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

Martin, D. P. et al. (2022) Selection analysis identifies clusters of unusual mutational changes in Omicron lineage BA.1 that likely impact Spike function. Molecular Biology and Evolution, 39(4), msac061. (doi: 10.1093/molbev/msac061) (PMID:35325204) (PMCID:PMC9037384)

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Among the 30 nonsynonymous 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 (1) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (2) interactions of Spike with ACE2 receptors, and (3) 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 virus 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, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron overall 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:MacLean, Dr Oscar and Lytras, Spyros and Robertson, Professor David and Orton, Dr Richard
Authors: Martin, D. P., Lytras, S., Lucaci, A. G., Maier, W., Grüning, B., Shank, S. D., Weaver, S., MacLean, O. A., Orton, R. J., Lemey, P., Boni, M. F., Tegally, H., Harkins, G. W., Scheepers, C., Bhiman, J. N., Everatt, J., Amoako, D. G., San, J. E., Giandhari, J., Sigal, A., Williamson, C., Hsiao, N.-y., von Gottberg, A., De Klerk, A., Shafer, R. W., Robertson, D. L., Wilkinson, R. J., Sewell, B. T., Lessells, R., Nekrutenko, A., Greaney, A. J., Starr, T. N., Bloom, J. D., Murrell, B., Wilkinson, E., Gupta, R. K., de Oliveira, T., and Kosakovsky Pond, S. L.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Molecular Biology and Evolution
Publisher:Oxford University Press
ISSN (Online):1537-1719
Published Online:24 March 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Molecular Biology and Evolution 39(4): msac061
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301049Host determinants of disease outcomes in arboviral infectionsMassimo PalmariniWellcome Trust (WELLCOTR)206369/Z/17/ZIII - Centre for Virus Research
172630014Cross-Cutting Programme – Viral Genomics and Bioinformatics (Programme 9)David RobertsonMedical Research Council (MRC)MC_UU_12014/12III - Centre for Virus Research