Molecular evolution and adaptation of SARS-CoV-2 omicron XBB sub-lineage Spike protein under African Selection pressure.
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The Omicron variant of SARS-CoV-2, which is a cause of concern, has various mutations in its spike protein. This protein is responsible for both viral infection and immunity. We have analyzed a particular sub-lineage of Omicron, designated XBB, which has undergone structural and functional changes in its spike protein as a response to the African selection pressures. Using molecular modeling, we compared the S protein structures of Omicron and XBB and discovered that XBB has a reduced receptor-binding domain (RBD) because of the loss of some β-sheets. This change may result in an increased affinity of XBB towards the human angiotensin-converting enzyme 2 (hACE2) receptor. We also conducted selection and recombination analysis of the S protein sequences of Omicron and XBB using Fast Unconstrained Bayesian Approximation (FUBAR) and Recombination Detection Program 4 (RDP 4). Our analysis detected signals of positive selection and recombination in the N-terminal domain (NTD) of the S1 subunit, which contains antibody-binding epitopes, and the RBD, which is involved in viral entry. Our findings reveal the structural and functional adaptation of the Omicron XBB variant in Africa and its potential implications for viral pathogenesis and immunity.
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Comments to Author
In this manuscript, Kambarami et al. employed molecular modeling to analyze the XBB sublineage and discovered that this sublineage has undergone a modification to its receptor binding site, exhibiting a loss of beta sheets in its structure. Furthermore, Bayesian and recombination detection models have identified instances of positive selection and recombination in the S1 subunit of the spike protein. The introduction is unduly lengthy and fails to provide sufficient focus on the subject matter of the article, namely receptor evolution and evolutionary selection. I propose the inclusion of a few select articles that could be incorporated into the introduction or discussion of results: 10.1038/s41467-021-27369-3 10.1073/pnas.2104241118 10.1128/msystems.00713-23 10.1371/journal.pbio.3001115
Comments to Author
In this manuscript, Kambarami et al. employed molecular modeling to analyze the XBB sublineage and discovered that this sublineage has undergone a modification to its receptor binding site, exhibiting a loss of beta sheets in its structure. Furthermore, Bayesian and recombination detection models have identified instances of positive selection and recombination in the S1 subunit of the spike protein. The introduction is unduly lengthy and fails to provide sufficient focus on the subject matter of the article, namely receptor evolution and evolutionary selection. I propose the inclusion of a few select articles that could be incorporated into the introduction or discussion of results: 10.1038/s41467-021-27369-3 10.1073/pnas.2104241118 10.1128/msystems.00713-23 10.1371/journal.pbio.3001115 10.1093/ve/veaa098 it is evident that there needs to be a distinction between M&M and the results. Furthermore, there are only references to the programs used in the results section. There should be a comparison of their results with what is presented in the literature, with appropriate reference. In certain respects, the methodology is not sufficiently rigorous from a scientific standpoint. For instance, the selection of the S gene could have been more precisely and rigorously identified had a structural annotation of the genomes been performed. This deficiency may impact the subsequent alignment for evolutionary pressure calculations, which are highly dependent on the accurate determination of the nucleotide position. In the event of an insertion or deletion, the subsequent analyses would be rendered inaccurate. Furthermore, the sequences that were analysed are not accompanied by any information. It is unclear whether all existing sequences of this sublineage were used. It would be beneficial to understand at what point the analyses transition from nucleotide to amino acid sequence. This information should be reflected in the document. It is my understanding that figure 1 has been calculated at the amino acid sequence level, although it is typical practice in evolutionary analyses to perform the calculations at the position level within a nucleotide sequence. This is also the case with regard to Figure 2. Figure 3, however, is based on the nucleotide sequence and is particularly challenging to interpret all the results. It is unexpected that the positive selection around position 2000 (nucleotide sequence) is relatively low, given that this region has been previously described as accumulating a large number of changes (in different variants of the virus). What could be the underlying cause of this phenomenon? It is recommended that the 3D structure prediction be calculated using more up-to-date models, such as AlphaFold. Please explain the rationale behind the choice of PHYRE. Also, you could describe the methodology employed for the structural comparison between proteins, as illustrated in Figure 4. Please indicate the value of structural similarity obtained. It is unclear whether this absence of beta sheet is a genuine phenomenon or the result of misalignment or the aforementioned sequence acquisition system. Does the analysis employ sequences of differing sizes?
