scholarly journals Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases

2021 ◽  
Author(s):  
Renan Sauteraud ◽  
Jill M. Stahl ◽  
Jesica James ◽  
Marisa Englebright ◽  
Fang Chen ◽  
...  
Keyword(s):  
X Chromosome ◽  
Association Studies ◽  
Large Population ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Autosomal Gene ◽  
Homologous Gene ◽  
Data Sets ◽  
Rna Seq ◽  
Data Set

The X Chromosome plays an important role in human development and disease. However, functional genomic and disease association studies of X genes greatly lag behind autosomal gene studies, in part owing to the unique biology of X-Chromosome inactivation (XCI). Because of XCI, most genes are only expressed from one allele. Yet, ∼30% of X genes “escape” XCI and are transcribed from both alleles, many only in a proportion of the population. Such interindividual differences are likely to be disease relevant, particularly for sex-biased disorders. To understand the functional biology for X-linked genes, we developed X-Chromosome inactivation for RNA-seq (XCIR), a novel approach to identify escape genes using bulk RNA-seq data. Our method, available as an R package, is more powerful than alternative approaches and is computationally efficient to handle large population-scale data sets. Using annotated XCI states, we examined the contribution of X-linked genes to the disease heritability in the United Kingdom Biobank data set. We show that escape and variable escape genes explain the largest proportion of X heritability, which is in large part attributable to X genes with Y homology. Finally, we investigated the role of each XCI state in sex-biased diseases and found that although XY homologous gene pairs have a larger overall effect size, enrichment for variable escape genes is significantly increased in female-biased diseases. Our results, for the first time, quantitate the importance of variable escape genes for the etiology of sex-biased disease, and our pipeline allows analysis of larger data sets for a broad range of phenotypes.

scholarly journals Single Cell Expression Data Reveal Human Genes that Escape X-Chromosome Inactivation

2016 ◽  
Author(s):  
Kerem Wainer-Katsir ◽  
Michal Linial
Keyword(s):  
X Chromosome ◽  
Direct Method ◽  
Single Cells ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
P Value ◽  
Expression Data ◽  
Rna Seq ◽  
Specific Expression ◽  
Biallelic Expression

ABSTRACTSex chromosomes pose an inherent genetic imbalance between genders. In mammals, one of the female’s X-chromosomes undergoes inactivation (Xi). Indirect measurements estimate that about 20% of Xi genes completely or partially escape inactivation. The identity of these escapee genes and their propensity to escape inactivation remain unsolved. A direct method for identifying escapees was applied by quantifying differential allelic expression from single cells. RNA-Seq fragments were assigned to informative SNPs which were labeled by the appropriate parental haplotype. This method was applied for measuring allelic specific expression from Chromosome-X (ChrX) and an autosomal chromosome as a control. We applied the protocol for measuring biallelic expression from ChrX to 104 primary fibroblasts. Out of 215 genes that were considered, only 13 genes (6%) were associated with biallelic expression. The sensitivity of escapees' identification was increased by combining SNP mapping for parental diploid genomes together with RNA-Seq from clonal single cells (25 lymphoblasts). Using complementary protocols, referred to as strict and relaxed, we confidently identified 25 and 31escapee genes, respectively. When pooled versions of 30 and 100 cells were used, <50% of these genes were revealed. We assessed the generality of our protocols in view of an escapee catalog compiled from indirect methods. The overlap between the escapee catalog and the genes’ list from this study is statistically significant (P-value of E-07). We conclude that single cells’ expression data are instrumental for studying X-inactivation with an improved sensitivity. Finally, our results support the emerging notion of the non-deterministic nature of genes that escape X-chromosome inactivation.

scholarly journals Diverse developmental strategies of X chromosome dosage compensation in eutherian mammals

2019 ◽  
Vol 63 (3-4-5) ◽  
pp. 223-233 ◽  
Author(s):  
Alexander I. Shevchenko ◽  
Elena V. Dementyeva ◽  
Irina S. Zakharova ◽  
Suren M. Zakian
Keyword(s):  
Gene Expression ◽  
X Chromosome ◽  
Dosage Compensation ◽  
Mammalian Species ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Autosomal Gene ◽  
Mammalian Development ◽  
Compensation Mechanisms ◽  
Early Mammalian Development

In eutherian mammals, dosage compensation arose to balance X-linked gene expression between sexes and relatively to autosomal gene expression in the evolution of sex chromosomes. Dosage compensation occurs in early mammalian development and comprises X chromosome upregulation and inactivation that are tightly coordinated epigenetic processes. Despite a uniform principle of dosage compensation, mechanisms of X chromosome inactivation and upregulation demonstrate a significant variability depending on sex, developmental stage, cell type, individual, and mammalian species. The review focuses on relationships between X chromosome inactivation and upregulation in mammalian early development.

