Evolution of Delta variant by non-Spike signature co-appearing mutations: trailblazer of COVID-19 disease outcome

  1. Anindita Banerjee
  2. Anup Mazumder
  3. Jayita Roy
  4. Agniva Majumdar
  5. Ananya Chatterjee
  6. Nidhan K Biswas
  7. Mamta Chawla Sarkar
  8. Arindam Maitra
  9. Shanta Dutta
  10. Saumitra Das

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Abstract

The high transmissibility and infectivity of a SARS-CoV-2 variant is usually ascribed to the Spike mutations, while emerging non-spike mutations might be a serious threat to the current Spike-recombinant vaccines. In addition to mutations in structural Spike glycoprotein, rapid accumulation of mutations across non-structural genes is leading to continuous virus evolution, altering its pathogenicity. We performed whole genome sequencing of SARS-CoV-2 positive samples collected from different clinical groups from eastern India, during the second pandemic wave (April-May, 2021). In addition to the several common spike mutations in Delta variant, two mutually explicit signature constellations of non-spike co-appearing mutations were identified, driving symptomatic and asymptomatic infections. We attempted to correlate these unique signatures of non-Spike co-appearing mutations to COVID-19 disease outcome. Results revealed that the Delta strains harboring a unique constellation of 9 non-spike co-appearing mutations could be the wheeler and dealer of symptomatic infection, even post vaccination. The strains predominantly driving asymptomatic infection possessed 7 non-spike co-appearing mutations, which were mutually exclusive in contrast to the set of mutations causing symptomatic disease. Phylodynamic analysis depicted high probability of emergence of these unique sub-clusters within India, with subsequent spread worldwide. Interestingly, some mutations of this signature were selected in Omicron and IHU variants, which suggest that gradual accumulation of such co-existing mutations may lead to emergence of more “vaccine-evading variants” in future. Hence, unfaltering genome sequencing and tracking of non-Spike mutations might be significant in formulation of any future vaccines against emerging SARS-CoV-2 variants that might evade the current vaccine-induced immunity.

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    SciScore for 10.1101/2022.04.05.487103: (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
    Phylogenetic analyses: Genome sequences of reference SARS-CoV-2 strains (collected from GISAID and NCBI) belonging to different clades/variants circulating worldwide as well as representative strains from the study were aligned by multiple alignment program MAFFT version 7.
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    Phylogenetic analysis was done using Molecular Evolutionary Genetics Analysis (MEGA) version XI by maximum-likelihood method using the best fit statistical model general time reversal (GTR) with 1000 bootstrap replicates.
    MEGA
    suggested: (Mega BLAST, RRID:SCR_011920)
    Further, we have refined the PatchDock output using the FireDock (https://bioinfo3d.cs.tau.ac.il/FireDock/) web server where the global energy value was depicted [22].
    PatchDock
    suggested: (PatchDock, RRID:SCR_017589)

    Results from OddPub: Thank you for sharing your 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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  2. Version published to 10.1101/2022.04.05.487103v1 on bioRxiv