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Results for “Locus Control Region”

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PubMed1993

Mapping loci influencing the persistence of Theiler's virus in the murine central nervous system.

Inbred strains of mice differ greatly in their susceptibility to the demyelinating disease caused by Theiler's Murine Encephalomyelitis Virus. In this murine disease, which is an animal model for the study of multiple sclerosis, demyelination depends on the persistent infection of the central nervous system. Previous studies identified a locus in the H-2D region of the major histocompatibility complex which controls susceptibility to the persistent infection, and also showed that other loci are involved. In order to identify these loci, we screened the genome of a set of backcross animals with a combination of polymorphic microsatellites and restriction enzymes sites. We now show that viral persistence is also controlled by a locus close to Ifg on chromosome 10 and possibly by a locus near Mbp on chromosome 18.

Animals↗
PubMed2005

Comparative analyses of genomic imprinting and CpG island-methylation in mouse Murr1 and human MURR1 loci revealed a putative imprinting control region in mice.

Human MURR1 is an orthologue of mouse Murr1 gene, which was previously reported to be imprinted only in adult brain with a maternal allele-predominant expression and to contain another imprinted gene, U2af1-rs1, in the first intron. Human MURR1 was found not to harbor the U2af1-rs1 orthologue and to be expressed biallelically in tissues, including adult brain. Three genes identified around Murr1 and their orthologues around MURR1 were expressed biallelically. These findings suggest that the mouse imprinting locus is limited to a small region and the introduction of U2af1-rs1 in mouse causes the imprinting of this locus. The CpG island (CGI) at U2af1-rs1 with maternal methylation was the only differentially methylated region among CGIs found in these loci. Detailed methylation analyses of the U2af1-rs1 CGI in germ cells led to identification of a region with oocyte-specific methylation. These results suggest that this region is the imprinting control region of the Murr1/U2af1-rs1 locus in mouse.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Electron microscope mapping of the pericentric and intercalary heterochromatic regions of the polytene chromosomes of the mutant Suppressor of underreplication in Drosophila melanogaster.

Breaks and ectopic contacts in the heterochromatic regions of Drosophila melanogaster polytene chromosomes are the manifestations of the cytological effects of DNA underreplication. Their appearance makes these regions difficult to map. The Su(UR)ES gene, which controls the phenomenon, has been described recently. Mutation of this locus gives rise to new blocks of material in the pericentric heterochromatic regions and causes the disappearance of breaks and ectopic contacts in the intercalary heterochromatic regions, thereby making the banding pattern distinct and providing better opportunities for mapping of the heterochromatic regions in polytene chromosomes. Here, we present the results of an electron microscope study of the heterochromatic regions. In the wild-type salivary glands, the pericentric regions correspond to the beta-heterochromatin and do not show the banding pattern. The most conspicuous cytological effect of the Su(UR)ES mutation is the formation of a large banded chromosome fragment comprising at least 25 bands at the site where the 3L and 3R proximal arms connect. In the other pericentric regions, 20CF, 40BF and 41BC, 15, 12 and 9 new bands were revealed, respectively. A large block of densely packed material appears in the most proximal part of the fourth chromosome. An electron microscope analysis of 26 polytene chromosome regions showing the characteristic features of intercalary heterochromatin was also performed. Suppression of DNA underreplication in the mutant transforms the bands with weak spots into large single bands.

Animals↗
PubMed2003

Epigenetic gene regulation by noncoding RNAs.

Functional noncoding RNAs have distinct roles in epigenetic gene regulation. Large RNAs have been shown to control gene expression from a single locus (Tsix RNA), from chromosomal regions (Air RNA), and from entire chromosomes (roX and Xist RNAs). These RNAs regulate genes in cis; although the Drosophila roX RNAs can also function in trans. The chromatin modifications mediated by these RNAs can increase or decrease gene expression. These results suggest that the primary role of RNA molecules in epigenetic gene regulation is to restrict chromatin modifications to particular regions of the genome. However, given that RNA has been shown to be at the catalytic core of other ribonucleoprotein complexes, it is also possible that RNA also plays a role in modulating changes in chromatin structure.

Animals↗
PubMed1996

Aod2, the locus controlling development of atrophy in neonatal thymectomy-induced autoimmune ovarian dysgenesis, co-localizes with Il2, Fgfb, and Idd3.

