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PubMed1980

Radiation-induced meiotic autosomal non-disjunction in male mice. The effects of low doses of fission neutrons and X-rays in meiosis I and II of a Robertsonian translocation heterozygote.

Male mice, heterozygous for the Rb(11.13)4Bnr translocation, were irradiated for 14.5 min with either a dose of 15-rad fission neutrons or 60-rad X-rays. Animals of this karyotype are known to show high levels of spontaneous autosomal non-disjunction (20--30%) after anaphase I. The effects of the irradiation on this process were determined after 2 and 3 h in air-dried preparations. The length of the period from the end of meiosis I till the end of meiosis II was assessed autoradiographically, with the aid of cells showing a labelled Y chromosome only and appeared to last less than 3 h. Inter-mouse variation with regard to the duration of the period "last premeiotic S-phase till diakinesis/metaphase I" prevented a more accurate estimate. On the basis of this 3-h datum, the induced effects were studied at intervals of 2 and 3 h after the start of the irradiation. The influence of irradiation was assessed by scoring: (1) univalents in primary spermatocytes, (2) deletions, aneuploid chromosome counts and precocious centromere separation in secondary spermatocytes, and (3) chromatid gaps and breaks in both cell types. Both radiation types induced comparable levels of chromosomal damage. A neutron-X-rays RBE value for these parameters was calculated to be 5.4 for the MI stage and 3.3 for the MII stage. The significantly higher incidence of cells showing damage at MII than at diakinesis/MI is not believed to indicate a difference in radiation sensitivity, but is believed to be merely the consequence of the different chromosomal processes taking place during the irradiation-fixation time interval.

Aneuploidy↗
PubMed1981

The response of germ cells of the mouse to the induction of non-disjunction by X-rays.

The sensitivity of male and female pre-meiotic germ cells of the mouse to the induction of non-disjunction by low doses of X-rays, has been tested. No enhancement with 5 rad was observed over control values in dictyate oocytes irradiated from young or aged females. In males, a 3-fold increase in overall chromosome abnormalities (aneuploids, polyploids and mosaics) was found following the treatment of germ cells sampled in the 7th week after irradiation (spermatogonia and early primary spermatocytes) with 100 rad. The increase in aneuploidy alone was not however significant at the 5% level of probability. Primary spermatocytes sampled in week 5 after irradiation were generally insensitive to the induction of chromosome abnormalities.

Animals↗
PubMed1988

Synaptonemal complex damage induced by clastogenic and anti-mitotic chemicals: implications for non-disjunction and aneuploidy.

Mice were treated with mitomycin C, cyclophosphamide, amsacrine, colchicine, or vinblastine sulfate, and meiotic prophase cells analyzed for synaptonemal complex (SC) damage. All test agents caused synaptonemal complex breakage and synapsis irregularities, although propensities for inducing specific types of damage at S-phase or prophase stages varied among the chemicals. The data indicate that SC analysis can reveal chemical-specific alterations to meiotic homologue pairing/synapsis which have not generally been recognized, and which theoretically may be implicated in non-disjunction.

Aneuploidy↗
PubMed1977

Attention and cardiac activity: heart rate responses during a variable foreperiod, disjunctive reaction time task.

A variable foreperiod disjunctive reaction time task was used to evaluate the effects of stimulus discriminability on cardiac activity. In two sessions, 20 male undergraduates received easy or difficult auditory discrimination trials in blocked and random series. In the random session only, when the warning stimulus provided information about the difficulty of the subsequent discrimination, difficult trials were associated with greater foreperiod deceleration. Cardiac accelerations also tended to be greater in the foreperiods of difficult trials. There was an effect of both warning and imperative stimuli on the heart rate of the cycle in which the stimuli occurred which depended on the difficulty of the trial. The results are discussed in terms of the psychological significance of the different heart rate responses.

Attention↗
PubMed1996

PRINS localization of centromeres and telomeres in micronuclei indicates that in mouse splenocytes chromatid non-disjunction is a major mechanism of aneuploidy.

