Alu-mediated RNA duplexes are associated with widespread exon skipping across primate transcriptomes

Alternative splicing patterns have diverged rapidly during vertebrate evolution. By integrating genome-wide predictions of stable RNA duplexes, alternative splicing profiles, and proximity ligation-detection of RNA-RNA interactions, we observe that the majority of long-range intronic RNA duplexes are mediated by inverted Alu-repeat elements, and that these structures are associated with divergent exon skipping patterns in primates. We further observe evidence that the RNA binding proteins HNRNPC, ILF2 and ILF3 directly control Alu duplex-associated alternative splicing levels. Collectively, our results provide evidence that Alu-derived RNA duplexes modulated by RNA binding proteins have contributed to the remarkable divergence in alternative splicing patterns during mammalian evolution.