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 networkmolecular evolution as awhole. In this study,we performed comparative genetic analyses of the p53 network to quantify thenumberofgeneswithin thenetwork that are rapidly evolvingandconstrained,andthe associationbetweenlifespanand 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 ofpositive selectionanddivergentmolecular evolution inmammalsandsauropsids. Specifically,we foundmore evidence of positive selection in sauropsids than mammals, indicating that sauropsids have different targets of selection. In sauropsids, more genes upstreamin the network exhibited positive selection, and this observation is driven by positive selection in squamates,which is consistentwith previouswork showing rapid divergence and adaptation ofmetabolic 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 specieswith 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.
Bibliographical noteFunding Information:
We thank members of the McGaugh, Brandvain, and Bronikowski labs for feedback on earlier drafts of the manuscript. We also thank the Minnesota Supercomputing Institute without which this work would not be possible. C.N.P and H.B. were supported by University of Minnesota Grand Challenges postdoctoral grants. S.P. was supported by a grant from the Iowa State University Center for Integrated Animal Genomics. T.S.S. was supported by Fellowships from the National Science Foundation (IGERT in Computational Biology 0504304, and GK-12 DGE-0947929). This work was supported by grants from the National Science Foundation (grant number IOS 09-22528) and the National Institutes of Health/ National Institute of Aging (grant number RO1-AG049416) (R01-AG049416) to A.M.B. We dedicate this research to the memory of M.C. McGaugh.
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
- divergent molecular evolution
- p53-signaling network
- positive selection