Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models.
Hashem A. Shihab,Julian Gough,David Neil Cooper,Peter D. Stenson,Gary L A Barker,Keith J. Edwards,Ian N. M. Day,Tom R. Gaunt +7 more
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TLDR
The Functional Analysis Through Hidden Markov Models (FATHMM) software and server is described: a species‐independent method with optional species‐specific weightings for the prediction of the functional effects of protein missense variants, demonstrating that FATHMM can be efficiently applied to high‐throughput/large‐scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations.Abstract:
The rate at which nonsynonymous single nucleotide polymorphisms (nsSNPs) are being identified in the human genome is increasing dramatically owing to advances in whole-genome/whole-exome sequencing technologies. Automated methods capable of accurately and reliably distinguishing between pathogenic and functionally neutral nsSNPs are therefore assuming ever-increasing importance. Here, we describe the Functional Analysis Through Hidden Markov Models (FATHMM) software and server: a species-independent method with optional species-specific weightings for the prediction of the functional effects of protein missense variants. Using a model weighted for human mutations, we obtained performance accuracies that outperformed traditional prediction methods (i.e., SIFT, PolyPhen, and PANTHER) on two separate benchmarks. Furthermore, in one benchmark, we achieve performance accuracies that outperform current state-of-the-art prediction methods (i.e., SNPs&GO and MutPred). We demonstrate that FATHMM can be efficiently applied to high-throughput/large-scale human and nonhuman genome sequencing projects with the added benefit of phenotypic outcome associations. To illustrate this, we evaluated nsSNPs in wheat (Triticum spp.) to identify some of the important genetic variants responsible for the phenotypic differences introduced by intense selection during domestication. A Web-based implementation of FATHMM, including a high-throughput batch facility and a downloadable standalone package, is available at http://fathmm.biocompute.org.uk.read more
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The structural effects of mutations can aid in differential phenotype prediction of beta-myosin heavy chain (Myosin-7) missense variants
Nouf S Al-Numair,Luis R. Lopes,Petros Syrris,Lorenzo Monserrat,Perry M. Elliott,Andrew J. Martin +5 more
TL;DR: This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes.
Journal ArticleDOI
Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation
Mohamed F. Alajmi,Shama Khan,Arunabh Choudhury,Taj Mohammad,Saba Noor,Afzal Hussain,Wenying Lu,Mathew Suji Eapen,Vrushali Chimankar,Vrushali Chimankar,Philip M. Hansbro,Sukhwinder Singh Sohal,Abdelbaset Mohamed Elasbali,Imtaiyaz Hassan +13 more
TL;DR: In this article, three amino acid substitutions, K127M, T256A, and Y298A, were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic simulations for 200 ns.
Posted ContentDOI
A comprehensive analysis of RNA sequences reveals macroscopic somatic clonal expansion across normal tissues
Keren Yizhak,François Aguet,Jaegil Kim,Julian M. Hess,K Kübler,Jonna Grimsby,Ruslana Frazer,Hailei Zhang,Nicholas J. Haradhvala,Daniel Rosebrock,Dimitri Livitz,Xiao Li,Eila Arich-Landkof,Noam Shoresh,Chip Stewart,Segrè Av,Philip A. Branton,Paz Polak,Kristin G. Ardlie,Gad Getz +19 more
TL;DR: This study is the first to analyze a large number of samples across multiple normal tissues, identifying clones with genomic aberrations observed in cancer, and finds that mutation burden is associated with both the age of the individual and tissue proliferation rate.
Journal ArticleDOI
Family-specific analysis of variant pathogenicity prediction tools
TL;DR: A protein family-specific benchmarking of tools for predicting the pathogenicity of single amino acid variants and a functional analysis of the sets of protein domains annotated exclusively by neutral or pathogenic mutations indicates that specific protein functions can be associated with a high or low sensitivity to mutations.
Journal ArticleDOI
Self-regulation of functional pathways by motifs inside the disordered tails of beta-catenin
TL;DR: In this paper, the authors focused on the characterization of sequential, structural, and functional features of the disordered tails of the same beta-catenin molecule, including the Nterminal tail, the middle armadillo domain, and the C-terminal tails.
References
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