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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↗
PubMed1987

A chromosomal breakpoint that separates the esterase D and retinoblastoma predisposition loci in a patient with del(13)(q14q31).

A patient with severe mental retardation and other congenital abnormalities who developed retinoblastoma was shown to have a deletion on the long arm of chromosome #13 with breakpoints in regions q14 and q31. Quantitation of enzyme activity of the esterase-D gene which, together with the retinoblastoma locus, is located in region 13q14 showed levels that were equal to those of normal controls. The 13q14 breakpoint, therefore, appears to have occurred between the two loci, which places the esterase D gene in a more proximal position in this band than the retinoblastoma locus.

Carboxylesterase↗
PubMed1993

Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli.

A 7.8-kbp fragment of chromosomal DNA from a region controlling multiple antibiotic resistance (Mar) in Escherichia coli has been sequenced. Within the fragment is a potential divergent promoter region including marO, which contains two pairs of direct repeats, suggesting possible operator-regulatory sites. To the left of marO (region I) are one or two transcriptional units with three putative open reading frames (ORFs) encoding 64, 157, and 70 amino acids. To the right (region II) is a transcriptional unit containing three putative ORFs (ORF125/144, ORF129, and ORF72). Of six independent Mar mutants, four had mutations within the ORF encoding the first putative protein (ORF125/144) downstream of marO, including three different single-point mutations and an IS2 insertion. One of the other mutations occurred in marO (20-bp duplication), and the other occurred in a site in marO or ORF144 (a 1-bp change). All six mutations led to increased transcription of the region II transcript. High-copy-number plasmids containing marO and the adjacent ORF125/144 region from a wild-type source but not from a Mar mutant reduced the antibiotic resistance of a Mar mutant to levels comparable to those of wild-type cells. High-copy-number plasmids containing wild-type marO alone caused an increase in resistance to tetracycline, chloramphenicol, and norfloxacin in a wild-type strain. The nature of the Mar mutations and the results of the complementation studies suggest that ORF125/144 encodes a repressor (designated MarR) which acts at marO. The second ORF (ORF129), designated marA, would encode a protein, MarA, whose sequence shows strong similarity to those of a family of positive transcriptional regulators. A Tn5 insertion in marA inactivated the multiresistance phenotype of Mar mutants. The function of ORF72, designated marB, encoding the third putative protein in the operon, and that of other ORFs detected within the 7.8-kb fragment have not yet been determined.

Amino Acid Sequence↗
PubMed1998

The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines.

Methylation of CpG sites in the control regions of tumor suppressor genes may be an important mechanism for their heritable, yet reversible, transcriptional inactivation. These changes in methylation may impair the proper expression and/or function of cell cycle regulatory genes and confer a selective growth advantage to affected cells. Detailed methylation analysis using genomic bisulfite sequencing was performed on a series of subclones of a bladder cancer cell line in which a hypermethylated p16 gene had been reactivated by transient treatment with 5-aza-2'-deoxycytidine. Methylation of the CpG island in the promoter of the p16 gene in human bladder cancer cells did not stop the formation of a transcript initiated 20 kb upstream by the p19 promoter but did prevent the expression of a p16 transcript. Furthermore, we show that reactivant clones that expressed p16 at varying levels contained heterogeneous methylation patterns, suggesting that p16 expression can occur even in the presence of a relatively heavily methylated coding region. We also present the first functional evidence that methylation of only a small number of CpG sites can significantly down-regulate p16 promoter activity, thus providing support for the model of progressive inactivation of this tumor suppressor gene by DNA methylation.

Azacitidine↗
PubMed1980

Duplicated genes producing transposable controlling elements for the mating-type differentiation in Saccharomyces cerevisiae.

