplin, Ryan; Rivas, Manuel A.; Ruano-Rubio, Valentin; Rose, Samuel A.; Ruderfer, Douglas M.; Shakir, Khalid; Stenson, Peter D.; Stevens, Christine; Thomas, Brett P.; Tiao, Grace; Tusie-Luna, Maria T.; Weisburd, Ben; Won, Hong Hee; Yu, Dongmei; Altshuler, David M.; Ardissino, Diego; Boehnke, Michael; Danesh, John; Donnelly, Stacey; Elosua, Roberto; Florez, Jose C.; Gabriel, Stacey B.; Getz, Gad; Glatt, Stephen J.; Hultman, Christina M.; Kathiresan, Sekar; Laakso, Markku; McCarroll, Steven; McCarthy, Mark I.; McGovern, Dermot; McPherson, Ruth; Neale, Benjamin M.; Palotie, Aarno; Purcell, Shaun M.; Saleheen, Danish; Scharf, Jeremiah M.; Sklar, Pamela; Sullivan, Patrick F.; Tuomilehto, Jaakko; Tsuang, Ming T.; Watkins, Hugh C.; Wilson, James G.; Daly, Mark J.; MacArthur, Daniel G.; Abboud, H. E.; Abecasis, G.; Aguilar-Salinas, C. A.; Arellano-Campos, O.; Atzmon, G.; Aukrust, I.; Barr, C. L.; Bell, G. I.; Bergen, S.; Bjørkhaug, L.; Blangero, J.; Bowden, D. W.; Budman, C. L.; Burtt, N. P.; Centeno-Cruz, F.; Chambers, J. C.; Chambert, K.; Clarke, R.; Collins, R.; Coppola, G.; Córdova, E. J.; Cortes, M. L.; Cox, N. J.; Duggirala, R.; Farrall, M.; Fernandez-Lopez, J. C.; Fontanillas, P.; Frayling, T. M.; Freimer, N. B.; Fuchsberger, C.; García-Ortiz, H.; Goel, A.; Gómez-Vázquez, M. J.; González-Villalpando, M. E.; González-Villalpando, C.; Grados, M. A.; Groop, L.; Haiman, C. A.; Hanis, C. L.; Hattersley, A. T.; Henderson, B. E.; Hopewell, J. C.; Huerta-Chagoya, A.; Islas-Andrade, S.; Jacobs, S. B.; Jalilzadeh, S.; Jenkinson, C. P.; Moran, J.; Jiménez-Morale, S.; Kähler, A.; King, R. A.; Kirov, G.; Kooner, J. S.; Kyriakou, T.; Lee, J. Y.; Lehman, D. M.; Lyon, G.; MacMahon, W.; Magnusson, P. K.; Mahajan, A.; Marrugat, J.; Martínez-Hernández, A.; Mathews, C. A.; McVean, G.; Meigs, J. B.; Meitinger, T.; Mendoza-Caamal, E.; Mercader, J. M.; Mohlke, K. L.; Moreno-Macías, H.; Morris, A. P.; Najmi, L. A.; Njølstad, P. R.; O'Donovan, M. C.; Ordóñez-Sánchez, M. L.; Owen, M. J.; Park, T.; Pauls, D. L.; Posthuma, D.; Revilla-Monsalve, C.; Riba, L.; Ripke, S.; Rodríguez-Guillén, R.; Rodríguez-Torres, M.; Sandor, P.; Seielstad, M.; Sladek, R.; Soberón, X.; Spector, T. D.; Tai, S. E.; Teslovich, T. M.; Walford, G.; Wilkens, L. R.; Williams, A. L.
In: Nature, Vol. 536, No. 7616, 17.08.2016, p. 285-291.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Analysis of protein-coding genetic variation in 60,706 humans
AU - Lek, Monkol
AU - Karczewski, Konrad J.
AU - Minikel, Eric V.
AU - Samocha, Kaitlin E.
AU - Banks, Eric
AU - Fennell, Timothy
AU - O'Donnell-Luria, Anne H.
AU - Ware, James S.
AU - Hill, Andrew J.
AU - Cummings, Beryl B.
AU - Tukiainen, Taru
AU - Birnbaum, Daniel P.
AU - Kosmicki, Jack A.
AU - Duncan, Laramie E.
AU - Estrada, Karol
AU - Zhao, Fengmei
AU - Zou, James
AU - Pierce-Hoffman, Emma
AU - Berghout, Joanne
AU - Cooper, David N.
AU - Deflaux, Nicole
AU - DePristo, Mark
AU - Do, Ron
AU - Flannick, Jason
AU - Fromer, Menachem
AU - Gauthier, Laura
AU - Goldstein, Jackie
AU - Gupta, Namrata
AU - Howrigan, Daniel
AU - Kiezun, Adam
AU - Kurki, Mitja I.
AU - Moonshine, Ami Levy
AU - Natarajan, Pradeep
AU - Orozco, Lorena
AU - Peloso, Gina M.
AU - Poplin, Ryan
AU - Rivas, Manuel A.
