ExonImpact: Prioritizing Pathogenic Alternative Splicing Events

Human Mutation
Meng LiYunlong Liu

Abstract

Alternative splicing (AS) is a closely regulated process that allows a single gene to encode multiple protein isoforms, thereby contributing to the diversity of the proteome. Dysregulation of the splicing process has been found to be associated with many inherited diseases. However, among the pathogenic AS events, there are numerous "passenger" events whose inclusion or exclusion does not lead to significant changes with respect to protein function. In this study, we evaluate the secondary and tertiary structural features of proteins associated with disease-causing and neutral AS events, and show that several structural features are strongly associated with the pathological impact of exon inclusion. We further develop a machine-learning-based computational model, ExonImpact, for prioritizing and evaluating the functional consequences of hitherto uncharacterized AS events. We evaluated our model using several strategies including cross-validation, and data from the Gene-Tissue Expression (GTEx) and ClinVar databases. ExonImpact is freely available at http://watson.compbio.iupui.edu/ExonImpact.

Citations

Feb 26, 2003·Genes & Development·Nuno André Faustino, Thomas A Cooper
Nov 9, 2010·Nature Methods·Yarden KatzChristopher B Burge
Jan 3, 2012·Journal of Biomolecular Structure & Dynamics·Tuo ZhangYaoqi Zhou
Jul 4, 2012·Molecular Cell·Jonathan D EllisBenjamin J Blencowe
May 30, 2013·Nature Genetics·GTEx Consortium
Nov 16, 2013·Nucleic Acids Research·Melissa J LandrumDonna R Maglott
Nov 2, 2014·Nucleic Acids Research·Kristian A GrayElspeth A Bruford
Dec 7, 2014·Proceedings of the National Academy of Sciences of the United States of America·Shihao ShenYi Xing
Oct 4, 2015·Nature·1000 Genomes Project ConsortiumGonçalo R Abecasis
Nov 19, 2015·Nucleic Acids Research·Kai-Yao HuangTzong-Yi Lee
Dec 18, 2015·Nucleic Acids Research·Robert D FinnAlex Bateman

Related Concepts

Study
Exons
Genes
Pathogenic Organism
Tertiary Protein Structure
Protein Function
Cross Validation
Brain Diseases, Metabolic, Inborn
Evaluation
Proteome

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