Adaptive convergent evolution of genome proofreading in SARS-CoV2: insights into the Eigen’s paradox

  1. Keerthic Aswin
  2. Srinivasan Ramachandran
  3. Vivek T Natarajan

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Abstract

Evolutionary history of coronaviruses holds the key to understand mutational behavior and prepare for possible future outbreaks. By performing comparative genome analysis of nidovirales that contain the family of coronaviruses, we traced the origin of proofreading, surprisingly to the eukaryotic antiviral component ZNFX1. This common recent ancestor contributes two zinc finger (ZnF) motifs that are unique to viral exonuclease, segregating them from DNA proof-readers. Phylogenetic analyses indicate that following acquisition, genomes of coronaviruses retained and further fine-tuned proofreading exonuclease, whereas related families harbor substitution of key residues in ZnF1 motif concomitant to a reduction in their genome sizes. Structural modelling followed by simulation suggests the role of ZnF in RNA binding. Key ZnF residues strongly coevolve with replicase, and the helicase involved in duplex RNA unwinding. Hence, fidelity of replication in coronaviruses is a result of convergent evolution, that enables maintenance of genome stability akin to cellular proofreading systems.

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    SciScore for 10.1101/2021.09.11.459886: (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
    SentencesResources
    Collection of sequences: All RNA viruses having the host specificity to human and viruses belonging to Nidovirales order were identified from ViralZone Expasy(Viralzone) website and further validated using International Committee on Taxonomy of Viruses (ICTV)(Lefkowitz et al. 2018) website.
    ViralZone Expasy(Viralzone
    suggested: None
    The tree was visualized using Figtree v1.4.4(Rambaut
    Figtree
    suggested: (FigTree, RRID:SCR_008515)
    The sequences of Tobaniviridae family were used as the query and distant orthologs were searched in Refseq protein database with default settings.
    Refseq
    suggested: (RefSeq, RRID:SCR_003496)
    Codon usage: The codon usage pattern of NSP12 and NSP14 ExoN in Tobaniviridae, Mesoniviridae and Coronaviridae was calculated using EMBOSS Cusp webserver(Rice et al. 2000) and visualized as a heatmap in RStudio.
    EMBOSS
    suggested: (EMBOSS, RRID:SCR_008493)
    The Euclidean distance between NSP12 and NSP14 ExoN was calculated using dist function in RStudio.
    RStudio
    suggested: (RStudio, RRID:SCR_000432)
    Structure modelling and validation: The structure of SARS-CoV2 NSP14 was modelled based on SARS-CoV NSP14 (PDB #5C8S) using I-TASSER web server(Zhang 2008).
    I-TASSER
    suggested: (I-TASSER, RRID:SCR_014627)
    Graphing, Advanced Computation and Exploration (GRACE) program, version 5.1.22 and MATLAB were used to construct graphs/plots.
    MATLAB
    suggested: (MATLAB, RRID:SCR_001622)
    The secondary structure prediction in the ZnF1 motif for Tobaniviridae, Mesoniviridae and Coronaviridae was done using Jpred tool(Cuff et al. 1998) in JALVIEW software(Waterhouse et al. 2009).
    Jpred
    suggested: (Jpred, RRID:SCR_016504)
    JALVIEW
    suggested: (Jalview, RRID:SCR_006459)
    The number of residues in each protein coevolving with the active site, ZnF1 and ZnF2 motifs of NSP14_ExoN were calculated and plotted as a circos plot using Circos package v0.69-9.
    Circos
    suggested: (Circos, RRID:SCR_011798)
    This heatmap was also depicted in the structure of ZnF1 and ZnF2 motifs using Chimera software to map coevolving residues between ZnFs and core replication machinery.
    Chimera
    suggested: (Chimera, RRID:SCR_002959)

    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.
    • 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 10.1101/2021.09.11.459886v1 on bioRxiv