Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function. 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., Scheepers, C., Bhiman, J. N, Everatt, J., Amoako, D. G, San, J. E., Giandhari, J., Sigal, A., NGS-SA, Williamson, C., Hsiao, N., von Gottberg, A., Klerk, A. D., 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., & Pond, S. L K. bioRxiv, Cold Spring Harbor Laboratory, jan, 2022.
Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function [link]Paper  doi  abstract   bibtex   
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.
@article{Martin2022,
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.},
author = {Martin, Darren P and Lytras, Spyros and Lucaci, Alexander G and Maier, Wolfgang and Gr{\"{u}}ning, Bj{\"{o}}rn and Shank, Stephen D and Weaver, Steven and MacLean, Oscar A and Orton, Richard J and Lemey, Philippe and Boni, Maciej F and Tegally, Houriiyah and Harkins, Gordon and Scheepers, Cathrine and Bhiman, Jinal N and Everatt, Josie and Amoako, Daniel G and San, James Emmanuel and Giandhari, Jennifer and Sigal, Alex and NGS-SA and Williamson, Carolyn and Hsiao, Nei-yuan and von Gottberg, Anne and Klerk, Arne De and Shafer, Robert W and Robertson, David L and Wilkinson, Robert J and Sewell, B Trevor and Lessells, Richard and Nekrutenko, Anton and Greaney, Allison J. and Starr, Tyler N. and Bloom, Jesse D. and Murrell, Ben and Wilkinson, Eduan and Gupta, Ravindra K and de Oliveira, Tulio and Pond, Sergei L Kosakovsky},
doi = {10.1101/2022.01.14.476382},
file = {:C$\backslash$:/Users/Claire/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Martin et al. - 2022 - Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spi.pdf:pdf},
journal = {bioRxiv},
keywords = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
pages = {2022.01.14.476382},
pmid = {35075456},
publisher = {Cold Spring Harbor Laboratory},
title = {{Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function}},
url = {https://www.biorxiv.org/content/10.1101/2022.01.14.476382v1 https://www.biorxiv.org/content/10.1101/2022.01.14.476382v1.abstract},
year = {2022}
}

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