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1.
Mammalian X-chromosome inactivation achieves dosage compensation between the sexes by the silencing of one X chromosome in females. In Eutheria, X inactivation is initiated by the large noncoding RNA Xist; however, it is unknown how this RNA results in silencing of the chromosome or why, at least in humans, many genes escape silencing in somatic cells. We have sequenced the coast mole Xist gene and compared the Xist RNA sequence among seven eutherians to provide insight into the structure of the RNA and origins of the gene. Using DNA methylation of promoter sequences to assess whether genes are silenced in females we report the inactivation status of seven X-linked genes in humans and mice as well as two additional eutherians, the mole and the cow, providing evidence that escape from inactivation is common among Eutheria. 相似文献
2.
Origin and evolution of X chromosome inactivation 总被引:1,自引:0,他引:1
Evolution of the mammalian sex chromosomes heavily impacts on the expression of X-encoded genes, both in marsupials and placental mammals. The loss of genes from the Y chromosome forced a two-fold upregulation of dose sensitive X-linked homologues. As a corollary, female cells would experience a lethal dose of X-linked genes, if this upregulation was not counteracted by evolution of X chromosome inactivation (XCI) that allows for only one active X chromosome per diploid genome. Marsupials rely on imprinted XCI, which inactivates always the paternally inherited X chromosome. In placental mammals, random XCI (rXCI) is the predominant form, inactivating either the maternal or paternal X. In this review, we discuss recent new insights in the regulation of XCI. Based on these findings, we propose an X inactivation center (Xic), composed of a cis-Xic and trans-Xic that encompass all elements and factors acting to control rXCI either in cis or in trans. We also highlight that XCI may have evolved from a very small nucleation site on the X chromosome in the vicinity of the Sox3 gene. Finally, we discuss the possible evolutionary road maps that resulted in imprinted XCI and rXCI as observed in present day mammals. 相似文献
3.
Molecular cytological differentiation of active from inactive X domains in interphase: implications for X chromosome inactivation 总被引:7,自引:0,他引:7
A fluorescence in situ hybridization method using a biotinylated DNA probe specific for the centromeric region of the human X chromosome was used to differentiate the genetically active from the inactive X in interphase cells. With this technique, we were able to interpret both the relative position and the degree of condensation of the X chromosomes within the nucleus. We first established the specificity of fluorescence labelling of the hybridized probe by comparing its location and appearance (either dense or diffuse) when associated with a sex chromatin body (SCB) in early passage normal human female fibroblasts. In these cells, where the presence of inactive X chromatin was verified by identification of a 4',6-diamidino-2-phenyl indole (DAPI)-positive SCB in 85% of the cells examined, the X chromatin fluorescence was always associated with the SCB. The signal was dense in structure in 98% and peripheral in location in 80% of the nuclei. A second type of signal, diffuse in form, was observed in 85% of the nuclei and presumably represents the location of the active X chromosome. It was located peripherally or centrally with equal frequency and was not associated with any identifiable nuclear component. This diffuse signal was the major type associated with human male fibroblasts. In rodent x human hybrid cells containing a human inactive X, the fluorescent signal was associated with an SCB-like structure in only 13% of the nuclei; it was dense in 66% of the nuclei and equally peripheral or central in location. This indicates an alteration in the interphase structure of the human inactive X chromosome in hybrid cells which may explain its known instability with respect to genetic activity in such systems. 相似文献
4.
To achieve a balanced gene expression dosage between males (XY) and females (XX), mammals have evolved a compensatory mechanism
to randomly inactivate one of the female X chromosomes. Despite this chromosome-wide silencing, a number of genes escape X
inactivation: in women about 15% of X-linked genes are bi-allelically expressed and in mice, about 3%. Expression from the
inactive X allele varies from a few percent of that from the active allele to near equal expression. While most genes have
a stable inactivation pattern, a subset of genes exhibit tissue-specific differences in escape from X inactivation. Escape
genes appear to be protected from the repressive chromatin modifications associated with X inactivation. Differences in the
identity and distribution of escape genes between species and tissues suggest a role for these genes in the evolution of sex
differences in specific phenotypes. The higher expression of escape genes in females than in males implies that they may have
female-specific roles and may be responsible for some of the phenotypes observed in X aneuploidy. 相似文献
5.
