Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination

Background: Non-crossover (NCO) refers to a mechanism of homologous recombination in which short tracks of DNA are copied between homologue chromatids. The allelic changes are typically restricted to one or few SNPs, which potentially allow for the gradual adaptation and maturation of haplotypes. It...

Full description

Bibliographic Details
Main Authors: Lee, Bernett, Cyrill, Samantha Leeanne, Lee, Wendy, Melchiotti, Rossella, Andiappan, Anand Kumar, Poidinger, Michael, Rötzschke, Olaf
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Journal Article
Language:English
Published: 2022
Subjects:
Online Access:https://hdl.handle.net/10356/161495
_version_ 1811693174342549504
author Lee, Bernett
Cyrill, Samantha Leeanne
Lee, Wendy
Melchiotti, Rossella
Andiappan, Anand Kumar
Poidinger, Michael
Rötzschke, Olaf
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Lee, Bernett
Cyrill, Samantha Leeanne
Lee, Wendy
Melchiotti, Rossella
Andiappan, Anand Kumar
Poidinger, Michael
Rötzschke, Olaf
author_sort Lee, Bernett
collection NTU
description Background: Non-crossover (NCO) refers to a mechanism of homologous recombination in which short tracks of DNA are copied between homologue chromatids. The allelic changes are typically restricted to one or few SNPs, which potentially allow for the gradual adaptation and maturation of haplotypes. It is assumed to be a stochastic process but the analysis of archaic and modern human haplotypes revealed a striking variability in local NCO recombination rates. Methods: NCO recombination rates of 1.9 million archaic SNPs shared with Denisovan hominids were defined by a linkage study and correlated with functional and genomic annotations as well as ChIP-Seq data from modern humans. Results: We detected a strong correlation between NCO recombination rates and the function of the respective region: low NCO rates were evident in introns and quiescent intergenic regions but high rates in splice sites, exons, 5′- and 3′-UTRs, as well as CpG islands. Correlations with ChIP-Seq data from ENCODE and other public sources further identified epigenetic modifications that associated directly with these recombination events. A particularly strong association was observed for 5-hydroxymethylcytosine marks (5hmC), which were enriched in virtually all of the functional regions associated with elevated NCO rates, including CpG islands and ‘poised’ bivalent regions. Conclusion: Our results suggest that 5hmC marks may guide the NCO machinery specifically towards functionally relevant regions and, as an intermediate of oxidative demethylation, may open a pathway for environmental influence by specifically targeting recently opened gene loci.
first_indexed 2024-10-01T06:47:29Z
format Journal Article
id ntu-10356/161495
institution Nanyang Technological University
language English
last_indexed 2024-10-01T06:47:29Z
publishDate 2022
record_format dspace
spelling ntu-10356/1614952023-03-05T16:52:04Z Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination Lee, Bernett Cyrill, Samantha Leeanne Lee, Wendy Melchiotti, Rossella Andiappan, Anand Kumar Poidinger, Michael Rötzschke, Olaf Lee Kong Chian School of Medicine (LKCMedicine) Singapore Immunology Network (SIgN) (A*STAR). Science::Medicine Meiotic Recombination Epigenetic Inheritance Background: Non-crossover (NCO) refers to a mechanism of homologous recombination in which short tracks of DNA are copied between homologue chromatids. The allelic changes are typically restricted to one or few SNPs, which potentially allow for the gradual adaptation and maturation of haplotypes. It is assumed to be a stochastic process but the analysis of archaic and modern human haplotypes revealed a striking variability in local NCO recombination rates. Methods: NCO recombination rates of 1.9 million archaic SNPs shared with Denisovan hominids were defined by a linkage study and correlated with functional and genomic annotations as well as ChIP-Seq data from modern humans. Results: We detected a strong correlation between NCO recombination rates and the function of the respective region: low NCO rates were evident in introns and quiescent intergenic regions but high rates in splice sites, exons, 5′- and 3′-UTRs, as well as CpG islands. Correlations with ChIP-Seq data from ENCODE and other public sources further identified epigenetic modifications that associated directly with these recombination events. A particularly strong association was observed for 5-hydroxymethylcytosine marks (5hmC), which were enriched in virtually all of the functional regions associated with elevated NCO rates, including CpG islands and ‘poised’ bivalent regions. Conclusion: Our results suggest that 5hmC marks may guide the NCO machinery specifically towards functionally relevant regions and, as an intermediate of oxidative demethylation, may open a pathway for environmental influence by specifically targeting recently opened gene loci. Agency for Science, Technology and Research (A*STAR) Published version All the Singapore Immunology Network authors are supported by the A*STAR/Singapore Immunology Network core grant. 2022-09-06T02:18:21Z 2022-09-06T02:18:21Z 2022 Journal Article Lee, B., Cyrill, S. L., Lee, W., Melchiotti, R., Andiappan, A. K., Poidinger, M. & Rötzschke, O. (2022). Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination. BMC Biology, 20(1). https://dx.doi.org/10.1186/s12915-022-01353-9 1741-7007 https://hdl.handle.net/10356/161495 10.1186/s12915-022-01353-9 20 2-s2.0-85135431244 1 20 en BMC Biology © The Author(s) 2022. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. application/pdf
spellingShingle Science::Medicine
Meiotic Recombination
Epigenetic Inheritance
Lee, Bernett
Cyrill, Samantha Leeanne
Lee, Wendy
Melchiotti, Rossella
Andiappan, Anand Kumar
Poidinger, Michael
Rötzschke, Olaf
Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination
title Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination
title_full Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination
title_fullStr Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination
title_full_unstemmed Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination
title_short Analysis of archaic human haplotypes suggests that 5hmC acts as an epigenetic guide for NCO recombination
title_sort analysis of archaic human haplotypes suggests that 5hmc acts as an epigenetic guide for nco recombination
topic Science::Medicine
Meiotic Recombination
Epigenetic Inheritance
url https://hdl.handle.net/10356/161495
work_keys_str_mv AT leebernett analysisofarchaichumanhaplotypessuggeststhat5hmcactsasanepigeneticguideforncorecombination
AT cyrillsamanthaleeanne analysisofarchaichumanhaplotypessuggeststhat5hmcactsasanepigeneticguideforncorecombination
AT leewendy analysisofarchaichumanhaplotypessuggeststhat5hmcactsasanepigeneticguideforncorecombination
AT melchiottirossella analysisofarchaichumanhaplotypessuggeststhat5hmcactsasanepigeneticguideforncorecombination
AT andiappananandkumar analysisofarchaichumanhaplotypessuggeststhat5hmcactsasanepigeneticguideforncorecombination
AT poidingermichael analysisofarchaichumanhaplotypessuggeststhat5hmcactsasanepigeneticguideforncorecombination
AT rotzschkeolaf analysisofarchaichumanhaplotypessuggeststhat5hmcactsasanepigeneticguideforncorecombination