title: EvoTol: a protein-sequence based evolutionary intolerance framework for disease-gene prioritization.
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.
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Owen J L
authors.initials: OJ
authors.lastname: Rackham
authors.affiliation: The Medical Research Council Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
authors.forename: Hashem A
authors.initials: HA
authors.lastname: Shihab
authors.affiliation: Division of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, London W12 0NN, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
authors.affiliation: Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore enrico.petretto@duke-nus.edu.sg.
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D019143:Evolution, Molecular; D059472:Exome / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D009154:Mutation; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps / Q000235:genetics; D011506:Proteins / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D011506:Proteins