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Medical Sciences, The University of Sydney, Sydney, Australia. 6​Tulane University, School of Medicine, Department of Microbiology and Immunology, New Orleans, LA, USA. 7​Zalgen Labs, LCC, Germantown, MD, USA. *Corresponding author: andersen@scripps.edu TO THE EDITOR - Since the first reports of novel pneumonia (COVID-19) in Wuhan, Hubei province, China​1,2 there has been considerable discussion on the origin of the causative virus SARS-CoV-2​3 (also referred to as HCoV-19)​4​. Infections with SARS-CoV-2 are now widespread, and as of 29 February 2020, 86,012 cases have been confirmed in more than 60 countries, with 2,941 deaths​5​. SARS-CoV-2 is the seventh coronavirus known to infect humans. SARS-CoV, MERS-CoV, and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E, are associated with mild symptoms​6​. Herein, we review what can be deduced about the origin of SARS-CoV-2 from the comparative analysis of genomic data. We offer a perspective on the notable features in the SARS-CoV-2 genome and discuss scenarios by which they could have arisen. Our analyses clearly show that SARS-CoV-2 is not a laboratory construct nor a purposefully manipulated virus. Notable features of the SARS-CoV-2 genome Our comparison of alpha- and betacoronaviruses identifies two notable genomic features of SARS-CoV-2: (​i​) based on structural studies​7-9 and biochemical experiments​1,9,10​, SARS-CoV-2 appears optimized for binding to the human ACE2 receptor; (​ii​) the spike (S) protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1/S2 boundary through the insertion of twelve nucleotides​8​. Additionally, this led to the predicted acquisition of three O-linked glycans around the site. 1. Mutations in the receptor binding domain of SARS-CoV-2 The receptor binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome​1,2​. Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and determining the host range of SARS-like viruses​7​. Using coordinates based on SARS-CoV, they are Y442, L472, N479, D480, T487, and Y4911 corresponding to L455, F486, Q493, S494, N501, and Y505 in SARS-CoV-2​7​. Five of these six residues differ between SARS-CoV-2 and SARS-CoV (​Fig. 1a​). Based on structural studies​7-9 and biochemical experiments​1,9,10​, SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from human, ferret, cat, and other species with high receptor homology​7​. While these analyses suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal​7 and the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding​7,11​. Thus, the high affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 permitting another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is ​not the product of purposeful manipulation. 2. Polybasic furin cleavage site and O-linked glycans The second notable feature of SARS-CoV-2 is a polybasic cleavage site (RRAR) at the S1/S2 junction, the two subunits of the spike (​Fig. 1b​)​8​. This allows effective cleavage by furin and other proteases and plays a role in determining virus infectivity and host range​12​. In addition, a leading proline is also inserted at this site in SARS-CoV-2; thus, the inserted sequence is PRRA (​Fig. 1b​). The turn created by the proline is predicted to result in the addition of O-linked glycans to S673, T678, and S686 flanking the cleavage site and are unique to SARS-CoV-2 (​Fig. 1b​). Polybasic cleavage sites have not been observed in related