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.
Highlights
Among the constraints on the evolution of large bodies and long lifespans in animals is an increased risk of developing cancer
We: (1) trace the evolution of body size and lifespan in Eutherian mammals, with particular reference to Afrotherians; (2) infer changes in cancer susceptibility across Afrotherian lineages; (3) use a genome-wide screen to identify gene duplications in Afrotherian genomes, including multiple living and extinct Proboscideans; and (4) show that while duplication of genes with tumor suppressor functions is pervasive in Afrotherian genomes, Proboscidean gene duplicates are enriched in unique pathways with tumor suppressor functions
While we found that duplication of tumor suppressor genes is common in Afrotheria, genes that duplicated in the Proboscidean stem-lineage (Figure 3A,B) were uniquely enriched in functions and pathways that may be related to the evolution of unique anti-cancer cellular phenotypes in the elephant lineage (Figure 3C)
Summary
Among the constraints on the evolution of large bodies and long lifespans in animals is an increased risk of developing cancer. If all cells in all organisms have a similar risk of malignant transformation and equivalent cancer suppression mechanisms, organisms with many cells should have a higher prevalence of cancer than organisms with fewer cells, because large and small animals have similar cell sizes (Savage et al, 2007). Consistent with this expectation there is a strong positive correlation between body size and cancer incidence within species; for example, cancer incidence increases with increasing adult height in humans (Million Women Study collaborators et al, 2011; Nunney, 2018) and with increasing body size in dogs, cats, and cattle (Dobson, 2013; Dorn et al, 1968; Lucena et al, 2011). The ultimate resolution to Peto’s Paradox is trivial, large-bodied and long-lived species evolved enhanced cancer protection mechanisms, but identifying and characterizing the mechanisms that underlie the evolution of augmented cancer protection has proven difficult (AshurFabian et al, 2004; Seluanov et al, 2008; Gorbunova et al, 2012; Tian et al, 2013; Sulak et al, 2016)
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