SARS-COV-2 C.1.2 variant is highly mutated but may possess reduced affinity for ACE2 receptor

  1. Xiang-Jiao Yang

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Abstract

SARS-COV-2 evolution generates different variants and drives the pandemic. As the current main driver, delta variant bears little resemblance to the other three variants of concern (alpha, beta and gamma), raising the question what features the future variants of concern may possess. To address this important question, I searched through the GISAID database for potential clues. While investigating how beta variant has been evolving in South Africa, I noticed a small group of genomes mainly classified as C.1.2 variant, with one-year old boy identified in March 2021 being the index case. Over 80% patients are younger than 60. At the average, there are 46-47 mutations per genome, making this variant one of the most mutated lineages identified. A signature substitution is spike Y449H. Like beta and gamma variants, C.1.2 possesses E484K and N501Y. The genomes are heterogenous and encode different subvariants. Like alpha variant, one such subvariant encodes the spike substitution P681H at the furin cleavage site. In a related genome, this substitution is replaced by P681R, which is present in delta variant. In addition, similar to this variant of concern, three C.1.2 subvariants also encode T478K. Mechanistically, spike Y449 recognizes two key residues of the cell-entry receptor ACE2 and Y449H is known to impair the binding to ACE2 receptor, so C.1.2 variant may show reduced affinity for this receptor. If so, this variant needs other mutations to compensate for such deficiency. These results raise the question whether C.1.2 variant is as virulent as suggested by its unexpected high number of mutations.

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    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
    SentencesResources
    The cleaned Fasta file was then uploaded to SnapGene (version 5.3.2) for multisequence analysis via the MAFFT tool.
    SnapGene
    suggested: (SnapGene, RRID:SCR_015052)
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    With these factors all considered, an optimal tree was selected from the 21 trees for re-rooting via FigTree (https://github.com/rambaut/figtree/releases/tag/v1.4.4).
    FigTree
    suggested: (FigTree, RRID:SCR_008515)
    The resulting tree was exported for image processing via Adobe Photoshop and subsequent presentation via Illustrator.
    Adobe Photoshop
    suggested: (Adobe Photoshop, RRID:SCR_014199)
    PyMol structural modeling: The PyMol molecular graphics system (version 2.4.2, https://pymol.org/2/) from Schrödinger, Inc. was used for downloading structure files from the PDB database for further analysis and image export.
    PyMol
    suggested: (PyMOL, RRID:SCR_000305)
    The images were cropped via Adobe Photoshop and further presentation using Illustrator.
    Illustrator
    suggested: (Adobe Illustrator, RRID:SCR_010279)

    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.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  2. Version published to 10.1101/2021.10.16.464644v1 on bioRxiv