Contrasting Patterns of Rapid Molecular Evolution within thep53Network across Mammal and Sauropsid Lineages

Abstract

Cancer is a threat to multicellular organisms, yet the molecular evolution of pathways that prevent the accumulation of genetic damage has been largely unexplored. The p53 network regulates how cells respond to DNA-damaging stressors. We know little about p53 network molecular evolution as a whole. In this study, we performed comparative genetic analyses of the p53 network to quantify the number of genes within the network that are rapidly evolving and constrained, and the association between lifespan and the patterns of evolution. Based on our previous published data set, we used genomes and transcriptomes of 34 sauropsids and 32 mammals to analyze the molecular evolution of 45 genes within the p53 network. We found that genes in the network exhibited evidence of positive selection and divergent molecular evolution in mammals and sauropsids. Specifically, we found more evidence of positive selection in sauropsids than mammals, indicating that sauropsids have different targets of selection. In sauropsids, more genes upstream in the network exhibited positive selection, and this observation is driven by positive selection in squamates, which is consistent with previous work showing rapid divergence and adaptation of metabolic and stress pathways in this group. Finally, we identified a negative correlation between maximum lifespan and the number of genes with evidence of divergent molecular evolution, indicating that species with longer lifespans likely experienced less variation in selection across the network. In summary, our study offers evidence that comparative genomic approaches can provide insights into how molecular networks have evolved across diverse species.

The untapped potential of reptile biodiversity for understanding how and why animals age

“…This is in contrast to the purifying selection on p53 across mammals (Gaur et al, 2017;Passow et al, 2019), with the exception of the branch leading to elephants (Passow et al, 2019). We also found that species with longer lifespans experienced less variation in selection across the p53 network, whereas those with shorter lifespans were equally likely to have both positive and purifying selection (Passow et al, 2019). A recent publication on Galapagos tortoise genomes (Quesada et al, 2019) identified variants in p53 that are associated with hypoxia tolerance in other species (Zhao et al, 2013), providing an interesting link between this network and stress resistance in an exceptionally long-live species.…”

“…death, senesce, repair), balancing anticancer and anti-ageing mechanisms. Recent work on the comparative genomics of the p53 molecular network provided evidence of positive selection on genes within p53 networks of reptile (both ecto-and endothermic) relative to mammals, with reptiles having more positive selection on upstream genes (p53 and its regulators), especially in lizards and snakes (Passow et al, 2019). This is in contrast to the purifying selection on p53 across mammals (Gaur et al, 2017;Passow et al, 2019), with the exception of the branch leading to elephants (Passow et al, 2019).…”

“…Recent work on the comparative genomics of the p53 molecular network provided evidence of positive selection on genes within p53 networks of reptile (both ecto-and endothermic) relative to mammals, with reptiles having more positive selection on upstream genes (p53 and its regulators), especially in lizards and snakes (Passow et al, 2019). This is in contrast to the purifying selection on p53 across mammals (Gaur et al, 2017;Passow et al, 2019), with the exception of the branch leading to elephants (Passow et al, 2019). We also found that species with longer lifespans experienced less variation in selection across the p53 network, whereas those with shorter lifespans were equally likely to have both positive and purifying selection (Passow et al, 2019).…”

The Changes in the p53 Protein across the Animal Kingdom Point to Its Involvement in Longevity

“…This observation may provide evidence for the convergent evolution of p53 proteins in organisms with extreme longevity. According to Passow and colleagues, taxa with evidence of positive selection in the TP53 gene are those with the lowest incidences of cancer reported in amniotes (elephants, snakes, lizards, crocodiles, and turtles) [55].…”

The changes in the p53 protein across the animal kingdom pointing to its involvement in longevity

“…This may be considered as a supportive evidence for the convergent evolution of p53 proteins in organisms with extreme longevity. According to Passow and colleagues, taxa with evidence of positive selection in the TP53 gene are those with the lowest incidences of cancer reported in amniotes (elephants, snakes and lizards, crocodiles and turtles) (Passow et al, 2019). Figure 15: Mutual information to infer convergent evolution of p53 core domains.…”