Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses

  1. Anna-Lena Sander
  2. Andres Moreira-Soto
  3. Stoian Yordanov
  4. Ivan Toplak
  5. Andrea Balboni
  6. Ramón Seage Ameneiros
  7. Victor Corman
  8. Christian Drosten
  9. Jan Felix Drexler

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Abstract

The furin cleavage site (FCS) in SARS-CoV-2 is unique within the Severe acute respiratory syndrome–related coronavirus ( SrC ) species. We re-assessed diverse SrC from European horseshoe bats and analyzed the spike-encoding genomic region harboring the FCS in SARS-CoV-2. We reveal molecular features in SrC such as purine richness and RNA secondary structures that resemble those required for FCS acquisition in avian influenza viruses. We discuss the potential acquisition of FCS through molecular mechanisms such as nucleotide substitution, insertion, or recombination, and show that a single nucleotide exchange in two European bat-associated SrC may suffice to enable furin cleavage. Furthermore, we show that FCS occurrence is variable in bat- and rodent-borne counterparts of human coronaviruses. Our results suggest that furin cleavage sites can be acquired in SrC via conserved molecular mechanisms known in other reservoir-bound RNA viruses and thus support a natural origin of SARS-CoV-2.

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  1. Version published to 10.1038/s42003-022-03421-w
  2. ScreenIT

    SciScore for 10.1101/2021.12.15.472779: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsField Sample Permit: Sample collection and processing: Bats were sampled with mist nets using minimally invasive methods under appropriate permits as described earlier (10, 11, 13).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Experimental Models: Organisms/Strains
    SentencesResources
    Phylogenetic analyses: A tblastx search of the complete spike sequence of the Bulgarian SrC (GenBank Acc No. GU190215) within the Taxa ID 11118 (Coronaviridae) excluding the Taxa ID 2697049 (SARS-CoV-2) was performed on 21 June 2021.
    ID 11118
    suggested: None
    Software and Algorithms
    SentencesResources
    Sequence reads obtained from the library were mapped against their corresponding S1/S2 genomic sequence obtained after PCR amplification in Geneious 9.1.8.
    Geneious
    suggested: (Geneious, RRID:SCR_010519)
    Maximum-likelihood phylogenies were generated using FastTree Version 2.1.10 using a GTR substitution model and 1,000 bootstrap replicates.
    FastTree
    suggested: (FastTree, RRID:SCR_015501)
    Sequences were retrieved from the NCBI Taxonomy website downloading all sequences of the species Duvinacovirus (HCoV-229E), Merbecovirus (MERS-CoV), Setracovirus (HCoV-NL63) and Embecovirus (HCoV-HKU1 and HCoV-OC43).
    Taxonomy
    suggested: (Taxonomy, RRID:SCR_004299)
    For Sarbecoviruses, the dataset of the tBlastx search used for the SrC-phylogeny of the Supplementary Figure 1 was used.
    tBlastx
    suggested: (TBLASTX, RRID:SCR_011823)

    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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  3. Version published to 10.1101/2021.12.15.472779v1 on bioRxiv