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Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution
Tyler N Starr1, Allison J Greaney1,2,3, William W Hannon1,4
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Science (New York, N.Y.)
|June 28, 2022
Summary
SARS-CoV-2 variants evolve through mutations in the spike protein's receptor-binding domain (RBD). These changes, influenced by epistasis, shape viral evolution and antibody escape, impacting future strains like Omicron.
Area of Science:
- Virology
- Molecular Biology
- Genetics
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants exhibit spike receptor-binding domain (RBD) substitutions impacting ACE2 binding and antibody recognition.
- These substitutions may influence future viral evolution through epistasis, where mutations at one site alter the effects of mutations at other sites.
Purpose of the Study:
- To investigate the role of epistasis in shaping SARS-CoV-2 evolution.
- To measure the impact of all single-amino acid mutations in the RBDs of various SARS-CoV-2 variants (Wuhan-Hu-1, Alpha, Beta, Delta, Eta) on ACE2 binding.
Main Methods:
- Deep mutational scanning was employed to assess the effects of all single-amino acid substitutions in the RBDs of specified SARS-CoV-2 variants.
- Analysis focused on changes in binding affinity to the human angiotensin-converting enzyme 2 (ACE2) receptor.
Main Results:
- Specific substitutions, notably Asn501Tyr (N501Y), induced epistatic shifts, altering the effects of mutations at other sites.
- These epistatic shifts were observed to facilitate subsequent evolutionary changes, including antibody escape mutations seen in the Omicron variant.
- Epistatic effects were evident despite the conserved overall structure of the RBD.
Conclusions:
- Epistasis plays a crucial role in the evolutionary trajectory of SARS-CoV-2, influencing the emergence of variants with altered binding and immune evasion properties.
- Understanding these sequence-function relationships in the RBD is vital for interpreting ongoing viral evolution and predicting future SARS-CoV-2 adaptations.
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