TY - JOUR
T1 - Escape from X-inactivation in twins exhibits intra- and inter-individual variability across tissues and is heritable
AU - Zito, Antonino
AU - Roberts, Amy
AU - Visconti, Alessia
AU - Rossi, Niccolo
AU - Andres Ejarque, Rosa
AU - Nardone, Stefano
AU - El-Sayed Moustafa, Julia
AU - Falchi, Mario
AU - Small, Kerrin
N1 - Copyright: © 2023 Zito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2023/2/21
Y1 - 2023/2/21
N2 - 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.
AB - 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.
KW - Humans
KW - Female
KW - X Chromosome Inactivation/genetics
KW - Chromosomes, Human, X/genetics
KW - Genes, X-Linked/genetics
KW - Twins, Monozygotic/genetics
KW - Phenotype
UR - http://www.scopus.com/inward/record.url?scp=85148396134&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1010556
DO - 10.1371/journal.pgen.1010556
M3 - Article
C2 - 36802379
SN - 1553-7390
VL - 19
JO - PLoS Genetics
JF - PLoS Genetics
IS - 2
M1 - e1010556
ER -