Showing papers on "Chromosomal region published in 1993"

The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex.

Abstract: Natural killer cells lyse tumor and virally infected cells in a specific manner that has not been molecularly characterized. Target cell expression of major histocompatibility complex (MHC) class I molecules is correlated with target cell resistance to natural killing. A mechanism to explain this observation is that NK cells may display two types of recognition and activation molecules that have opposing functions when bound to target cell ligands. One type of surface receptor such as the NKR-P1 molecule may activate NK activity whereas the other, represented by the mouse Ly-49 molecule, may engage target cell MHC molecules and inhibit cytotoxicity by transducing "negative" signals. NKR-P1 and Ly-49 are structurally related, and they are encoded by genetically linked loci in a chromosomal region, termed the NK gene complex (NKC), on distal mouse chromosome 6. Target cell susceptibility to natural killing may be dependent upon specific ligand-receptor interaction with these activating or inhibitory NKC-encoded molecules.

Nature of DNA polymorphism in the direct repeat cluster of Mycobacterium tuberculosis; application for strain differentiation by a novel typing method

Abstract: Summary Mycobacterium tuberculosis complex strains contain a unique chromosomal region, which consists of multiple 36bp direct repeats (DRs), which are interspersed by unique spacers 35 to 41 bp in length. In this study we investigated the nature of the DNA polymorphism of this DR cluster by sequencing part of this region in a large number of M. tuberculosis complex strains. Two types of genetic rearrangements were observed. One type consists of the variation in one or a few discrete, contiguous DRs plus spacer sequences. This variation is probably driven by homologous recombination between adjacent or distant DRs. The other type of polymorphism is probably driven by transpositional events of the insertion sequence, IS6110, which is almost invariably present in the DR cluster of M. tuberculosis complex strains. Based on the nature of the DNA polymorphism in the DR cluster, we developed a novel method of strain differentiation, direct variable repeat polymer chain reaction (DVR-PCR), which enables typing of individual M. tuberculosis strains in a single PCR. The method allows an excellent differentiation of epidemiologically unrelated isolates and, in principle, the DVR-PCR allows the detection of M. tuberculosis and strain differentiation at the same time.

Sequence and analysis of the genetic locus responsible for surfactin synthesis in Bacillus subtilis.

Abstract: The chromosomal region of Bacillus subtilis comprising the entire srfA operon, sfp and about four kilobases in between have been completely sequenced and functionally characterized. The srfA gene codes for three large subunits of surfactin synthetase, 402, 401 and 144 kDa, respectively, arranged in a series of seven amino acid activating domains which, as shown in the accompanying communication, recognize and bind the seven amino acids of the surfactin peptide. The srfA amino acid activating domains share homologies with similar domains of other peptide synthetases; in particular, regions can be identified which are more homologous in domains activating the same amino acid. A fourth gene in srfA encodes a polypeptide homologous to grsT. Four genes are positioned between srfA and sfp, the disruption of which does not affect surfactin biosynthesis.

Tumor-suppressive effect of the retinoic acid receptor beta in human epidermoid lung cancer cells.

Abstract: Retinoic acid receptor beta (RAR beta), which codes for a nuclear receptor for retinoic acid, is localized in a chromosomal region frequently deleted in lung cancer cells The gene is expressed in normal lung tissue and in the majority of the cell lines derived from lung tumors but not in most of the lines derived from lung tumors with epidermoid characteristics To study the possible role of RAR beta in growth control of epidermoid lung tumor-derived cells, transfectants expresing RAR beta were generated from nonexpressing epidermoid tumor-derived cell lines Four clones were derived from line CALU-1, three of which showed a 20-60% increase in doubling time in the presence of retinoic acid Parental and control-transfected cells were unaffected or slightly stimulated All four clones expressing RAR beta were less tumorigenic in nude mice than were the untransfected or control-transfected cells, with about a 50% incidence of take vs 95% When tumors did develop from RAR beta-positive cells, they showed a reduced rate of growth, an increased latency, and, in six of seven tumors tested, a much reduced level of RAR beta expression Transfectants derived from a second tumor line, H157, also showed a markedly reduced incidence of take in nude mice Together with the known effects of retinoic acid on differentiation and carcinogenesis, our results support the hypothesis that RAR beta functions as a tumor suppressor gene in epidermoid lung tumorigenesis

