Recurrent loss-of-function mutations reveal costs to OAS1 antiviral activity in primates

Abstract

Immune responses counteract infections and can also cause collateral damage to hosts. We investigated functional outcomes of variation in the rapidly evolving antiviral double-stranded RNA (dsRNA) sensing factor Oligoadenylate Synthetase 1 (OAS1) in primates as a model for understanding how individual immune pathways evolve to minimize deleterious effects on host fitness. Upon binding of dsRNAs, OAS1 polymerizes ATP into 2'-5' linked oligoadenylate (2-5A), which in turn activates Latent Ribonuclease (RNase L) to kill virus infected cells. OAS1 can undergo auto-activation by host encoded RNAs, raising the question of how it might evolve to mitigate RNase L-mediated cytotoxicity. Using a new yeast-based growth assay, we observed a pattern of frequent loss of 2-5A synthesis by OAS1 from several species. In gorillas, we identified a polymorphism in a conserved substrate binding residue that severely decreases catalytic function. In contrast, lowered 2-5A generation previously associated with variation in humans results from production of unstable OAS1 isoforms. Examination of OAS1 function in monkeys revealed a spectrum of activities, including the complete loss of 2-5A synthesis in tamarins. Frequent loss of catalytic activity in primates suggests that costs associated with OAS1 activation can be so detrimental to host fitness that its pathogen-protective effects are repeatedly forfeited.