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Theory suggests that changes to\n                  <jats:italic>cis<\/jats:italic>\n                  -regulatory elements such as promoters and enhancers may drive evolutionary adaptation, and DNA methylation is a key factor in transcriptional\n                  <jats:italic>cis<\/jats:italic>\n                  -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\n                  <jats:italic>cis<\/jats:italic>\n                  - vs.\n                  <jats:italic>trans<\/jats:italic>\n                  -acting methylation divergence across the genome. Across cell types, we found that methylation divergence is primarily driven in\n                  <jats:italic>cis<\/jats:italic>\n                  , which can be linked in some cases to nearby sequence variants such as CpG gains and losses. Although less common, regions with\n                  <jats:italic>trans<\/jats:italic>\n                  -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\n                  <jats:italic>cis<\/jats:italic>\n                  -regulatory divergence. Moreover, we identified lineage-specific selection shaping promoter methylation at the level of entire pathways including those associated with 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\n                  <jats:italic>cis<\/jats:italic>\n                  - and\n                  <jats:italic>trans<\/jats:italic>\n                  -acting factors on transcriptional networks, including those contributing to human-specific traits.\n                <\/jats:p>","DOI":"10.64898\/2026.01.20.700710","type":"posted-content","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T12:50:23Z","timestamp":1768999823000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Cis<\/i>\n                  -regulation and natural selection in the evolution of human DNA methylation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0107-7463","authenticated-orcid":false,"given":"Zhenzhen","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Biology, Stanford University, Stanford CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6297-9742","authenticated-orcid":false,"given":"Alexander L.","family":"Starr","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3536-9006","authenticated-orcid":false,"given":"David","family":"Gokhman","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8400-8541","authenticated-orcid":false,"given":"Hunter B.","family":"Fraser","sequence":"additional","affiliation":[{"name":"Department of Biology, Stanford University, Stanford CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026093016250910000_2026.01.20.700710v3.1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.152710.112"},{"key":"2026093016250910000_2026.01.20.700710v3.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1090005"},{"key":"2026093016250910000_2026.01.20.700710v3.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-090314-045935"},{"key":"2026093016250910000_2026.01.20.700710v3.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3229"},{"key":"2026093016250910000_2026.01.20.700710v3.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700488104"},{"key":"2026093016250910000_2026.01.20.700710v3.6","doi-asserted-by":"publisher","DOI":"10.1038\/nri3362"},{"key":"2026093016250910000_2026.01.20.700710v3.7","doi-asserted-by":"publisher","DOI":"10.1101\/gr.254904.119"},{"key":"2026093016250910000_2026.01.20.700710v3.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-020-0242-z"},{"key":"2026093016250910000_2026.01.20.700710v3.9","unstructured":"Ma, S. et al. 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