An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome

Abstract: ICF syndrome has been described as the association of variable immunodeficiency, facial anomalies and centromeric heterochromatin instability. Since the chromosome rearrangements seen in cells of ICF patients are reminiscent of the chromosomal changes induced by the undermethylating agent 5-azacytidine in the late S-phase, we have analyzed the methylation pattern of satellite sequences in four patients. These sequences are almost completely methylated in normal leukocyte DNA. When ICF DNA was tested with methyl-sensitive enzymes, several classical satellite families, but not alphoid sequences, showed a very low level of methylcytosine in leukocyte DNA, with an abnormal pattern compared to the normal germinal and extraembryonic methylation profile. The methylation deficiency affects classical satellite families built from distinct unit sequences but located in the same chromosomal region. This observation may have important implications for the mechanism of chromosomal rearrangements.

Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects.

Abstract: Congenital conotruncal cardiac defects occur with increased frequency in patients with DiGeorge syndrome (DGS). Previous studies have shown that the majority of patients with DGS or velocardiofacial syndrome (VCFS) have a microdeletion within chromosomal region 22q11. We hypothesised that patients with conotruncal defects who were not diagnosed with DGS or VCFS would also have 22q11 deletions. Seventeen non-syndromic patients with one of three types of conotruncal defects most commonly seen in DGS or VCFS were evaluated for a 22q11 deletion. DNA probes from within the DiGeorge critical region were used. Heterozygosity at a locus was assessed using restriction fragment length polymorphisms. Copy number was determined by dosage analysis using Southern blot analysis of fluorescence in situ hybridisation of metaphase spreads. Five of 17 patients were shown to have a 22q11 deletion when evaluated by dosage analysis. This study shows a genetic contribution to the development of some conotruncal cardiac malformations and alters knowledge regarding the risk of heritability of these defects in certain cases.

Polymorphism of the angiotensin I converting enzyme gene is apparently not related to high blood pressure: Dutch Hypertension and Offspring Study.

Abstract: Objective:Studies in genetically hypertensive rats and their normotensive Wistar-Kyoto control rats have revealed a linkage of a chromosomal region containing the angiotensin converting enzyme (ACE) gene with blood pressure. This led to the hypothesis that ACE is a possible candidate gene for primar

Deletion of the serine 34 codon from the major peripheral myelin protein P0 gene in Charcot-Marie-Tooth disease type 1B.

Abstract: Charcot-Marie-Tooth disease type 1B (CMT1B) is genetically linked to chromosome 1q21-23. The major peripheral myelin protein gene, P0, has been cloned and localized to the same chromosomal region. P0 is a 28 kDa glycoprotein involved in the compaction of the multilamellar myelin sheet and accounts for more than half of the peripheral myelin protein content. We checked whether P0 is altered in CMT1B, and show here that a 3 basepair deletion in exon 2 of the P0 gene is present in all affected individuals of a CMT1B family. The mutation results in the deletion of serine 34 in the extracellular domain of P0, suggesting that alterations of P0 cause CMT1B.

Genetic heterogeneity in families with hereditary multiple exostoses.

Abstract: The authors have carried out a linkage analysis on 11 families segregating gene(s) for hereditary multiple exostoses (EXT). Four highly informative, short tandem-repeat (STR) markers that have been physically mapped to an interval surrounding the Langer-Giedion chromosomal region (8q24.11-q24.13) were used in a multipoint linkage analysis. Significant evidence for linkage of EXT with genetic heterogeneity was found. A model of heterogeneity with linkage of the disease gene to the STR markers in 70% of the families (with a 95% confidence interval of 26%-96%) produced a maximum LOD score of 8.11, with the most likely position of EXT between D8S85 and D8S199. Thus there are at least two genes that are capable of causing hereditary multiple exostoses, one in the Langer-Giedion region and one at another, unlinked location. 20 refs., 3 figs., 2 tabs.

Diminished support for linkage between manic depressive illness and X-chromosome markers in three Israeli pedigrees.

