Comparative Genomics and Functional Evidence for Convergent Adaptation to Hypoxia in Mammals

The independent evolution of hypoxia tolerance across phylogenetically distinct species, including marine mammals, highland species, and subterranean mammals, represents a classic example of convergent evolution. Although these taxa produced similar physiological solutions to address comparable evolutionary challenges, the underlying genetic mechanisms of their convergent adaptation remain poorly understood. Here, we investigated genomic signatures of convergent evolution in hypoxia-tolerant mammals. Hypoxia-tolerant lineages exhibited accelerated rates of protein evolution relative to normoxia-adapted species. We identified 499 positively selected genes and 1585 rapidly evolving genes in hypoxia-tolerant mammals, with significant functional enrichment related to hypoxia response and cardiovascular regulation. We also detected 817 genes showing convergent shifts in relative evolutionary rates at the protein-coding level across hypoxia-tolerant species. Widespread lineage-specific amino acid substitutions were detected, a subset of which occur within key functional domains implicated in hypoxia adaptation. Remarkably, functional assays demonstrated that overexpression of cetacean HYOU1 (hypoxia up-regulated protein 1) significantly reduced malondialdehyde and reactive oxygen species levels, while suppressing hypoxia-induced target gene expression, compared with human ortholog and mutation constructs. Together, these findings provide genomic and functional evidence for convergent genetic mechanisms underlying hypoxia adaptation in mammals.