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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Abstract
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 |
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Status: | Published |
Refereed: | Yes |
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: | 0737-4038 |
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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