Larger Mammalian Body Size Leads to Lower Retroviral Activity

Abstract

Retroviruses have been infecting mammals for at least 100 million years, leaving descendants in host genomes known as endogenous retroviruses (ERVs). The abundance of ERVs is partly determined by their mode of replication, but it has also been suggested that host life history traits could enhance or suppress their activity. We show that larger bodied species have lower levels of ERV activity by reconstructing the rate of ERV integration across 38 mammalian species. Body size explains 37% of the variance in ERV integration rate over the last 10 million years, controlling for the effect of confounding due to other life history traits. Furthermore, 68% of the variance in the mean age of ERVs per genome can also be explained by body size. These results indicate that body size limits the number of recently replicating ERVs due to their detrimental effects on their host. To comprehend the possible mechanistic links between body size and ERV integration we built a mathematical model, which shows that ERV abundance is favored by lower body size and higher horizontal transmission rates. We argue that because retroviral integration is tumorigenic, the negative correlation between body size and ERV numbers results from the necessity to reduce the risk of cancer, under the assumption that this risk scales positively with body size. Our model also fits the empirical observation that the lifetime risk of cancer is relatively invariant among mammals regardless of their body size, known as Peto's paradox, and indicates that larger bodied mammals may have evolved mechanisms to limit ERV activity.

Author Summary

Retroviruses have been invading mammalian genomes for over 100 million years, leaving traces known as endogenous retroviruses (ERVs). Early genome sequencing studies revealed a marked difference in the activity of retroviruses among species, with humans largely containing inactive lineages of ERVs, while the mouse contains numerous lineages of active ERVs. We explore the hypothesis that life history traits determine the activity of ERVs in mammalian genomes, and show that larger mammals have fewer ERV copies over recent evolutionary time (the last 10 million years) compared to smaller mammals. This association is determined by body size independently of any confounding variables. We build a mathematical model that shows that ERV abundance in genomes decreases with larger body size and increases with horizontal transmission. Retroviral integration can cause cancer, and our analysis suggests that larger bodied animals control ERV replication in order to postpone cancer until a post-reproductive age. This is in line with a long-standing observation that cancer rates do not fluctuate among mammals of different body size, a phenomenon known as Peto's paradox, and opens up the possibility that larger animals have evolved mechanisms to limit ERV activity.