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Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function
Darren P Martin; Spyro Lytras; Alexander G Lucaci; Wolfgang Maier; Bjorn Gruning; Stephen D Shank; Steven Weaver; Oscar S MacLean; Richard J Orton; Philippe Lemey; Maciej F Boni; Houriiyah Tegally; Gordon W 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; Brian 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.
Affiliation
  • Darren P Martin; Institute of Infectious Diseases and Molecular Medicine, Division Of Computational Biology, Department of Integrative Biomedical Sciences, University of Cape To
  • Spyro Lytras; MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK
  • Alexander G Lucaci; Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
  • Wolfgang Maier; Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany, usegalaxy.eu
  • Bjorn Gruning; Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany, usegalaxy.eu
  • Stephen D Shank; Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
  • Steven Weaver; Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
  • Oscar S MacLean; MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK
  • Richard J Orton; MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK
  • Philippe Lemey; Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium
  • Maciej F Boni; Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, PA, USA
  • Houriiyah Tegally; KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South
  • Gordon W Harkins; South African National Bioinformatics Institute, University of the Western Cape, Cape Town, South Africa
  • Cathrine Scheepers; National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa; SA MRC Antibody Immunity Resea
  • Jinal N Bhiman; National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa; SA MRC Antibody Immunity Resea
  • Josie Everatt; National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa
  • Daniel G Amoako; National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Afric
  • James Emmanuel San; KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South
  • Jennifer Giandhari; KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South
  • Alex Sigal; Africa Health Research Institute, Durban, South Africa
  • - NGS-SA; -
  • Carolyn Williamson; Institute of Infectious Disease and Molecular Medicine, Department of Pathology, University of Cape Town, Cape Town, South Africa; Division of Medical Virology,
  • Nei-yuan Hsiao; Division of Medical Virology, University of Cape Town and National Health Laboratory Service, Cape Town South Africa
  • Anne von Gottberg; National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS), Johannesburg, South Africa; School of Pathology, Faculty
  • Arne De Klerk; Institute of Infectious Diseases and Molecular Medicine, Division Of Computational Biology, Department of Integrative Biomedical Sciences, University of Cape To
  • Robert W Shafer; Division of Infectious Diseases, Department of medicine, Stanford university, Stanford, CA, USA
  • David L Robertson; MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G61 1QH, UK
  • Robert J Wilkinson; Wellcome Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University of Cap
  • Brian Trevor Sewell; Structural Biology Research Unit, Department of Integrative Biomedical Sciences, Institute for Infectious Diseases and Molecular Medicine, University of Cape To
  • Richard Lessells; KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South
  • Anton Nekrutenko; Department Of Biochemistry and Molecular Biology, The Pennsylvania State University, usegalaxy.org
  • Allison J Greaney; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences & Medic
  • Tyler N Starr; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Seat
  • Jesse D Bloom; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Seat
  • Ben Murrell; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
  • Eduan Wilkinson; KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine & Medical Sciences, University of KwaZulu- Natal, Durban, South
  • Ravindra K Gupta; Cambridge Institute of Therapeutic Immunology and Infectious Diseases, University of Cambridge, Cambridge
  • Tulio de Oliveira; Centre for Epidemic Response and Innovation (CERI), School of Data Science, Stellenbosch University.
  • Sergei L Kosakovsky Pond; Institute for Genomics and Evolutionary Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
Preprint in En | PREPRINT-BIORXIV | ID: ppbiorxiv-476382
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.
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Full text: 1 Collection: 09-preprints Database: PREPRINT-BIORXIV Type of study: Experimental_studies / Prognostic_studies Language: En Year: 2022 Document type: Preprint
Full text: 1 Collection: 09-preprints Database: PREPRINT-BIORXIV Type of study: Experimental_studies / Prognostic_studies Language: En Year: 2022 Document type: Preprint