125 INCOMPLETE COMPENSATORY UP-REGULATION OF X-LINKED GENES IN BOVINE GERMLINE, EARLY EMBRYOS, AND SOMATIC TISSUES

2017 ◽  
Vol 29 (1) ◽  
pp. 171 ◽  
Author(s):  
J. Duan ◽  
N. K. Jue ◽  
Z. Jiang ◽  
R. O'Neill ◽  
E. Wolf ◽  
...  
Keyword(s):  
X Chromosome ◽  
Germ Cells ◽  
Dosage Compensation ◽  
Chromosome Inactivation ◽  
Data Sets ◽  
Rna Seq ◽  
Cell Stage ◽  
Embryonic Tissues ◽  
Early Embryos ◽  
Somatic Tissues

The maintenance of a proper gene dosage is essential in cellular networks. To resolve the dosage imbalance between eutherian females (XX) and male (XY), X chromosome inactivation (XCI) occurs in females, while X-chromosome dosage compensation up-regulates the active X to balance its expression with that of autosome pairs [Ohno’s hypothesis; Ohno 1967 Sex Chromosomes and Sex-linked Genes (Springer-Verlag), p. 99]. These phenomena have been well studied in humans and mice, despite many controversies over the existence of such up-regulation. Using RNA sequencing data, we determined X chromosome dosage compensation in the bovine by analysing the global expression profiles of germ cells, embryos, and somatic tissues. Eight bovine RNA-seq data sets were obtained in from the Gene Expression Omnibus, covering bovine immature/mature oocytes (GSE59186 and GSE52415), pre-implantation conceptuses (GSE59186, GSE52415, and GSE56513), extra-embryonic tissues (PRJNA229443), and male/female somatic tissues (GSE74076, GSE63509, PRJEB6377, and GSE65125). The RNAseq data were trimmed and non-uniquely (paralogs included) mapped to the bovine reference genome assembly UMD3.1.1 using Hisat2 (version 2.0.5) aligner. The mRNA level of each gene, estimated by transformed transcripts per kilobase million was quantified by IsoEM (version 1.1.5). These RNA-seq data sets represented 4 chromosome scenarios in cells: XXXX:AAAA (diploid immature oocyte with DNA duplication), XX:AA (haploid mature oocyte with DNA duplication), XX:AA and X:AA (gradual changed X status in bovine pre-implantation conceptuses), and X:AA (extra-embryonic tissues and somatic cells in female with one active X or XY male) were analysed for dosage compensation. A total of 959 X-linked genes and 20,316 autosome genes were used to calculate the relative X to autosomal gene (A) expression (RXE): log2 (X expression) − log2 (A expression). The following dosage determinations were made: RXE values ≥ 0: complete dosage compensation (or X: A ratio ≥ 1); RXE values < 0: in-complete dosage compensation; RXE value = −1: no dosage compensation (or X: A ratio = 0.5). Our analyses showed a decreased RXE after fertilization, from −0.33 in matured oocytes to −0.50 at the 2-cell stage, indicating that the sperm that undergo meiotic sex chromosome inactivation (MSCI) bring in inactive X chromosomes to the matured oocytes. Subsequently, the activation of the bovine embryonic genome at the 4- to 8-cell stage increased RXE from −0.54 to −0.05. This was followed by a sharp RXE decline from −0.02 at the 16-cell stage, 0.1 at the 32-cell stage to −0.29 at the compact morula stage, which is known as paternal X inactivation stage in the bovine. Finally, RXE was stabilised from blastocysts −0.19 through the Day 19 conceptuses −0.25 to somatic tissue average −0.21 with a pattern of incomplete X compensation. These findings support X expression up-regulation as proposed by Ohno. No significant RXE differences were observed between bovine female and male somatic tissues, further supporting Ohno’s hypothesis, which predicts a balance in the expression of X-linked genes to that of autosomes. This study confirms Ohno’s hypothesis of X dosage compensation in bovine germ cells, early embryos, and somatic tissues.

