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Studying premortem DNA methylation from ancient DNA (aDNA) provides a proxy for ancient gene activity patterns, and hence valuable information on evolutionary changes in gene regulation. Due to statistical limitations, current methods to reconstruct aDNA methylation maps are constrained to high-coverage shotgun samples, which comprise a small minority of available ancient samples. Most samples are sequenced using in-situ hybridization capture sequencing which targets a predefined set of genomic positions. Here, we develop methods to reconstruct aDNA methylation maps of samples that were not sequenced using high-coverage shotgun sequencing, by way of pooling together individuals to obtain a DNA methylation map that is characteristic of a population. We show that the resulting DNA methylation maps capture meaningful biological information and allow for the detection of differential methylation across populations. We offer guidelines on how to carry out comparative studies involving ancient populations, and how to control the rate of falsely discovered differentially methylated regions. The ability to reconstruct DNA methylation maps of past populations allows for the development of a whole new frontier in paleoepigenetic research, tracing DNA methylation changes throughout human history, using data from thousands of ancient samples., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Recent advances in ancient DNA extraction and high-throughput sequencing technologies enabled the high-quality sequencing of archaic genomes, including the Neanderthal and the Denisovan. While comparisons with modern humans revealed both archaic-specific and human-specific sequence changes, in the absence of gene expression information, understanding the functional implications of such genetic variations remains a major challenge. To study gene regulation in archaic humans, epigenetic research comes to our aid. DNA methylation, which is highly correlated with transcription, can be directly measured in modern samples, as well as reconstructed in ancient samples. This puts DNA methylation as a natural basis for comparative epigenetics between modern humans, archaic humans and nonhuman primates., (Copyright © 2020 Elsevier Ltd. All rights reserved.)