Tracking Co-Occurrence of N501Y, P681R, and Other Key Mutations in SARS-CoV-2 Spike for Surveillance

  1. Carol Lee
  2. Shruthi Mangalaganesh
  3. Laurence O. W. Wilson
  4. Michael J. Kuiper
  5. Trevor W. Drew
  6. Seshadri S. Vasan

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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has produced five variants of concern (VOC) to date. The important spike mutation ‘N501Y’ is common to Alpha, Beta, Gamma, and Omicron VOC, while the ‘P681R’ is key to Delta’s spread. We have analysed circa 10 million SARS-CoV-2 genome sequences from the world’s largest repository, ‘Global Initiative on Sharing All Influenza Data (GISAID)’, and demonstrated that these two mutations have co-occurred on the spike ‘D614G’ mutation background at least 5767 times from 12 May 2020 to 28 April 2022. In contrast, the Y501-H681 combination, which is common to Alpha and Omicron VOC, is present in circa 1.1 million entries. Over half of the 5767 co-occurrences were in France, Turkey, or US (East Coast), and the rest across 88 other countries; 36.1%, 3.9%, and 4.1% of the co-occurrences were Alpha’s Q.4, Gamma’s P.1.8, and Omicron’s BA.1.1 sub-lineages acquiring the P681R; 4.6% and 3.0% were Delta’s AY.5.7 sub-lineage and B.1.617.2 lineage acquiring the N501Y; the remaining 8.2% were in other variants. Despite the selective advantages individually conferred by N501Y and P681R, the Y501-R681 combination counterintuitively did not outcompete other variants in every instance we have examined. While this is a relief to worldwide public health efforts, in vitro and in vivo studies are urgently required in the absence of a strong in silico explanation for this phenomenon. This study demonstrates a pipeline to analyse combinations of key mutations from public domain information in a systematic manner and provide early warnings of spread. The study here demonstrates the usage of the pipeline using the key mutations N501Y, P681R, and D614G of SARS-CoV-2.

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  1. Version published to 10.3390/zoonoticdis2030014
  2. ScreenIT

    SciScore for 10.1101/2021.12.25.21268404: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Using a custom Python code, we identified the presence of the D614G, N501Y and P681R mutations, and combinations thereof (c.f. ‘Data Availability Statement’ for our code).
    Python
    suggested: (IPython, RRID:SCR_001658)
    Models were simulated in aqueous solution (TIP3, water, 0.15M ions, NVT ensemble, 310K) using NAMD 2.14 software [46].
    NAMD
    suggested: (NAMD, RRID:SCR_014894)

    Results from OddPub: Thank you for sharing your code and data.

    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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  3. Version published to 10.1101/2021.12.25.21268404v2 on medRxiv
  4. Version published to 10.1101/2021.12.25.21268404v1 on medRxiv