Kang, L., He, G., Sharp, A.K., Wang, X., Brown, A.M., Michalak P. & Weger-Lucarelli, J. 2021. A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation. Cell S0092-8674(21)00833-3.

The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signa-tures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and in-crease binding to human ACE2 (hACE2), the cellular receptor. This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays. We engineered the reversion mutant (A372T) and found that A372 (wild-type [WT]-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2 emergence from animal reservoirs or enabled sustained human-to-human transmission.

Structure-based analysis of SARS-CoV-2 S protein variants

(A) Visualization of the T372 and D614G mutants. The structure of S protein (PDB: 7A94) is displayed as a cartoon and colored by RBD (green), N-terminal domain (NTD; orange), central helix (CH;blue), FP (yellow), and connector domain (CD;pink). Glycans are displayed as spheres colored hot pink. The top panel shows the WT (A372) and T372 mutant, the center panel displays a glycosylated N370 T372 S protein with various rotamers of the GlcNAc-glycosylated N370, and the bottom panel shows the WT and G614 mutant.

(B and C) Surface map of the WT S protein (B) and the N370-glycosylated T372 S protein (C), colored by the residue side-chain properties: green for hydrophobic, blue for positively charged, red for negatively charged, teal for polar uncharged, and gray for neutral.

(D) Predicted N-glycosylated residues identified by Schro¨ dinger-Maestro’s BioLuminate (v.2020-2) Reactive Residue package with percent solvent-accessible surface area (SASA) exposure of each residue.

(E) Predicted N-glycosylated residues identified by the NetNGlyc 1.0 server with the probability of being glycosylated.