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7.
Sexual antagonism and the evolution of X chromosome inactivation 总被引:2,自引:0,他引:2
In most female mammals, one of the two X chromosomes is inactivated early in embryogenesis. Expression of most genes on this chromosome is shut down, and the inactive state is maintained throughout life in all somatic cells. It is generally believed that X-inactivation evolved as a means of achieving equal gene expression in males and females (dosage compensation). Following degeneration of genes on the Y chromosome, gene expression on X chromosomes in males and females is upregulated. This results in closer to optimal gene expression in males, but deleterious overexpression in females. In response, selection is proposed to favor inactivation of one of the X chromosomes in females, restoring optimal gene expression. Here, we make a first attempt at shedding light on this intricate process from a population genetic perspective, elucidating the sexually antagonistic selective forces involved. We derive conditions for the process to work and analyze evolutionary stability of the system. The implications of our results are discussed in the light of empirical findings and a recently proposed alternative hypothesis for the evolution of X-inactivation. 相似文献
8.
Localization of a gene that escapes inactivation to the X chromosome proximal short arm: implications for X inactivation. 总被引:9,自引:2,他引:7
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The process of mammalian X chromosome inactivation results in the inactivation of most, but not all, genes along one or the other of the two X chromosomes in females. On the human X chromosome, several genes have been described that "escape" inactivation and continue to be expressed from both homologues. All such previously mapped genes are located in the distal third of the short arm of the X chromosome, giving rise to the hypothesis of a region of the chromosome that remains noninactivated during development. The A1S9T gene, an X-linked locus that complements a mouse temperature-sensitive defect in DNA synthesis, escapes inactivation and has now been localized, in human-mouse somatic cell hybrids, to the proximal short arm, in Xp11.1 to Xp11.3. Thus, A1S9T lies in a region of the chromosome that is separate from the other genes known to escape inactivation and is located between other genes known to be subject to X inactivation. This finding both rules out models based on a single chromosomal region that escapes inactivation and suggests that X inactivation proceeds by a mechanism that allows considerable autonomy between different genes or regions on the chromosome. 相似文献
9.
Victor E. Kane 《Journal of mathematical biology》1979,7(3):199-218
Summary A multivariate Gaussian model for mammalian development is presented with the associated biological and mathematical assumptions. Many biological investigations use the female mammal X chromosome to test hypotheses and to estimate parameters of the developmental system. In particular, Lyon's (1961) hypotheses are used as a basis of the mathematical model. Experimental mouse data and three sets of human experimental data are analyzed using the hypothesized Gaussian model. The estimated biological parameters are consistent with some current biological theories. 相似文献
10.
Bruining H Swaab H de Sonneville LM van Rijn S van Engeland H Kas MJ 《Genes, Brain & Behavior》2011,10(6):658-662
The behavioral characterization of animals that carry genetic disorder abnormalities in a controlled genetic and environmental background may be used to identify human deficits that are significant to understand underlying neurobiological mechanisms. Here, we studied whether previously reported object recognition impairments in mice with a supernumerary X chromosome relate to specific cognitive deficits in Klinefelter syndrome (47,XXY). We aimed to optimize face validity by studying temporal object recognition in human cognitive assays. Thirty-four boys with Klinefelter syndrome (mean age 12.01) were compared with 90 age-matched normal controls, on a broad range of visual object memory tasks, including tests for pattern and temporal order discrimination. The results indicate that subjects with Klinefelter syndrome have difficulty in the processing of visual object and pattern information. Visual object patterns seem difficult to discriminate especially when temporal information needs to be processed and reproduced. On the basis of cross-species comparison, we propose that impaired temporal processing of object pattern information is an important deficit in Klinefelter syndrome. The current study shows how cross-species behavioral characterization may be used as a starting point to understand the neurobiology of syndromal phenotypic expression. The features of this study may serve as markers for interventions in Klinefelter syndrome. Similar cross-species evaluations of standard mouse behavioral paradigms in different genetic contexts may be powerful tools to optimize genotype-phenotype relationships. 相似文献
11.
