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This article is part of the supplement: Genetic Analysis Workshop 17: Unraveling Human Exome Data

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Prioritizing single-nucleotide variations that potentially regulate alternative splicing

Mingxiang Teng1, Yadong Wang1*, Guohua Wang1, Jeesun Jung23, Howard J Edenberg2345, Jeremy R Sanford6 and Yunlong Liu235*

Author Affiliations

1 School of Computer Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, China

2 Department of Medical and Molecular Genetics, Indiana University School of Medicine, 410 West 10th Street, Suite 5000, Indianapolis, IN 46202, USA

3 Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 410 West 10th Street, Suite 5000, Indianapolis, IN 46202, USA

4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS 4053, Indianapolis, IN 46202, USA

5 Center for Medical Genomics, Indiana University School of Medicine, 1345 West 16th Street, Indianapolis, IN 46202, USA

6 Department of Molecular, Cellular, and Developmental Biology, University of California, 1101 Pacific Avenue, Suite 200, Santa Cruz, CA 95060, USA

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BMC Proceedings 2011, 5(Suppl 9):S40  doi:10.1186/1753-6561-5-S9-S40

Published: 29 November 2011


Recent evidence suggests that many complex diseases are caused by genetic variations that play regulatory roles in controlling gene expression. Most genetic studies focus on nonsynonymous variations that can alter the amino acid composition of a protein and are therefore believed to have the highest impact on phenotype. Synonymous variations, however, can also play important roles in disease pathogenesis by regulating pre-mRNA processing and translational control. In this study, we systematically survey the effects of single-nucleotide variations (SNVs) on binding affinity of RNA-binding proteins (RBPs). Among the 10,113 synonymous SNVs identified in 697 individuals in the 1,000 Genomes Project and distributed by Genetic Analysis Workshop 17 (GAW17), we identified 182 variations located in alternatively spliced exons that can significantly change the binding affinity of nine RBPs whose binding preferences on 7-mer RNA sequences were previously reported. We found that the minor allele frequencies of these variations are similar to those of nonsynonymous SNVs, suggesting that they are in fact functional. We propose a workflow to identify phenotype-associated regulatory SNVs that might affect alternative splicing from exome-sequencing-derived genetic variations. Based on the affecting SNVs on the quantitative traits simulated in GAW17, we further identified two and four functional SNVs that are predicted to be involved in alternative splicing regulation in traits Q1 and Q2, respectively.