Genomic diversity of SARS-CoV-2 can be accelerated by mutations in the nsp14 gene

  1. Kosuke Takada
  2. Mahoko Takahashi Ueda
  3. Shintaro Shichinohe
  4. Yurie Kida
  5. Chikako Ono
  6. Yoshiharu Matsuura
  7. Tokiko Watanabe
  8. So Nakagawa

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Abstract

Coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), encode a proofreading exonuclease, nonstructural protein 14 (nsp14), that helps ensure replication competence at a low evolutionary rate compared with other RNA viruses. In the current pandemic, SARS-CoV-2 has accumulated diverse genomic mutations including in nsp14. Here, to clarify whether amino acid substitutions in nsp14 affect the genomic diversity and evolution of SARS-CoV-2, we searched for amino acid substitutions in nature that may interfere with nsp14 function. We found that viruses carrying a proline-to-leucine change at position 203 (P203L) have a high evolutionary rate and that a recombinant SARS-CoV-2 virus with the P203L mutation acquired more diverse genomic mutations than wild-type virus during its replication in hamsters. Our findings suggest that substitutions, such as P203L, in nsp14 may accelerate the genomic diversity of SARS-CoV-2, contributing to virus evolution during the pandemic.

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  1. Version published to 10.1101/2020.12.23.424231v4 on bioRxiv
  2. Version published to 10.1101/2020.12.23.424231v3 on bioRxiv
  3. Version published to 10.1101/2020.12.23.424231v2 on bioRxiv
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    SciScore for 10.1101/2020.12.23.424231: (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
    data: Amino acid sequences of open reading frame 1ab (ORF1ab) of the 62 representative CoVs (summarized in Supplementary Table 1) were obtained from NCBI (https://www.ncbi.nlm.nih.gov/) and the GISAID EpiCoV database (https://www.gisaid.org) as reported previously (Nakagawa and Miyazawa 2020)
    https://www.ncbi.nlm.nih.gov/
    suggested: (GENSAT at NCBI - Gene Expression Nervous System Atlas, RRID:SCR_003923)
    To detect amino acid replacements for each site, the amino acid sequence after the stop codon was removed and amino acid sequences were aligned using the L-INS-i program in MAFFT version v7.453 (Katoh and Standley 2013).
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    From the sequence alignment of nsp14 of the representative CoVs, the amino acids aligned at the amino acid positions of SARS-CoV are shown using WebLogo 3 (Crooks, et al. 2004).
    WebLogo
    suggested: (WEBLOGO, RRID:SCR_010236)
    To estimate the appropriate amino acid replacement model, we used ProtTest3 version 3.4.2 (Darriba, et al. 2011) based on the Bayesian information criterion (BIC) values.
    ProtTest3
    suggested: None
    We then computed a phylogenetic tree using RAxML-NG version 1.0.0 (Kozlov, et al. 2019) with rapid 1000 bootstrap replicates (Lanave, et al. 1984).
    RAxML-NG
    suggested: None
    Counting of the number of nucleotide substitution was conducted in MEGA X (Kumar, et al. 2018).
    MEGA
    suggested: (Mega BLAST, RRID:SCR_011920)
    The approximate straight line was calculated using the least-squares method using in-house python scripts.
    python
    suggested: (IPython, RRID:SCR_001658)
    To determine evolutionary selection pressures operating the nsp14 gene in CoVs, we computed the ratio of nonsynonymous substitution rates (dN) and synonymous substitution rates (dS) per site (dN/dS) using the Datamonkey software (Kosakovsky Pond and Frost 2005; Weaver, et al. 2018) through MEGA X (Kumar, et al. 2018).
    Datamonkey
    suggested: (DataMonkey, RRID:SCR_010278)
    The residues at the interface of the SARS-CoV nsp10-nsp14 docked complex were determined using the “InterfaceResidues” PyMol script (http://www.pymolwiki.org/index.php/InterfaceResidues/).
    PyMol
    suggested: (PyMOL, RRID:SCR_000305)

    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.

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  5. Version published to 10.1101/2020.12.23.424231v1 on bioRxiv