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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Survival of the cheapest: how proteome cost minimization drives evolution.
TL;DR: The authors argued that proteome cost minimization is the dominant, underlying "non-function" selection pressure controlling most of the evolution of already functionally adapted living systems, which has consequences for understanding evolutionary tradeoffs, aging, cancer, and neurodegenerative protein-misfolding diseases.
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A novel machine learning-based approach for the computational functional assessment of pharmacogenomic variants
Maria-Theodora Pandi,Maria Koromina,Iordanis Tsafaridis,Sotirios Patsilinakos,Evangelos Christoforou,Peter J. van der Spek,George P. Patrinos,George P. Patrinos +7 more
TL;DR: This study exploited thoroughly characterized in functional level SNVs within genes involved in drug metabolism and transport, to train a classifier that would categorize novel variants according to their expected effect on protein functionality.
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A Computational Approach to Identify a Potential Alternative Drug With Its Positive Impact Toward PMP22
TL;DR: It is predicted that estradiol could be a potential drug of choice for treating patients with CMT1A which needs larger attention from biologists in the near future.
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Diagnostic yield of clinical exome sequencing as a first-tier genetic test for the diagnosis of genetic disorders in pediatric patients: results from a referral center study.
Jean-Philippe Mergnac,Arnaud Wiedemann,Céline Chéry,Jean-Marie Ravel,Farès Namour,Jean-Louis Guéant,François Feillet,Abderrahim Oussalah +7 more
TL;DR: In this article, the diagnostic yield of clinical exome sequencing (CES) as a first-tier genetic test for diagnosing genetic disorders in 128 consecutive pediatric patients referred to a reference center in the North-East of France for a suspected genetic disorder, mainly an inborn error of metabolism between January 2016 and August 2020.
Journal ArticleDOI
The Functional Significance of Common Polymorphisms in Zinc Finger Transcription Factors
Sarah H. Lockwood,Anna Guan,Abigail S. Yu,Chi Zhang,Artem Zykovich,Ian F Korf,Bruce Rannala,David J. Segal +7 more
TL;DR: The overall conclusion was that common SNPs that alter the DNA-contacting residues of zinc finger transcription factors are unlikely to produce strong trans-eQTLs, consistent with the observations by others that trans- e QTLs in humans tend to be few and weak.
References
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