Primed In Situ DNA Synthesis (PRINS) of telomeric and centromeric (minor satellite DNA) sequences has been applied together with the cytokinesis block micronucleus (MN) assay in mouse splenocytes, with the aim of understanding the mechanism of origin of spontaneous and induced MN. Splenocyte cultures were treated in vitro either with the clastogenic agent mitomycin C or with the aneugenic compound colcemid. The relative proportions of MN carrying 1 to 4 telomeric signals were in agreement with the known mechanism of action of the chemicals tested, i.e., an higher number of MN with less than 4 telomeres were found in MMC-than in colcemid-treated cultures. No MN lacking the telomeric sequences (0 spot) were found, indicating that the observed distributions should not be affected by false-negative data. Furthermore, all MN carrying a single telomere were negative for the centromere, thus indicating that this class represents true chromosome acentric fragments. Finally, MN with 4 telomeric spots always carried the centromeric sequence, as expected on the hypothesis that these MN correspond to whole chromosomes. With respect to centromere-positive MN, more than one half carried 4 telomeric signals (whole chromosomes), and only 1/4 or less showed 2 telomeric signals (probably corresponding to a single chromatid). This difference was statistically significant, either in untreated cultures or in cultures exposed to mitomycin C or colcemid. On the whole, these data indicate that non-disjunction followed by whole chromosome loss (with the production of two daughter monosomic nuclei) may be the main mechanism of malsegregation leading to MN formation.

Aneuploidy↗
PubMed1997

The in vitro micronucleus test: a multi-endpoint assay to detect simultaneously mitotic delay, apoptosis, chromosome breakage, chromosome loss and non-disjunction.

Genotoxicity testing aims to detect a large range of genetic damage endpoints and evaluate such results in context of cell survival. The cytokinesis block micronucleus test offers the advantage to provide simultaneously information on both cell cycle progression and chromosome/genome mutations. Indeed, 1. frequencies of cytokinesis-blocked binucleated cells (and polynucleated) are good estimators of the mitotic rate; 2. frequencies of apoptotic figures in mononucleated and binucleated cells provide a measure for cell death before or after cell division; 3. combination of fluorescence in situ hybridization (FISH) for centromere/telomeres and micronucleus scoring allows discrimination between clastogenic and aneugenic events; 4. detection of FISH signals for chromosome specific sequences in both macronuclei and micronuclei, discriminates between aneuploidy due to chromosome non-disjunction or to chromosome loss. The cytokinesis block in vitro micronucleus test is thus a cytogenetic multi-test providing mechanistic information with a simple, rapid, objective, microscopical analysis.

Apoptosis↗
PubMed1996

Mapping heavy metals in polluted soil by disjunctive kriging.

The soil of some 50 km(2) around the town of Weinfelden in north-east Switzerland has been sampled and analysed to estimate and map the concentrations of heavy metals before an incinerator for the canton's waste is built. Given that the estimates are subject to error, the probabilities that true values exceed the maximum tolerable concentrations of the Swiss federal guide have also been estimated by disjunctive kriging. These may now be used by the local planners for making decisions. Of the metals examined, lead exceeded the guide value at several sampling points, and a moderate probability of excess of lead is fairly widespread. Copper exceeded the guide value in vineyards and orchards, but also in a few places elsewhere, and the estimated probabilities of excess were not negligible. The other two metals of concern, cadmium (with one exception) and zinc, had concentrations much less than the guide values. The patterns of distribution of the four metals were similar, the product-moment correlations among them are substantial, except in the vineyards and orchards, and it seems likely that they had common sources.

Journal Article↗
PubMed1998

Apolipoprotein E epsilon 4 alleles and meiotic origin of non-disjunction in Down syndrome children and in their corresponding fathers and mothers.

An increased risk of Alzheimer disease (AD) has been reported in young mothers of Down syndrome (DS) probands. Subsequently, an increased frequency of the apolipoprotein E (apoE) allele epsilon 4 has been found in mothers (< or = 32 years) of DS children due to meiosis II (MII) errors providing a potential explanation for the increased risk of AD in DS mothers. In the present study we genotyped apoE and determined the origin of non-disjunction of 132 mothers and the corresponding fathers and DS children from Spain. Unexpectedly no epsilon 4 alleles have been detected in MII mothers of < or = 32 years of age (P = 0.02). Thus our study not only fails to find the effect previously reported, but it detects an opposite correlation. An increase in the epsilon 4 frequency (0.227) is detected in MI mothers <28 as compared to the epsilon 4 frequency present in MI mothers >28 years of age (0.089), although the differences are not significant if correction for multiple comparisons is applied. The simplest overall interpretation of the previously reported and present findings is that the detected associations are due to random statistical variation rather than to some real effect of the epsilon 4 allele. However the important potential implications of alternative explanations imply that this issue deserves further clarification in independent studies in other populations.

