Placenta-Driven Evolution: Viral Gene Acquisition and PEG10’s Essential Roles in Eutherian Placenta

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript systematically explains the involvement of metaviral genes in mammalian placentation and describes how their gene expression in both the placenta and brain cells is linked to an origin in the yolk sac. Furthermore, the proposal that the placenta has repeatedly acquired virus-derived genes and co-evolved with them, leading to the formulation of the placenta-driven evolution hypothesis, is considered to be of significant academic importance.

However, there is sufficient evidence demonstrating that metavirus-derived GAG and ENV genes are involved in the process of placental formation. It would be valuable to address in the Discussion whether the POL gene is also involved. In addition, incorporating a discussion on how virus-derived genes produce proteins that contribute to major phenotypic traits in diverse mammalian and human tissues would greatly enhance the significance and overall value of this review article.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The review summarizes the estimated timing of when certain retrotransposon elements were acquired and how the evolved protein coding sequences were thought to contribute to various therian, metatherian, and eutherian lineages. The review provides a nice overview into how extraembryonic membranes may promote the retention of retroviral gene products by allowing them to be subjected to neutral/nearly-neutral selection and subsequent Darwinian selection of gene functions that are novel.  The presumption is that the extraembryonic tissues do not fully silence ‘foreign’ genes, such as integrated retroviral elements, thus allowing them an opportunity to undergo selection (the Placenta-Driven Evolution hypothesis described in the text). The fact that certain neuronal tissue components, such as microglia, are derived from yolk sac also might explain why some of the novel retroviral-derived genes are also present in the brain.   

 

The following are a few items that might be considered by the journal editor and the authors. 

 

1. What new information is provided in this review? There are other review articles already available that cover similar information. Consequently, it is not clear what new information or insights are represented in the current manuscript.  This reviewer suggests that the authors briefly clarify for the reader those aspects of the current review that distinguish it from others that cover similar topics.  

 

 

2. Figure 1. Some of the common structures were not labeled in all the images. It was not clear why that was the case. For example, the vessels representing the vitelline artery (VA) and vitelline vein (VV) were shown in the image of the mouse fetus and membranes, but not in the images for the Marsupials. In contrast, the allantois (al) was illustrated in all three vertebrate categories (avian, marsupials and eutherians).  It may be helpful to readers that are less familiar with comparative extraembryonic membrane structures to have a few more of the common structures labeled in the images.  The authors might want to consider if this is possible without making the final image overly complex.

 

 

3. Figure 2. It appears the some of the text in the body of the manuscript (lines 94-97) should more appropriately be in the legend for Figure 2.

 

4. Figure 5. This reviewer will make an admittedly subjective comment about one aspect of the figure. In the A (fetus) section, it seems like it would be more appropriate to change the phrase ‘Garbage in the genome’ to ‘retained in the genome’ or something similar. The reason for the comment is because the word ‘garbage’ in this context is jargon that would typically not be used in a scientific paper. However, if jargon is deemed appropriate for this context, the word ‘junk’ would be more fitting. ‘Junk’ describes unwanted or unneeded items that are retained. In contrast, ‘garbage’ describes unwanted or unneeded items that are discarded. In this case, the former term better reflects the situation shown in the figure.

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive review of eleven SIRH/RTL genes derived from metaviruses, with a particular focus on the evolution and functions of PEG10 and PEG11/RTL1. The writing is clear, and the overall narrative is logical.

A notable strength is the detailed evolutionary perspective that frames the discussion. However, the inclusion of Section 2.2, "Roles of SIRH/RTL genes in the brain: neurons and microglia," while interesting, feels somewhat disconnected from the manuscript's central theme. Given that the authors have previously published a thorough review on the roles of PEG10 and PEG11/RTL1 in neurological disorders (PMID: 37842090), the authors might consider removing this brain-specific section, instead citing their prior work, unless it contains critical new insights that warrant inclusion.

To further strengthen the manuscript, the addition of a comparative section or table would be highly valuable. Given that these genes are conserved between humans and mice but the placenta exhibits significant differences among them, a direct comparison would effectively clarify their distinct and conserved roles across species. This would significantly enhance the manuscript's utility for readers interested in evolutionary biology and translational research.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf