The low abundance of CpG in the SARS-CoV-2 genome is not an evolutionarily signature of ZAP

Abstract

The zinc finger antiviral protein (ZAP) is known to restrict viral replication by binding to the CpG rich regions of viral RNA, and subsequently inducing viral RNA degradation. This enzyme has recently been shown to be capable of restricting SARS-CoV-2. These data have led to the hypothesis that the low abundance of CpG in the SARS-CoV-2 genome is due to an evolutionary pressure exerted by the host ZAP. To investigate this hypothesis, we performed a detailed analysis of many coronavirus sequences and ZAP RNA binding preference data. Our analyses showed neither evidence for an evolutionary pressure acting specifically on CpG dinucleotides, nor a link between the activity of ZAP and the low CpG abundance of the SARS-CoV-2 genome.

Antiviral Activity of Zinc Finger Antiviral Protein (ZAP) in Different Virus Families

“…The molecular mechanisms underlying the restriction of SARS-CoV-2 by ZAP still need to be elucidated, as well as the different antiviral responses observed between ZAP isoforms and the involvement of ZAP cofactors in viral restriction [51]. Afrasiabi et al (2022) [137] showed that the low frequency of CpG dinucleotides in SARS-CoV-2 is not a result of evolutionary pressure mediated by ZAP activity. This leaves the question unanswered and calls for further investigation into other evolutionary forces that may have led to the decrease in CpG frequency in SARS-CoV-2 [137,138].…”

“…Afrasiabi et al (2022) [137] showed that the low frequency of CpG dinucleotides in SARS-CoV-2 is not a result of evolutionary pressure mediated by ZAP activity. This leaves the question unanswered and calls for further investigation into other evolutionary forces that may have led to the decrease in CpG frequency in SARS-CoV-2 [137,138].…”