Reduced meiotic recombination in rhesus macaques and the origin of the human recombination landscape

Cheng Xue; Navin Rustagi; Xiaoming Liu; Muthuswamy Raveendran; R. Alan Harris; Manjunath Gorentla Venkata; Jeffrey Rogers; Fuli Yu

doi:10.1371/journal.pone.0236285

Peer Review History

Original SubmissionMay 29, 2020
9 Jun 2020 Decision Letter - Karol Sestak, Editor PONE-D-20-16003 Reduced meiotic recombination in rhesus macaques and and the origin of the human recombination landscape PLOS ONE Dear Dr. Xue, Thank you for submitting your manuscript to PLOS ONE. 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. Please submit your revised manuscript by Jul 24 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Thank you for stating the following in the Acknowledgments Section of your manuscript: We thank Donna Muzny, Richard Gibbs and the staff of the Baylor College of Medicine Human Genome Sequencing Center for essential contributions to the production of the macaque SNP data. We are indebted to the following primate research centers for providing blood and/or DNA samples from the study macaques: California National Primate Research Center (NPRC), New England NPRC, Oregon NPRC, Southwest NPRC, Tulane NPRC, Wisconsin NPRC, Yerkes NPRC and the Caribbean Primate Research Center. We also thank Oak Ridge National Laboratory (ORNL) for providing their high-performance supercomputer resources for the analyses in this study. Kasper Munch provided valuable suggestions related to rhesus macaque effective population size, and two anonymous reviewers provided helpful comments, critiques and suggestions. This work was supported by National Institutes of Health (NIH) grants R24-OD011173 to J.R., U54-HG006484-01 to R. G. and 5R01HG008115 to F.Y. We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: No 3. Thank you for stating the following in your Competing Interests section: No Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. 4. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical. 5. Please amend the manuscript submission data (via Edit Submission) to include author Navin Rustagi, Xiaoming Liu, Muthuswamy Raveendran, R. Alan Harris, Manjunath Gorentla Venkata. 6. Please upload a copy of Supporting Information Table 1. which you refer to in your text on page 13. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 Reviewer #2: Yes ****** 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 Reviewer #2: Yes ****** 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: In this paper, Xue and colleagues infer a fine-scale recombination map in rhesus macaques by applying LDhat to 123 sequenced macaques. I find the results interesting and the genetic map will be useful for comparative studies but I am not convinced by the main result that there is reduced overall recombination in macaques. Major comments: One of the main results of the paper is that macaques have a lower overall recombination rate than other great apes. Because LDhat infers a population-scaled recombination rate, it can be difficult to disentangle differences in effective population size from differences in true recombination rate. The scaling gets even murkier when populations have undergone size changes (see Johnston and Cutler AJHG 2012; Kamm et al. Genetics 2016; Dapper and Payseur MBE 2017; and Spence and Song 2019). As a result, I would not put too much stock in the absolute rates of recombination. Relative rates, across the genome within a single species, are somewhat more robust to differences in demographic history, so I find the correlation results to be much more convincing. Figure S1 seems weird to me. I would expect r^2 to asymptote to something close to 1 / 2n, so 1 / 236, which is approximately 0.004, but it looks like r^2 is actually asymptoting to about 0.15, which seems very high. If this is not an error, it could suggest large amounts of population structure in the sample (leading to so-called "ancestry LD" at long ranges). Large amounts of population structure violate the panmixia assumptions of LDhat and could lead to downward biased recombination rate estimates. One way to assess population structure would be to visualize the genotype data with PCA or ADMIXTURE (Alexander, Novembre, and Lange, Genome Research, 2009) and see if the data show distinct clusters, or spread out along a cline. I find Figure S2 to be very interesting and matches the overall picture that has emerged that at very fine-scales recombination maps do not correlate well across great ape species, but they do at broader scales. This suggests a slow evolving broad-scale mechanism of recombination patterning, but a fast-evolving fine-scale mechanism (i.e., PRDM9). Minor comment: LDhat does not phase data but in the manuscript it says "We used LDhat software version 2.1 ... to phase the rhesus macaque haplotypes...". Were the data phased? If so, how? If the data were not phased, my experience has been the LDhat can produce downward biased recombination estimates, which would be consistent with the findings here. Reviewer #2: Well written manuscript with interesting data. There are few minor recommendation for improvement: 1) English grammar and symbol use should be improved. For example, Figures 1 and 2 (axes X and Y) are not properly labeled. Figures and their legends including coloration of these figures should be improved for the sake of clarity. ****** 6. 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 Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0236285.r001
Revision 1
30 Jun 2020 Author Response Dear Dr. Karol Sestak, We have revised our manuscript entitled “Reduced meiotic recombination in rhesus macaques and the origin of the human recombination landscape” in order to address comments from you and the reviewers. Please see our responses to these comments included below. Thank you for consideration. Best regards Fuli Yu, Jeffery Rogers and Cheng Xue 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Response: Thank you for reminding us of this. We revised the manuscript accordingly. 