Abstract: The hypothesis that chromosomal region Xq27-28 harbours a gene for manic-depression has been a focus of interest in human genetics. X-linked inheritance of manic depressive illness has been re-examined in 3 multigeneration Israeli kindreds. Extension and re-evaluation of pedigree data, including new individuals, diagnostic follow-up, and analysis with DNA markers, shows greatly diminished support for linkage to Xq28. The peak lod scores in two of the pedigrees have dropped several lod units to clearly negative values at the RCP-F8-G6PD gene cluster. On the other hand, positive lod scores (Zmax = 2.09) are sustained in another pedigree at the same map location. None of the pedigrees show linkage to more proximal markers, including the Xq27 locus DXS98. Our analysis underscores the uncertainties in studying complex disorders.

Clustered organization of homologous KRAB zinc-finger genes with enhanced expression in human T lymphoid cells.

Abstract: KRAB zinc-finger proteins (KRAB-ZFPs) constitute a large subfamily of ZFPs of the Kruppel C2H2 type. KRAB (Kruppel-associated box) is an evolutionarily conserved protein domain found N-terminally with respect to the finger repeats. We report here the characterization of a particular subgroup of highly related human KRAB-ZFPs. ZNF91 is one representative of this subgroup and contains 35 contiguous finger repeats at its C-terminus. Three mRNA isoforms with sequence identity to ZNF91 were isolated by the polymerase chain reaction. These encode proteins with a KRAB domain present, partially deleted or absent. Five genomic fragments were characterized, each encoding part of a gene: the ZNF91 gene or one of four distinct, related KRAB-ZFP genes. All exhibit a common exon/intron organization with the variant zinc finger repeats organized in a single exon and the KRAB domain encoded by two separate exons. This positioning of introns supports the hypothesis that the mRNA isoforms encoding polypeptides with variability in the KRAB domain could arise by alternative splicing. By in situ chromosomal mapping studies and by analysis of fragments from a human genomic yeast artificial chromosome library containing KRAB-ZFP genes, we show that these genes occur in clusters; in particular, a gene complex containing over 40 genes has been identified in chromosomal region 19p12-p13.1. These ZNF91-related genes probably arose late during evolution since no homologous genes are detected in the mouse and rat genomes. Although the transcription of members of this KRAB-ZFP gene subgroup is detectable in all human tissues, their expression is significantly higher in human T lymphoid cells.

Efficient and Dispersed Local P Element Transposition from Drosophila Females

Abstract: We have investigated how Drosophila P element insertions are distributed in the chromosomal region near their starting site. A single P element residing in the euchromatin of minichromosome Dp1187 was mobilized following a cross to the delta 2-3 (99B) strain, and progeny bearing transpositions were identified with a minimum of bias by performing Southern blots on progeny. Approximately 1-2% of all progeny minichromosomes contained new insertions. Many of these "local transpositions" landed very close to or within the starting P element; however, nearly 1% of all progeny chromosomes contained new insertions 1-180 kb from the donor element. More local insertions were observed in the progeny of females than from male parents, and most occurred in a preferred orientation relative to the starting element. These observations suggested that donor elements are frequently excised and reinserted locally without ever dissociating from a transposition complex. The high frequency and diverse distribution of local transpositions recovered from females suggested that the efficiency of insertional mutagenesis can be significantly enhanced by using a starting P element(s) located near the target of interest.

Drosophila tyrosine hydroxylase is encoded by the pale locus.

Abstract: We have reintroduced an 8 kb genomic fragment from the Drosophila tyrosine hydroxylase (DTH) locus into the genome of mutant pale (ple) flies. ple was first recovered as a recessive embryonic lethal by Jurgens et al. (1984) and maps to the same chromosomal region as DTH (65A-E). Mutant ple alleles affect pigmentation of the cuticle (L-DOPA, the product of the reaction catalyzed by TH, is an intermediate in the cuticular sclerotization and pigmentation pathways) and catecholamine biosynthesis. In this report we demonstrate that ple does encode the structural gene for TH, since the reintroduced sequences rescue ple flies from lethality to viable adults. Morphological, immunocytochemical, and behavioral characterization of three transformant lines suggests that the reintroduced sequences contain the necessary elements for correct temporal and spatial expression of the gene, but may not contain all the sequences essential for quantitative expression.

