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Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function

Darren P Martin, Spyros Lytras, Alexander G Lucaci, Wolfgang Maier, Björn Grüning, Stephen D Shank, Steven Weaver, Oscar A MacLean, Richard J Orton, Philippe Lemey, Maciej F Boni, Houriiyah Tegally, Gordon Harkins, Cathrine Scheepers, Jinal N Bhiman, Josie Everatt, Daniel G Amoako, James Emmanuel San, Jennifer Giandhari, Alex Sigal, NGS-SA, Carolyn Williamson, Nei-yuan Hsiao, Anne von Gottberg, Arne De Klerk, Robert W Shafer, David L Robertson, Robert J Wilkinson, B Trevor Sewell, Richard Lessells, Anton Nekrutenko, Allison J. Greaney, Tyler N. Starr, Jesse D. Bloom, Ben Murrell, Eduan Wilkinson, Ravindra K Gupta, Tulio de Oliveira, Sergei L Kosakovsky Pond
doi: https://doi.org/10.1101/2022.01.14.476382
Darren P Martin
1Institute of Infectious Diseases and Molecular Medicine, Division Of Computational Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town 7701, South Africa
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  • For correspondence: darrenpatrickmartin@gmail.com
Spyros Lytras
2MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK
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Alexander G Lucaci
3Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
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Wolfgang Maier
4Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany,
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Björn Grüning
4Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany,
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Stephen D Shank
3Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
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Steven Weaver
3Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
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Oscar A MacLean
2MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK
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Richard J Orton
2MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK
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Philippe Lemey
5Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
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Maciej F Boni
6Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, PA, USA
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Houriiyah Tegally
7KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South Africa
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Gordon Harkins
8South African National Bioinformatics Institute, University of the Western Cape, Cape Town, South Africa
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Cathrine Scheepers
9National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa
10SA MRC Antibody Immunity Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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Jinal N Bhiman
9National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa
10SA MRC Antibody Immunity Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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Josie Everatt
9National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa
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Daniel G Amoako
9National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa
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James Emmanuel San
7KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South Africa
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Jennifer Giandhari
7KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South Africa
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Alex Sigal
11Africa Health Research Institute, Durban, South Africa
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12
Carolyn Williamson
13Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town, South Africa
14Division of Medical Virology, University of Cape Town and National Health Laboratory Service, Cape Town South Africa
17Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, South Africa
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Nei-yuan Hsiao
14Division of Medical Virology, University of Cape Town and National Health Laboratory Service, Cape Town South Africa
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Anne von Gottberg
9National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa
15School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg
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Arne De Klerk
1Institute of Infectious Diseases and Molecular Medicine, Division Of Computational Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town 7701, South Africa
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Robert W Shafer
16Division of Infectious Diseases, Department of medicine, Stanford university, Stanford, CA, USA
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David L Robertson
2MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK
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Robert J Wilkinson
17Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cape Town, South Africa
18Francis Crick Institute, Midland Road, London NW1 1AT, UK
19Department of Infectious Diseases, Imperial College London, W12 0NN, UK
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B Trevor Sewell
20Structural Biology Research Unit, Department of Integrative Biomedical Sciences, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, South Africa
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Richard Lessells
7KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South Africa
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Anton Nekrutenko
21Department Of Biochemistry and Molecular Biology, The Pennsylvania State University,
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Allison J. Greaney
22Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
23Department of Genome Sciences & Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA3
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Tyler N. Starr
22Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
24Howard Hughes Medical Institute, Seattle, WA 98109, USA
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Jesse D. Bloom
22Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
24Howard Hughes Medical Institute, Seattle, WA 98109, USA
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Ben Murrell
25Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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Eduan Wilkinson
7KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South Africa
26Centre for Epidemic Response and Innovation (CERI), School of Data Science, Stellenbosch University
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Ravindra K Gupta
11Africa Health Research Institute, Durban, South Africa
27Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge
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Tulio de Oliveira
7KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South Africa
26Centre for Epidemic Response and Innovation (CERI), School of Data Science, Stellenbosch University
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Sergei L Kosakovsky Pond
3Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
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Abstract

Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any genomes within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.

Competing Interest Statement

JDB consults for Moderna, Flagship Labs 77, and Oncorus. JDB, AJG, and TNS are inventors on Fred Hutch licensed patents related to deep mutational scanning of viral proteins.

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 January 18, 2022.
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Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function
Darren P Martin, Spyros Lytras, Alexander G Lucaci, Wolfgang Maier, Björn Grüning, Stephen D Shank, Steven Weaver, Oscar A MacLean, Richard J Orton, Philippe Lemey, Maciej F Boni, Houriiyah Tegally, Gordon Harkins, Cathrine Scheepers, Jinal N Bhiman, Josie Everatt, Daniel G Amoako, James Emmanuel San, Jennifer Giandhari, Alex Sigal, NGS-SA, Carolyn Williamson, Nei-yuan Hsiao, Anne von Gottberg, Arne De Klerk, Robert W Shafer, David L Robertson, Robert J Wilkinson, B Trevor Sewell, Richard Lessells, Anton Nekrutenko, Allison J. Greaney, Tyler N. Starr, Jesse D. Bloom, Ben Murrell, Eduan Wilkinson, Ravindra K Gupta, Tulio de Oliveira, Sergei L Kosakovsky Pond
bioRxiv 2022.01.14.476382; doi: https://doi.org/10.1101/2022.01.14.476382
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Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function
Darren P Martin, Spyros Lytras, Alexander G Lucaci, Wolfgang Maier, Björn Grüning, Stephen D Shank, Steven Weaver, Oscar A MacLean, Richard J Orton, Philippe Lemey, Maciej F Boni, Houriiyah Tegally, Gordon Harkins, Cathrine Scheepers, Jinal N Bhiman, Josie Everatt, Daniel G Amoako, James Emmanuel San, Jennifer Giandhari, Alex Sigal, NGS-SA, Carolyn Williamson, Nei-yuan Hsiao, Anne von Gottberg, Arne De Klerk, Robert W Shafer, David L Robertson, Robert J Wilkinson, B Trevor Sewell, Richard Lessells, Anton Nekrutenko, Allison J. Greaney, Tyler N. Starr, Jesse D. Bloom, Ben Murrell, Eduan Wilkinson, Ravindra K Gupta, Tulio de Oliveira, Sergei L Kosakovsky Pond
bioRxiv 2022.01.14.476382; doi: https://doi.org/10.1101/2022.01.14.476382

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