2. Thank you for stating the following in the Acknowledgments Section of your manuscript: We thank Donna Muzny, Richard Gibbs and the staff of the Baylor College of Medicine Human Genome Sequencing Center for essential contributions to the production of the macaque SNP data. We are indebted to the following primate research centers for providing blood and/or DNA samples from the study macaques: California National Primate Research Center (NPRC), New England NPRC, Oregon NPRC, Southwest NPRC, Tulane NPRC, Wisconsin NPRC, Yerkes NPRC and the Caribbean Primate Research Center. We also thank Oak Ridge National Laboratory (ORNL) for providing their high-performance supercomputer resources for the analyses in this study. Kasper Munch provided valuable suggestions related to rhesus macaque effective population size, and two anonymous reviewers provided helpful comments, critiques and suggestions. This work was supported by National Institutes of Health (NIH) grants R24-OD011173 to J.R., U54-HG006484-01 to R. G. and 5R01HG008115 to F.Y. We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: No Response: We removed the funding-related text from the manuscript, and updated the Funding Statement in the submission. 3. Thank you for stating the following in your Competing Interests section: No Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now This information should be included in your cover letter; we will change the online submission form on your behalf. Response: We included the statement “The authors have declared that no competing interests exist.” in the cover letter and uploaded it to the submission site. We also updated the Competing Interests section in the submission. 4. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical. Response: Thanks for reminding us. We revised the title on the online submission. 5. Please amend the manuscript submission data (via Edit Submission) to include author Navin Rustagi, Xiaoming Liu, Muthuswamy Raveendran, R. Alan Harris, Manjunath Gorentla Venkata. Response: We added all authors in the online submission. 6. Please upload a copy of Supporting Information Table 1. which you refer to in your text on page 13. Response: We uploaded this table. ---------------------------------------------------------------- 5. Review Comments to the Author Reviewer #1: In this paper, Xue and colleagues infer a fine-scale recombination map in rhesus macaques by applying LDhat to 123 sequenced macaques. I find the results interesting and the genetic map will be useful for comparative studies but I am not convinced by the main result that there is reduced overall recombination in macaques. Major comments: One of the main results of the paper is that macaques have a lower overall recombination rate than other great apes. Because LDhat infers a population-scaled recombination rate, it can be difficult to disentangle differences in effective population size from differences in true recombination rate. The scaling gets even murkier when populations have undergone size changes (see Johnston and Cutler AJHG 2012; Kamm et al. Genetics 2016; Dapper and Payseur MBE 2017; and Spence and Song 2019). As a result, I would not put too much stock in the absolute rates of recombination. Relative rates, across the genome within a single species, are somewhat more robust to differences in demographic history, so I find the correlation results to be much more convincing. Response: We thank the Reviewer for the constructive suggestion. We revised and added text in the Discussion, “The explanation for this inter-species difference of genome-wide recombination rate is not readily apparent due to different effective population size and demographics”. Figure S1 seems weird to me. I would expect r^2 to asymptote to something close to 1 / 2n, so 1 / 236, which is approximately 0.004, but it looks like r^2 is actually asymptoting to about 0.15, which seems very high. If this is not an error, it could suggest large amounts of population structure in the sample (leading to so-called "ancestry LD" at long ranges). Large amounts of population structure violate the panmixia assumptions of LDhat and could lead to downward biased recombination rate estimates. One way to assess population structure would be to visualize the genotype data with PCA or ADMIXTURE (Alexander, Novembre, and Lange, Genome Research, 2009) and see if the data show distinct clusters, or spread out along a cline. Response: We did PCA analysis on the genotype data (Please see figure below). Samples from the National Primate Research Centers form a cline with no identifiable population structure. The Cayo Santiago animals from the Caribbean Primate Research Center (green color) do form a cluster based on PC1. The PC1 eigenvalue is 2.8. This accounts for 46.91% of the variance seen across the samples using a CNG scree test that retained the top 3 principal components. I find Figure S2 to be very interesting and matches the overall picture that has emerged that at very fine-scales recombination maps do not correlate well across great ape species, but they do at broader scales. This suggests a slow evolving broad-scale mechanism of recombination patterning, but a fast-evolving fine-scale mechanism (i.e., PRDM9). Minor comment: LDhat does not phase data but in the manuscript it says "We used LDhat software version 2.1 ... to phase the rhesus macaque haplotypes...". Were the data phased? If so, how? If the data were not phased, my experience has been the LDhat can produce downward biased recombination estimates, which would be consistent with the findings here. Response: The input data of LDhat is the phased data (Xue et al. 2016). The phased data can be accessed here ftp://ftp.hgsc.bcm.edu/ucscHub/rhesusSNVs/rheMac2/Genotype_biallelic_SNP_autosomes_rhesus_V2.0_Mar5-2015.for.hub.vcf.gz. Reviewer #2: Well written manuscript with interesting data. There are few minor recommendation for improvement: 1) English grammar and symbol use should be improved. For example, Figures 1 and 2 (axes X and Y) are not properly labeled. Figures and their legends including coloration of these figures should be improved for the sake of clarity. Response: We revised the figures’ labels and improved the resolution of figures. Attachments Attachment Submitted filename: response_to_reviewers.docx https://doi.org/10.1371/journal.pone.0236285.r002
6 Jul 2020 Decision Letter - Karol Sestak, Editor Reduced meiotic recombination in rhesus macaques and the origin of the human recombination landscape PONE-D-20-16003R1 Dear Dr. Xue, 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. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Karol Sestak Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0236285.r003
Formally Accepted
11 Aug 2020 Acceptance Letter - Karol Sestak, Editor PONE-D-20-16003R1 Reduced meiotic recombination in rhesus macaques and the origin of the human recombination landscape Dear Dr. Xue: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Karol Sestak Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0236285.r004

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