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Inferring the molecular and phenotypic impact of amino acid variants with MutPred2

Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns...

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Autores principales: Pejaver, Vikas, Urresti, Jorge, Lugo-Martinez, Jose, Pagel, Kymberleigh A., Lin, Guan Ning, Nam, Hyun-Jun, Mort, Matthew, Cooper, David N., Sebat, Jonathan, Iakoucheva, Lilia M., Mooney, Sean D., Radivojac, Predrag
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680112/
https://www.ncbi.nlm.nih.gov/pubmed/33219223
http://dx.doi.org/10.1038/s41467-020-19669-x
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author Pejaver, Vikas
Urresti, Jorge
Lugo-Martinez, Jose
Pagel, Kymberleigh A.
Lin, Guan Ning
Nam, Hyun-Jun
Mort, Matthew
Cooper, David N.
Sebat, Jonathan
Iakoucheva, Lilia M.
Mooney, Sean D.
Radivojac, Predrag
author_facet Pejaver, Vikas
Urresti, Jorge
Lugo-Martinez, Jose
Pagel, Kymberleigh A.
Lin, Guan Ning
Nam, Hyun-Jun
Mort, Matthew
Cooper, David N.
Sebat, Jonathan
Iakoucheva, Lilia M.
Mooney, Sean D.
Radivojac, Predrag
author_sort Pejaver, Vikas
collection PubMed
description Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants.
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spelling pubmed-76801122020-11-24 Inferring the molecular and phenotypic impact of amino acid variants with MutPred2 Pejaver, Vikas Urresti, Jorge Lugo-Martinez, Jose Pagel, Kymberleigh A. Lin, Guan Ning Nam, Hyun-Jun Mort, Matthew Cooper, David N. Sebat, Jonathan Iakoucheva, Lilia M. Mooney, Sean D. Radivojac, Predrag Nat Commun Article Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants. Nature Publishing Group UK 2020-11-20 /pmc/articles/PMC7680112/ /pubmed/33219223 http://dx.doi.org/10.1038/s41467-020-19669-x Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pejaver, Vikas
Urresti, Jorge
Lugo-Martinez, Jose
Pagel, Kymberleigh A.
Lin, Guan Ning
Nam, Hyun-Jun
Mort, Matthew
Cooper, David N.
Sebat, Jonathan
Iakoucheva, Lilia M.
Mooney, Sean D.
Radivojac, Predrag
Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
title Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
title_full Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
title_fullStr Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
title_full_unstemmed Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
title_short Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
title_sort inferring the molecular and phenotypic impact of amino acid variants with mutpred2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680112/
https://www.ncbi.nlm.nih.gov/pubmed/33219223
http://dx.doi.org/10.1038/s41467-020-19669-x
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