Please rate the manuscript for methodological rigour
Very poor
Please rate the quality of the presentation and structure of the manuscript
Poor
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Thank you for submitting your manuscript to Access Microbiology. It has now been reviewed by experts in the field whose comments are attached at the bottom of this letter. The reviewers have important concerns regarding multiple aspects of the manuscript and the experimental design. The format and structure is inadequate for a scientific article, the approach is not comprehensive with the current knowledge and the methods used here are currently outdated and not applied rigorously, thus compromising the interpretation of the results and the conclusions. Hence, a major revise of this work needs to be done before considering further progression in the peer-review process. Please provide a revised version of the manuscript (including a tracked-changes document) along with a point-by-point response to the reviewer comments and the …
Thank you for submitting your manuscript to Access Microbiology. It has now been reviewed by experts in the field whose comments are attached at the bottom of this letter. The reviewers have important concerns regarding multiple aspects of the manuscript and the experimental design. The format and structure is inadequate for a scientific article, the approach is not comprehensive with the current knowledge and the methods used here are currently outdated and not applied rigorously, thus compromising the interpretation of the results and the conclusions. Hence, a major revise of this work needs to be done before considering further progression in the peer-review process. Please provide a revised version of the manuscript (including a tracked-changes document) along with a point-by-point response to the reviewer comments and the editorial corrections within 3 months.
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Comments to Author
This paper describes the use of various IT programmes and publicly available genomic data to compare the structures of the spike proteins of the SARS-CoV-2 131 omicron sub-lineage XBB from various African countries and regions with that of the original COVID 19 virus. Although the information presented is essentially archival, it might prove to be useful in light of future similar analyses. The authors have submitted their results in an unusual format. There are three independent sections, each with its own methods section, results and brief conclusions. This format is accessible to the reader and unless the Editor objects, is acceptable for this reviewer. It is well referenced. Two features of the paper are commendable. First, each IT programme used is described in sufficient detail for the …
Comments to Author
This paper describes the use of various IT programmes and publicly available genomic data to compare the structures of the spike proteins of the SARS-CoV-2 131 omicron sub-lineage XBB from various African countries and regions with that of the original COVID 19 virus. Although the information presented is essentially archival, it might prove to be useful in light of future similar analyses. The authors have submitted their results in an unusual format. There are three independent sections, each with its own methods section, results and brief conclusions. This format is accessible to the reader and unless the Editor objects, is acceptable for this reviewer. It is well referenced. Two features of the paper are commendable. First, each IT programme used is described in sufficient detail for the non-specialist to appreciate why it was used. Secondly, there are adequate legends to enable the reader to understand each of the five figures without reference to the text. Repeatedly the authors state that the spike protein from the African variants is smaller than the original spike protein. The authors might wish to state the molecular masses of the two forms, noting the range of sizes found for the African variants. The text is clear and mainly well written. Any changes preferred by this reviewer would be pedantic in the extreme. One example would be that the authors repeatedly use the word "may" in their conclusions: the correct word is might!
Please rate the manuscript for methodological rigour
Good
Please rate the quality of the presentation and structure of the manuscript
Good
To what extent are the conclusions supported by the data?
Strongly support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Comments to Author
The manuscript by Kambarami et al attempts to study the SARS-CoV-2 omicron XBB sub-lineage based on its sequence and mutations as compared to its parental omicron variant. The main issue with this work is its methodology. The authors have used a number of available web-servers and software packages to do routine bioinformatic and structural analysis. All methods used are based on ready-to-use packages and webservers and can be done simply based on the available sequence of XBB in a short period of time. The work makes a good project for an undergraduate class but does not hold the standards of neither bioinformatics nor structural biology. For instance, the authors have used a web server to homology model the structure of XBB spike and then aligned it against the omicron spike (Fig. 4), showing in a …
Comments to Author
The manuscript by Kambarami et al attempts to study the SARS-CoV-2 omicron XBB sub-lineage based on its sequence and mutations as compared to its parental omicron variant. The main issue with this work is its methodology. The authors have used a number of available web-servers and software packages to do routine bioinformatic and structural analysis. All methods used are based on ready-to-use packages and webservers and can be done simply based on the available sequence of XBB in a short period of time. The work makes a good project for an undergraduate class but does not hold the standards of neither bioinformatics nor structural biology. For instance, the authors have used a web server to homology model the structure of XBB spike and then aligned it against the omicron spike (Fig. 4), showing in a primitive way, how the structures are compared. Not only the model is not reliable and is not using state-of-the-art homology modeling approaches, but also the representations are not made in a professional manner and this figure provides no useful information. I do not find this work of interest to the research community as it does not follow the guidelines of an original research paper appropriate for any scientific journal.
Please rate the manuscript for methodological rigour
Very poor
Please rate the quality of the presentation and structure of the manuscript
Very poor
To what extent are the conclusions supported by the data?
Not at all
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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