X-chromosome inactivation: a repeat hypothesis

Recent work has shown that X-chromosome inactivation is brought about by Xist mRNA, which coats the inactive X-chromosome. This paper presents a hypothesis on the function of this RNA. It is suggested that interspersed repetitive elements of the LINE type, in which the X-chromosome is particularly rich, act as booster elements to promote the spread of Xist mRNA. Contact with this RNA causes the LINE elements to be sensed as repeated elements by the cell's system for repeat-induced gene silencing. This leads to the silencing of these elements and the intervening unique sequences by their conversion to heterochromatin.     

X-chromosome inactivation in human liver: confirmation of X-linkage of ornithine transcarbamylase

Histochemical assay for ornithine transcarbamylase (OTC) activity in fixed frozen hepatic sections from a woman heterozygous for OTC deficiency revealed two populations of hepatocytes: those with normal activity and those with no activity. This observation, in conjunction with data from previous family studies, confirms the hypothesis that the gene for OTC is X-linked. It also provides the first cytologic demonstration of cellular mosaicism for a liver-specific cell product.     

A PCR-based non-radioactive X-chromosome inactivation assay for genetic counseling in X-linked primary immunodeficiencies

The Wiskott-Aldrich syndrome (WAS), X-linked severe combined immunodeficiency (SCIDX1), and X-linked agammaglobulinemia (XLA) are severe congenital immunodeficiencies with X-linked inheritance. Although rare, they are all associated with severe infections from early in life, and high morbidity and mortality. Female carriers of these diseases can be identified by a non-random pattern of X-chromosomal inactivation in cell lineages targeted by each gene defect. For patients with WAS, SCIDX1 or XLA, the demonstration of non random X-Chromosome inactivation in their mothers can be used to confirm clinical diagnosis. Furthermore, analysis of X-Chromosome inactivation in at risk females allows preconceptional carrier detection, thus representing an important aid in genetic counseling. For each disease we established a PCR-based, non radioactive assay at the human androgen receptor (HUMARA) locus, that allows analysis of X-Chromosome inactivation in the affected cell types and in tissue specific controls to exclude the issue of skewed X-chromosomal inactivation. In our study, 50 females with a known family history of XLA [19], WAS [18], and SCIDX1 [13],were examined. A carrier status was established in 19 females (7 XLA, 6 WAS, 6 SCIDX1) and excluded in 29 ( 11 XLA, 11 WAS, 7 SCIDX1). Only in 2 cases (4%) the assay was not informative.     

Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome

Hereditary hemochromatosis is one of the most common inherited disorders among Caucasians of European ancestry. Malregulation of iron absorption from the duodenum eventually leads to iron overload. Although the time required to become iron loaded is variable, it is clear that most homozygotes will eventually become symptomatic. The clinical manifestations can be prevented by prophylactic phlebotomy therapy. Screening young populations is therefore a key to the prevention of disease-related morbidity. Protocols based on the phenotype of high transferrin saturation already exist. The recent identification of a candidate gene for hemochromatosis now allows for a potential genetic screen. Both the phenotypic and the genotypic methods of screening have inherent advantages and disadvantages. Iron-depletion therapy of homozygotes before the development of disease-related morbidity results in normal longevity. National initiatives for hemochromatosis screening will prevent morbidity by identifying and treating young, healthy homozygotes. Healthy, iron-depleted homozygotes should be eligible for health and life insurance at standard rates. Furthermore, healthy homozygotes would make ideal blood donors.     

Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism

The inactivation of one X chromosome in females is normally random with regard to which X is inactivated. However, exclusive or almost-exclusive inactivation of one X may be observed in association with some X-autosomal rearrangements, mutations of the XIST gene, certain X-linked diseases, and MZ twinning. In the present study, a methylation difference near a polymorphism in the X-linked androgen-receptor gene was used to investigate the possibility that nonrandom X inactivation is increases in fetuses and newborns that are associated with confined placental mosaicism (CPM) involving an autosomal trisomy. Extreme skewing was observed in 7 (58%) of 12 cases with a meiotic origin of the trisomy, but in none of 10 cases examined with a somatic origin of the trisomy, and in only 1 (4%) of 27 control adult females. In addition, an extremely skewed X-inactivation pattern was observed in 3 of 10 informative cases of female uniparental disomy (UPD) of chromosome 15. This may reflect the fact that a proportion of UPD cases arise by "rescue" of a chromosomally abnormal conceptus and are therefore associated with CPM. A skewed pattern of X inactivation in CPM cases is hypothesized to result from a reduction in the size of the early-embryonic cell pool, because of either poor early growth or subsequent selection against the trisomic cells. Since approximately 2% of pregnancies detected by chorionic villus sampling are associated with CPM, this is likely a significant contributor to both skewed X inactivation observed in the newborn population and the expression of recessive X-linked diseases in females.     

