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M J Moses

Publications and source records attributed to M J Moses.

At least 19 recordsLinked to original sources
PubMed2006

Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele.

A susceptibility locus for bipolar disorder was previously localized to chromosome 4q35 by genetic linkage analysis. We have applied a positional cloning strategy, combined with association analysis and provide evidence that a cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts (allelic P-values range from 0.003 to 0.024). In two case-control cohorts, association was identified among bipolar cases with a family history of psychiatric illness, whereas in two cohorts of parent-proband trios, association was identified among bipolar cases who had exhibited psychosis. Pooled analysis of the case-control cohort data further supported association (P=0.0002, summary odds ratio=2.31, 95% CI: 1.49-3.59). We localized the bipolar-associated region of the FAT gene to an interval that encodes an intracellular EVH1 domain, a domain that interacts with Ena/VASP proteins, as well as putative beta-catenin binding sites. Expression of Fat, Catnb (beta-catenin), and the three genes (Enah, Evl and Vasp) encoding the Ena/VASP proteins, were investigated in mice following administration of the mood-stabilizing drugs, lithium and valproate. Fat was shown to be significantly downregulated (P=0.027), and Catnb and Enah were significantly upregulated (P=0.0003 and 0.005, respectively), in response to therapeutic doses of lithium. Using a protein interaction map, the expression of genes encoding murine homologs of the FAT (ft)-interacting proteins was investigated. Of 14 interacting molecules that showed expression following microarray analysis (including several members of the Wnt signaling pathway), eight showed significantly altered expression in response to therapeutic doses of lithium (binomial P=0.004). Together, these data provide convergent evidence that FAT and its protein partners may be components of a molecular pathway involved in susceptibility to bipolar disorder.

Adult↗
PubMed2002

A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19.

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13-pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P= 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.

Bipolar Disorder↗
PubMed2002

A transcript map encompassing a susceptibility locus for bipolar affective disorder on chromosome 4q35.

Bipolar affective disorder is one of the most common mental illnesses with a population prevalence of approximately 1%. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. However, the specific genetic variations and molecules involved in bipolar susceptibility and pathogenesis are yet to be identified. Genetic linkage analysis has identified a bipolar disorder susceptibility locus on chromosome 4q35, and the interval harbouring this susceptibility gene has been narrowed to a size that is amenable to positional cloning. We have used the resources of the Human Genome Project (HGP) and Celera Genomics to identify overlapping sequenced BAC clones and sequence contigs that represent the region implicated by linkage analysis. A combination of bioinformatic tools and laboratory techniques have been applied to annotate this DNA sequence data and establish a comprehensive transcript map that spans approximately 5.5 Mb. This map encompasses the chromosome 4q35 bipolar susceptibility locus, which localises to a "most probable" candidate interval of approximately 2.3 Mb, within a more conservative candidate interval of approximately 5 Mb. Localised within this map are 11 characterised genes and eight novel genes of unknown function, which together provide a collection of candidate transcripts that may be investigated for association with bipolar disorder. Overall, this region was shown to be very gene-poor, with a high incidence of pseudogenes, and redundant and novel repetitive elements. Our analysis of the interval has demonstrated a significant difference in the extent to which the current HGP and Celera sequence data sets represent this region.

Bipolar Disorder↗
PubMed2002

A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19.

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13 pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P = 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.

Bipolar Disorder↗
PubMed2001

A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q.

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. In this present study, we undertook a 10 cM genome screen using 400 microsatellite markers in a large multigenerational bipolar pedigree consisting of 40 individuals, including six affecteds. We found strongest evidence for linkage to chromosome 13q14. A maximum NPL score of 4.09 (P = 0.008) was obtained between markers D13S1272 and D13S153 using GENEHUNTER. A maximum two-point LOD score of 2.91 (theta = 0.0) was found for marker D13S153 and a maximum three-point LOD score of 3.0 was obtained between markers D13S291 and D13S153 under a recessive model with 90% maximum age-specific penetrance and including bipolar I and unipolar individuals as affected. Several other markers in the region, D13S175, D13S218, D13S263, and D13S156 had two-point LOD scores greater than 1.5. These results meet the criteria for evidence of suggestive linkage. Haplotype analysis enabled us to narrow the likely disease region to a 6 cM region between markers D13S1272 and D13S1319, which contains the serotonin 2A receptor candidate gene. Two single nucleotide polymorphisms were identified in this gene but we did not detect any significant differences in allele frequency in a case-control sample. The region on chromosome 13q14-32 has previously been implicated in other bipolar and schizophrenia cohorts. Our results provide further support for the existence of a susceptibility locus on chromosome 13q14.