In genetically susceptible strains of mice, such as A/J and (C57BL/6J x A/J)F1 hybrids, neonatal thymectomy-induced autoimmune ovarian dysgenesis (AOD) is characterized by the development of antiovarian autoantibodies, oophoritis, and atrophy. Temporally, atrophy may be observed during and after the regression of inflammatory infiltrates from the ovary. Histologically, lesions appear as areas devoid of ovarian follicles in all stages of development that have been replaced by luteinized interstitial cells. We report here the mapping of Aod2, the locus that controls this phenotype, to mouse chromosomes 3 within a region encoding Il2 and Fgfb. Most significant, however, is the co-localization of Aod2 to Idd3, a susceptibility gene that plays a role in autoimmune insulin-dependent type 1 diabetes mellitus in the nonobese diabetic mouse.

Animals↗
PubMed1990

Immunogenetics of mycobacterial infections: mouse-human homologies.

In the mouse, innate resistance or susceptibility to infection with numerous mycobacteria is controlled by the Bcg host resistance locus located on the centromeric region of chromosome 1. The resistance/susceptibility phenotype is expressed by the mature tissue macrophage and Bcg has been identified as a locus that is involved in the regulation of macrophage activation and in the modulation of acquired immune responses to mycobacteria. Experiments aimed at the cloning of the Bcg gene via a "reverse genetics" approach have generated a detailed genetic map in the immediate vicinity of the locus, placing Bcg within the reach of long-range eukaryotic cloning techniques. The chromosomal segment around Bcg in the mouse is exactly conserved onto the long arm (q) of human chromosome 2. Linkage of genetic markers from human chromosome 2q with susceptibility to leprosy or tuberculosis would support both the existence of a susceptibility gene in humans and the contention that this susceptibility gene is a homologue of the mouse Bcg locus.

Animals↗
PubMed1989

High-level, erythroid-specific expression of the human alpha-globin gene in transgenic mice and the production of human hemoglobin in murine erythrocytes.

Using the dominant control region (DCR) sequences that flank the beta-globin gene locus, we have been able to achieve high-level expression of the human alpha-globin gene in transgenic mice. Expression in fetal liver and blood is copy number dependent and at levels comparable to that of the endogenous mouse alpha-globin genes. Transgenic fetuses with high-copy numbers of the transgene suffer severe anemia and die before birth. Using a construct with both the human alpha- and beta-globin genes and the beta-globin DCR, live mice with low-copy numbers were obtained. Both human globin genes are expressed at high levels in adult red cells to give human hemoglobin HbA in amounts equal to or greater than endogenous mouse hemoglobin. Expression of HbA in murine red cells is not accompanied by any increase in mean corpuscular volume (MCV) or mean corpuscular hemoglobin concentration (MCHC). However, these transgenic mice tend to have an increased number of reticulocytes in peripheral blood; consistent with some degree of hemolysis. Metabolic labeling experiments showed balanced mouse globin synthesis, but imbalanced human globin synthesis, with an alpha/beta biosynthetic ratio of approximately 0.6. Thus, these mice have mild anemia. These results are discussed with relation to the coordinate regulation of alpha- and beta-globin synthesis in erythroid tissues.

Animals↗
PubMed2006

Brain-gut connections in functional GI disorders: anatomic and physiologic relationships.

Understanding the neural regulation of gut function and sensation makes it easier to understand the interrelatedness of emotionality, symptom-attentive behavior or hypervigilance, gut function and pain. The gut and the brain are highly integrated and communicate in a bidirectional fashion largely through the ANS and HPA axis. Within the CNS, the locus of gut control is chiefly within the limbic system, a region of the mammalian brain responsible for both the internal and external homeostasis of the organism. The limbic system also plays a central role in emotionality, which is a nonverbal system that facilitates survival and threat avoidance, social interaction and learning. The generation of emotion and associated physiologic changes are the work of the limbic system and, from a neuroanatomic perspective, the 'mind-body interaction' may largely arise in this region. Finally, the limbic system is also involved in the 'top down' modulation of visceral pain transmission as well as visceral perception. A better understanding of the interactions of the CNS, ENS and enteric immune system will significantly improve our understanding of 'functional' disorders and allow for a more pathophysiologic definition of categories of patients currently lumped under the broad umbrella of FGID.

Animals↗
PubMed2006

Delivery of large genomic DNA inserts >100 kb using HSV-1 amplicons.

