Emergence of SARS-CoV-2 through Recombination and Strong Purifying Selection

Xiaojun Li; Elena E. Giorgi; Manukumar Honnayakanahalli Marichann; Brian Foley; Chuan Xiao; Xiang-peng Kong; Yue Chen; Bette Korber; Feng Gao

Although both SARS-CoV and SARS-CoV-2 use the human ACE2 as their receptors (8, 20) they show a high level of genetic divergence (figs. 1 and S1). However, structures of the S1 unit of the S protein from both viruses are highly similar (21) (22) (23) , with the exception of a loop, not proximal to the binding site, that bends differently ( fig. 2C ). This suggests that viral entry through binding of ACE2 is structurally constrained to maintain the correct conformation. Among 17 distinct amino acids between SARS-CoV-2 and RaTG13 ( fig. 2A ), five contact sites are different, likely impacting RaTG13's binding to ACE2 ( fig. 2D and Table S1 ). The single amino acid difference (Q or H at position 498) between SARS-CoV-2 and Pan_SL-CoV_GD is at the edge of the ACE2 contact interface; neither Q or H at this position form hydrogen bonds with ACE2 residues ( fig. 2E ). Thus, a functional RBM nearly identical to the one in SARS-CoV-2 is naturally present in Pan_SL-CoV_GD viruses. The very distinctive RaTG13 RBM suggests that this virus is unlikely to infect human cells, and that the acquisition of a complete functional RBM by a RaTG13-like CoV through a recombination event with a Pan_SL-CoV_GD-like virus enabled it to use ACE2 for human infection.