Sharan K Sidhu Jakub Minks Samuel C Chang Allison M Cotton Carolyn J Brown 《Biochimie et biologie cellulaire》2008,86(5):370-379
The silent X chromosome in mammalian females is a classic example of facultative heterochromatin, the term highlighting the compacted and inactive nature of the chromosome. However, it is now clear that the heterochromatin of the inactive X is not homogeneous--as indeed, not all genes on the inactive X are silenced. We summarize known features and events of X inactivation in different mouse and human model systems, and highlight the heterogeneity of chromatin along the inactive X. Characterizing this heterogeneity is likely to provide insight into the cis-acting sequences involved in X chromosome inactivation. 相似文献
12.
Background
X chromosome inactivation is a spectacular example of epigenetic silencing. In order to deduce how this complex system evolved, we examined X inactivation in a model marsupial, the tammar wallaby (Macropus eugenii). In marsupials, X inactivation is known to be paternal, incomplete and tissue-specific, and occurs in the absence of an XIST orthologue. 相似文献13.
Migeon BR 《Cytogenetic and genome research》2002,99(1-4):8-16
My contribution to this special issue on Vertebrate Sex Chromosomes deals with the theme of X chromosome inactivation and its variations. I will argue that the single active X--characteristic of mammalian X dosage compensation--is unique to mammals, and that the major underlying mechanism(s) must be the same for most of them. The variable features reflect modifications that do not interfere with the basic theme. These variations were acquired during mammalian evolution--to solve special needs for imprinting and locking in the inactive state. Some of the adaptations reinforce the basic theme, and were needed because of species differences in the timing of interacting developmental events. Elucidating the molecular basis for the single active X requires that we distinguish the mechanisms essential for the basic theme from those responsible for its variations. 相似文献
14.
Karen Helene Ørstavik 《Human genetics》2009,126(3):363-373
15.
Differential X reactivation in human placental cells: implications for reversal of X inactivation
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X inactivation--the mammalian method of X chromosome dosage compensation--is extremely stable in human somatic cells; only fetal germ cells have a developmental program to reverse the process. The human placenta, at term, differs from other somatic tissues, since it has the ability to reverse the X-inactivation program. To determine whether reversal can be induced at other stages of placental development, we examined earlier placental specimens using a cell-hybridization assay. We found that global X reactivation is also inducible in villi cells from first-trimester spontaneous abortions but not from first-trimester elective terminations. These differences in inducibility are not associated with detectable variation in histone H4 acetylation, DNA methylation, or XIST expression--hallmarks of the inactivation process--so other factors must have a role. One notable feature is that the permissive cells, unlike nonpermissive ones, have ceased to proliferate in vivo and are either beginning or in the process of programmed cell death. Cessation of mitotic proliferation also characterizes oocytes at the stage at which they undergo X reactivation. We suggest that, along with undermethylation, the apoptotic changes accompanying cessation of cell proliferation contribute to the reversal of inactivation, not only in placental cells, but also in oocytes entering meiosis. 相似文献
16.
Tanya N. Eble V. Reid Sutton Haleh Sangi-Haghpeykar Xiaoling Wang Weihong Jin Richard A. Lewis Ignatia B. Van den Veyver 《Human genetics》2009,125(2):211-216
Most females have random X-chromosome inactivation (XCI), defined as an equal likelihood for inactivation of the maternally-
or paternally-derived X chromosome in each cell. Several X-linked disorders have been associated with a higher prevalence
of non-random XCI patterns, but previous studies on XCI patterns in Aicardi syndrome were limited by small numbers and older
methodologies, and have yielded conflicting results. We studied XCI patterns in DNA extracted from peripheral blood leukocytes
of 35 girls with typical Aicardi syndrome (AIC) from 0.25 to 16.42 years of age, using the human androgen receptor assay.