The principal aim of gene therapy for recessive genetic diseases is to supplement the loss of function of an endogenous gene. For the treatment of many diseases regulation of transgene expression at physiological levels, expression of multiple splice variants, and correct tissue specificity are of utmost importance for effective therapy. We therefore believe the use of a complete genomic locus, in which the native promoter and regulatory regions drive and control expression, is an elegant and effective alternative to traditional complementary DNA (cDNA) vectors utilising heterologous promoters. Viral vectors have proved, over the years, to be an effective means of gene delivery in vitro and in vivo, but the size of complete genomic loci precludes their use in most viral systems. One notable exception comprises the amplicon-type vectors based on human herpesviruses, such as the herpes simplex virus type I (HSV-1) amplicon vector. The large genome of HSV-1 (152 kb) confers upon HSV-1 amplicons a very large transgene capacity sufficient to accommodate approximately 95% of human genomic loci. The combination of the large transgene capacity, a broad range of cell tropism, and the ability to infect dividing and non-dividing cells makes HSV-1 amplicons an excellent vector system to develop for the delivery of large genomic loci. Here we review recent work which has shown that HSV-1 amplicons can be used for the delivery and expression of large genomic inserts >100 kb to cells in culture to rescue phenotypes in cellular models of genetic disease. We then discuss applications for high capacity HSV-1 amplicons in vivo and their potential to facilitate the use of large genomic inserts in gene therapy treatment regimes.

DNA↗
PubMed2003

Different dental tissues as source of DNA for human identification in forensic cases.

AIM: To evaluate different dental tissues (pulp, dentin, and cement) as sources of DNA for forensic analysis. METHODS: A total of 20 teeth were obtained from unidentified bodies buried at the Central Cemetary in Bogotá in 1995 and exhumed in 2000. The tissues from three teeth obtained after surgery were used as controls. The pulp cavity was exposed after cutting each tooth with a high-speed handpiece. The pulp was removed and processed separately from the dentin and cement. The dentin and cement were obtained by drilling with a high-speed handpiece and placed into separate tubes. DNA was extracted from mineralized tissues after a short decalcification step with EDTA. The DNA was quantified by dot-blot hybridization with D17Z1 probe, a primate- and human-specific alpha satellite DNA for the D17Z1 locus. Polymerase chain reaction was carried out for the hypervariable control region between nucleotides 29 and 408 bp (HV2 region) of the mitochondrial DNA, followed by gel electrophoresis to evaluate the amount and efficiency of the amplification. RESULTS: The pulp yielded the strongest amplification signals. The signals for dentin and cement were very similar because of the presence of cells of the periodontal ligament in the cement. The results of the amplification of the HV2 region of the mitochondrial DNA showed that dentin and cement acted as protective factors for the cells and allowed the conservation of the DNA. CONCLUSION: Cementoblasts and odontoblasts located within the cement and dentin are surrounded by the mineral matrix of the dental structure and thus protected from any environmental degradation forces, which makes them suitable sources for the DNA analysis.

Adult↗
PubMed1996

Extent of heterogeneity in mitochondrial DNA of ethnic Asian populations.

Variation in the mitochondrial DNA (mtDNA) control region as detected by sequence-specific oligonucleotide (SSO) probes is described for 993 individuals in 11 ethnic Asian populations. Estimates of diversity for mtDNA types exceed 0.94 in all populations, while 53% of the 255 types that were observed occur only once. Of 96 shared types, four occur at frequencies of greater than 10% but less than 17% in any one population. There is statistically significant heterogeneity among these 11 populations, however, an analysis of variance incorporating genetic distances between types shows that at least 95% of the variation present in the total sample is attributable to within-population diversity, while only 5% is due to between-population differences. Overall, heterogeneity with respect to mtDNA SSO types is grossly correlated with geographic distance between populations; the most extreme heterogeneity was observed between populations from East Asia and populations from West Asia. With respect to population genetics, the control region of mtDNA exhibits satisfactory qualities as a DNA typing locus.

Analysis of Variance↗
PubMed1998

Genetic structure of IDDM1: two separate regions in the major histocompatibility complex contribute to susceptibility or protection. Belgian Diabetes Registry.

We analyzed 11 markers in the IDDM1 region in 120 IDDM patients and 83 healthy control subjects who were fully matched for the highest risk HLA-DQA1*0301-DQB1 *0302/DQA1*0501-DQB1*0201 genotype. Our study provides strong evidence that two regions in the major histocompatibility complex contribute to IDDM susceptibility or protection. First, despite selection for highest IDDM-associated risk DQ genotypes, this region displays extensive linkage disequilibrium (LD) differences between IDDM patients and control subjects. A second critical region was mapped around the microsatellite locus D6S273 centromeric of TNF, and it is approximately 200 kb in size. LD analysis shows that "diabetogenic haplotypes" may have resulted from a recombination telomeric of D6S1014 in the region of D6S273 and TNFa. Haplotype analysis using HLA and microsatellite loci refines IDDM risk assessment in carriers of the HLA-DQ highest risk genotype.

