A Trade-Off between Body Mass and Cancer Resistance in Cetaceans Is Mediated by Cell Cycle-Related Gene Evolution.

Cetaceans, well-known for their exceptionally long lifespans and substantial body masses, demonstrate a lower risk of cancer mortality compared to other mammals, consistent with Peto's paradox. Yet, the underlying mechanisms of cancer resistance, possibly evolved due to large body size, remain largely unclear. Here, we conducted an evolutionary analysis of 50 cell cycle-related genes, which play crucial role in both cancer progression and organismal body mass modulation, to investigate the mechanisms underlying the trade-off between body size and cancer resistance in cetaceans. We found that 66.7% (4/6) rapidly evolving genes (i.e. CDK2, CDT1, ORC3, and DBF4) and 50% (2/4) positively selected genes (ORC2 and ORC3) identified in cetaceans are involved in regulating cell cycle checkpoints, which halt the cell cycle in response to damage to allow repair and prevent cancer induction. Additionally, we identified four-body mass-associated genes (CCNE1, ORC5, E2F3, and DBF4) known to regulate cell growth; mutations or dysregulation of these genes can drive uncontrolled proliferation and cancer development. Interestingly, convergent evolution was observed in the African elephant and the bowhead whale at the tumor suppressor gene MYT1, potentially revealing a convergent mechanism of cancer resistance in large-bodied species. Notably, in vitro assays revealed that a cetacean-specific mutation M155T in the rapidly evolving gene CCND1 more effectively suppressed tumor cell proliferation and migration. Overall, our study has provided new insights into how the evolution of cell cycle-related genes balances body mass and cancer resistance in cetaceans, offering molecular support for Peto's paradox.