Universität zu Köln

Iqbal, Sumaiya ORCID: 0000-0001-7700-4374, Perez-Palma, Eduardo ORCID: 0000-0003-0546-5141, Jespersen, Jakob B., May, Patrick ORCID: 0000-0001-8698-3770, Hoksza, David, Heyne, Henrike O., Ahmed, Shehab S., Rifat, Zaara T., Rahman, M. Sohel ORCID: 0000-0001-9419-6478, Lage, Kasper, Palotie, Aarno, Cottrell, Jeffrey R., Wagner, Florence F., Daly, Mark J., Campbell, Arthur J. and Lal, Dennis (2020). Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants. Proc. Natl. Acad. Sci. U. S. A., 117 (45). S. 28201 - 28212. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Iqbal, Sumaiya UNSPECIFIED orcid.org/0000-0001-7700-4374 UNSPECIFIED Perez-Palma, Eduardo UNSPECIFIED orcid.org/0000-0003-0546-5141 UNSPECIFIED Jespersen, Jakob B. UNSPECIFIED UNSPECIFIED UNSPECIFIED May, Patrick UNSPECIFIED orcid.org/0000-0001-8698-3770 UNSPECIFIED Hoksza, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Heyne, Henrike O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ahmed, Shehab S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rifat, Zaara T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahman, M. Sohel UNSPECIFIED orcid.org/0000-0001-9419-6478 UNSPECIFIED Lage, Kasper UNSPECIFIED UNSPECIFIED UNSPECIFIED Palotie, Aarno UNSPECIFIED UNSPECIFIED UNSPECIFIED Cottrell, Jeffrey R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagner, Florence F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Daly, Mark J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Campbell, Arthur J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-311728
DOI:	10.1073/pnas.2002660117
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	117
Number:	45
Page Range:	S. 28201 - 28212
Date:	2020
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DISEASE; MUTATIONS; SEQUENCE; PREDICTION; PATHOGENICITY; EVOLUTION; REGIONS; VERSION; SITES Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31172