Show Notes
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:
- article_doi
- article_title
- article_journal
- license
Factual Items Audited:
- Exon creation via transposable elements (TE exonization) contributes new exons (e.g., Alu-derived exons in immune genes like IFNAR2)
- Exon loss or skipping (e.g., TBXT exon 6) can drive phenotypic changes such as tail loss in hominoids
- Splicing-level changes (altered inclusion of exons) can reshape isoform outputs without changing gene presence
- MAPT exon 10 splicing, modulated by MBNL, shifts tau isoform ratios (3R/4R) and is linked to lineage-specific brain features
- Cis-regulatory changes predominantly drive lineage-specific AS patterns; Tc1 mouse study shows human exon splicing is recapitulated by cis elements rather than trans factors
QC result: Pass.