Adolescent↗
PubMed1998

A neural network classifier with disjunctive fuzzy information.

This paper presents a neural network classifier that learns disjunctive fuzzy information in the feature space. This neural network consists of two types of nodes in the hidden layer. The prototype nodes and exemplar nodes represent cluster centroids and exceptions in the feature space, respectively. This classifier automatically generates and refines prototypes for distinct clusters in the feature space. The number and sizes of these prototypes are not restricted, so the prototypes will form near-optimal decision regions to meet the distribution of input patterns and classify as many input patterns as possible. Next, exemplars will be created and expanded to learn the patterns that cannot be classified by the prototypes. Such a training strategy can reduce the memory requirement and speed up the process of non-linear classification. In addition, on-line learning is supplied in this classifier and the computational load is lightened. The experimental results manifest that this model can reduce the number of hidden nodes by determining the appropriate number of prototype nodes.

Journal Article↗
PubMed2002

The rodent carcinogens 1,4-dioxane and thiourea induce meiotic non-disjunction in Drosophila melanogaster females.

The ability of the rodent carcinogens 1,4-dioxane (DX) and thiourea (TU) to induce meiotic non-disjunction (ND) was assessed in 3- and 6-day-old Drosophila melanogaster females. The chemicals were administered orally and three 24 h and one 48 h broods were obtained after mating, to sample oocytes treated in increasingly earlier stages of development. The broods represent mainly mature oocytes (brood I), nearly mature oocytes (brood II), early oocytes (brood III) and very early oocytes (brood IV). The toxicity of DX increased with dose (1% (not toxic), 1.5, 2, 3, 3.5%) as well as a reduction in fecundity which was moderate. Induction of ND in mature oocytes was positive with 2, 3 and 3.5% concentrations and was not related to dose. In immature oocytes it was also positive though already at the lowest concentration tested (1%), suggesting a sensitivity higher than that of mature oocytes. TU at 0.10-10%, did not affect viability, but since fecundity was seriously impaired at high doses, ND was not assessed beyond the 1.5% concentration. TU also induced ND in mature and in immature oocytes; neither a threshold nor a dose effect was detected. The response of mature oocytes was lower than that of immature oocytes. TU induced increases of ND in the earliest cells tested in a more consistent fashion than DX. The data clearly show that both chemicals induced ND in mature oocytes and in the three subsets in which immature oocytes were fractionated. Though toxicity may play a significant unspecific role in the induction of chromosome malsegregation by DX and TU, the induction of ND at low doses, moderately toxic to the oocytes, suggests that the interaction with specific targets contributed to the results obtained.

Animals↗
PubMed1996

Do schizophrenic patients show a disjunctive relationship among expressive, experiential, and psychophysiological components of emotion?

Recent research has found a discrepancy between schizophrenic patients' outward expression of emotion and their reported emotional experience. In this study, which attempts to replicate and extend the findings of previous studies, participants with and without schizophrenia viewed emotional film clips while their facial expressions were videotaped and skin conductance was recorded. Participants also reported their subjective experience of emotion following each film. Those with schizophrenia were less facially expressive than controls during the emotional films and reported experiencing as much positive and negative emotion, replicating previous findings. Additionally, schizophrenic patients exhibited greater skin conductance reactivity to all films than controls. These findings suggest a disjunction among emotional response domains for schizophrenic patients; alternative explanations for the findings are considered as well as suggestions for future research.

Adult↗
PubMed2006

Meiosis in mammals: recombination, non-disjunction and the environment.

By comparison with other species, the meiotic process in the human female is extraordinarily error-prone. In addition to the well-known effect of advancing maternal age, recent studies have demonstrated that the number and location of meiotic recombination events influences the likelihood of meiotic non-disjunction in our species. Although this association extends to many other organisms, the factors that influence the number and placement of exchanges within a cell remain poorly understood. Like other aspects of meiosis, the control of recombination is likely to be subject to variation among species. In this review we summarize data from recent studies in mammals; the combined data suggest that both genetic and environmental factors influence recombination in mammals and, importantly, that control mechanisms probably differ between males and females.

