Alternative splicing is coupled to gene expression in a subset of variably expressed genes

Abstract

Numerous factors regulate alternative splicing of human genes at a co-transcriptional level. However, how alternative splicing depends on the regulation of gene expression is poorly understood. We leveraged data from the Genotype-Tissue Expression (GTEx) project to show a significant association of gene expression and splicing for 6874 (4.9%) of 141,043 exons in 1106 (13.3%) of 8314 genes with substantially variable expression in ten GTEx tissues. About half of these exons demonstrate higher inclusion with higher gene expression, and half demonstrate higher exclusion, with the observed direction of coupling being highly consistent across different tissues and in external datasets. The exons differ with respect to sequence characteristics, enriched sequence motifs, and RNA polymerase II binding. Pro-Seq data suggests that introns downstream of exons displaying coupled expression and splicing are transcribed at a slower rate than downstream introns of other exons. Our findings provide an extensive characterization of a class of exons associated with a coupling of expression and alternative splicing that can be observed in a substantial subset of genes.