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.
Highlights
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) pandemic, has a ~ 30 kb single-stranded positive RNA (+ssRNA) genome, which is one of the largest known viral RNA g enomes[1]
All 664 SARS-CoV-2 and several bat and pangolin coronaviruses formed a cluster (SARS-CoV-2-like group shown in a square in Fig. 1B; see Supplementary Table 4), which was separated from the rest of coronavirus sequences including human coronaviruses 229E, the rest of bat coronaviruses, human coronaviruses HKU1, MERS, murine coronaviruses, human coronaviruses NL63, human coronaviruses OC43, primate coronaviruses, and SARS coronaviruses (Tor[2], Urbani, Viverrids, Wtic-MB and GZ02, which we refer to as SARS-CoV here)
Previous studies have shown that CpG is depleted in the genome of SARS-CoV-2 and its related bat and pangolin coronaviruses
Summary
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) pandemic, has a ~ 30 kb single-stranded positive RNA (+ssRNA) genome, which is one of the largest known viral RNA g enomes[1]. It was postulated that dogs may have been the intermediate species for the emergence of SARS-CoV-2 This hypothesis is based on two assumptions, which are not likely to be correct: first, only the frequency of CpG (but not those of other 15 dinucleotides ApA, ApC, ..., UpU) is sufficient to make inferences about the origin of viruses, and second, ZAP is the main source of low CpG abundance in the SARS-CoV-2 genome. The authors argued that these genomic composition changes are more likely to be an ancestrally-driven traits related to the origin of these viruses in bats, not due to a post-zoonotic transfer selection force These data suggest that the overall CpG content alone is not a reliable index for inferring the host origin of v iruses[21]. Our results provide multiple lines of evidence against the role of ZAP in the evolution of the SARS-CoV-2 genome
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