Alleles↗
PubMed1999

Colchicine effects on meiosis in the male mouse. II. Inhibition of synapsis and induction of nondisjunction.

This report follows from our earlier study using synaptonemal complex (SC) analysis in which colchicine administered to mouse spermatocytes specifically at leptotene/zygotene blocks synapsis, resulting in univalents at early pachytene. Despite loss of severely damaged cells from the prophase population, substantial numbers of cells with lesser damage progress to late pachytene on schedule. The present study tests whether the surviving cells would continue through meiotic divisions and if so, whether the univalents at MI result in hyperploidy at MII. At 7 days after treatment (late pachytene) 5.9% of the surviving population contains at most four autosomal axial univalents. In whole chromosome preparations 10 days post-colchicine the highest frequency of MIs with univalents is 5.2%. The maximum number of autosomal "chromosomal" univalents per cell is four. The percentage of cells with autosomal univalents at late pachytene, is not significantly different from the percentage of cells with chromosomal univalents at MI. We infer from these observations that the two kinds of univalents are equivalent. At days 11-12 post-colchicine, hyper (and hypo) ploidy at AI-MII is observed. We conclude that univalents produced by colchicine-induced asynapsis at leptotene/zygotene persist and lead to nondisjunction at division I and hyperploidy at division II. If the hyperploid spermatids mature, they would give rise to aneuploid sperm, thus constituting a mechanism for inducing aneuploid (e.g., trisomic) zygotes after fertilization. It is also observed that chiasma frequency (number of chiasmata per bivalent, univalents excluded) is reduced by about 15% of the control. Nondisjunction is known to be the endpoint of colchicine action when administered at prometaphase-MI, interfering with the segregation of homologues through effects on the MI-AI spindle. We show that nondisjunction is also the endpoint of colchicine's effect at early pachytene, in this case causing synaptic inhibition that creates univalents which are then distributed randomly at first division. These conclusions draw special attention to predivision meiotic events, particularly those affecting synapsis, and their sensitivity to induced and/or inherent effects that may have consequences later at meiotic divisions, creating risk to the chromosomal constitution of the gametes.

Animals↗
PubMed1997

Colchicine effects on meiosis in the male mouse. I. Meiotic prophase: synaptic arrest, univalents, loss of damaged spermatocytes and a possible checkpoint at pachytene.

Antimitotic agents administered at the time of synapsis (leptotene/zygotene) have been shown to induce synaptic abnormalities visible during pachytene in the male mouse. The object of this study was to test the hypothesis that cells with relatively large amounts of colchicine-induced damage to the synaptonemal complex (SC) are eliminated from prophase whereas cells with relatively small amounts of SC damage proceed through to the end of prophase. Male mice were injected with tritiated thymidine to mark a cohort of spermatocytes at premeiotic S-phase for tracking through pachytene. Forty-eight hours later, when those cells were at leptotene/zygotene, colchicine was administered intratesticularly. Whole-mount SC spreads were made from animals sacrificed at various times following colchicine administration, and prepared for autoradiography. The marked cells were examined by light and electron microscopy and the kind and number of synaptic abnormalities were scored throughout pachytene. Colchicine-induced SC damage included single axial elements (univalents), together with partially synapsed and nonhomologously synapsed SCs. The amount of SC damage (amount and type per cell and frequency of cells with damage) scored at early pachytene exceeded by three- to fivefold the amount at late pachytene. This is consistent with spermatogenic cell loss from the seminiferous tubule via colchicine-induced destruction of Sertoli cell microtubules. The presence of spermatocytes with no more than four autosomal univalents at late pachytene indicates that some cells with low amounts of synaptic damage progress to the end of pachytene. The loss of the most severely damaged cells may represent a meiotic checkpoint at early pachytene in the male mouse.

