Mole-Rat Genes Evolving Faster Than Expected Reveal Secrets of Subterranean Life

Beneath the sun-baked soils of eastern and southern Africa, a family of rodents has quietly rewritten the rules of mammalian life. Naked mole-rats resist cancer, tolerate near-anoxic conditions and barely age. Damaraland mole-rats dig elaborate tunnel networks and live in eusocial colonies more reminiscent of insects than of mammals. Yet how these remarkable traits are encoded in their genomes has remained largely mysterious. A new study published in BMC Biology now offers one of the most detailed looks to date at the molecular machinery behind the mole-rat way of life, and its findings suggest that natural selection has acted as much on how genes are switched on and off as on the genes themselves.

The research, led by Maëlle Daunesse, Eulalie Liorzou, Elise Parey, Diego Villar and Camille Berthelot, tackles a problem that has long frustrated evolutionary biologists: distinguishing adaptive changes in gene expression from the background noise of neutral evolution. Over millions of years, transcriptomes—the complete sets of RNA molecules produced by tissues—accumulated countless random shifts in expression level. Most of these shifts mean nothing for survival. A minority, however, were driven by natural selection because they improved some aspect of physiology. Separating the two categories with confidence has been notoriously difficult, blurring the adaptive signatures written into mammalian genomes.

To cut through that noise, the team built a phylogeny-aware framework for modelling quantitative trait evolution, integrating comparative multiomics data across four rodent species. They generated RNA-sequencing data from liver and heart tissue in two mole-rats—the naked mole-rat (Heterocephalus glaber) and the Damaraland mole-rat (Fukomys damarensis)—and compared these profiles with two rodent outgroups, the guinea pig (Cavia porcellus) and the mouse (Mus musculus). The outgroups matter because they anchor the comparison: by modelling how expression levels should drift along each branch of the evolutionary tree, the researchers could flag genes whose expression had shifted faster in mole-rat lineages than neutral drift alone could plausibly explain.

The analysis, built around the Expression Variance and Evolution approach, revealed hundreds of genes whose expression levels had undergone lineage-specific acceleration consistent with directional selection rather than random walk. After careful normalisation—using variance-stabilising transformation and transcripts-per-million strategies validated through sensitivity analyses—the team confirmed that these shifts were not artefacts of sequencing depth, gene length or transcript annotation. Orthology reannotation and genome assembly quality checks further ensured that the genes being compared across species were true one-to-one counterparts, eliminating a common source of false positives in cross-species transcriptomics.

But identifying shifted genes was only half of the puzzle. To connect expression evolution with its underlying regulatory mechanisms, the researchers layered a second data type onto the transcriptomic map: epigenomic profiles of cis-regulatory elements, the DNA sequences near genes that control when, where and how strongly they are transcribed. Cis-regulatory landscapes are known to turn over rapidly in mammalian evolution, and regulatory changes are widely hypothesised to be a major engine of phenotypic innovation. If a gene’s expression truly evolved under selection in mole-rats, the logic goes, the regulatory elements governing it should show signs of accelerated change as well.

That is precisely what the team found. Genes with lineage-specific expression shifts were surrounded by epigenomic landscapes that also displayed signals of accelerated evolution—a concordance that is difficult to explain by chance or by neutral genomic processes diverging at different rates. The researchers developed a weighted regulatory score, assigning regulatory elements to nearby genes within optimised genomic windows, and showed that genes exhibiting both transcriptomic and regulatory shifts cluster at specific loci. At these candidate loci, the two independent lines of evidence—expression and regulation—point in the same direction, strengthening the case that selection, not drift, drove the change.

The functional identities of these fast-evolving loci are as striking as the methodological rigour behind them. Enrichment analyses showed that genes with evidence of selection at both expression and regulatory levels cluster in pathways central to mole-rat physiology, including metabolism and stress responses. For animals that spend their entire lives underground in hypoxic, carbon dioxide-rich burrows, metabolic rewiring is not a luxury but a necessity. Cellular stress pathways, likewise, must cope with the oxidative and environmental challenges of the subterranean niche. The study’s molecular signatures suggest that selective pressures honed exactly those biological systems a burrowing mammal would need to tune.

Among the genes implicated by the analysis is Pygl, encoding liver glycogen phosphorylase, a key enzyme in glycogen breakdown. RNA-sequencing read coverage across the Pygl locus, presented in the study’s supplementary figures, illustrates how expression and regulatory profiles diverge across the four species in ways consistent with lineage-specific tuning. Genes of this kind offer testable hypotheses for experimental follow-up: if regulatory sequences around Pygl indeed evolved adaptively in mole-rats, they could contribute to the extraordinary metabolic flexibility these animals display when oxygen is scarce.

Beyond the mole-rat findings themselves, the study’s framework carries broader significance for evolutionary genomics. Comparative multiomics studies have often treated gene expression and gene regulation as separate domains, analysed with different toolkits and interpreted in isolation. By jointly modelling both within a single phylogenetic framework, the Berthelot and Villar teams demonstrate that concordant evidence across molecular layers is a far stronger indicator of adaptive evolution than either layer alone. The approach could be applied to any group of organisms with multiple genome assemblies and tissue-specific expression data, from cavefish to high-altitude mammals, wherever convergent adaptation to extreme environments raises similar questions.

The work also underscores how much biology remains hidden in species that were long considered curiosities. Mole-rats have already reshaped research on ageing, cancer suppression and pain insensitivity, and the loci flagged by this study provide a molecular shortlist for understanding traits that could eventually inform human medicine. As the authors note, their results illuminate how gene regulation and expression evolve in concert in this mammalian model, and they highlight genomic loci where multiple lines of evidence converge on a single conclusion: these are the places in the mole-rat genome where natural selection left its clearest fingerprints, shaping a lineage into one of the most unusual mammals on Earth.

Subject of Research: Comparative multiomics analysis of gene expression and regulatory evolution in African mole-rats

Article Title: Coordinated shifts in gene expression and regulation identify fast evolving loci linked to unique mole-rat traits

Article References: Daunesse, M., Liorzou, E., Parey, E., Villar, D., & Berthelot, C. (2026). Coordinated shifts in gene expression and regulation identify fast evolving loci linked to unique mole-rat traits. BMC Biology. https://doi.org/10.1186/s12915-026-02713-5

Image Credits: AI Generated

DOI: 10.1186/s12915-026-02713-5

Keywords: mole-rats, evolutionary genomics, gene expression, gene regulation, adaptive evolution, cis-regulatory elements, comparative multiomics, phylogenetic modelling, BMC Biology, naked mole-rat, Damaraland mole-rat, subterranean adaptation