Silencing XIST on the future active X: Searching human and bovine preimplantation embryos for the repressor.

X inactivation is the means of equalizing the dosage of X chromosomal genes in male and female eutherian mammals, so that only one X is active in each cell. The XIST locus (in cis) on each additional X chromosome initiates the transcriptional silence of that chromosome, making it an inactive X. How the active X in both males and females is protected from inactivation by its own XIST locus is not well understood in any mammal.

Reflections on the history of genetic medicine at Johns Hopkins University.

Two members of the faculty-who witnessed the birth of Genetic Medicine and remained to see it evolve-present their reflections about the history of genetic medicine at the Johns Hopkins Medical Institutions. They tell how the genetic units in Pediatrics and Medicine that were initiated by Barton Childs and Victor McKusick, respectively, became the McKusick Nathans Department of Genetic Medicine in 2020.

Stochastic gene expression and chromosome interactions in protecting the human active X from silencing by .

Mammals use X chromosome inactivation to compensate for the sex difference in numbers of X chromosomes. A relatively unexplored question is how the active X is protected from inactivation by its own XIST gene, the long non-coding RNA, which initiates silence of the inactive X.  Previous studies of autosomal duplications show that human chromosome 19 plays a critical role in protecting the active X.

X-linked diseases: susceptible females.

The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females.

The Non-random Location of Autosomal Genes That Participate in X Inactivation.

Mammals compensate for sex differences in the number of X chromosomes by inactivating all but one X chromosome. Although they differ in the details of X inactivation, all mammals use long non-coding RNAs in the silencing process. By transcribing XIST RNA, the human inactive X chromosome has a prime role in X-dosage compensation.

Choosing the Active X: The Human Version of X Inactivation.

Humans and rodents differ in how they carry out X inactivation (XI), the mammalian method to compensate for the different number of X chromosomes in males and females. Evolutionary changes in staging embryogenesis and in mutations within the XI center alter the process among mammals. The mouse model of XI is predicated on X counting and subsequently choosing the X to 'inactivate'.

Embryonic loss of human females with partial trisomy 19 identifies region critical for the single active X.

To compensate for the sex difference in the number of X chromosomes, human females, like human males have only one active X. The other X chromosomes in cells of both sexes are silenced in utero by XIST, the Inactive X Specific Transcript gene, that is present on all X chromosomes. To investigate the means by which the human active X is protected from silencing by XIST, we updated the search for a key dosage sensitive XIST repressor using new cytogenetic data with more precise resolution.

An overview of X inactivation based on species differences.

X inactivation, a developmental process that takes place in early stages of mammalian embryogenesis, balances the sex difference in dosage of X-linked genes. Although all mammals use this form of dosage compensation, the details differ from one species to another because of variations in the staging of embryogenesis and evolutionary tinkering with the DNA blueprint for development. Such differences provide a broader view of the process than that afforded by a single species.

Titles and abstracts of scientific reports ignore variation among species.

An analysis of more than 1000 research articles in biology reveals that the name of the species being studied is not mentioned in the title or abstract of many articles. Consequently, such data are not easily accessible in the PubMed database. These omissions can mislead readers about the true nature of developmental processes and delay the acceptance of valid species differences.

The single active X in human cells: evolutionary tinkering personified.

All mammals compensate for sex differences in numbers of X chromosomes by transcribing only a single X chromosome in cells of both sexes; however, they differ from one another in the details of the compensatory mechanisms. These species variations result from chance mutations, species differences in the staging of developmental events, and interactions between events that occur concurrently. Such variations, which have only recently been appreciated, do not interfere with the strategy of establishing a single active X, but they influence how it is carried out.

X inactivation, female mosaicism, and sex differences in renal diseases.

A good deal of sex differences in kidney disease is attributable to sex differences in the function of genes on the X chromosome. Males are uniquely vulnerable to mutations in their single copy of X-linked genes, whereas females are often mosaic, having a mixture of cells expressing different sets of X-linked genes. This cellular mosaicism created by X inactivation in females is most often advantageous, protecting carriers of X-linked mutations from the severe clinical manifestations seen in males.

X inactivation in triploidy and trisomy: the search for autosomal transfactors that choose the active X.

Only one X chromosome functions in diploid human cells irrespective of the sex of the individual and the number of X chromosomes. Yet, as we show, more than one X is active in the majority of human triploid cells. Therefore, we suggest that (i) the active X is chosen by repression of its XIST locus, (ii) the repressor is encoded by an autosome and is dosage sensitive, and (iii) the extra dose of this key repressor enables the expression of more than one X in triploid cells.

Why females are mosaics, X-chromosome inactivation, and sex differences in disease.

