Giuseppe Michieli
Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution
Author summary SARS-CoV-2 variants evolve in part via mutations in the spike receptor-binding domain (RBD) that impact the ability of this domain to evade binding by neutralizing antibodies while maintaining high-affinity binding to ACE2 receptor. To aid in ongoing viral forecasting and surveillance, we conducted high-throughput measurements of the impacts of all possible amino acid mutations or single-codon deletions on ACE2 binding in the newly evolved Omicron BQ.1.1 and XBB.1.5 variant backgrounds. We find that mutations and deletions are well-tolerated in these domains, consistent with the ongoing evolutionary potential of Omicron sub-variants. We show that the impacts of mutations on ACE2 binding continue to change over time due to the phenomenon of epistasis, though these shifts in mutational effect are less pronounced than epistatic shifts described in earlier variants of concern. Nonetheless, we show that this epistasis continues to enable SARS-CoV-2’s exploration of new mutational combinations as it evolves into new regions of sequence space, highlighting the ongoing evolutionary potential this virus will continue to exhibit.
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