biostudies-literatureZito ANIHR BioResourceEuropean Research CouncilMedical Research CouncilWellcome Truste1010556https://www.ebi.ac.uk/biostudies/studies/S-EPMC9942974biostudies-literatureUnknown19(2)X-chromosome inactivation (XCI) silences one X in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. To characterize incidence and variability of escape across individuals and tissues, we conducted a transcriptomic study of escape in adipose, skin, lymphoblastoid cell lines and immune cells in 248 healthy individuals exhibiting skewed XCI. We quantify XCI escape from a linear model of genes' allelic fold-change and XIST-based degree of XCI skewing. We identify 62 genes, including 19 lncRNAs, with previously unknown patterns of escape. We find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 23% demonstrating tissue-restricted escape, including cell type-specific escape across immune cells of the same individual. We also detect substantial inter-individual variability in escape. Monozygotic twins share more similar escape than dizygotic twins, indicating that genetic factors may underlie inter-individual differences in escape. However, discordant escape also occurs within monozygotic co-twins, suggesting environmental factors also influence escape. Altogether, these data indicate that XCI escape is an under-appreciated source of transcriptional differences, and an intricate phenotype impacting variable trait expressivity in females.PLoS geneticsEscape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable.PMC9942974MR/R023131/1European Community's Seventh Framework Programme (FP7/2007-2013) to TwinsUK studyWellcome Trust funds to TwinsUK studyMR/L016311/1NIHR BioResource to TwinsUK studyMR/L016311/1 to eMedLab Medical Bioinformatics infrastructureRoberts ALNardone SVisconti AAndres-Ejarque RSmall KSZito ARossi NEl-Sayed Moustafa JSFalchi MfalseEscape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable.X-chromosome inactivation (XCI) silences one X in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. To characterize incidence and variability of escape across individuals and tissues, we conducted a transcriptomic study of escape in adipose, skin, lymphoblastoid cell lines and immune cells in 248 healthy individuals exhibiting skewed XCI. We quantify XCI escape from a linear model of genes' allelic fold-change and XIST-based degree of XCI skewing. We identify 62 genes, including 19 lncRNAs, with previously unknown patterns of escape. We find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 23% demonstrating tissue-restricted escape, including cell type-specific escape across immune cells of the same individual. We also detect substantial inter-individual variability in escape. Monozygotic twins share more similar escape than dizygotic twins, indicating that genetic factors may underlie inter-individual differences in escape. However, discordant escape also occurs within monozygotic co-twins, suggesting environmental factors also influence escape. Altogether, these data indicate that XCI escape is an under-appreciated source of transcriptional differences, and an intricate phenotype impacting variable trait expressivity in females.2023-01-01T00:00:00Z2023 Feb2026-06-27T03:20:08.793Z2025-02-19T02:24:05.716ZS-EPMC99429743680237910.1371/journal.pgen.1010556