The impact of biological sex on alternative splicing

Abstract

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 oestrogen receptor binding sites affect sex-biased AS. We utilize hierarchical Bayesian modelling 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. Alternative splicing (AS), a process by which splice sites are used differentially to create protein diversity, plays an important role in development, 1 disease, 2 and aging. 3 Although some splicing isoforms are produced in the same proportions in all or most cell types, AS is often regulated by developmental or differential cues or in response to external stimuli. 4 Several mechanisms have been demonstrated to regulate AS, although their combinatorial interactions remain poorly understood. Binding of RNA-binding proteins (RBPs) to intronic or exonic cis-acting regulatory sequences may promote or suppress local AS events. 5 Additionally, chromatin-level mechanisms also play a role in AS regulation. Nucleosome density is higher within exons than in introns, suggesting the existence of RNA polymerase II (RNA Pol II)-mediated cross-talk between chromatin structure and exon-intron architecture. 6 Alternative exons with suboptimal splicing signals may require more time to be recognized by the splicing machinery, and faster transcriptional elongation by RNA Pol II may influence exon skipping. 7

Splicing factor gene mutations in acute myeloid leukemia offer additive value if incorporated in current risk classification

“…Several previous studies observed the same association in MDS and AML; however, it did not reach statistical significance in some cases because of small sample numbers. 25,26 Furthermore, it was suggested that sex has an impact on splicing profiles of various tissues, and the degree of global aberrant splicing was reported to be higher in men with MDS compared with women with the same disorder. 8,9 Future studies that are better designed to examine sex-specific genetic backgrounds and clinical associations with SF mutations, including treatment outcome, should be conducted.…”

In Vivo Validation of Alternative FDXR Transcripts in Human Blood in Response to Ionizing Radiation

“…FDXR-206 was the most responsive to IR in men. Sex differences in gene expression have been widely reported [33], and differences in gene variants distribution between genders have also been identified in humans [34,35] and mice [36]. Even though the gender groups were relatively small (n = 5) in the present study, gender bias was examined in eight variants, but no significant differences were identified apart from FDXR-206 at the single highest dose of 4 Gy.…”

A cross-cohort analysis of autosomal DNA methylation sex differences in the term placenta

“…Although 12% of the 65 genes overlapping the 162 DMPs showed sex-specific placental expression, the majority were not significantly differentially expressed by placental sex. This is may be related to the small sample size of the gene expression cohort utilized (n=34), the role of additional factors beyond DNAme in regulating gene expression, and the possibility of alternative splicing and sex-specific isoform expression, which would not be captured in microarray analysis (66). Additionally, sex differences in DNAme at these 162 DMPs may be involved in regulating the expression of genes beyond those they overlap, which would not have been captured in this candidate gene expression analysis.…”