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Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

View ORCID ProfileAlief Moulana, View ORCID ProfileThomas Dupic, View ORCID ProfileAngela M. Phillips, View ORCID ProfileJeffrey Chang, Serafina Nieves, Anne A. Roffler, View ORCID ProfileAllison J. Greaney, View ORCID ProfileTyler N. Starr, View ORCID ProfileJesse D. Bloom, View ORCID ProfileMichael M. Desai
doi: https://doi.org/10.1101/2022.06.17.496635
Alief Moulana
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
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Thomas Dupic
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
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Angela M. Phillips
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
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Jeffrey Chang
2Department of Physics, Harvard University, Cambridge, MA 02138
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Serafina Nieves
3Department of Molecular and Cellular Biology, Harvard University, Cambridge MA 02138
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Anne A. Roffler
4Biological and Biomedical Sciences, Harvard Medical School, Boston MA 02115
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Allison J. Greaney
5Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
6Department of Genome Sciences, University of Washington, Seattle, WA 98195
7Medical Scientist Training Program, University of Washington, Seattle, WA 98195
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Tyler N. Starr
5Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
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Jesse D. Bloom
5Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
6Department of Genome Sciences, University of Washington, Seattle, WA 98195
8Howard Hughes Medical Institute, Seattle, WA 98109
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Michael M. Desai
1Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138
2Department of Physics, Harvard University, Cambridge, MA 02138
9NSF-Simons Center for Mathematical and Statistical Analysis of Biology, Harvard University, Cambridge MA 02138
10Quantitative Biology Initiative, Harvard University, Cambridge MA 02138
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  • For correspondence: mdesai@oeb.harvard.edu
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Abstract

The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to the ancestral Wuhan Hu-1 strain and other pre-Omicron SARS-CoV-2 variants, BA.1 has many mutations, a number of which are known to enable antibody escape. Many of these antibody-escape mutations individually decrease the spike receptor-binding domain (RBD) affinity for ACE2 in the background of early SARS-CoV-2 variants, but BA.1 still binds ACE2 with high affinity. The fitness and evolution of the BA.1 lineage is therefore driven by the combined effects of numerous mutations. Here, we systematically map the epistatic interactions between the 15 mutations in the RBD of BA.1 relative to the Wuhan Hu-1 strain. Specifically, we measure the ACE2 affinity of all possible combinations of these 15 mutations (215 = 32,768 genotypes), spanning all possible evolutionary intermediates from the ancestral Wuhan Hu-1 strain to BA.1. We find that immune escape mutations in BA.1 individually reduce ACE2 affinity but are compensated by epistatic interactions with other affinity-enhancing mutations, including Q498R and N501Y. Thus, the ability of BA.1 to evade immunity while maintaining ACE2 affinity is contingent on acquiring multiple interacting mutations. Our results implicate compensatory epistasis as a key factor driving substantial evolutionary change for SARS-CoV-2 and are consistent with Omicron BA.1 arising from a chronic infection.

Competing Interest Statement

J.D.B. has or has recently consulted for Apriori Bio, Oncorus, Moderna, and Merck. J.D.B., A.J.G., and T.N.S. are inventors on Fred Hutch licensed patents related to viral deep mutational scanning. The other authors declare no competing financial interests.

Footnotes

  • https://github.com/desai-lab/compensatory_epistasis_omicron

  • https://desai-lab.github.io/wuhan_to_omicron/

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1
Alief Moulana, Thomas Dupic, Angela M. Phillips, Jeffrey Chang, Serafina Nieves, Anne A. Roffler, Allison J. Greaney, Tyler N. Starr, Jesse D. Bloom, Michael M. Desai
bioRxiv 2022.06.17.496635; doi: https://doi.org/10.1101/2022.06.17.496635
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Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1
Alief Moulana, Thomas Dupic, Angela M. Phillips, Jeffrey Chang, Serafina Nieves, Anne A. Roffler, Allison J. Greaney, Tyler N. Starr, Jesse D. Bloom, Michael M. Desai
bioRxiv 2022.06.17.496635; doi: https://doi.org/10.1101/2022.06.17.496635

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