294: Alternative splicing, exonization and lineage-specific isoforms: PTBP1, MAPT and TE-derived exons in mammalian evolution

Hunter CE et al., The EMBO Journal, doi:10.1038/s44318-025-00666-z - Review shows how alternative splicing, via TE exonization and cis-regulatory changes and revealed by long-read RNA-seq, reshapes gene regulation and drives phenotypic evolution in mammals. Key terms: alternative splicing, exonization, long-read RNA-seq, microexons, comparative transcriptomics. Study Highlights:This review synthesizes comparative transcriptomic studies across multicellular eukaryotes with emphasis on vertebrates and mammals. It highlights methods including short- and long-read RNA-seq, single-cell transcriptomics, and MS proteomics to map isoform diversity. The authors emphasize that lineage-specific AS is often driven by cis-regulatory changes and exonization of transposable elements, with trans-factor innovations (e.g., SRRM3/4, PTBP1 isoforms) modulating microexons and isoform ratios. Functional examples linking AS to phenotypes include an Alu-derived IFNAR2 decoy receptor reducing JAK/STAT signaling, TNNI3 exon3 loss or skipping associated with extreme heart rates, and hominoid shifts in MAPT exon10 splicing altering tau isoform proportion. Conclusion:Alternative splicing, shaped largely by cis-sequence changes and TE exonization and illuminated by long-read and single-cell transcriptomics, is a flexible evolutionary mechanism that can produce lineage-specific regulatory and phenotypic innovations. Music:Enjoy the music based on this article at the end of the episode. Article title:The splice of life: how alternative splicing shapes regulatory and phenotypic evolution First author:Hunter CE Journal:The EMBO Journal, doi:10.1038/s44318-025-00666-z DOI:10.1038/s44318-025-00666-z Reference:Hunter CE, Xing Y. The splice of life: how alternative splicing shapes regulatory and phenotypic evolution. The EMBO Journal. 2026. https://doi.org/10.1038/s44318-025-00666-z License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/alternative-splicing-exonization-evolution QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-18. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantively audited sections covering splicing mechanisms, exonization and TE-derived exons, three main evolutionary modes of AS, cis vs trans regulation, sequencing technologies (long-read, single-cell, proteomics), and case studies (TBXT tail loss, TNNI3, MAPT). Also reviewed Tc1 humanized mouse results and immune/- transcript topics: Basics of alternative splicing and spliceosome regulation; Exon creation via TE exonization (Alu elements) and exonization examples (IFNAR2); Exon loss and splicing level changes as evolutionary modes; Three case studies: TBXT tail loss via exon skipping; TNNI3 exon 3 loss/skip for high heart rate; MAPT exon 10 splicing and tau isoforms; Cis-regulatory vs trans-acting factors in splicing evolution (Tc1 human chromosome 21 study); Splicing regulators and microexons (SRRM3/4, PTBP1) and their evolutionary implications QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 5- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited: