Maternal uniparental disomy of chromosome 14 confined to an interstitial segment (14q23-14q24.2).
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Maternal uniparental disomy for the complete long arm of chromosome 14 has been reported in 14 patients to date and is associated with a specific pattern of malformation. We report a child with clinical features of this syndrome who exhibits maternal uniparental disomy confined to a specific interstitial segment of chromosome 14. (+info)
Altered dosage of the Saccharomyces cerevisiae spindle pole body duplication gene, NDC1, leads to aneuploidy and polyploidy.
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Saccharomyces cerevisiae cells are exquisitely sensitive to altered dosage of the spindle pole body duplication gene, NDC1. We show that the NDC1 locus is haploinsufficient because diploid yeast cells cannot survive with a single chromosomal copy of the NDC1 gene. Diploid cells with a single copy of NDC1 can survive by gaining an extra copy of the NDC1-containing chromosome. NDC1 haploinsufficiency is a dominant loss-of-function phenotype that leads to aneuploidy. Furthermore, we report that overexpression of NDC1 leads to spindle pole body duplication defects indistinguishable from those observed in ndc1-1 mutant cells. Cells overexpressing NDC1 arrest with monopolar spindles and exhibit increase-in-ploidy phenotypes. Thus, both increased and decreased NDC1 dosage can lead to aneuploidy. The striking sensitivity of yeast cells to changes in NDC1 gene dosage suggests a model for the behavior of some tumor suppressor genes and oncogenes in which loss-of-function mutations and overexpression, respectively, lead to increased genetic instability. (+info)
Positive outcome after preimplantation diagnosis of aneuploidy in human embryos.
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usromosomal abnormalities are responsible for a great deal of embryo wastage, which is reflected, at least partially, in decreased implantation and increased miscarriage in older women. To address this problem the transfer of only chromosomally normal embryos previously selected by preimplantation genetic diagnosis (PGD) has been proposed. We designed a multi-centre in-vitro fertilization (IVF) study to compare controls and a test group that underwent embryo biopsy and PGD for aneuploidy. Patients were matched retrospectively, but blindly, for average maternal age, number of previous IVF cycles, duration of stimulation, oestradiol concentrations on day +1, and average mature follicles. All these parameters were similar in test and control groups. Only embryos classified as normal for those chromosomes were transferred after PGD. The results showed that the rates of fetal heart beat (FHB)/embryo transferred between the control and test groups were similar. However, spontaneous abortions, measured as FHB aborted/FHB detected, decreased after PGD (P < 0.05), and ongoing pregnancies and delivered babies increased (P < 0.05) in the PGD group of patients. Two conclusions were obtained: (i) PGD of aneuploidy reduced embryo loss after implantation; (ii) implantation rates were not significantly improved, but the proportion of ongoing and delivered babies was increased. (+info)
Centromere mapping functions for aneuploid meiotic products: Analysis of rec8, rec10 and rec11 mutants of the fission yeast Schizosaccharomyces pombe.
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Recent evidence suggests that the position of reciprocal recombination events (crossovers) is important for the segregation of homologous chromosomes during meiosis I and sister chromatids during meiosis II. We developed genetic mapping functions that permit the simultaneous analysis of centromere-proximal crossover recombination and the type of segregation error leading to aneuploidy. The mapping functions were tested in a study of the rec8, rec10, and rec11 mutants of fission yeast. In each mutant we monitored each of the three chromosome pairs. Between 38 and 100% of the chromosome segregation errors in the rec8 mutants were due to meiosis I nondisjunction of homologous chromosomes. The remaining segregation errors were likely the result of precocious separation of sister chromatids, a previously described defect in the rec8 mutants. Between 47 and 100% of segregation errors in the rec10 and rec11 mutants were due to nondisjunction of sister chromatids during meiosis II. In addition, centromere-proximal recombination was reduced as much as 14-fold or more on chromosomes that had experienced nondisjunction. These results demonstrate the utility of the new mapping functions and support models in which sister chromatid cohesion and crossover position are important determinants for proper chromosome segregation in each meiotic division. (+info)
Meiotic chromosome dynamics dependent upon the rec8(+), rec10(+) and rec11(+) genes of the fission yeast Schizosaccharomyces pombe.
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During meiosis homologous chromosomes replicate once, pair, experience recombination, and undergo two rounds of segregation to produce haploid meiotic products. The rec8(+), rec10(+), and rec11(+) genes of the fission yeast Schizosaccharomyces pombe exhibit similar specificities for meiotic recombination and rec8(+) is required for sister chromatid cohesion and homolog pairing. We applied cytological and genetic approaches to identify potential genetic interactions and to gauge the fidelity of meiotic chromosome segregation in the mutants. The rec8(+) gene was epistatic to rec10(+) and to rec11(+), but there was no clear epistatic relationship between rec10(+) and rec11(+). Reciprocal (crossover) recombination in the central regions of all three chromosomes was compromised in the rec mutants, but recombination near the telomeres was nearly normal. Each of the mutants also exhibited a high rate of aberrant segregation for all three chromosomes. The rec8 mutations affected mainly meiosis I segregation. Remarkably, the rec10 and rec11 mutations, which compromised recombination during meiosis I, affected mainly meiosis II segregation. We propose that these genes encode regulators or components of a "meiotic chromatid cohesion" pathway involved in establishing, maintaining, and appropriately releasing meiotic interactions between chromosomes. A model of synergistic interactions between sister chromatid cohesion and crossover position suggests how crossovers and cohesion help ensure the proper segregation of chromosomes in each of the meiotic divisions. (+info)
Analysis of chromosome loss and non-disjunction in cytokinesis-blocked lymphocytes of 24 male subjects.
