Paper published in a journal (Scientific congresses, symposiums and conference proceedings)
Identification and Characterization of Variant Intolerant Sites across Human Protein 3-Dimensional Structures
Iqbal, Sumaiya; Berg Jespersen, Jakob; Perez-Palma, Eduardo et al.
2018In Biophysical Journal, 114 (3, Suppl. 1), p. 664
Peer Reviewed verified by ORBi
 

Files


Full Text
PIIS0006349517348154.pdf
Publisher postprint (47.18 kB)
Request a copy

All documents in ORBilu are protected by a user license.

Send to



Details



Keywords :
3D structure; variants; genetics
Abstract :
[en] The functional interpretation of genetic variation in disease-associated genes is far outpaced by data generation. Existing algorithms for prediction of variant consequences do not adequately distinguish pathogenic variants from benign rare variants. This lack of statistical and bioinformatics analyses, accompanied by an ever-increasing number of identified variants in biomedical research and clinical applications, has become a major challenge. Established methods to predict the functional effect of genetic variation use the degree of amino acid conservation across species in linear protein sequence alignment. More recent methods include the spatial distribution pattern of known patient and control variants. Here, we propose to combine the linear conservation and spatial constrained based scores to devise a novel score that incorporates 3-dimensional structural properties of amino acid residues, such as the solvent-accessible surface area, degree of flexibility, secondary structure propensity and binding tendency, to quantify the effect of amino acid substitutions. For this study, we develop a framework for large-scale mapping of established linear sequence-based paralog and ortholog conservation scores onto the tertiary structures of human proteins. This framework can be utilized to map the spatial distribution of mutations on solved protein structures as well as homology models. As a proof of concept, using a homology model of the human Nav1.2 voltage-gated sodium channel structure, we observe spatial clustering in distinct domains of mutations, associated with Autism Spectrum Disorder (>20 variants) and Epilepsy (>100 variants), that exert opposing effects on channel function. We are currently characterizing all variants (>300k individuals) found in ClinVar, the largest disease variant database, as well as variants identified in >140k individuals from general population. The variant mapping framework and our score, informed with structural information, will be useful in identifying structural motifs of proteins associated with disease risk.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Iqbal, Sumaiya
Berg Jespersen, Jakob
Perez-Palma, Eduardo
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Heyne, Henrike
Lage, Kasper
Steensbjerre Møller, Rikke
Wagner, Florence F.
Daly, Mark
Campbell, Arthur J.
Lal, Dennis
External co-authors :
yes
Language :
English
Title :
Identification and Characterization of Variant Intolerant Sites across Human Protein 3-Dimensional Structures
Publication date :
02 February 2018
Event name :
Biophysical Society Meeting
Event date :
2017
Audience :
International
Journal title :
Biophysical Journal
ISSN :
1542-0086
Publisher :
Biophysical Society, Bethesda, United States - Maryland
Volume :
114
Issue :
3, Suppl. 1
Pages :
p664a
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 10 February 2018

Statistics


Number of views
73 (2 by Unilu)
Number of downloads
0 (0 by Unilu)

WoS citations
 
0

Bibliography


Similar publications



Contact ORBilu