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A genomic mutational constraint map using variation in 76,156 human genomes.
Chen, Siwei; Francioli, Laurent C; Goodrich, Julia K; Collins, Ryan L; Kanai, Masahiro; Wang, Qingbo; Alföldi, Jessica; Watts, Nicholas A; Vittal, Christopher; Gauthier, Laura D; Poterba, Timothy; Wilson, Michael W; Tarasova, Yekaterina; Phu, William; Grant, Riley; Yohannes, Mary T; Koenig, Zan; Farjoun, Yossi; Banks, Eric; Donnelly, Stacey; Gabriel, Stacey; Gupta, Namrata; Ferriera, Steven; Tolonen, Charlotte; Novod, Sam; Bergelson, Louis; Roazen, David; Ruano-Rubio, Valentin; Covarrubias, Miguel; Llanwarne, Christopher; Petrillo, Nikelle; Wade, Gordon; Jeandet, Thibault; Munshi, Ruchi; Tibbetts, Kathleen; O'Donnell-Luria, Anne; Solomonson, Matthew; Seed, Cotton; Martin, Alicia R; Talkowski, Michael E; Rehm, Heidi L; Daly, Mark J; Tiao, Grace; Neale, Benjamin M; MacArthur, Daniel G; Karczewski, Konrad J.
Afiliación
  • Chen S; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. siwei@broadinstitute.org.
  • Francioli LC; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. siwei@broadinstitute.org.
  • Goodrich JK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Collins RL; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Kanai M; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wang Q; 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.
  • Watts NA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
  • Vittal C; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gauthier LD; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Poterba T; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wilson MW; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
  • Tarasova Y; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Phu W; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Grant R; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Yohannes MT; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Koenig Z; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Farjoun Y; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Banks E; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Donnelly S; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Gabriel S; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Gupta N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ferriera S; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tolonen C; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Novod S; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bergelson L; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Roazen D; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
  • Ruano-Rubio V; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Covarrubias M; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Llanwarne C; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Petrillo N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wade G; Richards Lab, Lady Davis Institute, Montreal, Quebec, Canada.
  • Jeandet T; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Munshi R; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tibbetts K; Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • O'Donnell-Luria A; Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Solomonson M; Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Seed C; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Martin AR; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Talkowski ME; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Rehm HL; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Daly MJ; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Tiao G; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Neale BM; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • MacArthur DG; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Karczewski KJ; Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature ; 625(7993): 92-100, 2024 Jan.
Article en En | MEDLINE | ID: mdl-38057664
ABSTRACT
The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Genoma Humano / Genómica / Modelos Genéticos / Mutación Límite: Humans Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Genoma Humano / Genómica / Modelos Genéticos / Mutación Límite: Humans Idioma: En Revista: Nature Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos