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

Three small insertions are identical in SARS-CoV-2 and RaTG13 but not found in other CoVs in the Sarbecovirus group (24) . The RaTG13 sequence was sampled in 2013, years before SARS-CoV-2 was first identified. It is unlikely that both SARS-CoV-2 and RaTG13 independently acquired identical insertions at three different locations in the S gene. Thus, it is plausible that an RaTG13-like virus served as a progenitor to generate SARS-CoV-2 by gaining a complete human ACE2 binding RBM from Pan_SL-CoV_GD-like viruses through recombination. Genetic divergence at the nucleic acid level between Wuhan-Hu-1 and Pan_SL-CoV_GD viruses is significantly reduced from 13.9% ( fig. 1E ) to 1.4% at the amino acid level ( fig. 2B ) in the RBM region, indicating recombination between RaTG13-like CoVs and Pan_SL-CoV_GD-like CoVs. Furthermore, SARS-CoV-2 has a unique furin cleavage site insertion (PRRA) not found in any other CoVs in the Sarbecovirus group (24), although similar motifs are also found in MERS and more divergent bat CoVs (25) (Fig. S3 ). This PRRA motif makes the S1/S2 cleavage in SARS-CoV-2 much more efficiently than in SARS-CoV and may expand its tropism and/or enhance its transmissibility (23) . A recent study of bat CoVs in Yunnan, China, identified a three-amino acid insertion (PAA) at the same site (26) . Although it is not known if this PAA motif can function like the PRRA motif, the presence of a similar insertion at the same site indicates that such insertion may already be present in the wild bat CoVs. The more efficient cleavage of S1 and S2 units of the spike glycoprotein (25) and efficient binding to ACE2 by SARS-CoV-2 (22, 27) may have allowed SARS-CoV-2 to jump to humans, leading to the rapid spread of SARS-CoV-2 in China and the rest of the world.