Pervasive duplication of tumor suppressors in afrotherians during the evolution of large bodies and reduced cancer risk

Abstract

The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppressor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk. There is an incredible diversity of body sizes and lifespans among living mammals, remarkably even larger mammals lived in the recent past but are now extinct. In living mammals, an individual’s body size and lifespan are among the greatest predictors for the likelihood of developing cancer, taller and older humans, for example, have a greater cancer risk than shorter and younger people. Between species, however, body size and lifespan are poor predictors of cancer risk, thus big and long lived species must have evolved ways to reduce their risk of developing cancer. By understanding how big, long-lived species evolved their enhanced tumor suppression mechanisms we can improve our understanding of genes involved in human cancer and inspire new cancer treatments. We tracked how body size and the copy number of most protein coding genes changed elephants and their smaller bodies relatives. We found that as large bodied elephants evolved from smaller bodied ancestors, their cancer risk decreased. While genes involved in tumor suppression were commonly duplicated in elephants and their relatives, elephants have a unique repertoire of tumor suppressor genes that evolved alongside their recent increase in body size. These data show that duplication of tumor suppressor genes facilitated the evolution of large body size by compensating for increasing cancer risk.