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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Case Report: Compound Heterozygous Variants in MOCS3 Identified in a Chinese Infant With Molybdenum Cofactor Deficiency
TL;DR: In this article, the authors described the clinical presentations of an infant, born to a non-consanguineous healthy family, diagnosed as having MOCS3 variants caused molybdenum cofactor deficiency and showing typical features of Moco deficiency including severe neurologic symptoms and cystic encephalomalacia in the brain MRI, resulting in neonatal death.
Performance-Based Modeling of Spatial and Temporal Variability of Treated Wastewater Quality for Improved Nutrient Management
TL;DR: In this article, a hierarchical modeling approach is used to diagnose the variability of US wastewater treatment facility compliance with existing ammonia discharge permit limits using Discharge Monthly Report (DMR) data for the period 2004 2008 from a sample of 106 municipal plants.
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PGP-UK: a research and citizen science hybrid project in support of personalized medicine
Stephan Beck,Alison Berner,Bignell G,Bond M,Callanan Mj,Olga Chervova,Lucia Conde,Manuel Corpas,Simone Ecker,Hannah R Elliott,Fioramonti Sa,Adrienne M. Flanagan,Gaentzsch R,David Graham,D Gribbin,José Afonso Guerra-Assunção,Rifat Hamoudi,Harding,Harrison Pl,Javier Herrero,Hofmann J,E Jones,Saif Khan,Jane Kaye,Kerr P,Emanuele Libertini,L McCormack,Ismail Moghul,Nikolas Pontikos,Rajanayagam S,K Rana,M Semega-Janneh,Colin P. Smith,L Strom,S Umur,Amy P. Webster,K Wint,John N. Wood +37 more
TL;DR: The findings demonstrate that citizen science-based approaches like PGP-UK have an important role to play in the public awareness, acceptance and implementation of genomics and personalized medicine.
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Prediction of deleterious nonsynonymous SNPs by integrating multiple classifiers – An application to neurodegenerative diseases
TL;DR: This logistic regression model is proposed to classify deleterious missense mutation from a list of nonsynonymous SNPs – where multiple features (i.e. rank scores of 18 classifiers) from dbNSFP v2.5 were combined for 44,702 UniProt human polymorphisms and disease mutations.
Journal ArticleDOI
Comprehensive in silico mutational-sensitivity analysis of PTEN establishes signature regions implicated in pathogenesis of Autism Spectrum Disorders.
TL;DR: An extensively studied cancer and Autism Spectrum Disorders (ASD) gene PTEN provided an exclusive opportunity to map its mutational-landscape, compare and establish plausible genotypic predictors of ASD-associated phenotypic outcomes, and an exhaustive in silico analysis on 4252 SNPs identified increasedmutational-density in exon7.
References
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Marco Punta,Penny Coggill,Ruth Y. Eberhardt,Jaina Mistry,John Tate,Chris Boursnell,Ningze Pang,Kristoffer Forslund,Goran Ceric,Jody Clements,Andreas Heger,Liisa Holm,Erik L. L. Sonnhammer,Sean R. Eddy,Alex Bateman,Robert D. Finn +15 more
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