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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Advances and challenges in targeting FGFR signalling in cancer
TL;DR: The increasing understanding of the differences between diverse mechanisms of oncogenic activation of FGFR, and the factors that determine response and resistance to FGFR targeting are discussed.
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Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.
Humsa S. Venkatesh,Tessa Johung,Viola Caretti,Alyssa Noll,Yujie Tang,Surya Nagaraja,Erin M. Gibson,Christopher Mount,Jai S. Polepalli,Siddhartha Mitra,Pamelyn Woo,Robert C. Malenka,Hannes Vogel,Markus Bredel,Parag Mallick,Michelle Monje +15 more
TL;DR: Findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.
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Oncotator: Cancer Variant Annotation Tool
Alex H. Ramos,Lee Lichtenstein,Manaswi Gupta,Michael S. Lawrence,Trevor J. Pugh,Trevor J. Pugh,Gordon Saksena,Matthew Meyerson,Matthew Meyerson,Gad Getz,Gad Getz +10 more
TL;DR: Oncotator is a tool for annotating genomic point mutations and short nucleotide insertions/deletions (indels) with variant‐ and gene‐centric information relevant to cancer researchers that is drawn from 14 different publicly available resources that have been pooled and indexed.
Journal ArticleDOI
Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
Giulio Genovese,Menachem Fromer,Eli A. Stahl,Douglas M. Ruderfer,Kimberly Chambert,Mikael Landén,Jennifer L. Moran,Shaun Purcell,Pamela Sklar,Patrick F. Sullivan,Christina M. Hultman,Steven A. McCarroll,Steven A. McCarroll +12 more
TL;DR: It was found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls, suggesting that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
Journal ArticleDOI
RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues
Keren Yizhak,François Aguet,Jaegil Kim,Julian M. Hess,K Kübler,K Kübler,Jonna Grimsby,Ruslana Frazer,Hailei Zhang,Nicholas J. Haradhvala,Nicholas J. Haradhvala,Daniel Rosebrock,Dimitri Livitz,Xiao Li,Eila Arich-Landkof,Eila Arich-Landkof,Noam Shoresh,Chip Stewart,Ayellet V. Segrè,Ayellet V. Segrè,Ayellet V. Segrè,Philip A. Branton,Paz Polak,Kristin G. Ardlie,Gad Getz +24 more
TL;DR: A new method, called RNA-MuTect, is developed to identify somatic mutations using a tissue-derived RNA sample and its matched-normal DNA, enabling the discovery of most driver events and mutational processes from TCGA tumor RNA data.
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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