Cancer suppression and the evolution of multiple retrogene copies of TP53 in elephants: A re-evaluation.

Evolving to become bigger and/or longer lived should increase cancer susceptibility, but this predicted increase is not observed, a contradiction named Peto's paradox. A solution is that cancer suppression evolves to minimize cancer susceptibility, and the discovery of 19 retrogene (RTG) copies of the tumor suppressor gene TP53 in the African elephant () is increasingly cited as a classic example of such adaptive suppression. However, classic examples need rigorous evaluation and an alternative hypothesis is that the RTGs spread by genetic drift. This study shows that before its duplication, the ancestral elephant RTG was already truncated from 390 amino acids to 157 by a frameshift mutation, and that 14 of the 19 copies are now truncated to ≤88 amino acids. There was no compelling evidence of either positive or negative selection acting on these 88 codons, and the pattern of RTG accumulation fits a neutral model with a duplication rate of ~10 per generation. It is concluded that there is no evidence supporting the hypothesis that the 19 elephant RTGs spread to fixation by selection; instead, the evidence indicates that these RTGs accumulated primarily by segmental duplication and drift. It is shown that the evolutionary multistage model of carcinogenesis (EMMC) predicts the recruitment of 1-2 independently acting tumor suppressor genes to suppress the increased cancer risk in elephants, so it is possible that one or a few RTGs may have been favored by selection resulting in the known enhanced sensitivity of elephant cells to DNA damage. However, the analysis does not provide any support for either a direct (via conserved TP53 activity) or indirect (via supporting canonical TP53 function) role of the RTGs sequences, so that the presence of multiple copies of TP53 retrogenes in elephants needs to be further justified before being used as a classic example of tumor suppression in large-bodied animals.