Animals↗
PubMed1990

Bleomycin effects on mouse meiotic chromosomes.

The effects of a radiomimetic chemical, bleomycin (BLM), on meiotic chromosomes was evaluated in mice treated by intraperitoneal (i.p.) or intratesticular (i.t.) injection. Chromosome aberrations were analyzed at meiotic metaphase I, and damage to the synaptonemal complex (SC) was analyzed in meiotic prophase cells. In the metaphase aberration studies, an i.p. injection of 80 mg/kg BLM, timed to precede or coincide with pre-meiotic S phase, led to a significant increase in structural damage (P less than 0.01) in cells reaching metaphase I 12 days after treatment. However, no increases in clastogenic effects were observed at metaphase I after treatment of cells during various stages of prophase. SC analyses in pachytene cells following an i.p. or i.t. injection at S phase revealed various forms of synaptic errors and structural anomalies, including qualitative changes similar to those observed following irradiation. I.p. doses ranging from 25 to 100 mg/kg, and i.t. doses as low as 0.5 mg/kg, caused roughly 6-fold increases over control levels in the number of damaged cells. SC analyses in pachytene cells following BLM treatments 2 days earlier (at leptotene-zygotene) or 16 h earlier (at early-mid pachytene), also revealed induced structural and synaptic anomalies. Following the treatment at early-mid pachytene, there was some suggestion of interference with chiasma formation as evidenced by univalent-like configurations detected at diakinesis-metaphase. It was concluded that BLM is clastogenic for meiotic chromosomes; however, it does not reveal the strong S-independent clastogenic activity at meiosis that is characteristic of its activity at meiosis. SC analysis indicated that some damage is induced at meiotic prophase, although structurally aberrant cells are not recoverable at meiotic metaphase I. The results call forth various possible explanations for germ-line specific responses to BLM clastogenic activity.

Animals↗
PubMed1989

Association of foreign DNA sequence with male sterility and translocation in a line of transgenic mice.

We have analyzed a line of transgenic mice derived from injection of a cloned human interferon cDNA. This line manifests total male sterility of males carrying the human sequence, while male littermates not harboring the foreign DNA are fertile. All females are fertile. Karyotypes of transgenic animals show 2:12 translocation. The microinjected sequence maps to one of the translocation chromosomes composed of a large portion of chromosome 12 to which has been translocated a segment of chromosome 2. Analysis of the sterile males reveals significant abnormalities of spermatogenesis and faulty chromosome synapsis that involves the translocation chromosomes. These findings show that transfer of foreign DNA into mouse embryos may lead to chromatin breakage and infertility of transgenic animals.

Animals↗
PubMed1988

Synaptonemal complex damage as a measure of genotoxicity at meiosis.

Synaptonemal complex aberrations can provide a sensitive measure of chemical-specific alterations to meiotic chromosomes. Mitomycin C, cyclophosphamide, amsacrine, ellipticine, colchicine, vinblastine sulfate, and cis-platin exposures in mice have been shown to cause various patterns of synaptonemal complex structural damage and synaptic irregularity. These effects are suggestive of abnormal homologue pairing/synapsis/recombination effects which, theoretically, could be implicated in mechanisms leading to aneuploidy and other potentially heritable chromosomal disorders.

Alkaloids↗
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↗
PubMed1988

Synaptonemal complex damage in relation to meiotic chromosome aberrations after exposure of male mice to cyclophosphamide.

