Predicting the Functional, Molecular, and Phenotypic Consequences of Amino Acid Substitutions using Hidden Markov Models

TLDR

The rapid increase in identified nonsynonymous SNPs due to genome sequencing demands accurate methods to distinguish pathogenic from neutral variants. We aim to develop FATHMM to predict functional effects of missense variants and to identify key genetic variants underlying domestication‑related phenotypic differences. FATHMM uses hidden Markov models with species‑specific weightings, was evaluated on wheat nsSNPs, and is available as a web server and standalone package. FATHMM achieves higher accuracy than SIFT, PolyPhen, PANTHER, SNPs&GO, and MutPred on two benchmarks and can be applied efficiently to large‑scale sequencing projects with 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.