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A structural variation reference for medical and population genetics.
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; 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.
Afiliação
  • Collins RL; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Brand H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Karczewski KJ; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
  • Zhao X; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Alföldi J; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Francioli LC; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Khera AV; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lowther C; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Gauthier LD; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wang H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Watts NA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Solomonson M; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • O'Donnell-Luria A; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Baumann A; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Munshi R; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Walker M; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Whelan CW; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Huang Y; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Brookings T; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sharpe T; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Stone MR; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Valkanas E; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Fu J; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tiao G; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Laricchia KM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Ruano-Rubio V; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Stevens C; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Gupta N; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Cusick C; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Margolin L; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Taylor KD; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lin HJ; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Rich SS; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Post WS; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Chen YI; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Rotter JI; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Nusbaum C; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Philippakis A; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lander E; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Gabriel S; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Neale BM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Kathiresan S; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
  • Daly MJ; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Banks E; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • MacArthur DG; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Talkowski ME; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature ; 581(7809): 444-451, 2020 05.
Article em En | MEDLINE | ID: mdl-32461652
ABSTRACT
Structural 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Variação Genética / Genoma Humano / Doença / Genética Médica / Genética Populacional Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Variação Genética / Genoma Humano / Doença / Genética Médica / Genética Populacional Idioma: En Ano de publicação: 2020 Tipo de documento: Article