Animals↗
PubMed2001

Effects of population disjunction on isozyme variation in the widespread Pilgerodendron uviferum.

Geographical range is considered a good predictor of the levels of isozyme variation in plants. Widespread species, often consisting of historically larger and more continuous populations, maintain higher polymorphism and are less affected by drift, which tends to erode genetic variation in more geographically restricted species. However, widespread species occurring in small and disjunct populations may not fit this pattern. In this study we examined genetic variation in Pilgerodendron uviferum, a conifer endemic to temperate forests of southern South America, and is such a widespread and habitat-restricted species. Twenty populations along the whole range of Pilgerodendron were analysed by isozyme electrophoresis to resolve 14 putative genetic loci. Eleven were polymorphic in at least one population although only six of them were polymorphic in more than one population. We found reduced within-population levels of isozyme variation, with only 11% polymorphic loci (0.95 criterion), 1.2 mean number of alleles per locus, and mean observed and expected heterozygosities of 0.024 and 0.033, respectively. Most genetic diversity was found within populations (H(T)=0.039, H(S)=0.033, F(ST) 15%). Greater polymorphism and lower divergence was estimated in the more geographically restricted and closely related Fitzroya. Thus, total range, in combination with information on the degree of among-population isolation, may be a better predictor of the levels of polymorphism than range size alone.

Genetic Variation↗
PubMed2003

Disjunct distribution of highly diverged mitochondrial lineage clade and population subdivision in a marine bivalve with pelagic larval dispersal.

Mitochondrial DNA sequence data for 295 individuals of the marine bivalve Macoma balthica (L.) were collected from 10 sites across the European distribution, and from Alaska. The data were used to infer population subdivision history and estimate current levels of gene flow. Inferred historical biogeography was expected to be congruent with colonization of the Atlantic Ocean from the Pacific Ocean after the opening of the Bering Strait 3.5 Ma. In addition, the last glacial maximum, about 18000 years ago, was expected to have been responsible for most of the present-day distribution of molecular variation within Europe, because the area must have been recolonized after confinement to France and the south of the British Isles during the last glacial maximum. Current gene flow was hypothesized to be high, because the larvae of M. balthica spend 2-5 weeks drifting in the water column. The geographical distribution of one highly diverged haplotype clade was found to be disjunct and was encountered exclusively in samples from the Baltic Sea and Alaska. A molecular clock calibration for marine bivalve cytochrome-c-oxidase I dates this clade as having split off from the other haplotypes 9.8-39 Ma. Multiple colonizations of the Atlantic Ocean from the Pacific by M. balthica may explain the strong differences found between Baltic Sea and other European populations of this species. The sympatric occurrence of the highly diverged mitochondrial lineages in western parts of the Baltic Sea points to secondary admixture. With the use of coalescent analysis, population divergence times for French vs. other non-Baltic European populations ('Atlantic population assemblage') were estimated at a minimum of about 110000 years ago, well before the last glacial maximum 18000 years ago. Signatures of population divergence of M. balthica that appear to have originated during the Pleistocene have thus survived the last glacial maximum. Some of the populations within the Atlantic assemblage are currently isolated, while others appear to be connected by gene flow. Apparently, populations of this species can remain highly subdivided in spite of the potential for high gene flow, implying that their population and evolutionary dynamics can be independent.

Alaska↗
PubMed1997

Kinetic mechanism of monomeric non-claret disjunctional protein (Ncd) ATPase.

