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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Assessing performance of pathogenicity predictors using clinically relevant variant datasets
Adam C. Gunning,Verity Fryer,James Fasham,Andrew H. Crosby,Sian Ellard,Emma L. Baple,Caroline F. Wright +6 more
TL;DR: The results support the adoption of meta-predictors over traditional in silico tools, but do not support a consensus-based approach as in current practice.
Journal ArticleDOI
Development of Bioinformatics Infrastructure for Genomics Research
Nicola Mulder,Ezekiel Adebiyi,Marion O. Adebiyi,Seun Adeyemi,Azza Ahmed,Rehab Ahmed,Bola Akanle,Mohamed Alibi,Don Armstrong,Shaun Aron,Efejiro Ashano,Shakuntala Baichoo,Alia Benkahla,David K. Brown,Emile R. Chimusa,Faisal M. Fadlelmola,Dare Falola,Segun Fatumo,Kais Ghedira,Amel Ghouila,Scott Hazelhurst,Itunuoluwa Isewon,Segun Jung,Samar K. Kassim,Jonathan K. Kayondo,Mamana Mbiyavanga,Ayton Meintjes,Somia Mohammed,Abayomi Mosaku,Ahmed Moussa,Mustafa Muhammd,Zahra Mungloo-Dilmohamud,Oyekanmi Nashiru,Trust Odia,Adaobi Okafor,Olaleye Oladipo,Victor Chukwudi Osamor,Jellili Oyelade,Khalid Sadki,Samson Pandam Salifu,Jumoke Soyemi,Sumir Panji,Fouzia Radouani,Oussama Souiai,Özlem Tastan Bishop +44 more
TL;DR: The infrastructure and how it has affected genomics and bioinformatics research in Africa are described and significantly contributed to the establishment of African scientific networks, data analysis facilities, and training programs.
Journal ArticleDOI
Phyllodes tumors with and without fibroadenoma-like areas display distinct genomic features and may evolve through distinct pathways
Fresia Pareja,Felipe C Geyer,Rajesh Kumar,Pier Selenica,Salvatore Piscuoglio,Salvatore Piscuoglio,Charlotte K.Y. Ng,Charlotte K.Y. Ng,Charlotte K.Y. Ng,Kathleen A. Burke,Marcia Edelweiss,Melissa Murray,Edi Brogi,Britta Weigelt,Jorge S. Reis-Filho +14 more
TL;DR: The data suggest that the development of phyllode tumors might follow two different evolutionary pathways: a MED12-mutant pathway that involves the progression from a fibroadenoma to a malignant phyllodes tumor; and a MED 12-wild-type pathway, where malignantPhyllodes tumors arise de novo through the acquisition of genetic alterations targeting cancer genes.
Journal ArticleDOI
Phosphorylation of the RSRSP stretch is critical for splicing regulation by RNA-Binding Motif Protein 20 (RBM20) through nuclear localization.
Rie Murayama,Mariko Kimura-Asami,Marina Togo-Ohno,Yumiko Yamasaki-Kato,Taeko Naruse,Takeshi Yamamoto,Takeharu Hayashi,Tomohiko Ai,Katherine G. Spoonamore,Richard J. Kovacs,Matteo Vatta,Mai Iizuka,Masumi Saito,Shotaro Wani,Yuichi Hiraoka,Akinori Kimura,Hidehito Kuroyanagi +16 more
TL;DR: In this paper, the authors identify an R634W missense mutation within the stretch and a G1031X nonsense mutation in cohorts of DCM patients and demonstrate that the two serine residues in the RSRSP stretch are constitutively phosphorylated and mutations in the stretch disturb nuclear localization of RBM20.
Journal ArticleDOI
PaPI: pseudo amino acid composition to score human protein-coding variants
TL;DR: PaPI is presented, a new machine-learning approach to classify and score human coding variants by estimating the probability to damage their protein-related function and it is shown how the combination of amphiphilic pseudo amino acid composition, evolutionary conservation and homologous proteins based methods outperforms several prediction algorithms.
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