Allele-specific alternative splicing and its functional genetic variants in human tissues
- Kofi Amoah1,6,
- Yun-Hua Esther Hsiao2,6,
- Jae Hoon Bahn3,6,
- Yiwei Sun3,
- Christina Burghard1,
- Boon Xin Tan3,
- Ei-Wen Yang3 and
- Xinshu Xiao1,2,3,4,5
- 1Bioinformatics Interdepartmental Program, University of California, Los Angeles, California 90095, USA;
- 2Department of Bioengineering, University of California, Los Angeles, California 90095, USA;
- 3Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA;
- 4Molecular Biology Institute, University of California, Los Angeles, California 90095, USA;
- 5Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California 90095, USA
-
↵6 These authors contributed equally to this work.
Abstract
Alternative splicing is an RNA processing mechanism that affects most genes in human, contributing to disease mechanisms and phenotypic diversity. The regulation of splicing involves an intricate network of cis-regulatory elements and trans-acting factors. Due to their high sequence specificity, cis-regulation of splicing can be altered by genetic variants, significantly affecting splicing outcomes. Recently, multiple methods have been applied to understanding the regulatory effects of genetic variants on splicing. However, it is still challenging to go beyond apparent association to pinpoint functional variants. To fill in this gap, we utilized large-scale data sets of the Genotype-Tissue Expression (GTEx) project to study genetically modulated alternative splicing (GMAS) via identification of allele-specific splicing events. We demonstrate that GMAS events are shared across tissues and individuals more often than expected by chance, consistent with their genetically driven nature. Moreover, although the allelic bias of GMAS exons varies across samples, the degree of variation is similar across tissues versus individuals. Thus, genetic background drives the GMAS pattern to a similar degree as tissue-specific splicing mechanisms. Leveraging the genetically driven nature of GMAS, we developed a new method to predict functional splicing-altering variants, built upon a genotype-phenotype concordance model across samples. Complemented by experimental validations, this method predicted >1000 functional variants, many of which may alter RNA-protein interactions. Lastly, 72% of GMAS-associated SNPs were in linkage disequilibrium with GWAS-reported SNPs, and such association was enriched in tissues of relevance for specific traits/diseases. Our study enables a comprehensive view of genetically driven splicing variations in human tissues.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.265637.120.
- Received May 5, 2020.
- Accepted January 14, 2021.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://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/.
