Abstract
A diverse subset of pattern recognition receptors (PRRs) detects pathogen-associated nucleic acids to initiate crucial innate immune responses in host organisms. Reflecting their importance for host defense, pathogens encode various countermeasures to evade or inhibit these immune effectors. PRRs directly engaged by pathogen inhibitors often evolve under recurrent bouts of positive selection that have been described as molecular ‘arms races.’ Cyclic GMP-AMP synthase (cGAS) was recently identified as a key PRR. Upon binding cytoplasmic double-stranded DNA (dsDNA) from various viruses, cGAS generates the small nucleotide secondary messenger cGAMP to signal activation of innate defenses. Here we report an evolutionary history of cGAS with recurrent positive selection in the primate lineage. Recent studies indicate a high degree of structural similarity between cGAS and 2’-5’-oligoadenylate synthase 1 (OAS1), a PRR that detects double-stranded RNA (dsRNA), despite low sequence identity between the respective genes. We present comprehensive comparative evolutionary analysis of cGAS and OAS1 primate sequences and observe positive selection at nucleic acid binding interfaces and distributed throughout both genes. Our data revealed homologous regions with strong signatures of positive selection, suggesting common mechanisms employed by unknown pathogen encoded inhibitors and similar modes of evasion from antagonism. Our analysis of cGAS diversification also identified alternately spliced forms missing multiple sites under positive selection. Further analysis of selection on the OAS family in primates, which comprises OAS1, OAS2, OAS3 and OASL, suggests a hypothesis where gene duplications and domain fusion events result in paralogs that provide another means of escaping pathogen inhibitors. Together our comparative evolutionary analysis of cGAS and OAS provides new insights into distinct mechanisms by which key molecular sentinels of the innate immune system have adapted to circumvent viral-encoded inhibitors.
Highlights
Pathogens constantly drive the evolution of populations they infect [1,2]
The sites model implemented in Phylogenetic Analysis by Maximum Likelihood (PAML) [44] calculates dN/dS values per amino acid position and compares models that omit or accommodate elevated dN/dS to test for positive selection
These data further predict the existence of at least several pathogen-encoded inhibitors of Cyclic GMP-AMP synthase (cGAS), which will be important to identify and characterize to gain a better understanding of the role of cGAS in countering infections. Another insight into cGAS evolution was the recent observation of extensive overlap in structure with the nucleic acid sensor, oligoadenylate synthase 1 (OAS1) [9,10,11,48]
Summary
Pathogens constantly drive the evolution of populations they infect [1,2]. The burden of pathogens on host fitness results in selective pressure on both genes involved in immunity and host factors that are hijacked to promote infection. Changes in the rate of nonsynonymous amino acid substitutions (dN) relative to the rate of synonymous changes (dS)— referred to as ω—can indicate recurrent positive selection common to host-pathogen interfaces [2]. Other mechanisms of adaptation might be common at these interfaces as well. Evasion might proceed through alternate splicing events that result in isoforms missing surfaces recognized by pathogen inhibitors, but to date few studies have considered alternate mechanisms of adaptive evolution at host-pathogen interfaces
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