Modification of 15q11 — q13 DNA methylation imprints in unique Angelman and Prader — Willi patients

Abstract: The clearest example of genomic imprinting in humans comes from studies of the Angelman (AS) and Prader-Willi (PWS) syndromes. Although these are clinically distinct disorders, both typically result from a loss of the same chromosomal region, 15q11-q13. AS usually results from either a maternal deletion of this region, or paternal uniparental disomy (UPD; both chromosomes 15 inherited from the father). PWS results from paternal deletion of 15q11-q13 or maternal UPD of chromosome 15. We have recently described a parent-specific DNA methylation imprint in a gene at the D15S9 locus (new gene symbol, ZNF127), within the 15q11-q13 region, that identifies AS and PWS patients with either a deletion or UPD. Here we describe an AS sibship and three PWS patients in which chromosome 15 rearrangements alter the methylation state at ZNF127, even though this locus is not directly involved in the rearrangement. Parent-specific DNA methylation imprints are also altered at ZNF127 and D15S63 (another locus with a parent-specific methylation imprint) in an AS sibship which have no detectable deletion or UPD of chromosome 15. These unique patients may provide insight into the imprinting process that occurs in proximal chromosome 15 in humans.

A major susceptibility locus to murine lung carcinogenesis maps on chromosome 6

Abstract: Lung tumours represent a major cause of death in humans, and although smoking represents the main pathogenetic factor, inheritance also plays a part. However, the identification of possible predisposing genetic factors is difficult, because of their low penetrance. We took advantage of murine strains that are genetically susceptible or resistant to lung tumour development, to map murine genes associated with susceptibility to lung carcinogenesis. An F2 population of urethan-treated A/J x C3H/He mice was scored with 83 genetic markers. A chromosome 6 distal region, spanning mice was scored with 83 genetic markers. A chromosome 6 distal region, spanning 35 centiMorgans, contained a major lung tumour susceptibility locus. No other chromosomal region was significantly associated with lung tumour development.

Microsatellite mapping of the gene causing weaver disease in cattle will allow the study of an associated quantitative trait locus.

Abstract: A genetic disease in cattle, progressive degenerative myeloencephalopathy (weaver disease), is associated with increased milk production. This association could result from population stratification, from a pleiotropic effect of a single gene, or from linkage disequilibrium between the gene causing weaver disease and a quantitative trait locus (QTL) for milk production. To test these hypotheses, we performed an extensive linkage study in a bovine pedigree segregating for the weaver condition and identified a microsatellite locus (TGLA116) closely linked to the weaver gene (zmax, 8.15; theta, 0.03). TGLA116 and, by extension, the weaver locus were assigned to bovine synteny group 13. This microsatellite can be used to identify weaver carriers, to select against this genetic defect, and to study the effect of the corresponding chromosomal region on milk production in Brown Swiss and other breeds of cattle.

Loss of heterozygosity and amplification on chromosome 11q in human ovarian cancer.

Abstract: The 11q13 chromosomal region encodes oncogenes relevant to a variety of human cancers as well as a tumour suppressor gene implicated in multiple endocrine neoplasia type 1. In addition, high affinity folate receptor (FOLR1), which maps to 11q13.3-13.5, is expressed at an elevated level on the surface of over 80% of nonmucinous epithelial ovarian cancers. Further telomeric, 11q breakpoints are found in many cancers. We studied the involvement of 11q markers in ovarian cancer by looking for tumour-specific loss of heterozygosity (LOH), as well as amplification or rearrangements that might explain the overexpression of FOLR1. Twenty eight epithelial ovarian cancers, along with lymphocyte DNA from the same individual were used for Southern blotting with polymorphic probes from 11q. PCR primers from 11q23.3 were also used. The 11q13 band was amplified in four out of 28 cancers. The amplicon included the probe D11S146 as well as FGF3 (formerly INT2) and FOLR1 in one out of these four cases, thus crossing the bcl1 translocation breakpoint. LOH was seen in three out of 16 cases with FGF3 (11q13). A much higher frequency of LOH (8/12) was found at 11q23.3-qter, implying the presence of a tumour suppressor gene in this region.