Adult↗
PubMed2004

Fine mapping of the region including hypogonadism (hgn) locus on rat chromosome 10.

The hypogonadic rat (hgn/hgn) shows male sterility, reduced female fertility, and renal hypoplasia, controlled by a single recessive gene located on rat chromosome 10. We developed a fine map around the hgn locus using 565 rat backcross progeny and a Rat/Hamster radiation hybrid panel. The hgn locus was linked to Aldoc (aldolase c) and whn (winged helix of nude), and located in a 0.34-cM region between D10Rat30 and D10Rat68. The distance of the region was approximately 840-kb on rat physical map. Neither loci responsible for male sterility nor renal hypoplasia has been mapped on the homologous regions of mouse chromosome 11 and human chromosome 17. Identification of the gene responsible for the hgn mutation would provide important information on urogenital development.

Animals↗
PubMed1997

Genetic background of the differences in timing of meiotic maturation in mouse oocytes: a study using recombinant inbred strains.

Recombinant inbred strains of mice derived from CBA and KE strains were used for studying the genetic background of the duration of the first meiotic cycle which differs in oocytes from progenitor strains. Oocytes were screened in vitro for the timing of germinal vesicle breakdown as well as for the timing of first polar body extrusion, and the approximate duration of the first meiotic M-phase was calculated. Although oocytes from progenitor strains did not differ in the duration of germinal vesicle breakdown, this characteristic segregated in recombinant strains showing involvement of at least two genes. Because of the similar duration of germinal vesicle breakdown in CBA and KE oocytes, the difference in timing of first polar body extrusion (9 h and 12 h for CBA and KE, respectively) reflects the difference in the duration of the first meiotic M-phase. The timing of germinal vesicle breakdown and the duration of M-phase in recombinant strains were negatively correlated (P < 0.01); in general, the more time needed for breakdown of the germinal vesicle, the shorter the M-phase. The timing of first polar body extrusion varied among strains: in some it was similar to one of the parental strains; in others it was intermediate between the two, which again shows the involvement of at least two genes in the control of this character. The linkage analysis suggests that one of the putative genes influencing the timing of first polar body extrusion may be situated near the Gpi-1 locus on chromosome 7, that is, in the region containing the locus for cyclin E. The possible involvement of cyclin E in the control of the timing of first meiosis in mouse oocytes is discussed.

Animals↗
PubMed1994

Identification of a cis-acting gene regulatory element from the lemdr1 locus of Leishmania enriettii.

The goal of this work is to identify those elements which control gene expression in the parasitic protozoan, Leishmania enriettii. To date there has been no report of a transcriptional controlling element identified in this parasite. In the present study, we have found that a region of the lemdr1 locus of L. enriettii can down-regulate the steady state mRNA level of the reporter neomycin phosphotransferase gene when it is placed in an extrachromosomal expression vector, pALTneo. Through deletion analysis, we have mapped a putative regulatory sequence to the flanking region upstream of the lemdr1 gene. This cis regulatory element is shown to control gene expression in an orientation-dependent and position independent manner. By performing nuclear run-on analysis, we have demonstrated that this element mainly exerts its effect at the transcriptional level by determining the strandedness of transcription on the pALTneo vector. The identification of this novel cis regulatory element should further our understanding of the transcriptional process in Leishmania and other related trypanosomatids.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Gender-specific association between -1082 IL-10 promoter polymorphism and longevity.

