Escape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable

• Published in: PLoS genetics Vol. 19; no. 2; p. e1010556
• Main Authors: Zito, Antonino, Roberts, Amy L., Visconti, Alessia, Rossi, Niccolo’, Andres-Ejarque, Rosa, Nardone, Stefano, El-Sayed Moustafa, Julia S., Falchi, Mario, Small, Kerrin S.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.02.2023; Public Library of Science (PLoS)
• Subjects: Analysis; Annotations; Biology and Life Sciences; Chromosomes, Human, X - genetics; Computer and Information Sciences; Datasets; Environmental factors; Epigenetics; Female; Females; Gender differences; Genes; Genes, X-Linked - genetics; Genetic aspects; Genetic factors; Genetic transcription; Humans; Lymphoblastoid cell lines; Medicine and Health Sciences; Phenotype; Phenotypes; RNA-protein interactions; Sexes; Skin; Transcriptomics; Twins; Twins, Monozygotic - genetics; X chromosome inactivation; X Chromosome Inactivation - genetics; X chromosomes; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1010556

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.