Base Transitions Are the Most Frequent Genetic Changes at P53 in Gastric Cancer

Abstract: We searched for P53 mutations in gastric carcinoma by analyzing tumor DNAs from 29 patients. We detected 13 different somatic mutations in 15 patients (52%) and a biallelic polymorphism in exon 6 (5 heterozygous subjects). The somatic mutations were mainly localized in the sequences corresponding to the highly conserved domains of the protein. Twelve samples showed a single base change: 11 missense and 1 nonsense mutations. Three samples showed deletions leading to a frame shift, to the in-frame loss of 2 amino acids, and to the deletion of a splicing site. All point mutations, except one, were transitions, and 91% of them were G:C-->A:T changes. We previously analyzed this panel of tumors for allelic loss at the 17p13 chromosomal region, where the P53 gene had previously been located: the results showed an increasing incidence of allelic loss in late-stage tumors. On the contrary, in the present study no trend between P53 mutations and tumor stages was found. This observation indicates that mutation events precede allelic loss in gastric cancer. Half (54%) of the mutations occurred in samples without allelic loss, suggesting that specific mutated alleles, acting in a dominant negative fashion, can alter in vivo the P53 protein function.

Translocation of BCR to Chromosome 9: A New Cytogenetic Variant Detected by FISH in Two Ph-Negative, BCR-Positive Patients With Chronic Myeloid Leukemia

Abstract: Leukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: I) Cytogenetics showed a normal 46.XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2 (patient I) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5′ BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q 11 hybridized solely with chromosome 22. For the first time, a BCR-ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q 11. A rearrangement in the latter site is found in all Ph-positive CML and in almost all investigated CML with variant Ph or Ph-negative, BCR-positive cases. The few aberrant chromosomal localizations of BCR-ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR-ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region. The lymphocytes of patient 2 carried the maternal chromosome 9 alleles and were Ph-negative as evidenced by RFLP and FISH analyses, respectively. © 1993 Wiley-Liss, Inc.

A gene in the chromosomal region 3p21 with greatly reduced expression in lung-cancer is similar to the gene for ubiquitin-activating enzyme

Abstract: The chromosomal region 3p21 is thought to be the site of a lung tumor suppressor gene. We recently cloned a gene from this region that has greatly reduced expression in almost all lung tumor cell lines examined, in spite of being widely expressed in a variety of other tumor and nontumor cell types. We report here the sequence of this gene and show that it has significant homology to the genes encoding the ubiquitin-activating enzymes of three species, including humans. This suggests it is a second, autosomal member of this gene family in humans and may play a role in the ubiquitin conjugation pathway, which is of central importance in all eukaryotes.

A novel metalloprotease/disintegrin-like gene at 17q21.3 is somatically rearranged in two primary breast cancers.

Abstract: From chromosomal region 17q21.3, where a tumour suppressor gene(s) for breast and ovarian cancers is thought to be present, we have isolated a novel gene from a cosmid clone that revealed somatic rearrangements in two breast cancers. The gene (MDC) encodes a 524–amino acid metalloprotease–like, disintegrin–like and cysteine–rich protein with sequence similarity to members of the snake–venom metalloprotease/disintegrin family and guinea–pig sperm–surface protein PH–30. These proteins have been implicated in cell–cell or cell–extracellular matrix interactions. Rearrangements in both tumours involve multiple exons and disrupt the coding region of the new MDC.

Physical mapping of the holoprosencephaly critical region on chromosome 7q36.

Abstract: Holoprosencephaly (HPE) is a developmental field defect involving the brain and face. Cytogenetic deletions in patients with HPE have localized one of the HPE genes to chromosomal region 7q36. We have characterized the 7q deletions in thirteen HPE patients. The result is the construction of a high resolution physical map of 7q32–qter. As a first step towards cloning an HPE gene crucial for normal brain development, we have defined the HPE minimal critical region in 7q36 between D7S292 and D7S392.

