Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

  1. Yong Jia
  2. Gangxu Shen
  3. Stephanie Nguyen
  4. Yujuan Zhang
  5. Keng-Shiang Huang
  6. Hsing-Ying Ho
  7. Wei-Shio Hor
  8. Chih-Hui Yang
  9. John B Bruning
  10. Chengdao Li
  11. Wei-Lung Wang

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Abstract

Monitoring the mutation dynamics of SARS-CoV-2 is critical for the development of effective approaches to contain the pathogen. By analyzing 106 SARS-CoV-2 and 39 SARS genome sequences, we provided direct genetic evidence that SARS-CoV-2 has a much lower mutation rate than SARS. Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. The discrepant phylogenies for the spike protein and its receptor binding domain proved a previously reported structural rearrangement prior to the emergence of SARS-CoV-2. Despite that we found the spike glycoprotein of SARS-CoV-2 is particularly more conserved, we identified a receptor binding domain mutation that leads to weaker ACE2 binding capability based on in silico simulation, which concerns a SARS-CoV-2 sample collected on 27 th January 2020 from India. This represents the first report of a significant SARS-CoV-2 mutant, and requires attention from researchers working on vaccine development around the world.

Highlights

  • Based on the currently available genome sequence data, we provided direct genetic evidence that the SARS-COV-2 genome has a much lower mutation rate and genetic diversity than SARS during the 2002-2003 outbreak.

  • The spike (S) protein encoding gene of SARS-COV-2 is found relatively more conserved than other protein-encoding genes, which is a good indication for the ongoing antiviral drug and vaccine development.

  • Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history.

  • We confirmed a previously reported rearrangement in the S protein arrangement of SARS-COV-2, and propose that this rearrangement should have occurred between human SARS-CoV and a bat SARS-CoV, at a time point much earlier before SARS-COV-2 transmission to human.

  • We provided first evidence that a mutated SARS-COV-2 with reduced human ACE2 receptor binding affinity have emerged in India based on a sample collected on 27th January 2020.

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  1. Version published to 10.1101/2020.04.09.034942v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2020.04.09.034942: (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 gene model of SARS-CoV-2 was generated using the AnnotationSketch 18 tool based on the genome annotation data downloaded from NCBI database.
    NCBI
    suggested: (NCBI, RRID:SCR_006472)
    Phylogeny construction: Codon-based sequence alignment was performed for the conserved domain sequences (CDS) using the MUSCLE program (limited to 2 iterations for fast alignment of long sequences) 19.
    MUSCLE
    suggested: (MUSCLE, RRID:SCR_011812)
    The phylogenetic tree was developed in MEGA7.0 20 using the Minimum Evolution method with p-distance substitution model, and the Maximum Likelihood method (HKY+G+I, 500 times bootstrap test) for the S protein analyses.
    MEGA7.0
    suggested: None
    Tree annotation was carried out using Figtree software (http://tree.bio.ed.ac.uk/software/figtree/) and cophyloplot from ape 5.0 R package 21.
    Figtree
    suggested: (FigTree, RRID:SCR_008515)
    The obtained sequence alignment and phylogenetic tree files were used as PAML inputs for dN and dS calculations.
    PAML
    suggested: (PAML, RRID:SCR_014932)
    All structure visualization was carried out using PyMol (Version 2.2.3.
    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: Please consider improving the rainbow (“jet”) colormap(s) used on page 14. 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.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

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  3. Version published to 10.1101/2020.04.09.034942v1 on bioRxiv