Mutational Hotspot in the SARS-CoV-2 Spike Protein N-Terminal Domain Conferring Immune Escape Potential

  1. Slawomir Kubik
  2. Nils Arrigo
  3. Jaume Bonet
  4. Zhenyu Xu

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Abstract

Global efforts are being made to monitor the evolution of SARS-CoV-2, aiming for early identification of genotypes providing increased infectivity or virulence. However, viral lineage-focused tracking might fail in early detection of advantageous mutations emerging independently across phylogenies. Here, the emergence patterns of Spike mutations were investigated in sequences deposited in local and global databases to identify mutational hotspots across phylogenies and we evaluated their impact on SARS-CoV-2 evolution. We found a striking increase in the frequency of recruitment of diverse substitutions at a critical residue (W152), positioned in the N-terminal domain (NTD) of the Spike protein, observed repeatedly across independent phylogenetic and geographical contexts. These mutations might have an impact on the evasion of neutralizing antibodies. Finally, we found that NTD is a region exhibiting particularly high frequency of mutation recruitments, suggesting an evolutionary path in which the virus maintains optimal efficiency of ACE2 binding combined with the flexibility facilitating the immune escape. We conclude that adaptive mutations, frequently present outside of the receptor-binding domain, can emerge in virtually any SARS-CoV-2 lineage and at any geographical location. Therefore, surveillance should not be restricted to monitoring defined lineages alone.

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  1. Version published to 10.3390/v13112114
  2. ScreenIT

    SciScore for 10.1101/2021.05.28.446137: (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

    Antibodies
    SentencesResources
    Analysis of publicly available SARS-CoV-2 sequences: Structure-based prediction of the impact of the mutations on Spike interactions: We assessed the effect of W152 mutants on neutralizing antibody (nAb) recognition by generating single point mutants (W152C, W152L and W152R) and evaluating their changes in binding free energy (ddG) against 5 different NTD-target antibodies (1-87 and 5-24 (36), 4A8 (29), FC05 (37) and S2X333 (38), structures obtained from the Protein Data Bank (39)) using Rosetta (40).
    W152R
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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

    About SciScore

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  3. Version published to 10.1101/2021.05.28.446137v1 on bioRxiv