Regulation of ob gene expression in rodents and humans

The discovery of the obese gene in the mouse and its conserved homologue in humans has led to important discoveries in energy metabolism. One of the chief findings was the fact that the expression of the leptin gene was regulated and that it, in turn, could regulate metabolism and behavior. Much of the literature has focused on the physiological role of leptin in driving processes as diverse as reproduction, starvation defence, feeding behavior or body weight, all dependent on expression levels of the ob gene. Here, we will describe our work, in which we have begun to elucidate the regulatory processes controlling obese gene expression.     

The orphan granzymes of humans and mice

The granzyme/perforin pathway is a central pathway for lymphocyte-mediated killing in both the innate and adaptive immune systems. This pathway is important in a variety of host defenses, including viral clearance and tumor cell killing, and its dysregulation results in several human and rodent diseases. To date, the majority of reports in this field have concentrated on the functions of granzymes A and B. Recent reports, however, suggest that the non-A/non-B 'orphan' granzymes found in both humans and mice are potentially significant. Although the functions of these orphan granzymes have yet to be fully established, initial data suggests their importance in both immune and nonimmune cells.     

The moral status of mice and humans.

Suggests that H. A. Herzog's (1988) differentiation among the ethical protections afforded "good mice" (laboratory mice), "bad mice" (pests not in cages), and "feeders" (food for other species) offers roles and labels equally applicable to humans in the moral decisions of psychologists. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of plasma TNF-alpha on filgrastim-stimulated hematopoiesis in mice and humans

Marshall syndrome is a rare, autosomal dominant skeletal dysplasia that is phenotypically similar to the more common disorder Stickler syndrome. For a large kindred with Marshall syndrome, we demonstrate a splice-donor-site mutation in the COL11A1 gene that cosegregates with the phenotype. The G+1-->A transition causes in-frame skipping of a 54-bp exon and deletes amino acids 726-743 from the major triple-helical domain of the alpha1(XI) collagen polypeptide. The data support the hypothesis that the alpha1(XI) collagen polypeptide has an important role in skeletal morphogenesis that extends beyond its contribution to structural integrity of the cartilage extracellular matrix. Our results also demonstrate allelism of Marshall syndrome with the subset of Stickler syndrome families associated with COL11A1 mutations.     

Haldane's rule and X-chromosome size in Drosophila

The "dominance theory" of HALDANE'S rule postulates that hybrids of the heterogametic sex are more likely to be inviable or sterile than the homogametic sex because some of the epistatic incompatibilities contributing to postzygotic isolation behave as X-linked partial recessives. When this is true, pairs of taxa with relatively large X chromosomes should require less divergence time, on average, to produce HALDANE'S rule than pairs with smaller Xs. Similarly, if the dominance theory is correct and if the X chromosome evolves at a similar rate to the autosomes, the size of the X should not influence the rate at which homogametic hybrids become inviable or sterile. We use Drosophila data to examine both of these predictions. As expected under the dominance theory, pairs of taxa with large X chromosomes (approximately 40% of the nuclear genome) show HALDANE's rule for sterility at significantly smaller genetic distances than pairs with smaller X chromosomes (approximately 20% of the genome). As also predicted, the genetic distances between taxa that exhibit female inviability/sterility show no differences between "large X" vs. "small X" pairs. We present some simple mathematical models to relate these data to the dominance theory and alternative hypotheses involving faster evolution of the X vs. the autosomes and/or faster evolution of incompatibilities that produce male-specific vs. female-specific sterility. Although the data agree qualitatively with the predictions of the dominance theory, they depart significantly from the quantitative predictions of simple models of the dominance theory and the other hypotheses considered. These departures probably stem from the many simplifying assumptions needed to tractably model epistatic incompatibilities and to analyze heterogeneous data from many taxa.     

