Journal article

MTR3D: identifying regions within protein tertiary structures under purifying selection

Michael Silk, Douglas E Pires, Carlos HM Rodrigues, Elston N D'Souza, Moshe Olshansky, Natalie Thorne, David B Ascher

NUCLEIC ACIDS RESEARCH | OXFORD UNIV PRESS | Published : 2021

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 high..

View full abstract

Grants

Awarded by Newton Fund RCUK-CONFAP Grant by the Medical Research Council


Awarded by Jack Brockhoff Foundation (JBF)


Awarded by National Health and Medical Research Council (NHMRC) of Australia


Awarded by Wellcome Trust


Funding Acknowledgements

C.H.M.R. is funded by a Melbourne Research Scholarship; D.B.A. and D.E.V.P. were funded by a Newton Fund RCUK-CONFAP Grant awarded by the Medical Research Council [MR/M026302/1]; Jack Brockhoff Foundation (JBF) [4186, 2016]; D.B.A., M.S. and D.E.V.P. were funded by an Investigator Grant from the National Health and Medical Research Council (NHMRC) of Australia [GNT1174405]; D.B.A. was supported by the Wellcome Trust [200814/Z/16/Z]; Victorian Government's Operational Infrastructure Support Program (in part). This research has been conducted using theUKBiobankResource under Application Number 50000. Funding for open access charge: MRC.