How mobile elements contribute to a new mechanism of splicing
Splicing of RNA has evolved over time to promote diverse functions of the human genome. While we now have a good grasp of how sequences close to exons affect splicing, we do not know much about the effects of sequences that lie deeper within introns.
During my PhD, I became interested in Alu elements which can form loops within RNA transcripts. Alus are short repetitive mobile elements that “retrotranspose” or “copy-and-paste” themselves into the genome. They remain active in the human genome to this day! Lots of work has investigated the impact of these Alu pair loops on immune response since they can be recognized by immune double-stranded RNA sensing elements. Less is known, however, about their involvement in splicing. A recent n=1 case study purpoted the relevance of these Alu pair loops in splicing, specifically in mediating a new mechanism of splicing that involves looping out exons that are flanked by two inverted Alu elements. Even more exciting was that this phenomenon seemed to have influenced the loss of tails in hominoids (i.e. us)!
I love thinking about the shape of the genome and how different elements might interact, so I set out to perform a detailed and systematic analysis of all possible inverted Alu pairs across the human genome.
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Denisko D, Kim J, Ku J, Zhao B, Lee EA.
Inverted Alu repeats in loop-out exon skipping across hominoid evolution.
bioRxiv [Preprint]. 2025 Mar 10:2025.03.07.642063.
doi: 10.1101/2025.03.07.642063. PMID: 40161837; PMCID: PMC11952303.
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I think there’s so much more that can be done here (more features, more interactions, more layers…) so feedback is always welcome :)
References
2025
Inverted Alu repeats in loop-out exon skipping across hominoid evolution
Danielle Denisko, Jeonghyeon Kim, Jayoung Ku, and 2 more authors
Background: Changes in RNA splicing over the course of evolution have profoundly diversified the functional landscape of the human genome. While DNA sequences proximal to intron-exon junctions are known to be critical for RNA splicing, the impact of distal intronic sequences remains underexplored. Emerging evidence suggests that inverted pairs of intronic Alu elements can promote exon skipping by forming RNA stem-loop structures. However, their prevalence and influence throughout evolution remain unknown. Results: Here, we present a systematic analysis of inverted Alu pairs across the human genome to assess their impact on exon skipping through predicted RNA stem-loop formation and their relevance to hominoid evolution. We found that inverted Alu pairs, particularly pairs of AluY-AluSx1 and AluSz-AluSx, are enriched in the flanking regions of skippable exons genome-wide and are predicted to form stable stem-loop structures. Exons defined by weak 3’ acceptor and strong 5’ donor splice sites appear especially prone to this skipping mechanism. Through comparative genome analysis across nine primate species, we identified 67,126 hominoid-specific Alu insertions, primarily from AluY and AluS subfamilies, which form inverted pairs enriched across skippable exons in genes of ubiquitination-related pathways. Experimental validation of exon skipping among several hominoid-specific inverted Alu pairs further reinforced their potential evolutionary significance. Conclusion: This work extends our current knowledge of the roles of RNA secondary structure formed by inverted Alu pairs and details a newly emerging mechanism through which transposable elements have contributed to genomic innovation across hominoid evolution at the transcriptomic level.
@article{IRAlu,author={Denisko, Danielle and Kim, Jeonghyeon and Ku, Jayoung and Zhao, Boxun and Lee, Eunjung Alice},title={{Inverted Alu repeats in loop-out exon skipping across hominoid evolution}},journal={bioRxiv [Preprint]},year={2025},doi={10.1101/2025.03.07.642063},url={https://doi.org/10.1101/2025.03.07.642063},eprint={https://www.biorxiv.org/content/10.1101/2025.03.07.642063v1.full.pdf},}
