Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

Renault, Nicolas; Copeland, Emily; Howell, Robin E.; Greer, Wenda L.

doi:10.1038/jhg.2011.25

Cited by 10 publications

(9 citation statements)

References 51 publications

(77 reference statements)

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“…These findings are consistent with our genetically influenced models in which genotype determines the XIP at the time of choice (primary XIP), and other factors (environment, stochastic events, AAS etc) shift the pattern away from its primary value to the observable secondary XIP. Further studies [14][15][16][17] find that the inheritance pattern of XIPs in families can be explained by a co-dominant model following the rules of the mouse Xce model. Our findings contrast with a recent report by Bolduc et al, 31 however, which stated that XIPs result from completely random XCI and selective pressures, and are not heritable through a single cis-acting locus such as the XCE.…”

Section: Discussionmentioning

confidence: 99%

“…If it is genetically influenced, this would have important implications for the risk of disease expression in some females. Experimental data do support a human XCE hypothesis, [13][14][15][16][17] though definitively answering the question has been difficult due to the challenges in defining and assigning XIP phenotypes. Defining XIP phenotypes is challenging because of its continuous nature.…”

Section: Introductionmentioning

confidence: 94%

“…17 One model suggests that cohesin could bind together the two X-inactivation centres (XIC) during their obligatory co-localisation 35 prior to XCI initiation, and, given the asymmetrical structure of the cohesion complex, could potentially affect transcriptional activity within a single XIC. 17 Genetics could influence choice by altering the expression, stability, localisation, orientation, or binding of any of these elements. Additional biological data and mathematical modelling will be required to determine if any of these possibilities is accurate.…”

Section: Discussionmentioning

confidence: 99%

“…29 A small c could be consistent with this latest finding if the progenitor pool in question is not the total number of cells in the embryo at the time of choice, but the number of cells in a subpopulation giving rise to the blood cells from which the XIP is determined. However, several studies show a good correlation between XCI ratios in tissues derived from each of the three germ layers, 17,30 suggesting that if choice occurs completely randomly, it must occur in a progenitor pool giving rise to all three germ layers. Therefore, c would have to represent at least the number of cells giving rise to the embryo proper.…”

Section: Analysis Of Folded Xipsmentioning

confidence: 99%

“…[13][14][15][16][17] In order to test whether distributions of XIPs in large populations of unrelated females would also be consistent with the human XCE hypothesis, models of genetically influenced XCI choice were generated. That is, models representing a single, co-dominant locus with large effect.…”

Section: Fits Of Genetically Influenced Modelsmentioning

confidence: 99%

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Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice

et al. 2013

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In eutherian mammals, one X-chromosome in every XX somatic cell is transcriptionally silenced through the process of X-chromosome inactivation (XCI). Females are thus functional mosaics, where some cells express genes from the paternal X, and the others from the maternal X. The relative abundance of the two cell populations (X-inactivation pattern, XIP) can have significant medical implications for some females. In mice, the 'choice' of which X to inactivate, maternal or paternal, in each cell of the early embryo is genetically influenced. In humans, the timing of XCI choice and whether choice occurs completely randomly or under a genetic influence is debated. Here, we explore these questions by analysing the distribution of XIPs in large populations of normal females. Models were generated to predict XIP distributions resulting from completely random or genetically influenced choice. Each model describes the discrete primary distribution at the onset of XCI, and the continuous secondary distribution accounting for changes to the XIP as a result of development and ageing. Statistical methods are used to compare models with empirical data from Danish and Utah populations. A rigorous data treatment strategy maximises information content and allows for unbiased use of unphased XIP data. The Anderson-Darling goodness-of-fit statistics and likelihood ratio tests indicate that a model of genetically influenced XCI choice better fits the empirical data than models of completely random choice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Folded Xipsmentioning

confidence: 99%

Section: Fits Of Genetically Influenced Modelsmentioning

confidence: 99%

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Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice

et al. 2013

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De novo loss‐of‐function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies

Mullegama

Klein

Mulatinho

et al. 2017

American J of Med Genetics Pt A

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The cohesin complex is an evolutionarily conserved multi-subunit protein complex which regulates sister chromatid cohesion during mitosis and meiosis. Additionally, the cohesin complex regulates DNA replication, DNA repair, and transcription. The core of the complex consists of four subunits: SMC1A, SMC3, RAD21, and STAG1/2. Loss-of-function mutations in many of these proteins have been implicated in human developmental disorders collectively termed "cohesinopathies." Through clinical exome sequencing (CES) of an 8-year-old girl with a clinical history of global developmental delay, microcephaly, microtia with hearing loss, language delay, ADHD, and dysmorphic features, we describe a heterozygous de novo variant (c.205C>T; p.(Arg69*)) in the integral cohesin structural protein, STAG2. This variant is associated with decreased STAG2 protein expression. The analyses of metaphase spreads did not exhibit premature sister chromatid separation; however, delayed sister chromatid cohesion was observed. To further support the pathogenicity of STAG2 variants, we identified two additional female cases from the DECIPHER research database with mutations in STAG2 and phenotypes similar to our patient. Interestingly, the clinical features of these three cases are remarkably similar to those observed in other well-established cohesinopathies. Herein, we suggest that STAG2 is a dosage-sensitive gene and that heterozygous loss-of-function variants lead to a cohesinopathy.

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Epigenetic and transcriptomic consequences of excess X‐chromosome material in 47,XXX syndrome—A comparison with Turner syndrome and 46,XX females

Nielsen

Trolle

Vang

et al. 2020

American J of Med Genetics Pt C

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Abstract47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X‐chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may ensue from increased or decreased expression from the genes that escape X inactivation, as well as from incomplete X chromosome inactivation in 47,XXX. We aim to study genome‐wide DNA‐methylation and RNA‐expression changes can explain phenotypic traits in 47,XXX syndrome. We compare DNA‐methylation and RNA‐expression data derived from white blood cells of seven women with 47,XXX syndrome, with data from seven female controls, as well as with seven women with Turner syndrome (45,X). To address these questions, we explored genome‐wide DNA‐methylation and transcriptome data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven karyotypically normal females (46,XX). Based on promoter methylation, we describe a demethylation of six X‐chromosomal genes (AMOT, HTR2C, IL1RAPL2, STAG2, TCEANC, ZNF673), increased methylation for GEMIN8, and four differentially methylated autosomal regions related to four genes (SPEG, MUC4, SP6, and ZNF492). We illustrate how these changes seem compensated at the transcriptome level although several genes show differential exon usage. In conclusion, our results suggest an impact of the supernumerary X chromosome in 47,XXX syndrome on the methylation status of selected genes despite an overall comparable expression profile.

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Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

Cited by 10 publications

References 51 publications

Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice

Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice

De novo loss‐of‐function variants in STAG2 are associated with developmental delay, microcephaly, and congenital anomalies

Epigenetic and transcriptomic consequences of excess X‐chromosome material in 47,XXX syndrome—A comparison with Turner syndrome and 46,XX females

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