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EvoTol: a protein-sequence based evolutionary intolerance framework for disease-gene prioritization

Title: EvoTol: a protein-sequence based evolutionary intolerance framework for disease-gene prioritization
Authors: Rackham, OJL
Shihab, HA
Johnson, MR
Petretto, E
Item Type: Journal Article
Abstract: Methods to interpret personal genome sequences are increasingly required. Here, we report a novel framework (EvoTol) to identify disease-causing genes using patient sequence data from within protein coding-regions. EvoTol quantifies a gene's intolerance to mutation using evolutionary conservation of protein sequences and can incorporate tissue-specific gene expression data. We apply this framework to the analysis of whole-exome sequence data in epilepsy and congenital heart disease, and demonstrate EvoTol's ability to identify known disease-causing genes is unmatched by competing methods. Application of EvoTol to the human interactome revealed networks enriched for genes intolerant to protein sequence variation, informing novel polygenic contributions to human disease.
Issue Date: 29-Dec-2014
Date of Acceptance: 5-Dec-2014
URI: http://hdl.handle.net/10044/1/57229
DOI: https://dx.doi.org/10.1093/nar/gku1322
ISSN: 0305-1048
Publisher: Oxford University Press
Journal / Book Title: Nucleic Acids Research
Volume: 43
Issue: 5
Copyright Statement: © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
DE-NOVO MUTATIONS
INTERACTION NETWORKS
ATRIAL-FIBRILLATION
DATABASE
EPILEPSY
EXPRESSION
RECEPTORS
COMPLEXES
HEART
MICE
Amino Acid Sequence
Computational Biology
Evolution, Molecular
Exome
Genetic Predisposition to Disease
Heart Defects, Congenital
Humans
Mutation
Phylogeny
Polymorphism, Single Nucleotide
Protein Interaction Maps
Proteins
Reproducibility of Results
Sequence Analysis, DNA
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Developmental Biology
Publication Status: Published
Article Number: ARTN e33
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine



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