Analysis of a second family with hereditary non-chromaffin paragangliomas locates the underlying gene at the proximal region of chromosome 11q

Abstract: The gene for autosomal, dominantly inherited, non-chromaffin paragangliomas has previously been mapped at 11q23-qter by linkage analysis of a single family. In the present study, we have used genetic markers from 11q for the analysis of two distantly related pedigrees with the same disorder. Linkage analysis and haplotyping indicate that the gene underlying the disorder in the present family is located on chromosome 11q proximal to the tyrosinase gene locus (11q14-q21). Closely linked markers are the human homologue of the murine INT2 protooncogene and the anonymous DNA marker D11S527. A maximum lod score of 5.4 (theta = 0.0) has been obtained for linkage between the disorder and the chromosomal region defined by these markers. The human INT2 gene can be regarded as a candidate for the disorder on the basis of its expression pattern during embryogenesis in the mouse. However, haplotype analysis indicates that this gene is probably not the predisposing genetic factor in the present family.

Coincidence of genetic loci for plasma cholesterol levels and obesity in a multifactorial mouse model.

Abstract: We have examined backcross progeny derived from a cross of Mus spretus with C57BL/6J, that range from 1 to 50% carcass lipid (n = 215), and from 22 to 130 mg/dl plasma total cholesterol (n = 238). Statistical analysis revealed that distal mouse chromosome 7 exhibits significant linkage both to plasma total cholesterol (likelihood of the odds [LOD] 5.8) and to carcass lipid (LOD 3.8). A locus on chromosome 6 also shows significant linkage to plasma total cholesterol (LOD 5.6), but no linkage to carcass lipid. Neither chromosomal region contains any previously mapped genes likely to influence lipoprotein metabolism, indicating that novel genetic factors contributing to plasma lipoprotein levels have been identified.

Evaluation of potential models for imprinted and nonimprinted components of human chromosome 15q11-q13 syndromes by fine-structure homology mapping in the mouse.

Abstract: Prader-Willi and Angelman syndromes are complex neurobehavioral contiguous gene syndromes whose expression depends on the unmasking of genomic imprinting for different genetic loci in human chromosome 15q11-q13. The homologous chromosomal region in the mouse genome has been fine-mapped by using interspecific (Mus spretus) crosses and overlapping, radiation-induced deletions to evaluate potential animal models for both imprinted and nonimprinted components of these syndromes. Four evolutionarily conserved sequences from human 15q11-q13, including two cDNAs from fetal brain (DN10, D15S12h; DN34, D15S9h-1), a microdissected clone (MN7; D15F37S1h) expressed in mouse brain, and the gene for the beta 3 subunit of the gamma-aminobutyric acid type A receptor (Gabrb3), were mapped in mouse chromosome 7 by analysis of deletions at the pink-eyed dilution (p) locus. Three of these loci are deleted in pre- and postnatally lethal p-locus mutations, which extend up to 5.5 +/- 1.7 centimorgans (cM) proximal to p; D15S9h-1, which maps 1.1 +/- 0.8 cM distal to p and is the mouse homolog of the human gene D15S9 (which shows a DNA methylation imprint), is not deleted in any of the p-locus deletion series. A transcript from the Gabrb3 gene, but not the transcript detected by MN7 at the D15F37S1h locus, is expressed in mice homozygous for the p6H deletion, which have an abnormal neurological phenotype. Furthermore, the Gabrb3 transcript is expressed equally well from the maternal or paternal chromosome 7 and, therefore, its expression is not imprinted in mouse brain. Deletions at the mouse p locus should serve as intermediate genetic reagents and models with which to analyze the genetics and etiology of individual components of human 15q11-q13 disorders.

The control in cis of the position and the amount of the ARG4 meiotic double-strand break of Saccharomyces cerevisiae.

Abstract: During meiosis, a transient DNA double-strand break (DSB) occurs in the promoter region (positions -200/-185) of the Saccharomyces cerevisiae ARG4 gene and is a likely intermediate in the initiation of meiotic gene conversion events in this region. We report here a functional analysis of the ARG4 DSB based on the study of various deletions in this chromosomal region. We have identified several cis-acting elements located within the -465/+3 region of the ARG4 promoter that control the formation of this DSB. The -465/-317 region includes a transcription terminator and is necessary for a normal amount of ARG4 DSB, but not for its positioning. The -316/-140 region can be replaced by an unrelated DNA sequence where a meiotic DSB then occurs, suggesting that the site of DSB is not sequence-specific, but is positioned at a fixed distance from the adjacent -139/+3 region. Also, in all strains constructed, the amount of meiotic DSB is correlated with the frequency of gene conversion in ARG4, which provides a strong argument for the initiation of gene conversion by a DSB in this region of the yeast genome.

