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.
Highlights
Mammalian genomes contain large numbers of endogenous retroviruses (ERVs), derived from multiple independent germline invasions over evolutionary time
By analysing 38 mammalian genomes over approximately the last 10 my period we find a negative relationship between the number of integrated ERVs and body size (Figure 1b, Figure 2a)
We find that the number of ERV integrations in mammals is negatively correlated to body size
Summary
Mammalian genomes contain large numbers of endogenous retroviruses (ERVs), derived from multiple independent germline invasions over evolutionary time. The human genome contains 31–40 such ERV invasions, termed ‘families’, each derived from a distinct ancestral exogenous retrovirus [1,2]. These ERVs can continue proliferating after the initial germline invasion until they are inactivated, either through the acquisition of substitutions that occur at the host background level (,1023 per base per my) or by recombinational deletion [3,4]. A small number of ERVs have been exapted and have beneficial functions in their host [10,11,12], but the integration of retroviruses into or near host genes can have highly deleterious effects, as the consequent disruption or alteration of gene expression can lead to malignant transformation [13]. The uncontrolled proliferation of ERVs would be extremely detrimental to their host [14], and this process must be limited either by cessation of replication activity, or by host mediated suppression [15].Vertebrate genomes have evolved a range of responses that act at various stages of the viral life cycle to limit retroviral replication and its associated tumorigenic potential [16,17]
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