X-linked CNV and skewed X-chromosome inactivation

2020 ◽  
pp. 19-21
Author(s):  
Е.А. Фонова ◽  
Е.Н. Толмачева ◽  
А.А. Кашеварова ◽  
М.Е. Лопаткина ◽  
К.А. Павлова ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Intellectual Disability ◽  
X Chromosome ◽  
Copy Number ◽  
Copy Number Variations ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Chromosome X ◽  
Skewed X Chromosome Inactivation

Смещение инактивации Х-хромосомы может быть следствием и маркером нарушения клеточной пролиферации при вариациях числа копий ДНК на Х-хромосоме. Х-сцепленные CNV выявляются как у женщин с невынашиванием беременности и смещением инактивации Х-хромосомы (с частотой 33,3%), так и у пациентов с умственной отсталостью и смещением инактивацией у их матерей (с частотой 40%). A skewed X-chromosome inactivation can be a consequence and a marker of impaired cell proliferation in the presence of copy number variations (CNV) on the X chromosome. X-linked CNVs are detected in women with miscarriages and a skewed X-chromosome inactivation (with a frequency of 33.3%), as well as in patients with intellectual disability and skewed X-chromosome inactivation in their mothers (with a frequency of 40%).

scholarly journals X-Linked Emery–Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 919 ◽  
Author(s):  
Viggiano ◽  
Madej-Pilarczyk ◽  
Carboni ◽  
Picillo ◽  
Ergoli ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
X Chromosome ◽  
Clinical Symptoms ◽  
Fibrous Tissue ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Cardiac Conduction ◽  
Asymptomatic Carriers ◽  
Cardiac Symptoms ◽  
Female Carriers

X-linked Emery–Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers—25 familial and 5 sporadic cases—seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue.

scholarly journals Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects

Cell Reports ◽  
2019 ◽  
Vol 27 (2) ◽  
pp. 442-454.e5 ◽  
Author(s):  
Alex R.D. Delbridge ◽  
Andrew J. Kueh ◽  
Francine Ke ◽  
Natasha M. Zamudio ◽  
Farrah El-Saafin ◽  
...  
Keyword(s):  
X Chromosome ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Female Specific

Spread of X‐chromosome inactivation into autosomal regions in patients with unbalanced X‐autosome translocations and its phenotypic effects

2021 ◽  
Author(s):  
Bianca Pereira Favilla ◽  
Vera Ayres Meloni ◽  
Ana Beatriz Perez ◽  
Danilo Moretti‐Ferreira ◽  
Deise Helena Souza ◽  
...  
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation

scholarly journals XChromosome Effect on Maternal Recombination and Meiotic Drive in the Mouse

Genetics ◽  
2002 ◽  
Vol 161 (4) ◽  
pp. 1651-1659 ◽  
Author(s):  
Elena de la Casa-Esperón ◽  
J Concepción Loredo-Osti ◽  
Fernando Pardo-Manuel de Villena ◽  
Tammi L Briscoe ◽  
Jan Michel Malette ◽  
...  
Keyword(s):  
Mouse Chromosome ◽  
X Chromosome ◽  
Meiotic Recombination ◽  
Meiotic Drive ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Chromosome 11 ◽  
Genome Wide ◽  
Mouse Chromosome 11 ◽  
Segregation Of Chromosomes

AbstractWe observed that maternal meiotic drive favoring the inheritance of DDK alleles at the Om locus on mouse chromosome 11 was correlated with the X chromosome inactivation phenotype of (C57BL/ 6-Pgk1a × DDK)F1 mothers. The basis for this unexpected observation appears to lie in the well-documented effect of recombination on meiotic drive that results from nonrandom segregation of chromosomes. Our analysis of genome-wide levels of meiotic recombination in females that vary in their X-inactivation phenotype indicates that an allelic difference at an X-linked locus is responsible for modulating levels of recombination in oocytes.

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