The evolution of cancer suppression:Solutions to Peto's Paradox revealed by genomic analyses of elephants and whales

Large body size has evolved at least 11 times during mammalian evolution, exemplified by the proboscidean( elephant) and cetacean (whale) lineages. These species should face a higher lifetime risk of cancer due to the greater probability of oncogenic mutations occurring during somatic evolution in an organism containing 100 to1000X more cells than a human. However, zoo necropsy data reveals elephants have only a 1-3% probability of death from cancer compared to 11-25% for humans. We find elephant genomes harbor up to 40 alleles of the tumor suppressor gene TP53, and at least some TP53 retrogene copies are transcribed and translated.Functional assays demonstrate TP53 redundancy in elephants is related to an increased apoptotic response toDNA damage in elephant cells when compared to human cells. To investigate cancer suppression in giganticbaleen whales, we have sequenced and assembled the genome of the humpback whale (Megaptera novaeangliae). We find that cancer suppression in cetaceans is associated with positive selection onprotein-coding genes involved in cell signaling, cell proliferation, apoptosis, as well as cancer. Our findings suggest independent evolution towards gigantism during the mammalian radiation was accompanied by divergent cancer suppression mechanisms, expanding our knowledge of “nature’s toolkit” in fighting tumorigenesi