title: The intolerance to functional genetic variation of protein domains predicts the localization of pathogenic mutations within genes.
abstract: Ranking human genes based on their tolerance to functional genetic variation can greatly facilitate patient genome interpretation. It is well established, however, that different parts of proteins can have different functions, suggesting that it will ultimately be more informative to focus attention on functionally distinct portions of genes. Here we evaluate the intolerance of genic sub-regions using two biological sub-region classifications. We show that the intolerance scores of these sub-regions significantly correlate with reported pathogenic mutations. This observation extends the utility of intolerance scores to indicating where pathogenic mutations are mostly likely to fall within genes.
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY, USA. abg2164@columbia.edu.|Program in Computational Biology and Bioinformatics, Duke University, Durham, NC, USA. abg2164@columbia.edu.
authors.forename: Ayal B
authors.initials: AB
authors.lastname: Gussow
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY, USA. sp3347@cumc.columbia.edu.|Department of Medicine, The University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, VIC, Australia. sp3347@cumc.columbia.edu.
authors.forename: Slavé
authors.initials: S
authors.lastname: Petrovski
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY, USA. qw2192@cumc.columbia.edu.
authors.forename: Quanli
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA. andrew.s.allen@duke.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Allen
authors.affiliation: Institute for Genomic Medicine, Columbia University, New York, NY, USA. dg2875@cumc.columbia.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D005091:Exons / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics*