Butler, G.; Ramakrishnan, S.; Collins, T.; Baker, J.; Amend, S. R.; The Vertebrate Genomes Project Consortium Phase I, ; Schatz, M. C.; Venditti, C.; Pienta, K. J.

Tumour prevalence varies dramatically throughout the animal kingdom despite broadly conserved cellular and developmental processes, raising the question of how evolution has shaped susceptibility 1,2. Here, we link macroevolutionary variation in tumour prevalence to gene-level selection by integrating comparative genomics data from 109 species of birds and mammals using a Bayesian phylogenetic framework to estimate pangenome-wide rates of genetic evolution across >150 million years of evolutionary change. We identify 3,206 genes in which natural selection is associated with shifts in tumour prevalence, with more than 80% of which are linked to reduced prevalence, suggesting pervasive selection for cancer suppression. Using causal phylogenetic inference, we show that genes associated with reduced tumour prevalence act predominantly through indirect effects on body size, revealing growth as a key mediator of cancer risk across species. In contrast, genes associated with increased tumour prevalence exert direct effects independent of body size. Finally, at the species-level, we demonstrate that exceptionally low rates of benign tumours do not necessarily coincide with reduced malignancy, revealing that benign and malignant tumour processes are evolutionarily decoupled. Together, these results reveal how natural selection has fine-tuned the link between genotype, phenotype, and cancer risk across species.