<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>13</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Ma, Zhenzhen</style></author><author><style face="normal" font="default" size="100%">Starr, Alexander L</style></author><author><style face="normal" font="default" size="100%">Gokhman, David</style></author><author><style face="normal" font="default" size="100%">Fraser, Hunter B</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">The causes and consequences of human-specific DNA methylation</style></title></titles><dates><year><style  face="normal" font="default" size="100%">2026</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2026/04/28</style></date></pub-dates></dates><urls><web-urls><url><style face="normal" font="default" size="100%">https://elifesciences.org/reviewed-preprints/110575v1</style></url></web-urls></urls><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;meta charset=&quot;UTF-8&quot; /&gt;The vast collection of human-specific traits&amp;ndash; such as our unique morphology, cognition, behavior, and diseases&amp;ndash; has long been attributed to gene expression divergence between us and our closest living relatives, chimpanzees. Theory suggests that changes to&amp;nbsp;&lt;em&gt;cis&lt;/em&gt;-regulatory elements such as promoters and enhancers may drive evolutionary adaptation, and DNA methylation is a key factor in transcriptional&amp;nbsp;&lt;em&gt;cis&lt;/em&gt;-regulation. However, we still lack an understanding of 1) how species-specific methylation patterns arise; 2) their downstream effects; and 3) whether they are a common target of natural selection. In this study, we investigated these three questions. By combining a novel hypothesis testing framework with DNA methylation data from six human and chimpanzee cell types, as well as fused interspecies hybrid cells, we disentangled&amp;nbsp;&lt;em&gt;cis&lt;/em&gt;- vs.&amp;nbsp;&lt;em&gt;trans&lt;/em&gt;-acting methylation divergence across the genome. Across cell types, we found that methylation divergence is primarily driven in&amp;nbsp;&lt;em&gt;cis&lt;/em&gt;, which can be linked in some cases to nearby sequence variants such as CpG gains and losses. Although less common, regions with&amp;nbsp;&lt;em&gt;trans&lt;/em&gt;-acting methylation divergence were enriched for specific transcription factor (TF) binding motifs, suggesting a role of TFs such as FOXM1 in these differences. Having established these causes of methylation divergence, we then examined the functional consequences of differential methylation. Although methylation lacks a consistent relationship with transcription, we observed that associations between methylation and gene expression are stronger for genes with&amp;nbsp;&lt;em&gt;cis&lt;/em&gt;-regulatory divergence. Moreover, we identified lineage-specific selection shaping promoter methylation at the level of entire pathways including those affecting human-specific traits such as speech, cognition, and susceptibility to infection with hepatitis C. Collectively, our findings provide a mechanistic framework suggesting that DNA methylation may occupy a key position, mediating the effects of both&amp;nbsp;&lt;em&gt;cis&lt;/em&gt;- and&amp;nbsp;&lt;em&gt;trans&lt;/em&gt;-acting factors on transcriptional networks, including those contributing to human-specific traits.&lt;/p&gt;
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