Convergent evolution of glutathione metabolism pathway genes in marine mammals

Oxidative stress, triggered by hypoxia during repetitive diving, represents a notable environmental adaptation of marine mammals. Glutathione (GSH) is a widely acknowledged antioxidant that protects crucial cellular elements from damage by reactive oxygen species (ROS). Nevertheless, the role of the glutathione metabolism pathway in shaping the adaptation to oxidative stress in marine mammals is not fully elucidated. In this study, we conducted evolutionary analyses on 37 genes related to GSH metabolism pathway in marine and terrestrial mammals. We found that in comparison with their terrestrial relatives, marine mammals showed convergently accelerated evolution on the core modules of GSH metabolism. Specifically, we identified a total of 16 genes with significant evolution signals unique to marine mammals, and several genes (e.g., rapidly evolving genes: RRM1 and SMS, positively selected genes: ANPEP and GCLC) were shared in marine mammal lineages. Eight genes were discovered to possess specific amino acid modifications that are common among all marine mammals. Functional assays of dolphin GCLC showed a downregulation of HIF-1α and enhanced GSH levels under hypoxic conditions, suggesting heightened protection of marine mammals against oxidative stress induced by hypoxia. Our study revealed crucial genes displaying notable evolutionary signals among marine mammals, offering genomic and functional validation for convergent hypoxia adaptation mechanisms in this group.