MTR3D: identifying regions within protein tertiary structures under purifying selection.

ABSTRACT: The identification of disease-causal variants is non-trivial. By mapping population variation from over 448,000 exome and genome sequences to over 81,000 experimental structures and homology models of the human proteome, we have calculated both regional intolerance to missense variation (Missense Tolerance Ratio, MTR), using a sliding window of 21-41 codons, and introduce a new 3D spatial intolerance to missense variation score (3D Missense Tolerance Ratio, MTR3D), using spheres of 5-8 Å. We show that the MTR3D is less biased by regions with limited data and more accurately identifies regions under purifying selection than estimates relying on the sequence alone. Intolerant regions were highly enriched for both ClinVar pathogenic and COSMIC somatic missense variants (Mann-Whitney U test P

SUBMITTER: Silk M 

PROVIDER: S-EPMC8265191 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature