scholarly journals A robust test for X-chromosome genetic association accounting for X-chromosome inactivation and imprinting

2020 ◽  
Vol 102 ◽  
Author(s):  
Yu Zhang ◽  
Si-Qi Xu ◽  
Wei Liu ◽  
Wing Kam Fung ◽  
Ji-Yuan Zhou
Keyword(s):  
X Chromosome ◽  
Type I Error ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
X Chromosomes ◽  
Robust Test ◽  
The Difference ◽  
And Performance

Abstract The X chromosome is known to play an important role in many sex-specific diseases. However, only a few single-nucleotide polymorphisms on the X chromosome have been found to be associated with diseases. Compared to the autosomes, conducting association tests on the X chromosome is more intractable due to the difference in the number of X chromosomes between females and males. On the other hand, X-chromosome inactivation takes place in female mammals, which is a phenomenon in which the expression of one copy of two X chromosomes in females is silenced in order to achieve the same gene expression level as that in males. In addition, imprinting effects may be related to certain diseases. Currently, there are some existing approaches taking X-chromosome inactivation into account when testing for associations on the X chromosome. However, none of them allows for imprinting effects. Therefore, in this paper, we propose a robust test, ZXCII, which accounts for both X-chromosome inactivation and imprinting effects without requiring specifying the genetic models in advance. Simulation studies are conducted in order to investigate the validity and performance of ZXCII under various scenarios of different parameter values. The simulation results show that ZXCII controls the type I error rate well when there is no association. Furthermore, with regards to power, ZXCII is robust in all of the situations considered and generally outperforms most of the existing methods in the presence of imprinting effects, especially under complete imprinting effects.

scholarly journals Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

2021 ◽  
Vol 22 (3) ◽  
pp. 1114
Author(s):  
Ali Youness ◽  
Charles-Henry Miquel ◽  
Jean-Charles Guéry
Keyword(s):  
Autoimmune Diseases ◽  
X Chromosome ◽  
Gene Dosage ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Female Sex Hormones ◽  
Inactive X Chromosome ◽  
Immune Related Genes ◽  
Female Specific

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

Random X-chromosome inactivation in female primordial germ cells in the mouse

Development ◽  
1981 ◽  
Vol 64 (1) ◽  
pp. 251-258
Author(s):  
Andy McMahon ◽  
Mandy Fosten ◽  
Marilyn Monk
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Germ Line ◽  
Primordial Germ Cells ◽  
Phosphoglycerate Kinase ◽  
X Chromosome Inactivation ◽  
Yolk Sac ◽  
Chromosome Inactivation ◽  
X Chromosomes

The pattern of expression of the two X chromosomes was investigated in pre-meiotic germ cells from 12½-day-old female embryos heterozygous for the variant electrophoretic forms of the X-linked enzyme phosphoglycerate kinase (PGK-1). If such germ cells carry the preferentially active Searle's translocated X chromosome (Lyon, Searle, Ford & Ohno, 1964), then only the Pgk-1 allele on this chromosome is expressed. This confirms Johnston's evidence (1979,1981) that Pgk-1 expression reflects a single active X chromosome at this time. Extracts of 12½-day germ cells from heterozygous females carrying two normal X chromosomes show both the A and the B forms of PGK; since only one X chromosome in each cell is active, different alleles must be expressed in different cells, suggesting that X-chromosome inactivation is normally random in the germ line. This result makes it unlikely that germ cells are derived from the yolk-sac endoderm where the paternally derived X chromosome is preferentially inactivated. In their pattern of X-chromosome inactivation, germ cells evidently resemble other tissues derived from the epiblast.

scholarly journals Selection of X-chromosome Inactivation Model

2017 ◽  
Vol 16 ◽  
pp. 117693511774727 ◽  
Author(s):  
Jian Wang ◽  
Rajesh Talluri ◽  
Sanjay Shete
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Association Test ◽  
Chromosome Inactivation ◽  
Simulation Studies ◽  
Nucleotide Polymorphisms ◽  
Unified Approach ◽  
Cancer Genetic ◽  
Single Nucleotide ◽  
Selection Of

To address the complexity of the X-chromosome inactivation (XCI) process, we previously developed a unified approach for the association test for X-chromosomal single-nucleotide polymorphisms (SNPs) and the disease of interest, accounting for different biological possibilities of XCI: random, skewed, and escaping XCI. In the original study, we focused on the SNP-disease association test but did not provide knowledge regarding the underlying XCI models. One can use the highest likelihood ratio (LLR) to select XCI models (max-LLR approach). However, that approach does not formally compare the LLRs corresponding to different XCI models to assess whether the models are distinguishable. Therefore, we propose an LLR comparison procedure (comp-LLR approach), inspired by the Cox test, to formally compare the LLRs of different XCI models to select the most likely XCI model that describes the underlying XCI process. We conduct simulation studies to investigate the max-LLR and comp-LLR approaches. The simulation results show that compared with the max-LLR, the comp-LLR approach has higher probability of identifying the correct underlying XCI model for the scenarios when the underlying XCI process is random XCI, escaping XCI, or skewed XCI to the deleterious allele. We applied both approaches to a head and neck cancer genetic study to investigate the underlying XCI processes for the X-chromosomal genetic variants.

Regulation of imprinted X-chromosome inactivation in mice by Tsix

Development ◽  
2001 ◽  
Vol 128 (8) ◽  
pp. 1275-1286 ◽  
Author(s):  
T. Sado ◽  
Z. Wang ◽  
H. Sasaki ◽  
E. Li
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Maternal Allele ◽  
Xist Expression ◽  
Developmental Defects ◽  
X Chromosomes ◽  
Embryonic Tissues ◽  
Early Embryonic Lethality

In mammals, X-chromosome inactivation is imprinted in the extra-embryonic lineages with paternal X chromosome being preferentially inactivated. In this study, we investigate the role of Tsix, the antisense transcript from the Xist locus, in regulation of Xist expression and X-inactivation. We show that Tsix is transcribed from two putative promoters and its transcripts are processed. Expression of Tsix is first detected in blastocysts and is imprinted with only the maternal allele transcribed. The imprinted expression of Tsix persists in the extra-embryonic tissues after implantation, but is erased in embryonic tissues. To investigate the function of Tsix in X-inactivation, we disrupted Tsix by insertion of an IRES(β)geo cassette in the second exon, which blocked transcripts from both promoters. While disruption of the paternal Tsix allele has no adverse effects on embryonic development, inheritance of a disrupted maternal allele results in ectopic Xist expression and early embryonic lethality, owing to inactivation of both X chromosomes in females and single X chromosome in males. Further, early developmental defects of female embryos with maternal transmission of Tsix mutation can be rescued by paternal inheritance of the Xist deletion. These results provide genetic evidence that Tsix plays a crucial role in maintaining Xist silencing in cis and in regulation of imprinted X-inactivation in the extra-embryonic tissues.

scholarly journals Localized accumulation of Xist RNA in X chromosome inactivation

Open Biology ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 190213 ◽  
Author(s):  
Neil Brockdorff
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Non Coding Rna ◽  
Xist Rna ◽  
Analogous Manner ◽  
Mammalian Embryos ◽  
Non Coding Rnas ◽  
In Cis

The non-coding RNA Xist regulates the process of X chromosome inactivation, in which one of the two X chromosomes present in cells of early female mammalian embryos is selectively and coordinately shut down. Remarkably Xist RNA functions in cis , affecting only the chromosome from which it is transcribed. This feature is attributable to the unique propensity of Xist RNA to accumulate over the territory of the chromosome on which it is synthesized, contrasting with the majority of RNAs that are rapidly exported out of the cell nucleus. In this review I provide an overview of the progress that has been made towards understanding localized accumulation of Xist RNA, drawing attention to evidence that some other non-coding RNAs probably function in a highly analogous manner. I describe a simple model for localized accumulation of Xist RNA and discuss key unresolved questions that need to be addressed in future studies.

scholarly journals Landscape of X chromosome inactivation across human tissues

Nature ◽  
2017 ◽  
Vol 550 (7675) ◽  
pp. 244-248 ◽  
Author(s):  
Taru Tukiainen ◽  
◽  
Alexandra-Chloé Villani ◽  
Angela Yen ◽  
Manuel A. Rivas ◽  
...  
Keyword(s):  
Gene Expression ◽  
X Chromosome ◽  
Mammalian Cells ◽  
Phenotypic Diversity ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Phenotypic Traits ◽  
Human Tissues ◽  
X Chromosomes ◽  
Chromosomal Genes