The genetic implications of induced synaptonemal complex (SC) damage are not known. However, on theoretical grounds, such aberrations could be involved in mechanisms leading to potentially heritable defects. Cyclophosphamide (CP), a chemical reported to cause structural and numerical chromosomal aberrations in the mouse, was used to determine if SC damage observed in meiotic prophase is related to subsequent metaphase chromosomal aberrations. Male mice were injected i.p. with CP. In some instances, mice were also injected simultaneously with tritiated thymidine to label DNA so that cells could be tracked autoradiographically through spermatogenesis. Prophase, primary metaphase (M1), and secondary metaphase (M2) samples were sequentially harvested at appropriate times from the same individual, and nuclei were examined for aberrations. Correlation coefficients between SC and metaphase chromosome aberrations were calculated. The inclusion of tritium labeling increased the number and significance of positive correlations. Positive correlations were found between (1) dose-dependent total SC damage and damage to M1, and to a lesser extent, M2 chromosomes; (2) SC breaks/fragments and M1 chains/rings as well as isochromatid breaks/fragments; (3) SC asynapsis and M1 chromatid breaks/fragments; (4) SC multi-axial configurations and M1 chains/rings as well as isochromatid and chromatid breaks/fragments; and (5) SC multi-axial configurations and M2 hyperploidy. These correlations do not define mechanistic or causal relationships between SC and chromosomal damage. However, taken together with the observation that induced SC damage is many times greater than ensuing metaphase chromosome damage, they substantiate SC analysis as a highly sensitive indicator of potentially heritable effects of this (and presumably other) genotoxic agents.

Aneuploidy↗
PubMed1987

Synaptonemal complex damage as a measure of chemical mutagen effects on mammalian germ cells.

As heritable chromosome anomalies are implicated in a variety of human disabilities, their induction in germ cells by environmental chemicals is viewed as a threat to health (National Research Council, 1982; Hook, 1983). Synaptonemal complex (SC) analysis is a novel approach for the detection of germ-line chromosomal damage. This sensitive cytological procedure reveals induced structural damage and pairing abnormalities in SCs of meiotic prophase chromosomes, together with other germ-line toxic effects, in the testes of rodents treated with mitomycin C and cyclophosphamide. Our results demonstrate the effectiveness of SC analysis as a rapid and practical in vivo germ-line mutagen assay that lacks many of the short-comings of existing tests.

Animals↗
PubMed1984

Pachytene chromosomes in male and female mice heterozygous for the Is(7;1)40H insertion.

Pairing of pachytene chromosomes was studied in oocytes and spermatocytes of mice heterozygous for the male-sterile Is(7;1)40H insertion using light and electron microscopy for synaptonemal complex analysis in surface-spread, silver-stained preparations. The data comprised four males and four female embryos. The insertion/deletion configurations appeared as either two bivalents or one quadrivalent in both sexes, but the proportion of bivalents was higher in oocytes. Some insertion and deletion bivalents showed synaptic adjustment. The insertion/deletion configurations were associated with, or adjacent to, the XY bivalent in the majority of spermatocytes. End-to-end association of different bivalents was more frequent in oocytes than in spermatocytes. It is suggested that physiological differences between male and female gametocytes may lead to the difference in their reproductive potential.

Animals↗
PubMed1984

Composition and role of the synaptonemal complex.

The role of the synaptonemal complex (SC) in synapsis during meiotic prophase is examined in spermatocytes and oocytes of mice heterozygous for rearrangements, using light and electron microscopy of whole mount spreads. The duration of cytologically-characterized substages provides a morphological time axis for synaptic events. At zygotene, synapsis is restricted to homologous regions. A second phase of synapsis, indifferent to homology, follows in early pachytene. By a progressive process of synaptic adjustment, SC configurations, such as duplication buckles and inversion loops, are regularly eliminated and form straight, non-homologously synapsed SCs by late pachytene. In the mouse, crossing over probably occurs during the period of homologous synapsis in the first half of pachytene, suggesting an association between recombination events and synaptic adjustment. During this period, a low level of DNA synthesis, distinct from S-phase replication, is found by 3H-thymidine autoradiography to be localized to the SC, as would be expected if repair synthesis involved with crossing over occurred in SC-associated DNA. This DNA synthesis reaches a peak in pachytene concurrently with synaptic adjustment, suggesting that the two events may be related, possibly through the mediation of DNA-binding SC proteins. Using immunocytological techniques to identify SC proteins, a monoclonal antibody has been isolated that binds to formed SCs but not unpaired axes. Apparently specific for a central region component, the antibody also binds to intermediate filaments in the cytoplasm of cultured somatic cells, indicating possible functional attributes common to the meiotic and mitotic proteins.

Animals↗