Population Epigenetics: The Extent of DNA Methylation Variation in Wild Animal Populations
Round 1
Reviewer 1 Report
The manuscript provides a highly interesting and comprehensive summary of the most recent literature on DNA methylation variation in natural animal populations. The review is well written and gives an overview on DNA methylation diversity and its correlation with genetic variation in wild animal populations, geographical and ecological processes affecting DNA methylation dynamics, as well as potential role of DNA methylation variation in evolutionary changes. The authors also touch upon future research directions of ecological epigenetics. In total, this is a timely review that will be of interest to many researchers.
I only have a few comments as listed below:
1. It would be nice if the authors could graphically include the described geographical and ecological processes that induce epigenetic/genetic variations in Section 4.
2. In the discussion, the authors should briefly mention the potential implications of this study have on the studies of epigenetic variation in human population.
3. Page 314, line 306: “epigenetic variation is not necessarily completely dependent on genetic variation”. Please remove the word “completely”.
Author Response
Response to Reviewer 1 Comments
Point 1: It would be nice if the authors could graphically include the described geographical and ecological processes that induce epigenetic/genetic variations in Section 4.
Response 1: I have done my best to summarize the section 4 in a new figure, see Figure 2.
Point 2: In the discussion, the authors should briefly mention the potential implications of this study have on the studies of epigenetic variation in human population.
Response 2: We have avoided talking about epigenetic variation in human populations, as it is beyond the scope of the review.
Point 3: Page 314, line 306: “epigenetic variation is not necessarily completely dependent on genetic variation”. Please remove the word “completely”.
Response 3: Done.
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
In this manuscript, Chapelle and Silvestre summarized the emerging field of population epigenetics and provided new avenues for research. This review is timely, as more and more epigenetic studies are being conducted in an ecological context and this new research can go a long way in our understanding of how epigenetic mechanisms may impact evolutionary trajectories. There were numerous examples of studies on wild populations, while not ignoring the biomedical research that forms the basis of epigenetic research. I have mainly minor comments to help with clarity.
Lines 60-62 and 662-665: I think the sections on genetic accommodation could be expanded on. There is not enough detail on how genetic accommodation is occurring. For example, I think lines 60-62 and 662-665 are vague on this point and just lists that it occurs and doesn’t really detail the process.
Lines 149-151: It may be useful to include some discussion of allele specific methylation/strand-specific methylation here since it doesn’t come up until the end of the manuscript.
Lines 218-219: Do you mean site-specific differences in methylation?
Lines 225-226: I do not understand what this line means “…making the final value of epigenetic diversity the addition of these different sources”. Can this be expanded on?
Lines 226-228: I am not sure I agree with this- it is too strong of a statement. In the sense that all DNA methylation is partially under genetic control (i.e. methylation occurs at specific genetic motifs, generally CpG sites). Also, even if methylation doesn't specifically correlate with phenotypic variation doesn't mean it doesn't play another role. The presence of methylation in CpG islands can buffer against the ability for methylation to be variable. The presence of methylation can even be a mutagen, which is directly relevant to evolution. I do agree it is interesting to investigate, pure, facilitated, obligatory origins as mentioned below. This statement is questioned by the authors further in lines 267-268.
Lines 244-245: I think those of us in the ecological epigenetics field would agree, but it would be useful to detail why it is expected that laboratory conditions are expected to give rise to mostly obligatory DNA methylation.
Line 388: By defect, do you mean the 5% inaccuracy?
Lines 396-397: Maybe a higher likelihood, but would this be limited to these events?
Lines 430-432: Could you provide a citation for the consortium?
Glossary: The definition of epigenetic potential is incorrect- epigenome should be changed to genomic. It should read “The genomic capacity for environmentally-induced phenotypic change (i.e., plasticity) via epigenetic modifications”
I did not proofread as I know that will occur at a later stage, but I caught a few typos that may impact the meaning of the text I wanted to call attention to:
Line 195: “A larger” should be changed to “higher”
Line 550: remove “effect of” before epigenetic inheritance
Author Response
Response to Reviewer 2 Comments
Point 1: Lines 60-62 and 662-665: I think the sections on genetic accommodation could be expanded on. There is not enough detail on how genetic accommodation is occurring. For example, I think lines 60-62 and 662-665 are vague on this point and just lists that it occurs and doesn’t really detail the process.
