Evidence of recombination in coronaviruses implicating pangolin origins of nCoV-2019

Matthew C. Wong; Sara J. Javornik Cregeen; Nadim J. Ajami; Joseph F. Petrosino

The coronavirus spike protein is a trimeric protein that mediates virus entry into the host cell. It is composed of two domains: S1 and S2. The S1 domain contains two subdomains: S1-NTD and S1-CTD, also known as the receptor binding domain (RBD). The S2 domain encodes the stalk of the spike protein and is highly conserved across the SARS-like coronaviruses 4 . In order to infect a host cell, the RBD must first bind to a surface protein on the host cell. In the case of SARS-CoV and nCoV-2019, this is the angiotensin converting enzyme 2 (ACE2) receptor, expressed in human airway epithelia as well as lung parenchyma among other tissues. Following RBD binding, the S1/S2 junction must be cleaved by a surface protease 4 . Zhou et al. (2020) 2 have reported noticeable decreased amino acid homology between the RBD of the spike protein in RaTG13 and nCoV-2019. A further analysis of the RBD in RaTG13 showed the majority of the divergence was restricted to amino acid residues 435 to 510 (75% nucleotide identity and 78% amino acid identity). This region corresponds to the receptor binding motif (RBM), which is responsible for host specificity. Such divergence at the RBM could indicate the possibility of an alternate source for the RBM coding sequence in nCoV-2019. To explore this, we examined several viral metagenomic datasets for potential coronaviruses that could harbor RBMs closer to nCoV-2019.