Conservation analysis of SARS-CoV-2 spike suggests complicated viral adaptation history from bat to human

Lei, Kuan Cheok; Zhang, Xiaohua Douglas

BACKGROUND: The current COVID-19 pandemic, caused by SARS-CoV-2, has become the most devastating public health emergency in the twenty-first century and one of the most influential plagues in history. Studies on the origin of SARS-CoV-2 have generally agreed that the virus probably comes from bat, closely related to a bat CoV named BCoV-RaTG13 taken from horseshoe bat (Rhinolophus affinis), with Malayan pangolin (Manis javanica) being a plausible intermediate host. However, due to the relatively low number of SARS-CoV-2 related strains available in public domain, the evolutionary history remains unclear. METHODOLOGY: 995 coronavirus sequences from NCBI Genbank and GISAID were obtained and multiple sequence alignment was carried out to categorize SARS-CoV-2 related groups. Spike sequences were analyzed using similarity analysis and conservation analyses. Mutation analysis was used to identify variations within receptor-binding domain in spike for SARS-CoV-2 related strains. RESULTS: We identified a family of SARS-CoV-2 related strains, including the closest relatives, bat CoV RaTG13 and pangolin CoV strains. Sequence similarity analysis and conservation analysis on spike sequence identified that N-terminal domain, receptor binding domain (RBD) and S2 subunit display different degrees of conservation with several coronavirus strains. Mutation analysis on contact sites in SARS-CoV-2 RBD reveals that human-susceptibility probably emerges in pangolin. CONCLUSION & IMPLICATION: We conclude that the spike sequence of SARS-CoV-2 is the result of multiple recombination events during its transmission from bat to human, and we propose a framework of evolutionary history that resolve the relationship of BCoV-RaTG13 and pangolin coronaviruses with SARS-CoV-2. LAY SUMMARY: This study analyses whole-genome and spike sequences of coronavirus from NCBI using phylogenetic and conservation analyses to reconstruct the evolutionary history of SARS-CoV-2, and proposes an evolutionary history of spike in the progenitors of SARS-CoV-2 from bat to human through mammal hosts before they recombine into the current form.