Evidence for ZAP-independent CpG reduction in SARS-CoV-2 genome, and pangolin coronavirus origin of 5'UTR

SARS-CoV-2, the causative agent of COVID-19, has an RNA genome, which is, overall, closely related to the bat coronavirus sequence RaTG13. However, the ACE2-binding domain of this virus is more similar to a coronavirus isolated from a Guangdong pangolin. In addition to this unique feature, the genome of SARS-CoV-2 (and its closely related coronaviruses) has a low CpG content. This has been postulated to be the signature of an evolutionary pressure exerted by the host antiviral protein ZAP. Here, we analyzed the sequences of a wide range of viruses using both alignment-based and alignment free approaches to investigate the origin of SARS-CoV-2 genome. Our analyses revealed a high level of similarity between the 5UTR of SARS-CoV-2 and that of the Guangdong pangolin coronavirus. This suggests bat and pangolin coronaviruses might have recombined at least twice (in the 5UTR and ACE2 binding regions) to seed the formation of SARS-CoV-2. An alternative hypothesis is that the lineage preceding SARS-CoV-2 is a yet to be sampled bat coronavirus whose ACE2 binding domain and 5UTR are distinct from other known bat coronaviruses. Additionally, we performed a detailed analysis of viral genome compositions as well as expression and RNA binding data of ZAP to show that the low CpG abundance in SARS-CoV-2 is not related to an evolutionary pressure from ZAP.