Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

  1. Changshuo Wei
  2. Ke-Jia Shan
  3. Weiguang Wang
  4. Shuya Zhang
  5. Qing Huan
  6. Wenfeng Qian

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Abstract

The rapid accumulation of mutations in the SARS-CoV-2 Omicron variant that enabled its outbreak raises questions as to whether its proximal origin occurred in humans or another mammalian host. Here, we identified 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage. We found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting the possibility of host-jumping. The molecular spectrum ( i . e ., the relative frequency of the twelve types of base substitutions) of mutations acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients, but was highly consistent with spectra associated with evolution in a mouse cellular environment. Furthermore, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.

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    SciScore for 10.1101/2021.12.14.472632: (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
    The phylogenetic tree and ancestral sequences were reconstructed using FastML v3.11 (Ashkenazy et al., 2012) with default parameters.
    FastML
    suggested: (Fastml, RRID:SCR_016092)
    The numbers of synonymous and nonsynonymous sites in ORF S of SARS-CoV-2 were estimated by PAML in a previous study (Wei et al., 2021).
    PAML
    suggested: (PAML, RRID:SCR_014932)
    The virus genome sequences were aligned by MUSCLE, and the phylogenetic trees and ancestral sequences were reconstructed using FastML.
    MUSCLE
    suggested: (MUSCLE, RRID:SCR_011812)
    BLASTx was performed to identify ORF S in each variant, and mutations were identified at the same time.
    BLASTx
    suggested: (BLASTX, RRID:SCR_001653)
    Three species (Mesocricetus auratus, Chlorocebus sabaeus, and Puma concolor) were discarded because they harbored less than three single amino acid mutations.
    Puma
    suggested: (PUMA, RRID:SCR_002057)
    The structure models of the Omicron RBD and the RBD with five mutations (K417N, E484A, Q493R, Q498R, and N501Y) were generated using SWISS-MODEL (Waterhouse et al., 2018), and those of other RBD variants were generated using PyMOL “mutagenesis” (https://pymol.org/).
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)

    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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  2. Version published to 10.1101/2021.12.14.472632v1 on bioRxiv
  3. Version published to 10.1016/j.jgg.2021.12.003