Abstract X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of ‘escape’ from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

scholarly journals Histone H3 Lysine 36 Trimethylation Is Established over theXistPromoter by AntisenseTsixTranscription and Contributes to RepressingXistExpression

2015 ◽  
Vol 35 (22) ◽  
pp. 3909-3920 ◽  
Author(s):  
Tatsuya Ohhata ◽  
Mika Matsumoto ◽  
Martin Leeb ◽  
Shinwa Shibata ◽  
Satoshi Sakai ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
X Chromosome ◽  
Antisense Rna ◽  
Histone H3 ◽  
Embryonic Stem ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Histone H3.3

One of the two X chromosomes in female mammals is inactivated by the noncodingXistRNA. In mice, X chromosome inactivation (XCI) is regulated by the antisense RNATsix, which repressesXiston the active X chromosome. In the absence ofTsix, PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) is established over theXistpromoter. Simultaneous disruption ofTsixand PRC2 leads to derepression ofXistand in turn silencing of the single X chromosome in male embryonic stem cells. Here, we identified histone H3 lysine 36 trimethylation (H3K36me3) as a modification that is recruited byTsixcotranscriptionally and extends over theXistpromoter. Reduction of H3K36me3 by expression of a mutated histone H3.3 with a substitution of methionine for lysine at position 36 causes a significant derepression ofXist. Moreover, depletion of the H3K36 methylaseSetd2leads to upregulation ofXist, suggesting H3K36me3 as a modification that contributes to the mechanism ofTsixfunction in regulating XCI. Furthermore, we found that reduction of H3K36me3 does not facilitate an increase in H3K27me3 over theXistpromoter, indicating that additional mechanisms exist by whichTsixblocks PRC2 recruitment to theXistpromoter.

scholarly journals Do LINEs Have a Role in X-Chromosome Inactivation?

2006 ◽  
Vol 2006 ◽  
pp. 1-6 ◽  
Author(s):  
Mary F. Lyon
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Current Evidence ◽  
X Chromosomes ◽  
Repeat Elements ◽  
Sequencing Project ◽  
Human Genome Sequencing ◽  
Human And Mouse

There is longstanding evidence that X-chromosome inactivation (XCI) travels less successfully in autosomal than in X-chromosomal chromatin. The interspersed repeat elements LINE1s (L1s) have been suggested as candidates for “boosters” which promote the spread of XCI in the X-chromosome. The present paper reviews the current evidence concerning the possible role of L1s in XCI. Recent evidence, accruing from the human genome sequencing project and other sources, confirms that mammalian X-chromosomes are indeed rich in L1s, except in regions where there are many genes escaping XCI. The density of L1s is the highest in the evolutionarily oldest regions. Recent work on X; autosome translocations in human and mouse suggested failure of stabilization of XCI in autosomal material, so that genes are reactivated, but resistance of autosomal genes to the original silencing is not excluded. The accumulation of L1s on the X-chromosome may have resulted from reduced recombination or late replication. Whether L1s are part of the mechanism of XCI or a result of it remains enigmatic.

scholarly journals Case Report: Wiskott-Aldrich Syndrome Caused by Extremely Skewed X-Chromosome Inactivation in a Chinese Girl

2021 ◽  
Vol 9 ◽  
Author(s):  
Xuening Hou ◽  
Jie Sun ◽  
Chen Liu ◽  
Jihong Hao
Keyword(s):  
X Chromosome ◽  
Clinical Manifestations ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Chinese Girl ◽  
Skewed X Chromosome Inactivation ◽  
Female Carriers

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of Wiskott-Aldrich syndrome protein due to WAS gene mutation, which is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high risk of autoimmune complications and hematological malignancies. Although affected males with WAS usually manifest severe symptoms, female carriers have no significant clinical manifestations. Here, we describe a Chinese girl diagnosed with WAS carrying a heterozygous missense mutation in exon 2 of the WAS gene. The patient presented with persistent thrombocytopenia with small platelets and decreased WAS protein detected by flow cytometry and western blot analysis. The methylation analysis of the HUMARA gene displayed an extremely skewed X-chromosome inactivation (SXCI) pattern, where the X-chromosomes bearing normal WAS gene were predominantly inactivated, leaving the mutant gene active. Hence, our results suggest that completely inactivating the unaffected paternal X-chromosomes may be the reason for such phenotype in this female patient. SXCI has important implications for genetic counseling of female carriers with a family history of WAS.

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