The impact of sex on alternative splicing

Over 95% of human genes undergo alternative splicing (AS) in a developmental, tissue-specific, or signal transduction-dependent manner. A number of factors including binding of cis-acting sequences by RNA-binding proteins (RBPs) are known to affect AS, but the combinatorial mechanisms leading to the distribution of spliced isoforms remain largely unstudied. Here, in 9011 samples from 532 individuals across 53 tissues from the Genotype-Tissue Expression (GTEx) resource, we identified 4,135 genes with sex-biased expression and 5,925 sex-biased AS events. We find that factors including escape from X-chromosomal inactivation, presence of Alu elements, and estrogen receptor binding sites affect sex-biased AS. We utilize hierarchical Bayesian modeling to characterize the interactions of exon skipping, gene expression, and RBPs, and demonstrate two categories of sex-biased AS that differ with respect to splice site scores, gene expression, RBP levels, and skipping/inclusion ratio.