The landscape of regional missense mutational intolerance quantified from 125,748 exomes
The landscape of regional missense mutational intolerance quantified from 125,748 exomes
Abstract Missense variants can have a range of functional impacts depending on factors such as the specific amino acid substitution and location within the gene. To interpret their deleteriousness, studies have sought to identify regions within genes that are specifically intolerant of missense variation1–12. Here, we leverage the patterns of rare missense variation in 125,748 individuals in the Genome Aggregation Database (gnomAD)13 against a null mutational model to identify transcripts that display regional differences in missense constraint. Missense-depleted regions are enriched for ClinVar14 pathogenic variants, de novo missense variants from individuals with neurodevelopmental disorders (NDDs)15,16, and complex trait heritability. Following ClinGen calibration recommendations for the ACMG/AMP guidelines, we establish that regions with less than 20% of their expected missense variation achieve moderate support for pathogenicity. We create a missense deleteriousness metric (MPC) that incorporates regional constraint and outperforms other deleteriousness scores at stratifying case and control de novo missense variation, with a strong enrichment in NDDs. These results provide additional tools to aid in missense variant interpretation.
Compitello John、gnomAD Consortium、Poterba Timothy、Panchal Ruchit、Liao Calwing、Abderrazzaq Haneen、Ye Robert、Kosmicki Jack A.、Grant Riley H.、Phu William、Wilson Michael W.、Goldstein Daniel、Vittal Christopher、Watts Nicholas A.、MacArthur Daniel G.、O?ˉDonnell-Luria Anne、Karczewski Konrad J.、Laricchia Kristen M.、Tiao Grace、Goodrich Julia K.、Baxter Samantha、Talkowski Michael E.、Neale Benjamin M.、Schultz Patrick、Goldstein Jacqueline I.、Daly Mark J.、Samocha Kaitlin E.、Weisburd Ben、Chao Katherine R.、Solomonson Matthew、Wang Lily、Radivojac Predrag、Rehm Heidi L.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard||Department of Medicine, Harvard Medical SchoolKhoury College of Computer Sciences, Northeastern UniversityAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardBioinformatics and Integrative Genomics Program, Harvard Medical School||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Centre for Population Genomics, Garvan Institute of Medical Research and UNSW Sydney||Centre for Population Genomics, Murdoch Children?ˉs Research InstituteProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General Hospital||Division of Genetics and Genomics, Boston Children?ˉs HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Stanley Center for Psychiatric Research, Broad Institute of MIT and HarvardProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Institute for Molecular Medicine Finland (FIMM)Program in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General Hospital||Analytic and Translational Genetics Unit, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Analytic and Translational Genetics Unit, Massachusetts General HospitalProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General Hospital||Bioinformatics and Integrative Genomics Program, Harvard Medical SchoolKhoury College of Computer Sciences, Northeastern UniversityProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard||Center for Genomic Medicine, Massachusetts General Hospital
基础医学遗传学分子生物学
Compitello John,gnomAD Consortium,Poterba Timothy,Panchal Ruchit,Liao Calwing,Abderrazzaq Haneen,Ye Robert,Kosmicki Jack A.,Grant Riley H.,Phu William,Wilson Michael W.,Goldstein Daniel,Vittal Christopher,Watts Nicholas A.,MacArthur Daniel G.,O?ˉDonnell-Luria Anne,Karczewski Konrad J.,Laricchia Kristen M.,Tiao Grace,Goodrich Julia K.,Baxter Samantha,Talkowski Michael E.,Neale Benjamin M.,Schultz Patrick,Goldstein Jacqueline I.,Daly Mark J.,Samocha Kaitlin E.,Weisburd Ben,Chao Katherine R.,Solomonson Matthew,Wang Lily,Radivojac Predrag,Rehm Heidi L..The landscape of regional missense mutational intolerance quantified from 125,748 exomes[EB/OL].(2025-03-28)[2025-07-16].https://www.biorxiv.org/content/10.1101/2024.04.11.588920.点此复制
评论