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Chromosome malsegregation in peripheral blood lymphocytes of 24 healthy male subjects was analysed by means of fluorescence in situ hybridization with centromeric probes of chromosomes 7, 11, 18 and X. On the basis of the distribution of centromeric signals in cytokinesis-blocked cells, both loss (leading to centromere-positive micronuclei) and non-disjunction (resulting in an unbalanced distribution of signals in the main nuclei) of the hybridized chromosomes in vitro were identified. In addition, the incidence of binucleated cells with two hyperploid nuclei, possibly arising from mitotic division of trisomic types, was determined. In this way, the incidence of chromosome malsegregation in vivo and in vitro could be compared in the same cell samples. The results obtained show that ageing is positively correlated with the incidence of malsegregation of chromosome X in peripheral lymphocytes of male subjects and confirm the higher susceptibility of chromosome X to malsegregation in comparison with autosomes. A positive correlation between in vitro and in vivo malsegregation rates was observed for both chromosome X and for autosomes. Finally, relatively high frequencies of multiple malsegregation events, greater than expected for independent events, were recorded for both chromosome X and for autosomes, indicating that the abnormal segregation of chromosomes may be connected to a general dysfunction of the mitotic apparatus. The correlation observed between in vitro and in vivo malsegregation frequencies and the association of both parameters with ageing suggest that analysis of chromosome malsegregation in binucleated cells is a useful tool in the study of genomic instability in human populations. (+info)
Noscapine hydrochloride disrupts the mitotic spindle in mammalian cells and induces aneuploidy as well as polyploidy in cultured human lymphocytes.
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Noscapine hydrochloride is a centrally acting antitussive opium derivative widely used in cough suppressants. Recent studies have reported that noscapine is a potent inducer of polyploidy but not of aneuploidy in vitro. To obtain more comprehensive information about the cytogenetic effects of this compound, we treated cultured human lymphocytes (HPL) and Chinese hamster ovary (CHO) cells with various concentrations of noscapine hydrochloride. Using a differential staining technique noscapine was shown to disrupt the mitotic spindle at concentrations < 5 micrograms/ml in both cell types. The use of multicolor fluorescence in situ hybridization (FISH) on noscapine-treated human lymphocytes showed a dose-dependent induction of hyperdiploidy of chromosome 1 but not of chromosomal breakage in the 1cen-q12 region under in vitro conditions, indicating that noscapine is specifically inducing numerical chromosomal aberrations. FISH with probes targeting different chromosomes revealed that noscapine is capable of inducing both polyploidy and true hyperdiploidy. Our results show that noscapine, by disrupting the function of the mitotic spindle, has the ability to induce aneuploidy and not uniquely polyploidy as previously reported. By using these types of molecular cytogenetic techniques, it should be possible to evaluate the ability of noscapine to induce aneuploidy in the upper intestinal tract in vivo. (+info)
Abnormal cytogenetics predict poor survival after high-dose therapy and autologous blood cell transplantation in multiple myeloma.
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We compared the prognostic value of conventional cytogenetic analysis and established factors such as beta2-microglobulin and plasma cell labeling index in 70 patients undergoing autologous blood cell transplantation for multiple myeloma. Patients underwent transplantation 5 to 88 months (median, 20 months) after the initial diagnosis of myeloma. Factors studied were age, sex, beta2-microglobulin, response to prior therapy, plasma cell labeling index, cytogenetic analysis, bone marrow plasma cell percentage, lactate dehydrogenase and C-reactive protein. Twenty-eight of 65 patients (43%) had abnormal marrow cytogenetics. Overall survival measured from transplantation was significantly better in patients with normal cytogenetics than in those with abnormal cytogenetics (median survival, 25 vs 12 months, P = 0.003). Progression-free survival was better, with median times of 12 vs7 months, respectively (P = 0.005); overall survival measured from the time myeloma was first diagnosed was also longer, with median survivals of 62 and 39 months, respectively (P = 0.001). Median plasma cell labeling index was 1.5% in patients with abnormal cytogenetics and 0. 2% in those with normal cytogenetics (P < 0.001). Abnormal bone marrow cytogenetics predict poor survival after blood cell transplantation for myeloma. There is a significant correlation between abnormal cytogenetics and high plasma cell labeling index, suggesting that certain cytogenetic abnormalities may offer a proliferative advantage to myeloma cells. (+info)