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
Exome sequencing identifies SLC26A4, GJB2, SCARB2 and DUOX2 mutations in 2 siblings with Pendred syndrome in a Malaysian family
Yock Ping Chow,Nor Azian Abdul Murad,Zamzureena Mohd Rani,Jia-Shiun Khoo,Pei-Sin Chong,Loo-Ling Wu,Rahman Jamal +6 more
TL;DR: In this article, the authors described the possible PDS causal mutations in a Malaysian family with 2 daughters diagnosed with bilateral hearing loss and hypothyroidism, and proposed that PDS in this family could be a polygenic disorder which possibly arises from a combination of heterozygous mutations in SLC26A4, GJB2 and SCARB2 which associated with deafness, as well as compound heter-ozygous DUOX2 mutations associated with thyroid dysfunction.
Journal ArticleDOI
Structural and functional analysis of disease-associated mutations in GOT1 gene: An in silico study.
Sidharth Saxena,Sai Achyuth B,T. P. Krishna Murthy,Vivek Chandramohan,Arvind Kumar Yadav,Tiratha Raj Singh +5 more
TL;DR: In this article, a comprehensive in-silico analysis of the disease-associated single nucleotide polymorphisms (SNPs) of human Gutamic-oxaloacetic transaminase 1 (GOT1) was carried out.
Book ChapterDOI
A Broad Overview of Computational Methods for Predicting the Pathophysiological Effects of Non-synonymous Variants
TL;DR: An exhaustive and up-to-dated survey of the algorithms and software packages conceived for the estimation of the putative pathogenicity of mutations, along with a description of the most popular mutation datasets that these tools used as training sets.
Journal ArticleDOI
A pan-cancer analysis reveals nonstop extension mutations causing SMAD4 tumour suppressor degradation.
Sonam Dhamija,Sonam Dhamija,Chul Min Yang,Jeanette Seiler,Ksenia Myacheva,Ksenia Myacheva,Maïwen Caudron-Herger,Angela Wieland,Mahmoud Abdelkarim,Yogita Sharma,Marisa Riester,Matthias Groß,Jochen Maurer,Jochen Maurer,Sven Diederichs,Sven Diederichs +15 more
TL;DR: It is discovered that nonstop mutations can be functionally important in cancer and characterize their loss-of-function impact on the tumour suppressor SMAD4.
Journal ArticleDOI
Clinical Impact of Detecting Low-Frequency Variants in Cell-Free DNA on Treatment of Castration-Resistant Prostate Cancer.
Kei Mizuno,Takayuki Sumiyoshi,Takatsugu Okegawa,Naoki Terada,Satoshi Ishitoya,Yu Miyazaki,Takahiro Kojima,Hiromichi Katayama,Naohiro Fujimoto,Shingo Hatakeyama,Masaki Shiota,Koji Yoshimura,Yoshiyuki Matsui,Shintaro Narita,Hiroaki Matsumoto,Ryoma Kurahashi,Hidenori Kanno,Katsuhiro Ito,Hiroko Kimura,Yuki Kamiyama,Takuro Sunada,Takayuki Goto,Takashi Kobayashi,Hitoshi Yamada,Norihiko Tsuchiya,Tomomi Kamba,Hideyasu Matsuyama,Tomonori Habuchi,Masatoshi Eto,Chikara Ohyama,Akihiro Ito,Hiroyuki Nishiyama,Hiroshi Okuno,Toshiyuki Kamoto,Akihiro Fujimoto,Osamu Ogawa,Shusuke Akamatsu +36 more
TL;DR: In this paper, low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC) were detected using an in-house pipeline.
References
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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.