Impact of the Zinc Antiviral Protein on the Genomic Composition of RNA Viruses Infecting Vertebrates

The composition of viral genomes, influenced by host-specific biases, offers insights into their evolutionary history. Vertebrate cells counter viral infection with interferons (IFNs) that activate IFN-stimulated genes, including the zinc-finger antiviral protein (ZAP), which binds CpG-rich single-stranded viral RNA (ssRNA). We trace the origin of ZAP along the vertebrate phylogeny and highlight its earlier emergence than previously described. Our analysis of ZAP orthologs shows that ZAP originated from a PARP12-like ancestor in the last common ancestor of tetrapods and lungfishes, more than 400 million years ago. Amphibian ZAP shares structural domains with its mammalian counterpart, though it typically lacks the C-terminal CAAX-box motif. The conserved RNA-binding domain in lungfish and tetrapod suggests an early functional reassignment. Subsequently, we found that CpG suppression in ssRNA viral genomes increases with the phylogenetic proximity of hosts to mammals, with amniote-infecting viruses showing the strongest bias, likely reflecting adaptation to ZAP-mediated immunity. These findings suggest that ZAP’s evolutionary steps include gene duplication in jawed vertebrates, structural adaptations in sarcopterygians, and membrane targeting capabilities in an early tetrapod, reflecting the complex co-evolution of host antiviral defenses and viral evasion strategies.