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In this study, we investigate whether variation in Xi expression among genes predicts transcriptional and phenotypic consequences of X-linked variation. We find that Xi expression levels are a strong linear predictor of female-male expression differences, suggesting that other compensatory or regulatory mechanisms play a more minor role in sex differences in X-linked gene expression. Among females, we identify traits\u2014including BMI, estradiol, and testosterone levels\u2014for which higher Xi expression correlates with the strength of evidence for either additive or dominance effects on the trait. We hypothesize that an underappreciated mechanism could generate dominance effects of X-linked variants on a trait\u2014specifically when the variant influences skew in X inactivation. The work establishes Xi expression as important for understanding transcriptional sex differences and the physiological variation among females.<\/jats:p>","DOI":"10.1101\/2025.08.01.668097","type":"posted-content","created":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T03:00:14Z","timestamp":1754190014000},"source":"Crossref","is-referenced-by-count":0,"title":["Escape from X inactivation drives sex differences in gene expression"],"prefix":"10.64898","author":[{"given":"Carrie","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Integrative Biology, University of Texas at Austin, Austin, TX, USA"},{"name":"Department of Population Health, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7198-3353","authenticated-orcid":false,"given":"Liaoyi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology, University of Texas at Austin, Austin, TX, USA"},{"name":"Department of Population Health, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3655-748X","authenticated-orcid":false,"given":"Arbel","family":"Harpak","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology, University of Texas at Austin, Austin, TX, USA"},{"name":"Department of Population Health, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026010105272848000_2025.08.01.668097v3.1","doi-asserted-by":"publisher","DOI":"10.1038\/190372a0"},{"key":"2026010105272848000_2025.08.01.668097v3.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-110711-155454"},{"key":"2026010105272848000_2025.08.01.668097v3.3","doi-asserted-by":"publisher","DOI":"10.1159\/000071572"},{"key":"2026010105272848000_2025.08.01.668097v3.4","doi-asserted-by":"crossref","unstructured":"Posynick, B. 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