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Alternative splicing contributes to plasticity and regulatory divergence in locally adapted house mice from the Americas
Journal article   Open access   Peer reviewed

Alternative splicing contributes to plasticity and regulatory divergence in locally adapted house mice from the Americas

Megan Phifer-Rixey, Joseph R Ward and Katya L Mack
Molecular biology and evolution, v 43(1), msaf332
01 Jan 2026
DOI: https://doi.org/10.1093/molbev/msaf332
PMID: 41457019
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1093/molbev/msaf332View
Published, Version of Record (VoR) Open

Abstract

Adaptation, Physiological - genetics Alternative Splicing Animals Diet, High-Fat Female Gene-Environment Interaction Genetic Variation Male Mice - genetics
Alternative splicing is a major driver of transcriptome and proteome variation, but the role of alternative splicing in regulatory evolution is often overlooked. Alternative splicing can also contribute to phenotypic plasticity, which may be critical when taxa colonize new environments. Here, we investigate variation in alternative splicing among new wild-derived strains of mice from different climates in the Americas on both a standard and high-fat diet. We show that alternative splicing is widespread and highly context-dependent, underscoring its potential as a substrate for adaptation and plasticity. Comparisons between strains on different diets revealed abundant gene-by-environment interactions affecting alternative splicing. Most genes showed strain- and sex-specific diet responses, highlighting the importance of incorporating sex, genetic diversity, and environmental variation in studies of gene regulation. More often than not, genes that were differentially spliced between strains were not differentially expressed, adding to evidence that the 2 regulatory mechanisms often act independently. Moreover, patterns of expression and network analyses suggest that the 2 mechanisms differ in pleiotropic constraint. Importantly, divergence in alternative splicing was predominantly driven by cis-regulatory changes. However, trans changes affecting splicing may be central to plasticity, as they were impacted more by environmental variation. Finally, we performed scans for selection and found that, while genes with splicing divergence more often co-localized with genomic outliers associated with metabolic traits, they were not enriched for genomic outliers. Overall, our results provide evidence that alternative splicing plays an important role in gene regulation in house mice, contributing to divergence and plasticity.

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Evolutionary Biology
Genetics & Heredity
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