Selection analysis identifies clusters of unusual mutational changes in omicron lineage ba.1 that likely impact spike function
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Date
2022
Journal Title
Journal ISSN
Volume Title
Publisher
Oxford University Press
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.
Description
Keywords
Epistasis, Biology, COVID-19, Spike Glycoprotein, Omicron
Citation
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. https://doi.org/10.1093/molbev/msac061