Tracking SARS-CoV-2 Spike Protein Mutations in the United States (January 2020—March 2021) Using a Statistical Learning Strategy

  1. Lue Ping Zhao
  2. Terry P. Lybrand
  3. Peter B. Gilbert
  4. Thomas R. Hawn
  5. Joshua T. Schiffer
  6. Leonidas Stamatatos
  7. Thomas H. Payne
  8. Lindsay N. Carpp
  9. Daniel E. Geraghty
  10. Keith R. Jerome

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

The emergence and establishment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of interest (VOIs) and variants of concern (VOCs) highlight the importance of genomic surveillance. We propose a statistical learning strategy (SLS) for identifying and spatiotemporally tracking potentially relevant Spike protein mutations. We analyzed 167,893 Spike protein sequences from coronavirus disease 2019 (COVID-19) cases in the United States (excluding 21,391 sequences from VOI/VOC strains) deposited at GISAID from 19 January 2020 to 15 March 2021. Alignment against the reference Spike protein sequence led to the identification of viral residue variants (VRVs), i.e., residues harboring a substitution compared to the reference strain. Next, generalized additive models were applied to model VRV temporal dynamics and to identify VRVs with significant and substantial dynamics (false discovery rate q-value < 0.01; maximum VRV proportion >10% on at least one day). Unsupervised learning was then applied to hierarchically organize VRVs by spatiotemporal patterns and identify VRV-haplotypes. Finally, homology modeling was performed to gain insight into the potential impact of VRVs on Spike protein structure. We identified 90 VRVs, 71 of which had not previously been observed in a VOI/VOC, and 35 of which have emerged recently and are durably present. Our analysis identified 17 VRVs ~91 days earlier than their first corresponding VOI/VOC publication. Unsupervised learning revealed eight VRV-haplotypes of four VRVs or more, suggesting two emerging strains (B1.1.222 and B.1.234). Structural modeling supported a potential functional impact of the D1118H and L452R mutations. The SLS approach equally monitors all Spike residues over time, independently of existing phylogenic classifications, and is complementary to existing genomic surveillance methods.

Article activity feed

  1. Version published to 10.3390/v14010009
  2. ScreenIT

    SciScore for 10.1101/2021.06.15.448495: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Sequence Alignment and Transformation to VRV Indicators: Spike protein sequences were aligned to the Wuhan reference sequence (39) using MAFFT (40), yielding a complete “rectangular residue sequence matrix”.
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)

    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: We detected the following sentences addressing limitations in the study:
    A limitation of our approach is that it is constrained by intrinsic sampling limitations, since all sequences were collected and contributed by laboratories without consistent sampling protocols. Hence, despite the large size of our dataset, the analyzed sequences were not nationally representative. Further, it is important to interpret our results in terms of VRV proportions among reported sequence data, rather than incidences or prevalence of VRVs, in the absence of reliably estimated denominators. To overcome this limitation, public health agencies need to consider a uniformly developed surveillance protocol, to sequence COVID-19 cases from well-defined populations.

    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.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.06.15.448495v1 on bioRxiv