Immune evasion and ACE2 binding affinity contribute to SARS-CoV-2 evolution.

Mutations in the SARS-CoV-2 genome could confer resistance to pre-existing antibodies and/or increased transmissibility. The recently emerged Omicron subvariants exhibit a strong tendency for immune evasion, suggesting adaptive evolution. However, because previous studies have been limited to specific lineages or subsets of mutations, the overall evolutionary trajectory of SARS-CoV-2 and the underlying driving forces are still not fully understood. Here we analysed all open-access SARS-CoV-2 genomes (up to November 2022) and correlated the mutation incidence and fitness changes with the impacts of mutations on immune evasion and ACE2 binding affinity. Our results show that the Omicron lineage had an accelerated mutation rate in the RBD region, while the mutation incidence in other genomic regions did not change dramatically over time. Mutations in the RBD region exhibited a lineage-specific pattern and tended to become more aggregated over time, and the mutation incidence was positively correlated with the strength of antibody pressure. Additionally, mutation incidence was positively correlated with changes in ACE2 binding affinity, but with a lower correlation coefficient than with immune evasion. In contrast, the effect of mutations on fitness was more closely correlated with changes in ACE2 binding affinity than with immune evasion. Our findings suggest that immune evasion and ACE2 binding affinity play significant and diverse roles in the evolution of SARS-CoV-2.