A POMT2 missense substitution contributes to hypoxia adaptation in hibernating mammals.

Hibernation is an adaptive survival strategy used by animals to cope with extreme environmental conditions. Although this physiological process involves complex metabolic changes, its underlying biological mechanisms remain largely unknown. Through comparative genomic analysis of six hibernating species across five orders, we identified an ancient amino acid substitution in POMT2 (R708Q), exhibiting signals of both convergent and positive selection in hibernating mammals. Phylogenetic analysis using HeIST indicated hemiplasy as a possible explanation, though given mammalian divergence times and the broader evidence for convergence, this is best considered an alternative rather than the primary interpretation. Functional studies using transgenic mice demonstrated the contribution of this mutation to hypoxia adaptation. Notably, despite the absence of this mutation in Rodentia hibernators, we included Graphiurus kelleni as a positive control in physiological studies of transgenic mice carrying POMT2 (R708Q), given its remarkable hypoxia adaptation during hibernation. Our findings not only provide novel insights into the genetic basis of hypoxic adaptation in hibernating mammals but also suggest incomplete lineage sorting (hemiplasy) as a plausible evolutionary mechanism for this important adaptive trait.