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Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution

View ORCID ProfileTyler N. Starr, View ORCID ProfileAllison J. Greaney, William W. Hannon, Andrea N. Loes, Kevin Hauser, Josh R. Dillen, Elena Ferri, Ariana Ghez Farrell, Bernadeta Dadonaite, Matthew McCallum, Kenneth A. Matreyek, Davide Corti, David Veesler, Gyorgy Snell, View ORCID ProfileJesse D. Bloom
doi: https://doi.org/10.1101/2022.02.24.481899
Tyler N. Starr
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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  • For correspondence: tstarr@fredhutch.org jbloom@fredhutch.org
Allison J. Greaney
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA
3Medical Scientist Training Program, University of Washington, Seattle, WA 98109, USA
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William W. Hannon
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
4Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98109, USA
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Andrea N. Loes
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
5Howard Hughes Medical Institute, Seattle, WA 98109, USA
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Kevin Hauser
6Vir Biotechnology, San Francisco, CA 94158, USA
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Josh R. Dillen
6Vir Biotechnology, San Francisco, CA 94158, USA
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Elena Ferri
6Vir Biotechnology, San Francisco, CA 94158, USA
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Ariana Ghez Farrell
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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Bernadeta Dadonaite
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
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Matthew McCallum
7Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Kenneth A. Matreyek
8Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
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Davide Corti
9Humabs BioMed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland
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David Veesler
5Howard Hughes Medical Institute, Seattle, WA 98109, USA
7Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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Gyorgy Snell
6Vir Biotechnology, San Francisco, CA 94158, USA
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Jesse D. Bloom
1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
2Department of Genome Sciences, University of Washington, Seattle, WA 98109, USA
5Howard Hughes Medical Institute, Seattle, WA 98109, USA
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  • ORCID record for Jesse D. Bloom
  • For correspondence: tstarr@fredhutch.org jbloom@fredhutch.org
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Abstract

SARS-CoV-2 has evolved variants with substitutions in the spike receptor-binding domain (RBD) that impact its affinity for ACE2 receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites—a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single amino-acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently N501Y, cause epistatic shifts in the effects of mutations at other sites, thereby shaping subsequent evolutionary change. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.

Competing Interest Statement

JDB consults for Moderna on viral evolution and epidemiology and Flagship Labs 77 on deep mutational scanning. TNS, AJG, ANL, and JDB may receive a share of IP revenue as inventors on Fred Hutch-optioned technology/patents related to deep mutational scanning of viral proteins. KH, EF, JRD, DC, and GS are employees of Vir Biotechnology and may hold shares in Vir Biotechnology.

Footnotes

  • ↵* Co-first authors

  • https://github.com/jbloomlab/SARS-CoV-2-RBD_DMS_variants

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 4.0 International license.
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Posted February 26, 2022.
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Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution
Tyler N. Starr, Allison J. Greaney, William W. Hannon, Andrea N. Loes, Kevin Hauser, Josh R. Dillen, Elena Ferri, Ariana Ghez Farrell, Bernadeta Dadonaite, Matthew McCallum, Kenneth A. Matreyek, Davide Corti, David Veesler, Gyorgy Snell, Jesse D. Bloom
bioRxiv 2022.02.24.481899; doi: https://doi.org/10.1101/2022.02.24.481899
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Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution
Tyler N. Starr, Allison J. Greaney, William W. Hannon, Andrea N. Loes, Kevin Hauser, Josh R. Dillen, Elena Ferri, Ariana Ghez Farrell, Bernadeta Dadonaite, Matthew McCallum, Kenneth A. Matreyek, Davide Corti, David Veesler, Gyorgy Snell, Jesse D. Bloom
bioRxiv 2022.02.24.481899; doi: https://doi.org/10.1101/2022.02.24.481899

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