Parallel evolution of reduced cancer risk and tumor suppressor duplications in Xenarthra

Abstract

The risk of developing cancer is correlated with body size and lifespan within species, but there is no correlation between cancer and either body size or lifespan between species indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Previously we showed that several large bodied Afrotherian lineages evolved reduced intrinsic cancer risk, particularly elephants and their extinct relatives (Proboscideans), coincident with pervasive duplication of tumor suppressor genes (Vazquez and Lynch 2021). Unexpectedly, we also found that Xenarthrans (sloths, armadillos, and anteaters) evolved very low intrinsic cancer risk. Here, we show that: 1) several Xenarthran lineages that independently evolved large bodies, long lifespans, and reduced intrinsic cancer risk; 2) reduced cancer risk in the stem lineages of Xenarthra and Pilosa occurred coincident with bursts of tumor suppressor gene duplications; 3) cells from sloths proliferate extremely slowly while Xenarthran cells induce apoptosis are very low levels of DNA damage; and 4) the prevalence of cancer is extremely low Xenarthrans, and cancer is nearly absent from armadillos. These data implicate the duplication of tumor suppressor genes in the evolution of remarkably large body sizes and decreased cancer risk in Xenarthrans and suggest they are a remarkably cancer resistant group of mammals.

A CDKN2C retroduplication in Bowhead whales is associated with the evolution of extremely long lifespans and alerted cell cycle dynamics

“…Other studies, which had very large samples but that combined data from multiple species, reported cancer in only 14/1800 (0.78%, 95% CI: 0.04-0.13%) and 2/2000 (0.01%, 95% CI: 0.00–0.04%%) necropsies ( Figure 1A ; Figure 1 – source data 1 ). Next, we compared neoplasia prevalence in Cetacea to other Therian mammals from three published studies that included pathology reports from 37 (Boddy et al, 2020) and 191 (Vincze et al, 2022) species of Therian mammals, and a large dataset of Xenarthrans compiled from multiple published sources (Vazquez et al, 2022); The dataset includes cancer prevalence data from 244 species. As a group the mean prevalence of neoplasia in Cetacea was 1.4% (95% CI: 1.07– 1.70%) when aggregated across all datasets and excluding St. Lawrence estuary belugas ( Figure 1B ; Figure 1 – source data 2 ).…”

“…Population doubling time is proportional to the cumulative length of individual cell cycle phases, particularly the length of G 1 (Blank et al, 2018). Therefore, we performed a thorough literature review and assembled a dataset of population doubling times from 60 species of Eutherian mammals (Vazquez et al, 2022). While there was considerable variation in population doubling times between species, whale cells had similar doubling times as other species of mammals ( Figure 7A ).…”

“…For example, the average mammalian gene duplication rate, both segmental and retroduplication, is estimated to be 0.5-20×10 -3 per gene per million years (Lynch and Conery, 2000;Pan and Zhang, 2007), suggesting that there should be about one gene duplication unique to Bowhead whales given Bowhead and Right whales diverged only ~4-15 5 million years ago (Árnason et al, 2018;Dornburg et al, 2012;McGowen et al, 2009). These data indicate that gene duplication has likely played a minor, even if important, role in the evolution of long lifespans and reduced cancer risk in Bowhead whales unlike the pervasive role gene duplication appears to have played in the evolution of reduced cancer risk in elephants, Xenarthrans, and Galapagos tortoises (Glaberman et al, 2021;Vazquez et al, 2022;Vazquez and Lynch, 2021). Thus, other mechanisms must have played a more numerous role than copy number gains and losses, such as gene regulatory evolution.…”

“…(Arenales et al, 2020a, 2020b; Diniz and Oliveira, 1999; Diniz et al, 1995); The total dataset includes cancer prevalence data from 221 species. Neoplasia reports from Dasypus novemcinctus from Boddy et al were combined with cancer prevalence data from the NHDP colony (Vazquez et al, 2022) and Choloepus didactylus data from Vincze et al were combined with Choloepus didactylus data from (Arenales et al, 2020b). Confidence intervals (95%) on lifetime neoplasia prevalence were estimated in PropCI package (https://github.com/shearer/PropCIs) in R using the Clopper-Pearson exact CI function: exactci(x, n, conf.level=0.95), where x is the number of successes (necropsies with neoplasia), n is the total sample size (number of necropsies), and conf.level=0.95 is the 95% lower and upper confidence intervals.…”