Data on 33 informative samples showed non-random XCI in 11 (33%), defined as a >80:20% skewed ratio of one versus the other
X chromosome being active. In six (18%) of these, there was a >95:5% extremely skewed ratio of one versus the other X chromosome
being active. XCI patterns on maternal samples were not excessively skewed. The prevalence of non-random XCI in Aicardi syndrome
is significantly different from that in the general population (p < 0.0001) and provides additional support for the hypothesis that Aicardi syndrome is an X-linked disorder. We also investigated
the correlation between X-inactivation patterns and clinical severity and found that non-random XCI is associated with a high
neurological composite severity score. Conversely, a statistically significant association was found between random XCI and
the skeletal composite score. Correlations between X-inactivation patterns and individual features were made and we found
a significant association between vertebral anomalies and random XCI. 相似文献
17.
X chromosome inactivation mosaicism in the mouse 总被引:10,自引:0,他引:10
M N Nesbit 《Developmental biology》1971,26(2):252-263
A cytologically detectable mosaicism resulting from X-chromosome inactivation occurring in mice heterozygous for Cattanach's translocation has been used to examine the time of X chromosome inactivation, and the sizes of primordial precursor pools for lung, thymus, spleen, fascia, and melanocytes. The extent of covariance in mosaic composition among tissues within individuals suggests that, if X inactivation occurs randomly, it must occur after determination of embryoblast cells, at some time immediately before or after implantation, and that it must occur before divergence of mesoderm from ectoderm. The extent of independent variance among the various tissues is such as to suggest that none of them arise from primordial precursor pools smaller than 20 to 30 cells. 相似文献
18.
Alexandra M Lopes Paul S Burgoyne Andrew Ojarikre Julien Bauer Carole A Sargent António Amorim Nabeel A Affara 《BMC genomics》2010,11(1):1-13
Background
In many eukaryotes, microRNAs (miRNAs) bind to complementary sites in the 3'-untranslated regions (3'-UTRs) of target messenger RNAs (mRNAs) and regulate their expression at the stage of translation. Recent studies have revealed that many miRNAs are evolutionarily conserved; however, the evolution of their target genes has yet to be systematically characterized. We sought to elucidate a set of conserved miRNA/target-gene pairs and to analyse the mechanism underlying miRNA-mediated gene regulation in the early stage of bilaterian evolution.Results
Initially, we extracted five evolutionarily conserved miRNAs (let-7, miR-1, miR-124, miR-125/lin-4, and miR-34) among five diverse bilaterian animals. Subsequently, we designed a procedure to predict evolutionarily conserved miRNA/target-gene pairs by introducing orthologous gene information. As a result, we extracted 31 orthologous miRNA/target-gene pairs that were conserved among at least four diverse bilaterian animals; the prediction set showed prominent enrichment of orthologous miRNA/target-gene pairs that were verified experimentally. Approximately 84% of the target genes were regulated by three miRNAs (let-7, miR-1, and miR-124) and their function was classified mainly into the following categories: development, muscle formation, cell adhesion, and gene regulation. We used a reporter gene assay to experimentally verify the downregulation of six candidate pairs (out of six tested pairs) in HeLa cells.Conclusions
The application of our new method enables the identification of 31 miRNA/target-gene pairs that were expected to have been regulated from the era of the common bilaterian ancestor. The downregulation of all six candidate pairs suggests that orthologous information contributed to the elucidation of the primordial set of genes that has been regulated by miRNAs; it was also an efficient tool for the elimination of false positives from the predicted candidates. In conclusion, our study identified potentially important miRNA-target pairs that were evolutionarily conserved throughout diverse bilaterian animals and that may provide new insights into early-stage miRNA functions. 相似文献19.
20.
Unusual X chromosome inactivation in a mentally retarded girl with an interstitial deletion Xq27: implications for the fragile X syndrome 总被引:8,自引:0,他引:8
Malgorzata Schmidt Andrea Certoma Desirée Du Sart Paul Kalitsis Margaret Leversha Kerry Fowler Leslie Sheffield Ian Jack David M. Danks 《Human genetics》1990,84(4):347-352
Summary A de novo interstitial deletion (X)(q27.1q27.3), between the loci DXS 105 and F8, has been found in a mentally retarded female. The deleted X chromosome is preferentially early replicating in fibroblasts, B cells and T cells, suggesting that the missing region plays a role in inactivation of the X chromosome. None of the available DNA probes except DXS 98 maps to the deleted region of about 10000kb. The locus FRAXA is either included in the deletion, or located close to the distal break point. 相似文献