Recombination and purifying selection preserves covariant movements of mosaic SARS-CoV-2 protein S

  1. Massimiliano S. Tagliamonte
  2. Nabil Abid
  3. David A. Ostrov
  4. Giovanni Chillemi
  5. Sergei L. Kosakovsky Pond
  6. Marco Salemi
  7. Carla Mavian

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Abstract

In depth evolutionary and structural analyses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolated from bats, pangolins, and humans are necessary to assess the role of natural selection and recombination in the emergence of the current pandemic strain. The SARS-CoV-2 S glycoprotein unique features have been associated with efficient viral spread in the human population. Phylogeny-based and genetic algorithm methods clearly show that recombination events between viral progenitors infecting animal hosts led to a mosaic structure in the S gene. We identified recombination coldspots in the S glycoprotein and strong purifying selection. Moreover, although there is little evidence of diversifying positive selection during host-switching, structural analysis suggests that some of the residues emerged along the ancestral lineage of current pandemic strains may contribute to enhanced ability to infect human cells. Interestingly, recombination did not affect the long-range covariant movements of SARS-CoV-2 S glycoprotein monomer in pre-fusion conformation but, on the contrary, could contribute to the observed overall viral efficiency. Our dynamic simulations revealed that the movements between the host cell receptor binding domain (RBD) and the novel furin-like cleavage site are correlated. We identified threonine 333 (under purifying selection), at the beginning of the RBD, as the hinge of the opening/closing mechanism of the SARS-CoV-2 S glycoprotein monomer functional to hACE2 binding. Our findings support a scenario where ancestral recombination and fixation of amino acid residues in the RBD of the S glycoprotein generated a virus with unique features, capable of extremely efficient infection of the human host.

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  1. Version published to 10.1101/2020.03.30.015685v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.03.30.015685: (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
    To gather closely related CoVs BLASTn was performed using the ViPR database and keeping the first 100 hits.
    BLASTn
    suggested: (BLASTN, RRID:SCR_001598)
    ViPR
    suggested: (vipR, RRID:SCR_010685)
    Genome sequences were aligned using MAFFT (Katoh and Standley 2016) and refined manually.
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)
    Phylogenetic signal for the subset alignment including bat, human and pangolin CoV-2 sequences was l was confirmed with TREE-PUZZLE(Schmidt, et al. 2002), and weighted SH and AU tests (Shimodaira 2002) implemented in PAUP* v.4.04a build 167 (Hancock 2014)
    PAUP*
    suggested: None
    2.0 (Nguyen, et al. 2015) and MrBayes (Ronquist, et al. 2012); best models for the alignments were chosen using Model Finder (Kalyaanamoorthy, et al. 2017).
    MrBayes
    suggested: (MrBayes, RRID:SCR_012067)
    All selection analyses were carried out in HyPhy v2.5.14 (Pond, et al. 2005).
    HyPhy
    suggested: (HyPhy, RRID:SCR_016162)
    The 3D homology homo-trimer models were created with the Modeller v9.
    Modeller
    suggested: (MODELLER, RRID:SCR_008395)
    Visualization of the atomic models, including figures and movies, is made with Chimera v1.12 (Pettersen, et al. 2004) and VMD v1.9.2 (Humphrey, et al. 1996).
    Chimera
    suggested: (Chimera, RRID:SCR_002959)
    Then unrestrained MD simulations were carried out for a length of 100 ns for each system, with a time step of 2 fs, using GROMACS 2018.3 simulation package (Páll 2015)
    GROMACS
    suggested: (GROMACS, RRID:SCR_014565)

    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 33 and 20. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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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  3. Version published to 10.1101/2020.03.30.015685v1 on bioRxiv