Many mammals risk damage from oxidative stress stemming from frequent dives (i.e., cycles of ischemia/reperfusion and hypoxia/reoxygenation), high altitude and subterranean environments, or powered flight. Purine metabolism is an essential response to oxidative stress, and an imbalance between purine salvage and de novo biosynthesis pathways can generate damaging reactive oxygen species (ROS). Here, we examined the evolution of 117 purine metabolism-related genes to explore the accompanying molecular mechanisms of enhanced purine metabolism in mammals under high oxidative stress. We found that positively selected genes, convergent changes, and nonparallel amino acid substitutions are possibly associated with adaptation to oxidative stress in mammals. In particular, the evolution of convergent genes with cAMP and cGMP regulation roles may protect mammals from oxidative damage. Additionally, 32 genes were identified as under positive selection in cetaceans, including key purine salvage enzymes (i.e., HPRT1 ), suggesting improved re-utilization of non-recyclable purines avoid hypoxanthine accumulation and reduce oxidative stress. Most intriguingly, we found that six unique substitutions in cetacean xanthine dehydrogenase (XDH), an enzyme that regulates the generation of the ROS precursor xanthine oxidase (XO) during ischemic/hypoxic conditions, show enhanced enzyme activity and thermal stability and diminished XO conversion activity. These functional adaptations are likely beneficial for cetaceans by reducing radical oxygen species production during diving. In summary, our findings offer insights into the molecular and functional evolution of purine metabolism genes in mammalian oxidative stress adaptations.
Pattern recognition receptors (PRRs) are specialized receptors that represent a key component of the host innate immune system. Whether molecular evolutionary history of different PRR classes have involved different genetic mechanisms underlying diverse pathogen environment in mammals, and whether distinct ecology of mammals may have imposed divergent selective pressures on the evolution of the PRRs, remained unknown. To test these hypotheses, we investigated the characterization of 20 genes belonging to four PRR classes in mammals. Evidence of positive selection was found in most (17 of 20) PRR genes examined, and most positively selected sites (84%) undergoing radical changes were found to fall in important functional regions, consistent with the co-evolutionary dynamics between the hosts and their microbial counterparts. We found different evolutionary patterns in different PRR classes, with the highest level of positive selection in C-type lectin receptor (CLR) family, suggesting that the capability of CLRs in response to a wide variety of ligands might explain their malleability to selection pressures. Tests using branch models that partitioned the data along habitat and social behavior found significant evidence of divergent selective pressures of PRRs among mammalian groups. Interestingly, species-specific evolution was detected on RIG-I-like helicase genes (RLRs) in cetaceans, suggesting that RLRs might play a critical role in the defense against widespread marine RNA viruses during their divergence and radiation into marine habitats. This study provides a comprehensive look at the evolutionary patterns and implications of mammalian PRRs, and highlights the importance of ecological influences in molecular adaptation.
The oxidative phosphorylation (OXPHOS) pathway is an efficient way to produce energy via adenosine triphosphate (ATP), which is critical for sustaining an energy supply for cetaceans in a hypoxic environment. Several studies have shown that natural selection may shape the evolution of the genes involved in OXPHOS. However, how network architecture drives OXPHOS protein sequence evolution remains poorly explored. Here, we investigated the evolutionary patterns of genes in the OXPHOS pathway across six cetacean genomes within the framework of a functional network. Our results show a negative correlation between the strength of purifying selection and pathway position. This result indicates that downstream genes were subjected to stronger evolutionary constraints than upstream genes, which may be due to the dual function of ATP synthase in the OXPHOS pathway. Additionally, there was a positive correlation between codon usage bias and omega (ω = dN/dS) and a negative correlation with synonymous substitution rate (dS), indicating that the stronger selective constraint on genes (with less biased codon usage) along the OXPHOS pathway is attributable to an increase in the rate of synonymous substitution. Surprisingly, there was no significant correlation between protein-protein interactions and the evolutionary estimates, implying that highly connected enzymes may not always show greater evolutionary constraints. Compared with that observed for terrestrial mammals, we found that the signature of positive selection detected in five genes (ATP5J, LHPP, PPA1, UQCRC1 and UQCRQ) was cetacean-specific, reflecting the importance of OXPHOS for survival in hypoxic, aquatic environments.
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