A short chromosomal region with major roles in yeast chromosome III meiotic disjunction, recombination and double strand breaks.

Abstract: A multicopy plasmid was isolated from a yeast genomic library, whose presence resulted in a twofold increase in meiotic nondisjunction of chromosome III. The plasmid contains a 7.5-kb insert from the middle of the right arm of chromosome III, including the gene THR4. Using chromosomal fragments derived from chromosome III, we determined that the cloned region caused a significant, specific, cis-acting increase in chromosome III nondisjunction in the first meiotic division. The plasmid containing this segment exhibited high spontaneous meiotic integration into chromosome III (in 2.4% of the normal meiotic divisions) and a sixfold increase (15.5%) in integration in nondisjunctant meioses. Genetic analysis of the cloned region revealed that it contains a "hot spot" for meiotic recombination. In DNA of rad50S mutant cells, a strong meiosis-induced double strand break (DSB) signal was detected in this region. We discuss the possible relationships between meiosis-induced DSBs, recombination and chromosome disjunction, and propose that recombinational hot spots may be "pairing sites" for homologous chromosomes in meiosis.

Human smooth muscle myosin heavy chain gene mapped to chromosomal region 16q12

Abstract: The partial nucleotide sequence encoding the rod portion of the entire amino acid sequence of human smooth muscle myosin heavy chain (MHC) which corresponds to MYH11, according to Human Gene Mapping nomenclature, has been determined by cloning a complementary DNA (cDNA) and sequencing the cDNA (UMYHSM). Northern blot analysis with the UMYHSM fragment (4.3 Kb) showed that the smooth muscle MHC of the human umbilical artery is expressed in the human umbilical artery, bladder, esophagus and trachea. Southern blot analysis of human genomic DNA from human-mouse or human-Chinese hamster somatic cell hybrids demonstrated that the human smooth muscle MHC was mapped to human chromosome 16. Regional mapping of UMYHSM was performed using human cell lines with partial deletion and trisomy of chromosome 16. As a result, the human smooth muscle MHC gene segregated with 16p11-q12. In situ hybridization of biotin-labeled human smooth muscle MHC probe (UMYHSM fragment) to normal human metaphase chromosome independently showed that the human smooth muscle MHC gene (MYH11) is assigned to chromosome region 16q12. Analysis of early metaphase chromosomes showed that hybridization signals were in 16q12.1. In the human, although skeletal, cardiac, smooth muscle, and nonmuscle MHC genes are mapped to chromosomes 17, 14, 16, and 22, respectively, structural similarities of these MHC genes strongly suggest the common origin of these genes.

Exclusion of Linkage Between Schizophrenia and the D2 Dopamine Receptor Gene Region of Chromosome 11q in 112 Irish Multiplex Families

Abstract: • A leading theory hypothesizes that schizophrenia arises from dysregulation of the dopamine system in certain brain regions As this dysregulation could arise from abnormal expression of D 2 dopamine receptors, the D 2 receptor gene ( DRD2 ) on chromosome 11q is a candidate locus for schizophrenia We tested whether allelic variation at DRD2 and five surrounding loci cosegregated with schizophrenia in 112 small- to moderate-size Irish families containing two or more members affected with schizophrenia or schizoaffective disorder, defined by DSM-III-R Evidence of linkage was assessed using varying definitions of illness and modes of transmission Assuming genetic homogeneity, linkage between schizophrenia and large regions of 11q around DRD2 could be strongly excluded Assuming genetic heterogeneity, variation at the DRD2 locus could be rejected as a major risk factor for schizophrenia in more than 50% of these families for all models tested and in as few as 25% of the families for certain models The DRD2 linkage in fewer than 25% of these families could not be excluded under any of the models tested Our results suggest that the major component of genetic susceptibility to schizophrenia is not due to allelic variation at the DRD2 locus or other genes in the surrounding chromosomal region