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RNA-sequencing analysis of gene expression evolution in mole rats

ABSTRACT: Understanding the genetic basis of phenotypic adaptation poses a significant challenge in evolutionary genomics. Mutations in regulatory sequences that influence gene expression, such as tissue-specific enhancers, are widely recognised as key drivers of phenotypic evolution. However, because cis-regulatory elements evolve rapidly, linking changes in their activity to corresponding changes in gene expression across species is challenging. This study aims to identify and connect accelerated evolution (shifts) in gene expression and cis-regulatory elements, and assess their potential impact on phenotypic adaptations. Using African mole-rats as a model, we profiled gene expression in heart and liver tissues across two mole-rat species and two rodent outgroups, and applied a phylogenetic comparative approach to identify genes that have undergone expression shifts within the mole-rat clade and specific genera. The identified genes are associated with known adaptative functions, including metabolic rewiring such as increased glycolysis in the heart. We then integrated evolution of gene expression and the activity of promoters and enhancers into a unified phylogenetic framework by: (1) characterising the regulatory landscape around transcription start sites of genes with shifted expression across species, and (2) directly integrating regulatory and gene expression shifts. With both approaches, we identified a coordinated shift in regulatory activity and expression levels. Genes showing expression shifts enriched for shifted cis-regulatory elements, and the number of shifted promoters and enhancers correlated with the magnitude of gene expression changes. Our findings represent one of the first systematic demonstrations of parallel evolution acting on gene regulation and expression. Together, these results provide new insights into the molecular mechanisms underlying phenotypic evolution in mole-rats, and highlight the value of combining regulatory and expression-level data in comparative genomics.

ORGANISM(S): Mus musculus Heterocephalus glaber Cavia porcellus Fukomys damarensis

PROVIDER: GSE304970 | GEO | 2026/08/03

REPOSITORIES: GEO

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Project description:Changes in gene regulation have long been though to underlie most phenotypic differences between species. Subterranean rodents, and in particular the naked mole-rat (NMR), have attracted substantial attention due to their proposed phenotypic adaptations, which include hypoxia tolerance, metabolic changes and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the NMR, the mole-rat clade or also present in other mammals. Here, we undertook a comparative genomics approach to identify genome-wide promoter and enhancer regions harbouring epigenomic hallmarks of regulatory activity, in heart and liver from two mole-rat species (NMR and DMR) and two rodent outgroups. To identify promoters and enhancers displaying robust shifts in regulatory activity in the mole-rat clade, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous locations, while accounting for phylogenetic distance and inter-species variation. This method identified thousands of orthologous promoter and enhancer regions with increased activity in ancestral or single-species mole-rat branches, as well as hundreds of promoters and enhancers with reduced activity in mole-rats versus other rodents. These elements underlie both shared tissue-specific changes in gene regulation associated with mole-rat evolution, which include metabolic and functional adaptations in heart and liver. Moreover, by comparing mole-rat specific changes in promoters and enhancers between ancestral and single-species branches, our data revealed a number of candidate pathways with stepwise regulatory changes during mole-rat evolution. Lastly, we analysed the genomic properties of non-alignable promoters and enhancers in mole-rats, and report (i) their overlap with specific repetitive elements and transcription factor binding sites; and (ii) their association with metabolic gene functions. On the whole, these comparative analyses reveal mole-rat specific epigenomic changes across orthologous and non-mappable promoters and enhancers - which inform previously reported mole-rat adaptations from a gene regulation perspective.

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RNA-sequencing analysis of gene expression evolution in mole rats

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