Overlapping Patterns of Rapid Evolution in the Nucleic Acid Sensors cGAS and OAS1 Suggest a Common Mechanism of Pathogen Antagonism and Escape.
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.
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Dustin C
DC
Hancks
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Melissa K
MK
Hartley
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
Celia
C
Hagan
Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Nathan L
NL
Clark
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Nels C
NC
Elde
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics*; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D019143:Evolution, Molecular; D007109:Immunity / Q000235:genetics; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009696:Nucleic Acids / Q000235:genetics*; D009712:Nucleotides, Cyclic / Q000235:genetics*; D011323:Primates / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D012330:RNA, Double-Stranded / Q000235:genetics; D017422:Sequence Analysis, DNA
D009696:Nucleic Acids; D009712:Nucleotides, Cyclic; D012330:RNA, Double-Stranded; C584311:cyclic guanosine monophosphate-adenosine monophosphate; D015088:2',5'-Oligoadenylate Synthetase