Ageing is characterized by a pro-inflammatory status, which could contribute to the onset of major age-related diseases. Thus, genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. IL-10 is an appropriate candidate because it exerts powerful inhibitory effects on pro-inflammatory function. IL-10 production is controlled by several polymorphic elements in the 5' flanking region of IL-10 gene on 1q32 locus, involving alleles at two microsatellite regions and several polymorphisms in promoter region. We analysed in 190 Italian centenarians (>99 years old, 159 women and 31 men) and in 260 <60 years old control subjects (99 women and 161 men), matched for geographical distribution, genotype frequencies for -1082G-->A, -819C-->T and -592C-->A IL-10 proximal promoter gene biallelic polymorphisms by sequence specific probes. -1082G homozygous genotype was increased in centenarian men (P < 0.025) but not in centenarian women. No difference was found between centenarians and control subjects regarding the other two polymorphisms. The presence of -1082GG genotype, suggested to be associated with high IL-10 production, significantly increases the possibility to reach the extreme limit of human lifespan in men. Together with previous data on other polymorphic loci (Tyrosine Hydroxylase, mitochondrial DNA, IL-6, haemochromatosis, IFN-gamma), this finding points out that that gender is a major variable in the genetics of longevity, suggesting that men and women follow different strategies to reach longevity. Concerning the biological significance of this association, we have not searched for functional proves that IL-10 is involved. Thus, we should conclude that our data only suggest that a marker on 1q32 genomic region may be involved in successful ageing in man. However, recent data on IL-6 and IFN-gamma genes suggest that longevity is negatively associated with genotypes coding for a pro-inflammatory profile. Thus, it is intriguing that the possession of -1082G genotype, suggested to be associated with IL-10 high production, is significantly increased in centenarians.

Aged↗
PubMed1998

c-fos Expression in mesopontine noradrenergic and cholinergic neurons of the cat during carbachol-induced active sleep: a double-labeling study.

The interaction of cholinergic and catecholaminergic mechanisms in the mesopontine region has been hypothesized as being critical for the generation and maintenance of active (REM) sleep. To further examine this hypothesis, we sought to determine the pattern of neuronal activation (via c-fos expression) of catecholaminergic and cholinergic neurons in this region during active sleep induced by the pontine microapplication of carbachol (designated as active sleep-carbachol). Accordingly, we used two sets of double-labeling techniques; the first to identify tyrosine hydroxylase-containing neurons (putative catecholaminergic cells) which also express the c-fos protein product Fos, and the second to reveal choline acetyltransferase-containing neurons (putative cholinergic cells) which also express Fos. Compared to control cats, active sleep-carbachol cats exhibited a significantly greater number of Fos-expressing neurons in the dorsolateral region of the pons, which encompasses the locus coeruleus, the lateral pontine reticular formation, the peribrachial nuclei and the latero-dorsal and pedunculo-pontine tegmental nuclei. However, both control and active sleep-carbachol cats exhibited a similar number of catecholaminergic and cholinergic neurons in those regions that expressed Fos (i.e., double-labeled cells). A large number of c-fos-expressing neurons in the active sleep-carbachol cats whose neurotransmitter phenotype was not identified suggests that non-catecholaminergic, non-cholinergic neuronal populations in mesopontine regions are involved in the generation and maintenance of active sleep. The lack of increased c-fos expression in catecholaminergic neurons during active sleep-carbachol confirms and extends previous data that indicate that these cells are silent during active sleep-carbachol and naturally-occurring active sleep. The finding that cholinergic neurons of the dorsolateral pons were not activated either during wakefulness or active sleep-carbachol raises questions regarding the synaptic mechanisms of activation of these cells during these behavioral states.

Animals↗
PubMed1991

H-2 (I-A) control of the antibody repertoire to secreted antigens of Trichinella spiralis in infection and its relevance to resistance and susceptibility.

Humans infected with the parasitic nematode Trichinella spiralis vary in the specificity of their antibody responses to the antigens of the parasite. The possibility that such host variation in antigen recognition has a genetic basis was examined in infected inbred mice whose antigen recognition profiles were characterized by immunoprecipitation of biosynthetically labelled secreted materials of adult parasites and SDS-PAGE. The strains varied considerably in repertoire and none produced detectable antibody to all the potential antigens. Using a panel of H-2 congenic and recombinant strains it was established that the repertoire was determined by the major histocompatibility complex (MHC), the I-A region in particular. Other factors, such as level of infection and variation between individuals, affected antigen recognition profiles, but this was always within limits imposed by the MHC. Lastly, an attempt to correlate antibody repertoire with relative susceptibility or resistance to T. spiralis failed to reveal any clear association. This also applied to the AKR/J and AKR-Fv-1b strains, which are H-2-identical but differ in a non-MHC susceptibility locus. These findings would argue, therefore, that the I-A region controls the antibody repertoire in this nematode infection but that the repertoire overall has little influence on the efficiency with which the infections are controlled by the immune system. Should this also apply for other nematode infections, then antigen recognition profiles of infected individual humans and domestic animals might not, therefore, be useful indicators of relative resistance or susceptibility to infection.

Animals↗