title: regSNPs-splicing: a tool for prioritizing synonymous single-nucleotide substitution.
abstract: While synonymous single-nucleotide variants (sSNVs) have largely been unstudied, since they do not alter protein sequence, mounting evidence suggests that they may affect RNA conformation, splicing, and the stability of nascent-mRNAs to promote various diseases. Accurately prioritizing deleterious sSNVs from a pool of neutral ones can significantly improve our ability of selecting functional genetic variants identified from various genome-sequencing projects, and, therefore, advance our understanding of disease etiology. In this study, we develop a computational algorithm to prioritize sSNVs based on their impact on mRNA splicing and protein function. In addition to genomic features that potentially affect splicing regulation, our proposed algorithm also includes dozens structural features that characterize the functions of alternatively spliced exons on protein function. Our systematical evaluation on thousands of sSNVs suggests that several structural features, including intrinsic disorder protein scores, solvent accessible surface areas, protein secondary structures, and known and predicted protein family domains, show significant differences between disease-causing and neutral sSNVs. Our result suggests that the protein structure features offer an added dimension of information while distinguishing disease-causing and neutral synonymous variants. The inclusion of structural features increases the predictive accuracy for functional sSNV prioritization.
authors.affiliation: School of Informatics and Computing, Indiana University, Bloomington, IN, 47408, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 410 w 10th st, HS 5000, Indianapolis, IN, 46202, USA.
authors.forename: Xinjun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 410 w 10th st, HS 5000, Indianapolis, IN, 46202, USA.|Pattern Recognition and Intelligent System Institute, Automation College, Harbin Engineering University, Harbin, 150001, Heilongjiang, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 410 w 10th st, HS 5000, Indianapolis, IN, 46202, USA.|School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, IN, 46202, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 410 w 10th st, HS 5000, Indianapolis, IN, 46202, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Rao
authors.affiliation: Pattern Recognition and Intelligent System Institute, Automation College, Harbin Engineering University, Harbin, 150001, Heilongjiang, China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Feng
authors.affiliation: School of Information and Communication Technology, Gold Coast Campus, Griffith University, Southport, QLD, 4222, Australia.
authors.forename: Yuedong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mort
authors.affiliation: Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Departments of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Computer Science and Technology, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Clark
authors.initials: C
authors.lastname: Wells
authors.affiliation: Institute for Glycomics and School of Informatics and Communication Technology, Griffith University, Parklands Dr., Southport, QLD, 4215, Australia.
authors.forename: Yaoqi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 410 w 10th st, HS 5000, Indianapolis, IN, 46202, USA. yunliu@iu.edu.|Departments of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. yunliu@iu.edu.|Center for Medical Genomics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. yunliu@iu.edu.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000465:Algorithms; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing / Q000235:genetics*
keywords: Position Specific Score Matrix; Position Weight Matrix; Random Forest; Solvent Accessible Surface Area; Splice Site