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bioRxiv · 10.64898/2026.10.06.756961

Exitron-type splicing of intrinsically disordered regions recurs across jawed vertebrates despite sequence divergence: donor-proximal cis control in TARDBP

Yamagishi, T.·Koide, S.·Toyama, G.·Washida, A.·Okawara, S.·Yoshida, K.·Onodera, O.·Sugai, A.
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Abstract

Intrinsically disordered regions (IDRs) mediate molecular interactions but can also promote aberrant self-association. Using donors embedded within IDR-coding sequences, exitron-type splicing can remove these sequences, giving them both protein-coding and splice-regulatory roles. Yet IDR amino-acid sequences often diverge rapidly, raising the question of whether and how their coding sequences support IDR-removing splicing across species. Using RNA-seq data from jawed vertebrates, we identified events predicted to remove most of an IDR while preserving annotated structured regions. Across species, donor-flanking nucleotide identity exceeded expectations from synonymous alternatives encoding the same amino-acid sequence. TARDBP, which encodes TDP-43, provided a model for examining how coding sequences both encode IDRs and regulate exitron-type splicing. Sequence-divergent vertebrate TARDBP terminal regions supported this splicing in human cells. In teleosts, TARDBP ohnologs (tardbpa and tardbpb) encoded compositionally similar disordered tails but differed markedly in IDR-removing exitron-type splicing. Reciprocal donor-proximal substitutions in zebrafish minigenes redirected donor choice and altered the balance between IDR-retaining and IDR-removing transcripts. In corresponding reporters, these substitutions altered protein-product balance and cytoplasmic puncta formation. These findings show that IDR-removing exitron-type splicing can recur despite sequence divergence and that donor-proximal TARDBP sequences both encode IDR segments and regulate IDR inclusion, linking RNA processing to protein behavior.

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Yamagishi, T., Koide, S., Toyama, G., Washida, A., Okawara, S., Yoshida, K., Onodera, O., Sugai, A.. 2026-10-06. Exitron-type splicing of intrinsically disordered regions recurs across jawed vertebrates despite sequence divergence: donor-proximal cis control in TARDBP. https://doi.org/10.64898/2026.10.06.756961

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