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Open Access Methodology article

EFIN: predicting the functional impact of nonsynonymous single nucleotide polymorphisms in human genome

Shuai Zeng, Jing Yang, Brian Hon-Yin Chung, Yu Lung Lau and Wanling Yang*

Author Affiliations

Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, 5 Sassoon Road, Hong Kong, China

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BMC Genomics 2014, 15:455  doi:10.1186/1471-2164-15-455

Published: 10 June 2014

Abstract

Background

Predicting the functional impact of amino acid substitutions (AAS) caused by nonsynonymous single nucleotide polymorphisms (nsSNPs) is becoming increasingly important as more and more novel variants are being discovered. Bioinformatics analysis is essential to predict potentially causal or contributing AAS to human diseases for further analysis, as for each genome, thousands of rare or private AAS exist and only a very small number of which are related to an underlying disease. Existing algorithms in this field still have high false prediction rate and novel development is needed to take full advantage of vast amount of genomic data.

Results

Here we report a novel algorithm that features two innovative changes: 1. making better use of sequence conservation information by grouping the homologous protein sequences into six blocks according to evolutionary distances to human and evaluating sequence conservation in each block independently, and 2. including as many such homologous sequences as possible in analyses. Random forests are used to evaluate sequence conservation in each block and to predict potential impact of an AAS on protein function. Testing of this algorithm on a comprehensive dataset showed significant improvement on prediction accuracy upon currently widely-used programs. The algorithm and a web-based application tool implementing it, EFIN (Evaluation of Functional Impact of Nonsynonymous SNPs) were made freely available (http://paed.hku.hk/efin/ webcite) to the public.

Conclusions

Grouping homologous sequences into different blocks according to the evolutionary distance of the species to human and evaluating sequence conservation in each group independently significantly improved prediction accuracy. This approach may help us better understand the roles of genetic variants in human disease and health.

Keywords:
Coding mutation; nsSNP; Amino acid conservation; Functional impact; Evolutionary distance