# The splice of life: how alternative splicing shapes regulatory and phenotypic evolution

**Authors:** Carissa Emerson Hunter, Yi Xing

PMC · DOI: 10.1038/s44318-025-00666-z · The EMBO Journal · 2026-01-16

## TL;DR

This paper reviews how alternative splicing creates diversity in gene products and shapes evolution across species.

## Contribution

It synthesizes recent insights on how AS mechanisms drive functional and phenotypic evolution in multicellular organisms.

## Key findings

- AS generates lineage-specific transcriptomic and proteomic changes.
- Recent studies reveal how AS shapes phenotypic evolution in mammals.
- Technological advances are transforming our understanding of splicing evolution.

## Abstract

Alternative splicing (AS) is a key mechanism for generating regulatory and phenotypic diversity in multicellular eukaryotes. Large-scale comparative transcriptomic studies have revealed that AS leads to lineage-specific and tissue-specific transcriptomic and proteomic changes, underscoring its contribution to the evolution of gene products and functions. In this review, we highlight the patterns and mechanisms of AS evolution across species, exploring how technological advancements are transforming our understanding of splicing evolution. Furthermore, we discuss mechanistic and functional insights from recent studies, including groundbreaking discoveries on how AS has shaped phenotypic evolution in mammals.

How alternative splicing contributes to functional divergence and organismal evolution.

## Full-text entities

- **Genes:** TNNI3 (troponin I3, cardiac type) [NCBI Gene 7137] {aka CMD1FF, CMD2A, CMH7, RCM1, TNNC1, cTnI}, PTBP1 (polypyrimidine tract binding protein 1) [NCBI Gene 5725] {aka HNRNP-I, HNRNPI, HNRPI, PTB, PTB-1, PTB-T}, BMP4 (bone morphogenetic protein 4) [NCBI Gene 652] {aka BMP2B, BMP2B1, MCOPS6, OFC11, ZYME}, IFNAR2 (interferon alpha and beta receptor subunit 2) [NCBI Gene 3455] {aka IFN-R, IFN-R-2, IFN-alpha-REC, IFNABR, IFNARB, IMD45}, SRRM4 (serine/arginine repetitive matrix 4) [NCBI Gene 84530] {aka KIAA1853, MU-MB-2.76, nSR100}, TMEM191C (transmembrane protein 191C) [NCBI Gene 645426], IL13RA1 (interleukin 13 receptor subunit alpha 1) [NCBI Gene 3597] {aka CD213A1, CT19, IL-13Ra, NR4}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, IL4R (interleukin 4 receptor) [NCBI Gene 3566] {aka CD124, IL-4RA, IL4RA}, SRRM3 (serine/arginine repetitive matrix 3) [NCBI Gene 222183], LINC02605 (long intergenic non-protein coding RNA 2605) [NCBI Gene 112935892] {aka AS, IL-7, IL-7-AS}, CMAHP (cytidine monophospho-N-acetylneuraminic acid hydroxylase, pseudogene) [NCBI Gene 8418] {aka CMAH, CSAH}, LPAR2 (lysophosphatidic acid receptor 2) [NCBI Gene 9170] {aka EDG-4, EDG4, LPA-2, LPA2}, MBNL1 (muscleblind like splicing regulator 1) [NCBI Gene 4154] {aka EXP, MBNL}
- **Diseases:** tauopathies (MESH:D024801), AS (MESH:C536589)
- **Chemicals:** calcium (MESH:D002118), Neu5Gc (-)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], Cercopithecidae (monkey, family) [taxon 9527], Gallus gallus (bantam, species) [taxon 9031], Homo sapiens (human, species) [taxon 9606], Drosophila melanogaster (fruit fly, species) [taxon 7227]

## Full text

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## Figures

6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12992808/full.md

## References

1 references — full list in the complete paper: https://tomesphere.com/paper/PMC12992808/full.md

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Source: https://tomesphere.com/paper/PMC12992808