TP53 copy number expansion correlates with the evolution of increased body size and an enhanced DNA damage response in elephants

CC-BY-NC 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not. 2 SUMMARY A major constraint on the evolution of large body sizes in animals is an increased risk of developing cancer. There is no correlation, however, between body size and cancer risk. This lack of correlation is often referred to as 'Peto's Paradox'. Here we show that the elephant genome encodes 20 copies of the tumor suppressor gene TP53 and that the increase in TP53 copy number occurred coincident with the evolution of large body sizes in the elephant (Proboscidean) lineage. Furthermore we show that several of the TP53 retrogenes are transcribed and translated and contribute to an enhanced sensitivity of elephant cells to DNA damage and the induction of apoptosis via a hyperactive TP53 signaling pathway. These results suggest that an increase in the copy number of TP53 may have played a direct role in the evolution of very large body sizes and the resolution of Peto's paradox in Proboscideans.. CC-BY-NC 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not .