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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Journal ArticleDOI
Mitochondrial DNA mutations are associated with ulcerative colitis preneoplasia but tend to be negatively selected in cancer
Kathryn T. Baker,Daniela Nachmanson,Shilpa Kumar,Mary J. Emond,Cigdem Himmetoglu Ussakli,Teresa A. Brentnall,Scott R. Kennedy,Rosa Ana Risques +7 more
TL;DR: While mtDNA mutations might contribute to early ulcerative colitis tumorigenesis, they appear to be selected against in cancer, suggesting that functional mitochondria might be required for malignant transformation in ulceratives colitis.
Book ChapterDOI
Computational approaches and resources in single amino acid substitutions analysis toward clinical research.
TL;DR: An overview of the existing repositories of variant databases and computational methods in predicting the effects of functional SAPs on protein stability, structure, function, drug response, and protein dynamics is described.
Journal ArticleDOI
Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes
Line Skotte,João Fadista,Jonas Bybjerg-Grauholm,Vivek Appadurai,Michael S. Hildebrand,Thomas Hansen,Karina Banasik,Jakob Grove,Clara Albiñana,Frank Geller,Carmen Flores Bjurström,Bjarni J. Vilhjálmsson,Matthew Coleman,John A. Damiano,Rosemary Burgess,Ingrid E. Scheffer,Ole Birger Pedersen,Christian Erikstrup,David Westergaard,Kaspar René Nielsen,Erik Sørensen,Mie Topholm Bruun,Xueping Liu,Henrik Hjalgrim,Tune H. Pers,Preben Bo Mortensen,Ole Mors,Merete Nordentoft,Julie Werenberg Dreier,Anders D. Børglum,J. E. J. Christensen,David M. Hougaard,Alfonso Buil,Anders Hviid,Mads Melbye,Henrik Ullum,Samuel F. Berkovic,Thomas Werge,Bjarke Feenstra +38 more
TL;DR: This largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes.
Journal ArticleDOI
Delineating the relationship between amyotrophic lateral sclerosis and frontotemporal dementia: Sequence and structure-based predictions.
TL;DR: A comprehensive understanding of the mechanism of ALS is provided and the significance of structure-energy based studies in differentiating ALS and FTD mutations is illustrated.
Journal ArticleDOI
Familial Cancer Variant Prioritization Pipeline version 2 (FCVPPv2) applied to a papillary thyroid cancer family.
Abhishek Kumar,Obul Reddy Bandapalli,Nagarajan Paramasivam,Sara Giangiobbe,Chiara Diquigiovanni,Elena Bonora,Roland Eils,Roland Eils,Matthias Schlesner,Kari Hemminki,Kari Hemminki,Asta Försti,Asta Försti +12 more
TL;DR: Improvements are presented in this pedigree-based familial cancer variant prioritization pipeline referred as FCVPPv2, including 12 tools for evaluating deleteriousness and 5 intolerance scores for missense variants, a comprehensive approach for prediction of predisposing variants for high-risk cancer families.
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