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 suppresxssor 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.

Cancer risk and sexual conflict as constraints to body size evolution

“…Ontogenetic management evolution permits coadaptation to novel body sizes, but even then, cancer risk remained a factor that keeps organisms smaller: our alternative simulations where cancer is impossible led to manyfold larger body sizes in an equivalent evolutionary time, with this difference being marked for the largest lineages considered. These results link to empirical evidence and theoretical studies highlighting the role of cancer-related and ontogenetic adaptations (Abegglen et al, 2015;Caulin et al, 2015;Kokko and Hochberg, 2015;Sulak et al, 2016;Tollis et al, 2019;Martinez et al, 2020;Vazquez and Lynch, 2020;Erten and Kokko, 2020;Nunney, 2020). In our model, we either permitted or did not permit ontogenetic adaptation to occur throughout the simulation; in reality, genetic changes for higher cancer suppression may in some cases have preceded size increases (Vazquez et al, 2018).…”

“…A potential counterargument to the importance of cancer as a constraint to body size evolution is Peto's paradox, the observation that larger organisms do not appear to be more cancer prone than small ones in reality (Peto, 1977;Nunney, 1999). However, there is evidence that large-bodied lineages have had to evolve adaptations to reduce their cancer risk (Abegglen et al, 2015;Caulin et al, 2015;Sulak et al, 2016;Tollis et al, 2019;Martinez et al, 2020;Vazquez and Lynch, 2020). The problem may be solved in potentially lineage-specific ways, such as elephants refunctionalizing pre-existing pseudogenes (Vazquez et al, 2018).…”

Concurrent evolution of anti-aging gene duplications and cellular phenotypes in long-lived turtles

“…Previous studies have shown that large-bodied cancer resistant species such as elephants (Sulak et al, 2016; Vazquez and Lynch, 2021) and whales (Keane et al, 2015) evolved an increased number of tumor suppressors, suggesting that the same may be possible in giant, long-lived turtles. A previous study of Galapagos giant tortoises, for example, identified several gene duplications in pathways that might be related to body size evolution and reduced cancer risk (Quesada et al, 2019).…”

Alternative Animal Models of Aging Research

“…Similar to African mole-rats, blind mole rats (Spalax), e.g., are strong positive outliers from the lifespan to body mass correlation (Tacutu et al, 2018) and also extremely cancer resistant -the latter possibly mediated by a concerted necrotic cell death mechanism (Gorbunova et al, 2012). Also, elephants exhibit strong cancer resistance, which was associated with a high number of copies of tumor suppressor TP53 (Sulak et al, 2016) and further tumor suppressors (Vazquez and Lynch, 2021). Ant queens reach extreme lifespans of up to 45 years unexpected for their size and, moreover, usually live many times longer than workers (Giraldo and Traniello, 2014).…”

“…An interesting phenomenon observed in cetacean genomes is the duplication of genes related to cell cycle control and cancer protection, a phenomenon observed also in the elephant genome that contains multiple copies of the prototypical tumor suppressor TP53 (Sulak et al, 2016) and of further tumor suppressors (Vazquez and Lynch, 2021). Numerous duplicated genes have been described in the bowhead whale genome and some of these are of particular interest in the context of cell damage and survival: for example, the Proliferation Cell Nuclear Antigen plays a fundamental role in repairing DNA damage and is duplicated in the whale genome; both copies are expressed in different tissues and an amino acid substitution is present that alters its ability to interact with other effectors, and therefore its cellular function (Keane et al, 2015).…”