Response 1: I understand your comment. As it was not clear, I added information about the process, highlighting the role of minor advantagous genetic mutations in it. I also cited the conditions required for genetic assimilation to take place. I did not go into details because it has been done several times in the articles cited in this section.
Point 2: Lines 149-151: It may be useful to include some discussion of allele specific methylation/strand-specific methylation here since it doesn’t come up until the end of the manuscript.
Response 2: It is true that throughout the article, I talk about epigenetic variation between individuals, but not about the variability that can exist at the same locus, with one allele methylated and the other one unmethylated. I wrote "For a same allele, each CpG (and at a lower level each CHG and CHH - H being any base except G) can either be M or U producing a succession of single methylation polymorphisms", but mainly to introduce my definition of epigenetic variation. I did not want to introduce this notion of allele-specific methylation because I do not refer to it further, excepted in the “Future reasearch” section where I talked about allele specific expression.
Point 3: Lines 218-219: Do you mean site-specific differences in methylation?
Response 3: Yes I do. I added this missing word.
Point 4: Lines 225-226: I do not understand what this line means “…making the final value of epigenetic diversity the addition of these different sources”. Can this be expanded on?
Response 4: I agree, and reworded it.
Point 5: Lines 226-228: I am not sure I agree with this- it is too strong of a statement. In the sense that all DNA methylation is partially under genetic control (i.e. methylation occurs at specific genetic motifs, generally CpG sites). Also, even if methylation doesn't specifically correlate with phenotypic variation doesn't mean it doesn't play another role. The presence of methylation in CpG islands can buffer against the ability for methylation to be variable. The presence of methylation can even be a mutagen, which is directly relevant to evolution. I do agree it is interesting to investigate, pure, facilitated, obligatory origins as mentioned below. This statement is questioned by the authors further in lines 267-268.
Response 5: I agree. I wanted to say that according to some scientists, epigenetic variation under genetic control would be useless in terms of evolution, but that is not what I think. So I prefer to remove this part, and let the readers go through the next point “3. Correlation between epigenetic and genetic variation in natural animal populations” where I better nuance my ideas and progress in this subject.
Point 6: Lines 244-245: I think those of us in the ecological epigenetics field would agree, but it would be useful to detail why it is expected that laboratory conditions are expected to give rise to mostly obligatory DNA methylation.
Response 6: I don’t know if laboratory conditions increase the probability to have obligatory epimutation, but as environmental fluctuations are reduced, it also reduce environemnally-induced epimutations rate. I tried to summarize my ideas and added information about that.
Point 7: Line 388: By defect, do you mean the 5% inaccuracy?
Response 7: Yes, I do mean the 5% inaccuracy.
Point 8: Lines 396-397: Maybe a higher likelihood, but would this be limited to these events?
Response 8: I understand your comment. As I said at the beginning of this section, random epimutations can arise at any time in the lifespan. Cell division, gametogenesis and embryogenesis are big windows of susceptibility for random epigenetic alterations, but it is not limited to these events. I reworded it.
Point 9: Lines 430-432: Could you provide a citation for the consortium?
Response 9: Done.
Point 10: Glossary: The definition of epigenetic potential is incorrect- epigenome should be changed to genomic. It should read “The genomic capacity for environmentally-induced phenotypic change (i.e., plasticity) via epigenetic modifications”
Response 10: Done.
Point 11: I did not proofread as I know that will occur at a later stage, but I caught a few typos that may impact the meaning of the text I wanted to call attention to:
Line 195: “A larger” should be changed to “higher”
Line 550: remove “effect of” before epigenetic inheritance
Response 11: Done.
Please see the attachment
Author Response File: Author Response.pdf
Reviewer 3 Report
This manuscript is well prepared and I would like to recommend to accept this paper for publication.
Author Response
Thank you for your recommendation.
