Escape from X-inactivation in Twins Exhibits Intra- and Inter-individual Variability Across Tissues and is Heritable

Overview

Journal PLoS Genet

Specialty Genetics

Date 2023 Feb 21

PMID 36802379

Authors

Antonino Zito

Amy L Roberts

Alessia Visconti

Niccolo Rossi

Rosa Andres-Ejarque

Stefano Nardone

Julia S El-Sayed Moustafa

Mario Falchi

Kerrin S Small

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Escape of Kdm6a from X Chromosome Is Detrimental to Ischemic Brains via IRF5 Signaling.

Ngwa C, Misrani A, Manyam K, Xu Y, Qi S, Sharmeen R Transl Stroke Res. 2025; .

PMID: 39752046 DOI: 10.1007/s12975-024-01321-1.

Extreme hypernatremia after a laparoscopic hysterectomy and bilateral salpingo-oophorectomy: a case report and literature review.

Ding F, Nie X, Chen Y, Wang M, He Y Front Surg. 2024; 11:1462525.

PMID: 39474227 PMC: 11518838. DOI: 10.3389/fsurg.2024.1462525.

Sexual Dimorphism in Sex Hormone Metabolism in Human Skeletal Muscle Cells in Response to Different Testosterone Exposure.

Sgro P, Antinozzi C, Wasson C, Del Galdo F, Dimauro I, Di Luigi L Biology (Basel). 2024; 13(10).

PMID: 39452105 PMC: 11504033. DOI: 10.3390/biology13100796.

Escape of Kdm6a from X chromosome is detrimental to ischemic brains via IRF5 signaling.

Ngwa C, Misrani A, Manyam K, Xu Y, Qi S, Sharmeen R Res Sq. 2024; .

PMID: 39399684 PMC: 11469404. DOI: 10.21203/rs.3.rs-4986866/v1.

Stable and robust Xi and Y transcriptomes drive cell-type-specific autosomal and Xa responses in vivo and in vitro in four human cell types.

Blanton L, San Roman A, Wood G, Buscetta A, Banks N, Skaletsky H Cell Genom. 2024; 4(9):100628.

PMID: 39111319 PMC: 11480847. DOI: 10.1016/j.xgen.2024.100628.

References

Tukiainen T, Villani A, Yen A, Rivas M, Marshall J, Satija R . Landscape of X chromosome inactivation across human tissues. Nature. 2017; 550(7675):244-248. PMC: 5685192. DOI: 10.1038/nature24265. View

Wong C, Caspi A, Williams B, Houts R, Craig I, Mill J . A longitudinal twin study of skewed X chromosome-inactivation. PLoS One. 2011; 6(3):e17873. PMC: 3062559. DOI: 10.1371/journal.pone.0017873. View

Carrel L, Brown C . When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome. Philos Trans R Soc Lond B Biol Sci. 2017; 372(1733). PMC: 5627157. DOI: 10.1098/rstb.2016.0355. View

Hagerman R, Berry-Kravis E, Hazlett H, Bailey Jr D, Moine H, Kooy R . Fragile X syndrome. Nat Rev Dis Primers. 2017; 3:17065. DOI: 10.1038/nrdp.2017.65. View

Scofield R, Bruner G, Namjou B, Kimberly R, Ramsey-Goldman R, Petri M . Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum. 2008; 58(8):2511-7. PMC: 2824898. DOI: 10.1002/art.23701. View

Johnston C, Lovell F, Leongamornlert D, Stranger B, Dermitzakis E, Ross M . Large-scale population study of human cell lines indicates that dosage compensation is virtually complete. PLoS Genet. 2008; 4(1):e9. PMC: 2213701. DOI: 10.1371/journal.pgen.0040009. View

Grundberg E, Small K, Hedman A, Nica A, Buil A, Keildson S . Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet. 2012; 44(10):1084-9. PMC: 3784328. DOI: 10.1038/ng.2394. View

van de Geijn B, McVicker G, Gilad Y, Pritchard J . WASP: allele-specific software for robust molecular quantitative trait locus discovery. Nat Methods. 2015; 12(11):1061-3. PMC: 4626402. DOI: 10.1038/nmeth.3582. View

Buil A, Brown A, Lappalainen T, Vinuela A, Davies M, Zheng H . Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins. Nat Genet. 2014; 47(1):88-91. PMC: 4643454. DOI: 10.1038/ng.3162. View

10.

Engreitz J, Pandya-Jones A, McDonel P, Shishkin A, Sirokman K, Surka C . The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science. 2013; 341(6147):1237973. PMC: 3778663. DOI: 10.1126/science.1237973. View

11.

Seminog O, Seminog A, Yeates D, Goldacre M . Associations between Klinefelter's syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity. 2014; 48(2):125-8. DOI: 10.3109/08916934.2014.968918. View

12.

Naumova A, Plenge R, Bird L, Leppert M, Morgan K, Willard H . Heritability of X chromosome--inactivation phenotype in a large family. Am J Hum Genet. 1996; 58(6):1111-9. PMC: 1915075. View

13.

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

14.

Shvetsova E, Sofronova A, Monajemi R, Gagalova K, Draisma H, White S . Skewed X-inactivation is common in the general female population. Eur J Hum Genet. 2018; 27(3):455-465. PMC: 6460563. DOI: 10.1038/s41431-018-0291-3. View

15.

Long T, Hicks M, Yu H, Biggs W, Kirkness E, Menni C . Whole-genome sequencing identifies common-to-rare variants associated with human blood metabolites. Nat Genet. 2017; 49(4):568-578. DOI: 10.1038/ng.3809. View

16.

Garieri M, Stamoulis G, Blanc X, Falconnet E, Ribaux P, Borel C . Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts. Proc Natl Acad Sci U S A. 2018; 115(51):13015-13020. PMC: 6304968. DOI: 10.1073/pnas.1806811115. View

17.

Olney K, Brotman S, Andrews J, Valverde-Vesling V, Wilson M . Reference genome and transcriptome informed by the sex chromosome complement of the sample increase ability to detect sex differences in gene expression from RNA-Seq data. Biol Sex Differ. 2020; 11(1):42. PMC: 7374973. DOI: 10.1186/s13293-020-00312-9. View

18.

Adegbola A, Gao H, Sommer S, Browning M . A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD). Am J Med Genet A. 2008; 146A(4):505-11. DOI: 10.1002/ajmg.a.32142. View

19.

Tonon L, Bergamaschi G, Dellavecchia C, Rosti V, Lucotti C, Malabarba L . Unbalanced X-chromosome inactivation in haemopoietic cells from normal women. Br J Haematol. 1998; 102(4):996-1003. DOI: 10.1046/j.1365-2141.1998.00867.x. View

20.

Castel S, Aguet F, Mohammadi P, Ardlie K, Lappalainen T . A vast resource of allelic expression data spanning human tissues. Genome Biol. 2020; 21(1):234. PMC: 7488534. DOI: 10.1186/s13059-020-02122-z. View