title: Alternative splicing modulated by genetic variants demonstrates accelerated evolution regulated by highly conserved proteins.
abstract: Identification of functional genetic variants and elucidation of their regulatory mechanisms represent significant challenges of the post-genomic era. A poorly understood topic is the involvement of genetic variants in mediating post-transcriptional RNA processing, including alternative splicing. Thus far, little is known about the genomic, evolutionary, and regulatory features of genetically modulated alternative splicing (GMAS). Here, we systematically identified intronic tag variants for genetic modulation of alternative splicing using RNA-seq data specific to cellular compartments. Combined with our previous method that identifies exonic tags for GMAS, this study yielded 622 GMAS exons. We observed that GMAS events are highly cell type independent, indicating that splicing-altering genetic variants could have widespread function across cell types. Interestingly, GMAS genes, exons, and single-nucleotide variants (SNVs) all demonstrated positive selection or accelerated evolution in primates. We predicted that GMAS SNVs often alter binding of splicing factors, with SRSF1 affecting the most GMAS events and demonstrating global allelic binding bias. However, in contrast to their GMAS targets, the predicted splicing factors are more conserved than expected, suggesting that cis-regulatory variation is the major driving force of splicing evolution. Moreover, GMAS-related splicing factors had stronger consensus motifs than expected, consistent with their susceptibility to SNV disruption. Intriguingly, GMAS SNVs in general do not alter the strongest consensus position of the splicing factor motif, except the more than 100 GMAS SNVs in linkage disequilibrium with polymorphisms reported by genome-wide association studies. Our study reports many GMAS events and enables a better understanding of the evolutionary and regulatory features of this phenomenon.
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California 90095, USA; Department of Bioengineering, University of California Los Angeles, Los Angeles, California 90095, USA;
authors.forename: Yun-Hua Esther
authors.initials: YH
authors.lastname: Hsiao
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California 90095, USA;
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Bahn
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California 90095, USA;
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California 90095, USA;
authors.forename: Tak-Ming
authors.initials: TM
authors.lastname: Chan
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California 90095, USA;
authors.forename: Rena
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California 90095, USA; Department of Bioengineering, University of California Los Angeles, Los Angeles, California 90095, USA; Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California 90095, USA; Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Xinshu
authors.initials: X
authors.lastname: Xiao
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005091:Exons; D005786:Gene Expression Regulation; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011323:Primates / Q000235:genetics; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D015203:Reproducibility of Results
chemical_list: D011506:Proteins; D012313:RNA