Abstract
Lowland and highland Peromyscus maniculatus populations display divergent, locally adapted physiological phenotypes shaped by altitudinal differences in oxygen availability. Many physiological responses to hypoxia seem to have evolved in lowland ancestors to offset episodic and localised bouts of low internal oxygen availability. However, upon chronic hypoxia exposure at high elevation, these responses can lead to physiological complications. Therefore, highland ancestry is often associated with evolved hypoxia responses, particularly traits promoting tolerance of constant hypoxia. Environmentally induced DNA methylation can dynamically alter gene expression patterns, providing a proximate basis for phenotypic plasticity. Given each population's differential reliance on plasticity for hypoxia tolerance, we hypothesised that lowland mice have a more robust epigenetic response to hypoxia exposure, driving trait plasticity, than highland mice. Using DNA methylation data of tissues from the heart's left ventricle, we show that upon hypoxia exposure, lowland mice chemically modulate the epigenetic landscape to a greater extent than highland mice, especially at key hypoxia‐relevant genes such as Egln3 . This gene is a regulator of the gene Epas1 that is frequently targeted for positive selection at high elevation. We find higher methylation among wild highland mice at gene Egln3 compared to wild lowland mice, suggesting a shared epigenetic ancestral response to episodic and chronic hypoxia. These findings highlight each population's distinct reliance on molecular plasticity driven by their unique evolutionary histories.