X-chromosome inactivation: molecular mechanisms from the human perspective

Yang, Chengwei; Chapman, Andrew Glen; Kelsey, Angela D.; Minks, Jakub; Cotton, Allison M.; Brown, Carolyn J.

doi:10.1007/s00439-011-0994-9

Cited by 57 publications

(53 citation statements)

References 126 publications

(154 reference statements)

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“…One possible mechanism is that a paternal X chromosome retards development in such a way that female mortality rate increases; this has been confirmed in the mouse (100). Another possible mechanism is skewed X-inactivation (usually defined as >75% of cells sampled having, say, the paternal X chromosome inactivated), which can unmask recessive deleterious alleles (101,102); it can also mask them (103). Skewed inactivation is associated with female-biased pathology later in life (104)(105)(106) and also with an elevated risk of spontaneous abortion (107,108), although the sex ratio of the abortions appears to be unknown.…”

Section: Discussionmentioning

confidence: 99%

The human sex ratio from conception to birth

Orzack

Stubblefield

Akmaev³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

220

170

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We describe the trajectory of the human sex ratio from conception to birth by analyzing data from (i) 3-to 6-d-old embryos, (ii) induced abortions, (iii) chorionic villus sampling, (iv) amniocentesis, and (v) fetal deaths and live births. Our dataset is the most comprehensive and largest ever assembled to estimate the sex ratio at conception and the sex ratio trajectory and is the first, to our knowledge, to include all of these types of data. Our estimate of the sex ratio at conception is 0.5 (proportion male), which contradicts the common claim that the sex ratio at conception is malebiased. The sex ratio among abnormal embryos is male-biased, and the sex ratio among normal embryos is female-biased. These biases are associated with the abnormal/normal state of the sex chromosomes and of chromosomes 15 and 17. The sex ratio may decrease in the first week or so after conception (due to excess male mortality); it then increases for at least 10-15 wk (due to excess female mortality), levels off after ∼20 wk, and declines slowly from 28 to 35 wk (due to excess male mortality). Total female mortality during pregnancy exceeds total male mortality. The unbiased sex ratio at conception, the increase in the sex ratio during the first trimester, and total mortality during pregnancy being greater for females are fundamental insights into early human development.he sex ratio at conception in humans is unknown, despite hundreds of years of speculation and research. Investigations of the sex ratio date back at least as far as Graunt (1) who described a net excess of male births (2). By the late 1800s, it was clear that more males than females die during later pregnancy (3). Beyond these facts, the demographic and genetic dynamics of the sex ratio from conception to birth are poorly resolved.The claim that the conception or primary sex ratio (PSR) is more male-biased than the birth sex ratio appears often in textbooks (4, 5) and in the scientific literature (e.g., refs. 6-11), usually with little or no description of evidence. Estimates of the PSR in these studies are typically 0.56 (proportion males) or greater. Many fewer researchers have claimed that the PSR is unbiased or slightly male-biased (12-16). A handful of researchers has claimed or implied that the PSR is female-biased (17-19) or claimed that the PSR cannot be estimated due to lack of appropriate data and/or methodological problems (20)(21)(22).Previous estimates of the PSR have no meaningful basis in data from the time of conception (or within at least a month of it). At best, the PSR has been estimated via backward extrapolation from data on induced or spontaneous abortions, fetal deaths, or live births; most of the non-live-birth data stems from the second or third trimester of pregnancy. In addition, even if one ignores the fallibility of extrapolation, biased estimates of the PSR based on spontaneous abortions and fetal deaths have usually been regarded as arising from unbiased samples of a population of embryos or fetuses having a biased PSR. The alternativ...

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Section: Discussionmentioning

confidence: 99%

The human sex ratio from conception to birth

Orzack

Stubblefield

Akmaev³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

220

170

View full text Add to dashboard Cite

show abstract

“…Differences between human and mouse XCI also exist on several other levels, including the organization of the XIC, the number of genes escaping XCI and the chromatin status of the inactive X-chromosome. [98][99][100] These differences highlight the importance of more studies on XCI and XCR in humans, as findings from the well-studied mouse model system cannot always simply be extrapolated.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Payer

Lee

2014

RNA Biology

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X -chromosome inactivation (XCI)in female mammals is a dramatic example of epigenetic gene regulation, which entails the silencing of an entire chromosome through a wide range of mechanisms involving noncoding RNAs, chromatin-modifications, and DNAmethylation. While XCI is associated with the differentiated cell state, it is reversed by X-chromosome reactivation (XCR) ex vivo in pluripotent stem cells and in vivo in the early mouse embryo and the germline. Critical in the regulation of XCI vs. XCR is the X-inactivation center, a multigene locus on the X-chromosome harboring several long noncoding RNA genes including, most prominently, Xist and Tsix. These genes, which sit at the top of the XCI hierarchy, are by themselves controlled by pluripotency factors, coupling XCR with the naïve pluripotent stem cell state. In this point-of-view article we review the latest findings regarding this intricate relationship between cell differentiation state and epigenetic control of the X-chromosome. In particular, we discuss the emerging picture of complex multifactorial regulatory mechanisms, ensuring both a finetuned and robust X-reactivation process.

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“…Second, translocation of regulatory domains to another position on the genome might cause alternations in transcriptional regulation due to 'position effect' [Persani et al 2009]. Lastly, in female balanced X;autosome translocations carriers, the normal X chromosome is usually inactivated allowing full expression of genes on the translocated segments [ Schmidt and Du Sart 1992;Yang et al 2011]. Female balanced X; autosome translocation carriers are generally phenotypically normal because the normal X chromosome is completely inactivated in these patients as a result of phenotypic plasticity to prevent deleterious monosomy.…”

Section: Resultsmentioning

confidence: 99%

Disruption ofHDXgene in premature ovarian failure

Ökten

Güneş

Onat

et al. 2013

Systems Biology in Reproductive Medicine

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We present a case of a 19-year-old phenotypically normal girl with premature ovarian failure. Cytogenetic analysis using G banding and fluorescence in situ hybridization (FISH) from cultured peripheral blood lymphocytes of the patient and the family revealed a de novo X;15 translocation and the imbalance to be 46,X,t(X;15)(Xpter → Xq21::15q11 → 15qter;15pter → 15q11::Xq21 → Xqter).ish (CEPX+, wep15+, ISNRPN+, PML+, D15S10+, wcp15-, SNRRN-, PML-) [20]. The X chromosome inactivation (XCI) assay revealed a completely skewed XCI pattern in which selective pressure favors an active maternal allele. The Affymetrix 2.7 M cytogenetics whole-Genome array confirmed the chromosomal imbalance and identified disruption of the HDX gene at Xq21, the translocation breakpoint.

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X-chromosome inactivation: molecular mechanisms from the human perspective

Cited by 57 publications

References 126 publications

The human sex ratio from conception to birth

The human sex ratio from conception to birth

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Disruption ofHDXgene in premature ovarian failure

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