AU - Ruano-Rubio, Valentin
AU - Rose, Samuel A.
AU - Ruderfer, Douglas M.
AU - Shakir, Khalid
AU - Stenson, Peter D.
AU - Stevens, Christine
AU - Thomas, Brett P.
AU - Tiao, Grace
AU - Tusie-Luna, Maria T.
AU - Weisburd, Ben
AU - Won, Hong Hee
AU - Yu, Dongmei
AU - Altshuler, David M.
AU - Ardissino, Diego
AU - Boehnke, Michael
AU - Danesh, John
AU - Donnelly, Stacey
AU - Elosua, Roberto
AU - Florez, Jose C.
AU - Gabriel, Stacey B.
AU - Getz, Gad
AU - Glatt, Stephen J.
AU - Hultman, Christina M.
AU - Kathiresan, Sekar
AU - Laakso, Markku
AU - McCarroll, Steven
AU - McCarthy, Mark I.
AU - McGovern, Dermot
AU - McPherson, Ruth
AU - Neale, Benjamin M.
AU - Palotie, Aarno
AU - Purcell, Shaun M.
AU - Saleheen, Danish
AU - Scharf, Jeremiah M.
AU - Sklar, Pamela
AU - Sullivan, Patrick F.
AU - Tuomilehto, Jaakko
AU - Tsuang, Ming T.
AU - Watkins, Hugh C.
AU - Wilson, James G.
AU - Daly, Mark J.
AU - MacArthur, Daniel G.
AU - Abboud, H. E.
AU - Abecasis, G.
AU - Aguilar-Salinas, C. A.
AU - Arellano-Campos, O.
AU - Atzmon, G.
AU - Aukrust, I.
AU - Barr, C. L.
AU - Bell, G. I.
AU - Bergen, S.
AU - Bjørkhaug, L.
AU - Blangero, J.
AU - Bowden, D. W.
AU - Budman, C. L.
AU - Burtt, N. P.
AU - Centeno-Cruz, F.
AU - Chambers, J. C.
AU - Chambert, K.
AU - Clarke, R.
AU - Collins, R.
AU - Coppola, G.
AU - Córdova, E. J.
AU - Cortes, M. L.
AU - Cox, N. J.
AU - Duggirala, R.
AU - Farrall, M.
AU - Fernandez-Lopez, J. C.
AU - Fontanillas, P.
AU - Frayling, T. M.
AU - Freimer, N. B.
AU - Fuchsberger, C.
AU - García-Ortiz, H.
AU - Goel, A.
AU - Gómez-Vázquez, M. J.
AU - González-Villalpando, M. E.
AU - González-Villalpando, C.
AU - Grados, M. A.
AU - Groop, L.
AU - Haiman, C. A.
AU - Hanis, C. L.
AU - Hattersley, A. T.
AU - Henderson, B. E.
AU - Hopewell, J. C.
AU - Huerta-Chagoya, A.
AU - Islas-Andrade, S.
AU - Jacobs, S. B.
AU - Jalilzadeh, S.
AU - Jenkinson, C. P.
AU - Moran, J.
AU - Jiménez-Morale, S.
AU - Kähler, A.
AU - King, R. A.
AU - Kirov, G.
AU - Kooner, J. S.
AU - Kyriakou, T.
AU - Lee, J. Y.
AU - Lehman, D. M.
AU - Lyon, G.
AU - MacMahon, W.
AU - Magnusson, P. K.
AU - Mahajan, A.
AU - Marrugat, J.
AU - Martínez-Hernández, A.
AU - Mathews, C. A.
AU - McVean, G.
AU - Meigs, J. B.
AU - Meitinger, T.
AU - Mendoza-Caamal, E.
AU - Mercader, J. M.
AU - Mohlke, K. L.
AU - Moreno-Macías, H.
AU - Morris, A. P.
AU - Najmi, L. A.
AU - Njølstad, P. R.
AU - O'Donovan, M. C.
AU - Ordóñez-Sánchez, M. L.
AU - Owen, M. J.
AU - Park, T.
AU - Pauls, D. L.
AU - Posthuma, D.
AU - Revilla-Monsalve, C.
AU - Riba, L.
AU - Ripke, S.
AU - Rodríguez-Guillén, R.
AU - Rodríguez-Torres, M.
AU - Sandor, P.
AU - Seielstad, M.
AU - Sladek, R.
AU - Soberón, X.
AU - Spector, T. D.
AU - Tai, S. E.
AU - Teslovich, T. M.
AU - Walford, G.
AU - Wilkens, L. R.
AU - Williams, A. L.
N1 - Publisher Copyright: © 2016 Macmillan Publishers Limited. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2016/8/17
Y1 - 2016/8/17
N2 - Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
AB - Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
UR - http://www.scopus.com/inward/record.url?scp=84982253941&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84982253941&partnerID=8YFLogxK
U2 - 10.1038/nature19057
DO - 10.1038/nature19057
M3 - Article
C2 - 27535533
AN - SCOPUS:84982253941
VL - 536
SP - 285
EP - 291
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7616
ER -