Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense.

Wild mammalian species, including bats, constitute the natural reservoir of Betacoronavirus (including SARS, MERS, and the deadly SARS-CoV-2). Different hosts or host tissues provide different cellular environments, especially different antiviral and RNA modification activities that can alter RNA modification signatures observed in the viral RNA genome. The zinc finger antiviral protein (ZAP) binds specifically to CpG dinucleotides and recruits other proteins to degrade a variety of viral RNA genomes. Many mammalian RNA viruses have evolved CpG deficiency. Increasing CpG dinucleotides in these low-CpG viral genomes in the presence of ZAP consistently leads to decreased viral replication and virulence. Because ZAP exhibits tissue-specific expression, viruses infecting different tissues are expected to have different CpG signatures, suggesting a means to identify viral tissue-switching events. I show that SARS-CoV-2 has the most extreme CpG deficiency in all known Betacoronavirus genomes. This suggests that SARS-CoV-2 may have evolved in a new host (or new host tissue) with high ZAP expression. A survey of CpG deficiency in viral genomes identified a virulent canine coronavirus (Alphacoronavirus) as possessing the most extreme CpG deficiency, comparable to that observed in SARS-CoV-2. This suggests that the canine tissue infected by the canine coronavirus may provide a cellular environment strongly selecting against CpG. Thus, viral surveys focused on decreasing CpG in viral RNA genomes may provide important clues about the selective environments and viral defenses in the original hosts.