At every age, males have a higher risk of mortality than do females. This sex difference is most often attributed to the usual suspects: differences in hormones and life experiences. However, the fact that XY males have only one X chromosome undoubtedly contributes to this vulnerability, as any mutation that affects a gene on their X chromosome will affect their only copy of that gene.

The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases.

Sex-specific manifestations of disease are most often attributed to differences in the reproductive apparatus or in life experiences. However, a good deal of sex differences in health issues have their origins in the genes on the sex chromosomes themselves and in X inactivation-the developmental program that equalizes their expression in males and females. Most females are mosaics, having a mixture of cells expressing either their mother's or father's X-linked genes.

Differential X reactivation in human placental cells: implications for reversal of X inactivation.

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.

Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A.

A basic tenet of the Lyon hypothesis is that X inactivation occurs randomly with respect to parental origin of the X chromosome. Yet, nonrandom patterns of X inactivation are common - often ascertained in women who manifest recessive X-linked disorders despite being heterozygous for the mutation. Usually, the cause of skewing is cell selection disfavouring one of the cell lineages created by random X inactivation.

X chromosome inactivation: theme and variations.

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.

Species differences in TSIX/Tsix reveal the roles of these genes in X-chromosome inactivation.

Transcriptional silencing of the human inactive X chromosome is induced by the XIST gene within the human X-inactivation center. The XIST allele must be turned off on one X chromosome to maintain its activity in cells of both sexes. In the mouse placenta, where X inactivation is imprinted (the paternal X chromosome is always inactive), the maternal Xist allele is repressed by a cis-acting antisense transcript, encoded by the Tsix gene.

Multibiomarker responses in fish from the Moselle River (France).

The response of wild fish to pollutants was studied using two biomarkers in chub (Leuciscus cephalus) at five stations in the Moselle River (France) in 1998 and in 1999. The induction of cytochrome P450 1A was quantified by the ethoxyresorufin O-deethylase (EROD) activity in the liver and the level of DNA single-strand breaks was determined in erythrocytes using the comet assay. EROD activity was observed to be up to 10-fold induced in both males and females from the downstream stations in comparison to the fish from the upstream station.

Second trimester prenatal diagnosis of epignathus teratoma in ring X chromosome mosaicism with inactive ring X chromosome.

We report the second trimester prenatal echographic diagnosis of an epignathus teratoma in a female fetus with ring X chromosome mosaicism. The ring X chromosome mosaicism was present in the amniotic cell culture and in the teratoma and the ring X was inactive (X-inactive specific transcript (XIST) locus expressed). Hypoplastic left heart with valvular aortic stenosis and non-immune hydrops were additional findings, and are well-documented in Turner syndrome.

Identification of TSIX, encoding an RNA antisense to human XIST, reveals differences from its murine counterpart: implications for X inactivation.

X inactivation is the mammalian method for X-chromosome dosage compensation, but some features of this developmental process vary among mammals. Such species variations provide insights into the essential components of the pathway. Tsix encodes a transcript antisense to the murine Xist transcript and is expressed in the mouse embryo only during the initial stages of X inactivation; it has been shown to play a role in imprinted X inactivation in the mouse placenta.

A New Least Squares Based Calibration for an Ultrasound Tomography Scanner Using Radial Image Processing.

In the context of the development of an ultrasound scanner where a probe turns around the part of the body to be studied, a new tomographic technique has been developed: the Ultrasound Reflection-mode Tomography Using Radial Image Processing (URTURIP Technique). This technique is used when a unique B-scan image is insufficient to correctly describe a cross-section. It utilises B-scan images obtained under different angles of view in the same plane to reconstruct a better cross-sectional image.

Low-copy-number human transgene is recognized as an X inactivation center in mouse ES cells, but fails to induce cis-inactivation in chimeric mice.

X chromosome inactivation is initiated from a segment of the mammalian X chromosome called the X inactivation center. Transgenes from this region of the murine X chromosome are providing the means to identify the DNA needed for cis inactivation in mice. We recently showed that chimeric mice carrying transgenes from the human X inactivation center (XIC) region also provide a functional assay for human XIC activity; approximately 6 copies of a 480-kb human transgene (ES-10) were sufficient to initiate random X inactivation in cells of male chimeric mice (Migeon et al.

Severe phenotypes associated with inactive ring X chromosomes.

Mental retardation and congenital malformations in individuals with small ring X chromosomes are often due to the functional disomy that results from failure of these chromosomes to undergo X inactivation. Such chromosomes either lack the XIST locus or do not express it. We have carried out genetic analysis of the ring X chromosomes from two girls with a 45,X/46,X,r(X) karyotype, mental retardation, and a constellation of abnormalities characteristic of the severe phenotype due to X disomy.