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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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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. |
format | Online Article Text |
id | pubmed-7680112 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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