Evolutionary Dynamics of Oncosuppression Under Selection Pressure

Background and Objectives: Changes in the environment and physiology may be associated with an increased or decreased risk of cancer. Our study aims to evaluate the strength and the direction of the selection acting on oncosuppressor genes in association with phenotypic changes. Methods: We calculated the relative evolutionary rate (RER) using the converge method and linear regression on branches of phylogenetic trees. The association between changes in the evolutionary rate of oncosuppressors (DNA repair and cell cycle control genes) and trait selection was studied. The evolutionary rates of single oncosuppressor genes and pathways were evaluated. We studied two types of traits: those that are characteristic of vertebrates, such as homeothermy (the ability to maintain a constant body temperature), flight, and amnions; and those that are characteristic of mammals, such as high body mass and lifespan, an underground lifestyle, and hibernation. The analysis included 19,445 genes; 100 vertebrates and 46 mammalian species. We studied ancestral branches individually and all the clades having a trait. Results: Oncosuppressor genes accelerated in association with the ability to fly; p-value = 0.03 (positive or relaxed negative selection) and decelerated in homeothermic species; p-value = 0.04 (stabilizing selection). DNA repair genes were significantly accelerated in ancestral branches and in all clades of amniotic, homeothermic, and high-body-mass mammals (p-value < 0.05, FDR correction). Cell cycle control genes were under stabilizing selection in homeothermic animals, high-body-mass, long-lived, and underground mammals (p-value < 0.05, FDR correction). Data on the evolution of oncosuppressors are crucial for understanding the origin of cancer and will be important for future studies of tumor pathogenesis, pathomorphosis, and microevolution. Conclusions: The selection of traits associated with changes in cancer risk leads to positive/relaxed negative and stabilizing selection of oncosuppressor genes.