Alternative splicing modulated by genetic variants demonstrates accelerated evolution regulated by highly conserved proteins

Yun-Hua Esther Hsiao; Jae Hoon Bahn; Xianzhi Lin; Tak-Ming Chan; Rena Wang; Xinshu Xiao

doi:10.1101/gr.193359.115

Alternative splicing modulated by genetic variants demonstrates accelerated evolution regulated by highly conserved proteins

¹Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California 90095, USA;
²Department of Bioengineering, University of California Los Angeles, Los Angeles, California 90095, USA;
³Bioinformatics Interdepartmental Program, University of California Los Angeles, Los Angeles, California 90095, USA;
⁴Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA

Corresponding author: gxxiao{at}ucla.edu

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.

Footnotes

[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.193359.115.

Received April 20, 2015.
Accepted February 17, 2016.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.