Article (Scientific journals)
Comprehensive characterization of amino acidpositions in protein structures reveals moleculareffect of missense variants
iqbal, Sumaiya; Perez-Palma, Eduardo; Jespersen, Jakob B. et al.
2020In Proceedings of the National Academy of Sciences of the United States of America
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Keywords :
missense variant interpretation; machine learning; 3D mutational hotspot; protein structure and function; disease variation effect
Abstract :
[en] Interpretation of the colossal number of genetic variants identified from sequencing applications is one of the major bottlenecks in clinical genetics, with the inference of the effect of amino acid-substituting missense variations on protein structure and function being especially challenging. Here we characterize the three-dimensional (3D) amino acid positions affected in pathogenic and population variants from 1,330 disease-associated genes using over 14,000 experimentally solved human protein structures. By measuring the statistical burden of variations (i.e., point mutations) from all genes on 40 3D protein features, accounting for the structural, chemical, and functional context of the variations’ positions, we identify features that are generally associated with pathogenic and population missense variants. We then perform the same amino acid-level analysis individually for 24 protein functional classes, which reveals unique characteristics of the positions of the altered amino acids: We observe up to 46% divergence of the class-specific features from the general characteristics obtained by the analysis on all genes, which is consistent with the structural diversity of essential regions across different protein classes. We demonstrate that the function-specific 3D features of the variants match the readouts of mutagenesis experiments for BRCA1 and PTEN, and positively correlate with an independent set of clinically interpreted pathogenic and benign missense variants. Finally, we make our results available through a web server to foster accessibility and downstream research. Our findings represent a crucial step toward translational genetics, from highlighting the impact of mutations on protein structure to rationalizing the variants’ pathogenicity in terms of the perturbed molecular mechanisms.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
iqbal, Sumaiya
Perez-Palma, Eduardo
Jespersen, Jakob B.
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Hoksza, David ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Heyne, Henrike O.
Ahmed, Shehab S.
Rifat, Zaara T.
Rahman, M. Sohel
Lage, Kasper
Palotie, Aarno
Cottrell, Jeffrey R.
Wagner, Florence F.
Daly, Mark J.
Camphell, Arthur J.
Lal, Dennis
More authors (6 more) Less
External co-authors :
yes
Language :
English
Title :
Comprehensive characterization of amino acidpositions in protein structures reveals moleculareffect of missense variants
Publication date :
26 October 2020
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
1091-6490
Publisher :
National Academy of Sciences, Washington DC, United States - District of Columbia
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR11264123 - Ncer-pd, 2015 (01/01/2015-30/11/2020) - Rejko Krüger
Funders :
FNR/DFG Mitochondrial Risk factors in Parkinson disease (MiRisk-PD, Grant C17/BM/11676395)
Available on ORBilu :
since 26 October 2020

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