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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Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer.
Katrin Schmitt,Britta Molfenter,Natalia Koerich Laureano,Natalia Koerich Laureano,Natalia Koerich Laureano,Bouchra Tawk,Matthias Bieg,Xavier Pastor Hostench,Dieter Weichenhan,Nina D. Ullrich,Viny Shang,Daniela Richter,Fabian Stögbauer,Lea Schroeder,Bianca De Bem Prunes,Fernanda Visioli,Pantelis Varvaki Rados,Adriana Jou,Adriana Jou,Michaela Plath,P.A. Federspil,Julia Thierauf,J Döscher,Stephanie E. Weissinger,Thomas K. Hoffmann,Steffen Wagner,Claus Wittekindt,Naveed Ishaque,Roland Eils,Jens Peter Klussmann,Dana Holzinger,Christoph Plass,Amir Abdollahi,Kolja Freier,Wilko Weichert,Karim Zaoui,Jochen Hess,Jochen Hess +37 more
TL;DR: The data indicate that impaired RYR2 function by either somatic mutation or epigenetic silencing is a common event in HNSCC pathogenesis and detection of RYP2 expression and/or promoter methylation might enable risk assessment for malignant conversion of dysplastic lesions.
Journal ArticleDOI
Structure-Based Analysis of Single Nucleotide Variants in the Renin-Angiotensinogen Complex
TL;DR: A structure-based analysis of the effect of single nucleotide variants (SNVs) on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants for further inhibitor design purposes.
Journal ArticleDOI
Personal Genome Project UK (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 Marks,L McCormack,Ismail Moghul,Nikolas Pontikos,Rajanayagam S,K Rana,M Semega-Janneh,Colin P. Smith,L Strom,S Umur,Amy P. Webster,Elizabeth H. Williams,K Wint,John N. Wood +39 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.
Journal ArticleDOI
High Prevalence of Diabetes-Predisposing Variants in MODY Genes Among Danish Women With Gestational Diabetes Mellitus.
Anette P. Gjesing,Gao Rui,Jeannet Lauenborg,Christian Theil Have,Mette Hollensted,Ehm A. Andersson,Niels Grarup,Jihua Sun,Shi Quan,Ivan Brandslund,Peter Damm,Oluf Pedersen,Jun Wang,Torben Hansen +13 more
TL;DR: Almost 6% of Danish women with diet-treated GDM have possibly pathogenic variants in GCK, HNF1A, H NF4A,HNF1B, or INS, which means women at high risk of developing diabetes after pregnancy should be considered among women with GDM.
Journal ArticleDOI
The New Immortalized Uroepithelial Cell Line HBLAK Contains Defined Genetic Aberrations Typical of Early Stage Urothelial Tumors.
Michèle J. Hoffmann,Evangelia A. Koutsogiannouli,Margaretha A. Skowron,Maria Pinkerneil,Günter Niegisch,Artur Brandt,Stefanie Stepanow,Harald Rieder,Wolfgang A. Schulz +8 more
TL;DR: In this article, the authors describe characteristics of the new spontaneously immortalized cell line HBLAK derived from a primary culture of uroepithelial cells, and characterize the utility and limitations of this cell line as an urothelial cell culture model.
References
More filters
Journal ArticleDOI
Basic Local Alignment Search Tool
TL;DR: A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score.
Journal ArticleDOI
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.
Stephen F. Altschul,Thomas L. Madden,Alejandro A. Schäffer,Jinghui Zhang,Zheng Zhang,Webb Miller,David J. Lipman +6 more
TL;DR: A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original.
Journal ArticleDOI
Gene Ontology: tool for the unification of biology
M Ashburner,Catherine A. Ball,Judith A. Blake,David Botstein,Heather Butler,J. M. Cherry,Allan Peter Davis,Kara Dolinski,Selina S. Dwight,J.T. Eppig,Midori A. Harris,David P. Hill,Laurie Issel-Tarver,Andrew Kasarskis,Suzanna E. Lewis,John C. Matese,Joel E. Richardson,M. Ringwald,Gerald M. Rubin,Gavin Sherlock +19 more
TL;DR: The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing.
Journal ArticleDOI
The Pfam protein families database
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
TL;DR: The definition and use of family-specific, manually curated gathering thresholds are explained and some of the features of domains of unknown function (also known as DUFs) are discussed, which constitute a rapidly growing class of families within Pfam.