Germ cell loss in the XXY male mouse: altered X-chromosome dosage affects prenatal development

Attempts to describe the clinical heterogeneity of schizophrenia have consisted of categorical subtyping and a dimensional approach using factor analysis. The latter has yielded three dimensions or subsyndromes: positive, negative and disorganisation. The aim of this study is to explore to what degree these subsyndromes are correlated within 114 sibling pairs (185 individuals) with DSM-III-R schizophrenia or schizo-affective disorder who were assessed for the lifetime presence or absence of the positive, negative, affective and disorganisation subsyndromes. Ratings were based on the core symptoms of each subsyndrome using a modified Krawieka scale. First rank symptoms were also included in the analysis. Coincidence was assessed by application of the binomial theorem to the frequency of occurrence of subsyndromes in this set of siblings. The disorganisation subsyndrome was shared above chance expectation (chi2=9.15, P < 0.01 for all sibling pairs). The significant results for the disorganisation subsyndrome suggest that it may be a suitable phenotypic marker for genetic linkage studies.     

Tumour suppressor gene mutations in humans and mice: parallels and contrasts

Tumour suppressor genes prevent cancer development. They can be identified by studying humans, but a full understanding of the mechanisms of their action requires the production of animal models. Mice with mutations in tumour suppressor genes can be produced by gene targeting. The phenotypic consequences of tumour suppressor gene mutations in mice and humans show parallels and contrasts, and both can contribute to the elucidation of disease processes.     

Translocation breakpoint possibly predisposes to nonrandom X-chromosome inactivation in mouse embryos bearing Searle''s T(X;16)16H translocation

To clarify the sequence of events that ultimately achieves the nonrandom inactivation of the paternally inherited X chromosome in postpartum female mice heterozygous for T(X;16)16H, we set out to examine the expression of Xist alleles and the X-linked HMG-lacZ transgene in embryos recovered at the egg cylinder stage. Lack of expression of the Xist(b) allele on the 16X translocation chromosome in the embryonic region of 7.5 d postcoitum (dpc) X16/X(n)Xist(a);16(X)Xist(b)/16 embryos strongly suggested the occurrence of nonrandom inactivation in favor of the normal X chromosome. The simplest explanation would be biased choice, followed by postinactivation selection against genetically unbalanced cells. However, the frequency and distribution of beta-galactosidase-positive cells in X16/X(n)lacZ;16X/16 embryos at 6.5 and 7.5 dpc, together with earlier cytogenetic data, raised an intriguing possibility that the majority of 16X chromosomes were prevented from completing the inactivation process, when they had been chosen to be silenced. Phenotypes of female mice carrying a spontaneous recombination between Xn and 16X in the segment defined by the T16H breakpoint and the X-linked Ta locus suggested that the nonrandomness was brought about by disruption of an X-chromosomal sequence or structure at the translocation breakpoint.     

Regulation of IFN-gamma production in granulocyte-macrophage colony-stimulating factor-deficient mice

Granulocyte-macrophage colony-stimulating factor-deficient (GM-CSF-/-) mice produce far lower serum levels of IFN-gamma in response to LPS than GM-CSF+/+ mice. CD4+ and CD8+ T cells from LPS-injected GM-CSF-/- mice showed a deficiency in IFN-gamma production and proliferative activity in response to IL-2 and IL-12, whereas IFN-gamma production by NK cells was not compromised. These defects of T cells were reversed by administration of GM-CSF in vivo, but not by supplementation with GM-CSF in vitro. GM-CSF-/- mice do not have an intrinsic defect in IFN-gamma production, because IL-12 injection induces the same high levels of IFN-gamma in GM-CSF-/- and GM-CSF+/+ mice. To investigate the inhibitory effect of LPS on GM-CSF-/- T cells and the indirect restorative activity of GM-CSF, we tested the action of supernatants from cultured dendritic cells (DC). A factor or factors in the DC supernatant normalized serum IFN-gamma levels and T cell responses in LPS-injected GM-CSF-/- mice. IL-18 reproduced some but not all of these in vivo and in vitro effects of DC supernatants. Our results indicate that GM-CSF is important in protecting T cells from inhibitory signals generated during immunization or exposure to LPS, and that this effect of GM-CSF is indirect and mediated by factors produced by DC.