Evolution Of Cetacean Antioxidant Enzyme Genes And Their Relationship To Oxidative Stress Resistance

Cetaceans returned to the ocean 50 million years ago and successfully adapted to their aquatic environment.At the same time,a series of special physiological changes are formed to cope with different stress from aquatic environment.The phenomenon that cetaceans undergo repeated Ischemia Reperfusion(IRI)without oxidative injury has always attracted the attention of biologists.Reactive oxygen species(ROS)play an important role in oxidative stress induced by IRI.A large number of physiological experiments have shown that marine mammals have a high level of antioxidants compared with terrestrial mammals,suggesting that antioxidant system helps cetaceans eliminate the accumulation of free radicals caused by diving.However,the molecular mechanism of resistance to oxidative stress in cetaceans remains to be studied.In this study,two types of antioxidants in cetaceans,superoxide dismutase(SOD)family and glutathione peroxidase(GPX)family,were analyzed through a variety of bioinformatics methods to reveal the molecular mechanism of antioxidants in cetaceans' response to oxidative stress.We considered the structure and molecular evolution of the superoxide dismutase(SOD)gene family which encodes essential enzymes in the mammalian antioxidant system in order Cetartiodactyla.To this end,we juxtaposed cetaceans and their closest extant relatives(order Artiodactyla).We identified 94 genes in 23 species,of which 70 are bona fide intact genes.Although the SOD gene family is conserved in Cetartiodactyla,lineage-specific gene duplications and deletions were observed.Phylogenetic analyses show that the SOD2 subfamily diverged from the clade containing SOD1 and SOD3,suggesting that cytoplasmic,extracellular,and mitochondrial SODs have started down independent evolutionary paths.Interestingly,specific-amino acid mutations(e.g.,K130 N in SOD2)that might enhance ROS elimination were identified in cetaceans.A core transcription factor repertoire of cetartiodactyl SOD genes may include Sp1,NF-?B,Nrf2,and AHR.Additionally,transcription factors binding sites responding to hypoxia are found in the cetacean SOD1 gene(e.g.,Suppressor of Hairless;Su(H)).Cetaceans with different diving abilities also show divergent evolution of SOD1 and SOD2.Our genome-wide analysis of SOD genes helps clarify their relationship and evolutionary trajectory and identify putative functional changes in cetaceans.We consider the evolution of the glutathione peroxidase(GPX)family of antioxidant enzymes by interrogating publicly available genome data from 70 mammalian species from all major clades.We identified 8 GPX subclasses ubiquitous to all mammalian groups.Mammalian GPX gene families resolved into the GPX4/7/8and GPX1/2/3/5/6 groups and are characterized by several instances of gene duplication and loss,indicating a dynamic process of gene birth and death in mammals.Seven of the eight GPX subfamilies(all but GPX7)were under positive selection,with the residues under selection located at or close to active sites or at the dimer interface.We also reveal evidence of a correlation between ecological niches(e.g.high oxidative stress)and the divergent selection and gene copy number of GPX subclasses.Notably,a convergent expansion of GPX1 was observed in several independent lineages of mammals under oxidative stress and may be important for avoiding oxidative damage.Collectively,this study suggests that the GPX gene family has shaped the adaption of mammals to stressful environments.