Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function
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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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SciScore for 10.1101/2022.01.14.476382: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Analyses of selection in sarbecoviruses related to SARS-CoV-2: The whole genome sequences of 167 members of the Sarbecovirus subgenus (including SARS-CoV and SARS-CoV-2 Wuhan-Hu-1; See https://docs.google.com/spreadsheets/d/1sSt7fRiBYeW9z5Amj1_OywHhfxCnZ2wqo9gnLKsq74c/edit?usp=sharing for the full list of accession numbers) were aligned using MAFFT (with the localpair option 54). MAFFTsuggested: (MAFFT, RRID:SCR_011811)We used HyPhy v2.5.34 (http://www.hyphy.org/) 14 to perform a series of selection analyses. HyPhysuggested: (HyPhy, RRID:SCR_016162)Results from OddPub: Thank you for sharing …
SciScore for 10.1101/2022.01.14.476382: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources Analyses of selection in sarbecoviruses related to SARS-CoV-2: The whole genome sequences of 167 members of the Sarbecovirus subgenus (including SARS-CoV and SARS-CoV-2 Wuhan-Hu-1; See https://docs.google.com/spreadsheets/d/1sSt7fRiBYeW9z5Amj1_OywHhfxCnZ2wqo9gnLKsq74c/edit?usp=sharing for the full list of accession numbers) were aligned using MAFFT (with the localpair option 54). MAFFTsuggested: (MAFFT, RRID:SCR_011811)We used HyPhy v2.5.34 (http://www.hyphy.org/) 14 to perform a series of selection analyses. HyPhysuggested: (HyPhy, RRID:SCR_016162)Results from OddPub: Thank you for sharing your code.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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