INTRODUCTION
Telomeres are short repetitive DNA sequences that cap the ends of linear chromosomes and are highly conserved across most eukaryotic organisms (Meyne et al., 1989; Blackburn, 1991). Telomeres shorten during cell replication and may be further degraded due to oxidative stress (von Zglinicki, 2002). When telomeres get too short, the cell typically ceases to replicate. The enzyme telomerase can rebuild telomeres (Greider, 1990) but is normally repressed in somatic cells of many mammals, presumably as a tumor suppression mechanism (Gomes et al., 2010; Tian et al., 2018). In the absence of telomerase, telomere shortening triggers cell senescence, which can prevent proliferation of precancerous cells (Campisi, 2001). Thus, replicative senescence has been interpreted as an adaptive tumor-suppression mechanism (e.g. Campisi, 2001).
Cross-species analyses have furthered understandings of evolutionary trade-offs shaping telomere length (TL) and telomerase activity. Haussmann et al. (2003) showed that telomere loss rate, but not TL, was inversely correlated with maximum lifespan in birds, which has since been corroborated across tetrapod species (Dantzer & Fletcher, 2015; Sudyka et al., 2016; Tricola et al., 2018, Whittemore et al., 2019; Pepke & Eisenberg, 2020). Seluanov et al. (2007) found that telomerase activity was negatively correlated with body mass, but not lifespan in rodents. Since, all else equal, increased telomerase activity is expected to lead to slower telomere erosion, Seluanov et al.’s results apparently contrast with the results on telomere shortening rates reported above. Seluanov et al. also found no significant associations of TL with body mass or lifespan. In an analysis of 57 mammalian species, Gomes et al. (2011) reported a negative relationship between telomerase activity and mass, but not lifespan across mammals. Furthermore, Gomes et al. found that lifespan was inversely correlated with TL while accounting for body mass, but there was no independent association between TL and mass. Here we build on these past findings, first trying to replicate the analyses of Gomes et al., then proceeding to further examine how telomere biology may influence cross-species variation in cancer risk and finally how telomere biology may have been shaped by selection related to domestication.
Telomere biology is widely assumed to influence cancer risk and thus for different species to evolve different telomere dynamics in response to differing fitness costs of cancer. Cancer occurs in almost all vertebrates, but among wild animals, cancer incidence rates are little studied, but seem to vary considerably (Effron et al. 1977; Pesavento et al. 2018; Albuquerque et al. 2018; Boddy et al. 2020). For instance, cancer is rarely reported in long-lived whales, bats or naked mole-rats, while rats and mice are known to be much more prone to cancer (Albuquerque et al. 2018). Different species have evolved different anti-cancer strategies and mechanisms; e.g. long-lived species that reproduce late in life are expected to be under stronger selection pressure to evolve efficient cancer defenses compared to short-lived species (Weinstein and Ciszek, 2002; Seluanov et al. 2008; 2018). Despite larger and longer-lived species having more cells that exist for a longer duration, they do not show higher cancer rates than smaller, short-lived species (Peto et al. 1975). This phenomenon, known as ‘Peto’s Paradox’, is generally assumed to be explained by species with larger body sizes and longer lives having increased fitness costs from cancer development. Correspondingly larger and longer-lived species are thought to tend to evolve shorter telomeres and decreased telomerase activity (Caulin & Maley, 2011; Gomes et al., 2011; Tian et al., 2018; Risques & Promislow, 2018). Thus, longer telomeres are predicted to increase the risk of cancer (e.g. Aviv et al., 2017). However, there are reasons to question the associations between telomere length and cancer risk (reviewed in Eisenberg & Kuzawa, 2018). Shorter telomeres can cause chromosomal instability that promotes cancer. Longer telomeres improve immune function, which is important in combatting many infectious diseases which cause cancers and in combatting the development of malignancies. To better characterize the association between telomere biology and cancer, using cross-species datasets we examine whether longer telomeres and telomerase activity predict increased cancer incidence as is often assumed.
In both mice (Mus musculus and Peromyscus leucopus ) and pearl millet (Pennisetum glaucum ), domesticated strains have been observed to have longer TLs than their wild counterparts (Bickle et al., 1998; Hemann & Greider, 2000; Manning et al., 2002; Weinstein and Ciszek, 2002; Sridevi et al., 2002; Kotrschal et al., 2007; Seluanov et al., 2008). Multiple explanations for this putative association between domestication and longer TL have been suggested (Manning et al., 2002; Weinstein and Ciszek, 2002; Eisenberg, 2011). To better characterize how general the association between domestication and TL is, we examine this association across a cross-species dataset including 9 domesticated and 48 non-domesticated mammalian species.
Our analyses primarily build on a cross-species dataset generated by Gomes et al. (2011). Gomes et al. measured mean telomere length (TL) and telomerase activity among 43 mammal species and combined with comparable published measurements on 14 species. Gomes et al. then examined relationships between TL, telomerase activity, body mass and maximum lifespan. As a first step to test our hypotheses regarding domestication and cancer risk, we aimed to replicate the findings from Gomes et al.’s analysis. We found considerably discrepant results. To establish the robustness of the findings we conducted additional sensitivity analyses. Thus, in this manuscript we first present our re-analysis of Gomes et al. and try to explain these discrepant results. Then we proceed to test whether TL and TA predict cancer risk and that TL was elongated by domestication.