PONE-D-24-25424Classical cadherins evolutionary constraints in primates is associated with their expression in the central nervous system

PLOS ONE

Dear Dr. Brusés,

Thank you for submitting your manuscript to PLOS ONE and sorry for the delay in returning a decision.  I had trouble getting a second reviewer, so I reviewed it myself.  After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

First, please address the reviewer's comments point by point.  In my own review of the manuscript three points came up, the extend they require "major" review is unclear.  First, the abstract can be dramatically shortened to focus on the key observations; now it is too detailed.  Second (and minor), I would avoid definitive statements that go beyond observations throughout the ms., e.g. line 98 instead of "cadherins ... direct cell migration" better to say "cadherins ...  influence cell migration". This is particular important given that results from mouse mutations do not always translate easily to other (human) organisms. Consider, for example, the differences between early development in mouse and human.  

The final point is that I was surprised that the authors did not include genomic sequencing data from human, for example the ClinVar data available through gNomad (link to Cdh1  https://gnomad.broadinstitute.org/gene/ENSG00000039068?dataset=gnomad_r2_1).  How does  the diversity of pathogenic variants in various Catherine support or lead to rethinking of your conclusions?

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Michael Klymkowsky, Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper explores the evolution of cadherins in primates, finding that CDH2, CDH4, and most type II cadherins experience higher negative selective pressure, particularly due to their expression in the CNS. The research suggests that this strong selection is linked to their role in CNS development, which may have been crucial in primate evolution. The study also finds that while gene essentiality does not align with cadherin evolution rates, expression levels do.

To conduct this study, the authors examined evolutionary changes in classical cadherin orthologs across various primates by performing pairwise comparisons of synonymous and non-synonymous nucleotide substitutions to assess selective pressures on different cadherins. The ratio of non-synonymous to synonymous substitutions (dN/dS) was analyzed to measure the strength of selection. Additionally, the study evaluated gene essentiality and conducted Spearman's correlation analysis to explore the relationship between cadherin expression levels and evolutionary rates, with a particular focus on the central nervous system (CNS).

This work utilizes publicly available data on gene and protein sequences, expression levels of various classical cadherins, and gene essentiality information based on the existence of mutant mouse models for these genes to conduct the analyses mentioned. I find the work very interesting and relevant to the field. Although the paper is well-written, since it is exclusively a data analysis paper, the reading can be somewhat dense due to the extensive analysis of numerous genes and species. However, some of the figure legends are quite brief considering the amount of information each graph contains. Apart from these general considerations, I have only a few minor concerns that I believe the authors could easily address:

• On page 11, line 231, the authors discuss that “EC5 has been under higher negative selection in CDH2 and CDH4, possibly due to a functional role of this domain in these cadherins.” However, they do not provide supporting data for this statement regarding the function of this EC in those cadherins. The authors should elaborate on this issue according to the literature.

• On page 32, line 657, they discuss the association of CDH9 and CDH10 with ASD and, in line 660, how Cdh8 microdeletions and polymorphisms in humans are associated with the same syndrome. In both cases, they cite two papers (references 101 and 102). However, reference 101 relates only to CDH8, and 102 to CDH9 and CDH10.

• Authors should clarify the election of the different statistical test for the different analyses.

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Reviewer #1: No

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Classical cadherins evolutionary constraints in primates is associated with their expression in the central nervous system

PONE-D-24-25424R1

Dear Dr. Brusés,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Michael Klymkowsky, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have properly addressed my previous concerns about the manuscript, including the necessary information and correcting a previously detected error.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

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