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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Predicting survival in head and neck squamous cell carcinoma from TP53 mutation
David L. Masica,Shuli Li,Christopher Douville,Judith Manola,Robert L. Ferris,Barbara Burtness,Arlene A. Forastiere,Wayne M. Koch,Christine H. Chung,Rachel Karchin,Rachel Karchin +10 more
TL;DR: Assessment of the ability of 15 different methods to predict HNSCC patient survival from TP53 mutation and clinical data from patients enrolled in E4393 by the Eastern Cooperative Oncology Group (ECOG), which investigated whether TP53 mutations in surgical margins were predictive of disease recurrence.
Journal ArticleDOI
Importance of Genetic Studies in Consanguineous Populations for the Characterization of Novel Human Gene Functions
A. Mesut Erzurumluoglu,A. Mesut Erzurumluoglu,Hashem A. Shihab,Santiago Rodriguez,Tom R. Gaunt,Ian N. M. Day +5 more
TL;DR: It is suggested that studying consanguineous populations “as a whole” can speed up the characterisation of novel gene functions as well as indicating nonessential genes and/or regions in the human genome.
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POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.
Tomohiro Kitano,Maiko Miyagawa,Shin-ya Nishio,Hideaki Moteki,Kiyoshi Oda,Kenji Ohyama,Hiromitsu Miyazaki,Hiroshi Hidaka,Ken-ichi Nakamura,Takaaki Murata,Rina Matsuoka,Yoko Ohta,Nobuhiro Nishiyama,Kozo Kumakawa,Sakiko Furutate,Satoshi Iwasaki,Takechiyo Yamada,Yumi Ohta,Natsumi Uehara,Yoshihiro Noguchi,Shin-ichi Usami +20 more
TL;DR: It was showed that variants in POU4F3 were a common cause of autosomal dominant HL, and individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants.
Journal ArticleDOI
WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis.
Masafumi Kobayashi,Maiko Miyagawa,Shin-ya Nishio,Hideaki Moteki,Taro Fujikawa,Kenji Ohyama,Hirofumi Sakaguchi,Ikuyo Miyanohara,Akiko Sugaya,Yasushi Naito,Shinya Morita,Yukihiko Kanda,Masahiro Takahashi,Kotaro Ishikawa,Yuki Nagano,Tetsuya Tono,Chie Oshikawa,Chiharu Kihara,Haruo Takahashi,Yoshihiro Noguchi,Shin-ichi Usami +20 more
TL;DR: New insights are provided into the audiovestibular phenotypes in patients with WFS1 mutations and in the onset of HL as well as in the presence of progressive HL and tinnitus.
Journal ArticleDOI
PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing
Jennifer R. Taube,Karen Sperle,Linda Banser,Pavel Seeman,Barbra Charina V. Cavan,James Y. Garbern,Grace M. Hobson,Grace M. Hobson,Grace M. Hobson +8 more
TL;DR: In this paper, the authors investigated the ability of sequences throughout PLP1 intron 3 to regulate alternative splicing using a splicing minigene construct transfected into the oligodendrocyte cell line, Oli-neu.
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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