The non-claret disjunctional protein (Ncd) is a kinesin-related microtubule motor that moves toward the negative end of microtubules. The kinetic mechanism of the monomer motor domain, residues 335-700, satisfied a simple scheme for the binding of 2'-3'-O-(N-methylanthraniloyl) (MANT) ATP, the hydrolysis step, and the binding and release of MANT ADP, where T, D, and Pi refer to nucleotide triphosphate, nucleotide diphosphate, and inorganic phosphate, respectively, and MtN is the complex of an Ncd motor domain with a microtubule site. Rate constants k1 and k-4 are the rates of a first order step, an isomerization induced by nucleotide binding. The apparent second order rate constants for the binding steps are 1.5 x 10(6) M-1 s-1 for MANT ATP and 3.5 x 10(6) M-1 s-1 for MANT ADP (conditions, 50 mM NaCl, pH 6.9, 21 degrees C). The rate constant of the hydrolysis step (k2) was obtained from quench flow measurements of the phosphate burst phase corrected for the contribution of the rate of product release to the transient rate constant. The rate of phosphate dissociation was not measured; the value was assigned to account for a steady state rate of 3 s-1. The MtN complex is dissociated by ATP at a rate of 10 s-1 based on light scattering measurements. Dissociation constants of Ncd-nucleotide complexes from microtubules increased in the order adenosine 5'-O-(thiotriphosphate) (ATPgammaS) < ADP-AlF4 < ATP < ADP < ADP-vanadate. Comparison of the properties of Ncd with a monomeric kinesin K332 (Ma and Taylor (1997) J. Biol. Chem. 272, 717-723) showed a close similarity, except that the rate constants for the hydrolysis and ADP release steps and the steady state rate are approximately 15-20 times smaller for Ncd. There are two differences that may affect the reaction pathway. The rate of dissociation of MtN by ATP is comparable to the rate of the hydrolysis step, and N.T may dissociate in the cycle, whereas for kinesin, dissociation occurs after hydrolysis. The rate of dissociation of MtN by ADP is larger than the rate of ADP release from MtN.D, whereas for the microtubule-kinesin complex, the rate of dissociation by ADP is smaller than the rate of ADP release. The monomeric Mt.Ncd complex is not processive.

Adenosine Diphosphate↗
PubMed1998

Equilibrium binding studies of non-claret disjunctional protein (Ncd) reveal cooperative interactions between the motor domains.

Non-claret disjunctional protein (Ncd) is a minus end-directed microtubule motor required for normal spindle assembly and integrity during Drosophila oogenesis. We have pursued equilibrium binding experiments to examine the affinity of Ncd for microtubules in the presence of the ATP nonhydrolyzable analog 5'-adenylyl-beta, gamma-imidodiphosphate (AMP-PNP), ADP, or ADP + Pi using both dimeric (MC1) and monomeric (MC6) Ncd constructs expressed in Escherichia coli. Both MC1 and MC6 sediment with microtubules in the absence of added nucleotide as well as in the presence of either ADP or AMP-PNP. Yet, in the presence of ADP + Pi, there is a decrease in the affinity of both MC1 and MC6 for microtubules. The data for dimeric MC1 show that release of the dimer to the supernatant is sigmoidal with the apparent Kd(Pi) for the two phosphate sites at 23.3 and 1.9 mM, respectively. The results indicate that binding at the first phosphate site enhances binding at the second site, thus cooperatively stimulating release. Stopped-flow kinetics indicate that MgATP promotes dissociation of the Mt.MC1 complex at 14 s-1, yet AMP-PNP has no effect on the Mt.MC1 complex. These results are consistent with a model for the ATPase cycle in which ATP hydrolysis occurs on the microtubule followed by detachment as the Ncd.ADP.Pi intermediate.

Adenosine Diphosphate↗
PubMed2001

Conformation of the Drosophila motor protein non-claret disjunctional in solution from X-ray and neutron scattering.

The quaternary structures of monomeric and dimeric Drosophila non-claret disjunctional (ncd) constructs were investigated using synchrotron x-ray and neutron solution scattering, and their low resolution shapes were restored ab initio from the scattering data. The experimental curves were further compared with those computed from crystallographic models of one monomeric and three available dimeric ncd structures in the microtubule-independent ADP-bound state. These comparisons indicate that accounting for the missing parts in the crystal structures for all these constructs is indispensable to obtain reasonable fits to the scattering patterns. A ncd construct (MC6) lacking the coiled-coil region is monomeric in solution, but the calculated scattering from the crystallographic monomer yields a poor fit to the data. A tentative configuration of the missing C-terminal residues in the form of an antiparallel beta-sheet was found that significantly improves the fit. The atomic model of a short dimeric ncd construct (MC5) without 2-fold symmetry is found to fit the data better than the symmetric models. Addition of the C-terminal residues to both head domains gives an excellent fit to the x-ray and neutron experimental data, although the orientation of the beta-sheet differs from that of the monomer. The solution structure of the long ncd construct (MC1) including complete N-terminal coiled-coil and motor domains is modeled by adding a straight coiled-coil section to the model of MC5.

Animals↗