Allele-specific alternative splicing and its functional genetic variants in human tissues

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 splicingaltering 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.

The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype

“…Also, the capture of the host B cell antigen proliferation pathways by EBNA2 [37] likely involves interactions with some host polymorphisms that have little effect on EBV infection, although this is less likely where the SNPs are also associated with MS. The consequences of the allelic imbalance on binding are likely to extend beyond affecting expression levels, as splicing [47] , timing of response, conditions used for testing response and inhibition, and interaction with other genes and genetic variants [48] are all likely to be important. Further, the statistical power to evaluate these effects requires much larger samples than were available for this study.…”

scAllele: A versatile tool for the detection and analysis of variants in scRNA-seq

“…To this end, RNA-seq data have unique advantages given the afforded multilevel information: gene expression, transcript isoforms, and sequence variations. Using bulk RNA-seq, numerous studies leveraged this strength to uncover allelic bias of genetic variants in gene expression or splicing (12,13), which, for example, can lead to discovery of functional cis-acting variants that alter splicing (13)(14)(15)(16). Despite their typical low coverage, scRNA-seq data provide similar multilevel information.…”

d-StructMAn: Containerized structural annotation on the scale from genetic variants to whole proteomes

“…Additional sources of indels are alternatively spliced isoforms that result in retaining or skipping exons or parts of introns in the translated sequence. Alternative splicing is widespread across eukaryotes and human tissues [ 4 ]. UniProt lists an average of approximately 4 isoforms per a protein-coding gene in its reference human proteome.…”