Mutation of the two homothallic genes, HML alpha/HMLa and HMRa/HMR alpha, in homothallic strains of Saccharomyces cerevisiae was studied. Of 11 mutants of the HML alpha gene, eight were due to a phenotypic mutation from HML alpha to HMLa, i.e., a mutation causing a change in function of the original HML allele to that of the other HML allele (functional mutation), and three were due to a defective mutation at the HML alpha gene, i.e., a mutation causing a nonfunctional allele (nonfunctional mutation). All 14 mutants of the HMRa gene, on the other hand, were due to a phenotypic mutation from HMRa to HMR alpha i.e., a functional mutation. Phenotypic reverse mutations, i.e., HMLa to HML alpha and HMR alpha to HMRa, were also observed in the cultivation of EMS (ethyl methanesulfonate) treated spores having the HO HMR alpha HMLa genotype. Mutation from heterothallic cells to homothallism was observed in a nonfunctional mutant of the HML alpha gene, by mutagenesis with EMS, but not in the functional mutants of the HML alpha and HMRa genes or in the authentic strains having the alpha HO HMR alpha HML alpha (alpha Hp) and a HO HMRa HMLa (a Hq) genotypes. These observations suggest that the functional mutation is not caused by the direct mutation from a homothallic allele to the opposite, but by replacement of a transposable genic element produced from a homothallic locus with a region of a different homothallic locus. These observations also support the controlling-element model and the cassette model, which have been proposed to explain the mating-type differentiation by the homothallic genes.

DNA Transposable Elements↗
PubMed1999

[Viral infection of the central nervous system: from experimental model to human application].

The Daniel's strain of Theiler's virus, a murine picorna virus, induces a neurological disease characterized by an acute encephalomyelitis, followed by a persistent infection of the white matter. This late demyelinating disease is studied as a model for multiple sclerosis because of its chronicity and similarity to the histology of the lesions. This mouse model of viral infection allows a review of the various major aspects of the immune response to an infection of the central nervous system. The observation that inbred strains of mice differ in their susceptibility to the demyelinating disease provided the base for genetic studies that were informative for the involved functional immunological mechanisms. A locus in the H-2D region of the major histocompatibility complex was shown to control susceptibility to the persistent infection, leading to approach the key role of CTLs. Non-H-2 genes were also implicated, one of which was mapped close to the IFN-gamma locus on chromosome 10. The key role of IFN-gamma was demonstrated, and led to a further investigation of the function of the potential producers of this cytokine, namely NK, CD8+, and CD4+ Th1 cells. Finally, non-immune factors were also shown to play a role in resistance. A personal view of the antiviral immune responses emerged from this review.

Animals↗
PubMed1998

Linkage analysis of blood Plasmodium falciparum levels: interest of the 5q31-q33 chromosome region.

There is accumulating evidence for the involvement of genetic factors in the human response to malaria infection, mostly based on results obtained in studies of severe clinical malaria. The role of major gene(s) controlling blood parasitemia levels in human malaria has also been detected by means of segregation analysis. To confirm and to localize such gene(s), we performed a sib-pair linkage analysis investigating the role of five candidate chromosomal regions: 6p21 (HLA-tumor necrosis factor region), 2q13-q21 (genes coding for interleukin-1 alpha and beta), 14q11 (locus coding for the alpha chain of T cell antigen receptor), 7q35 (gene cluster for the beta subunit of T cell receptor), and 5q31-q33, which includes several candidate genes and was recently linked to a locus controlling infection levels by Schistosoma mansoni, denoted as SM1. The analysis was carried out on nine families from a southern Cameroon village, and the phenotype under study was blood infection levels with Plasmodium falciparum. No linkage was found with any of the four markers outside the 5q31-q33 region. A trend in favor of linkage was observed in the distal part of the 5q31-q33 region, especially with the marker D5S636 (P < 0.05 using the Monte Carlo P value), which was the marker that provided the highest evidence for linkage with SM1. These results suggest that a locus influencing P. falciparum levels in malaria could be located in the same genetic region as that containing SM1, indicating that the 5q31-q33 region may be critical in the control of different parasite infections.

Adolescent↗
PubMed1997

Genetic influences on sarcoidosis.

To investigate the genetic influences underlying the development of sarcoidosis, HLA class II genotyping was performed in Japanese patients with sarcoidosis and healthy controls using the PCR-RFLP method. The frequencies of both DR52 group antigen-associated alleles (HLA-DRB1*11, -DRB1*12 and -DRB1*14) and DRB1*08 alleles were higher in the patient group, suggesting that the common, specific amino acid residue on the DRB1 molecule of these alleles may determine susceptibility to sarcoidosis. Alternatively, it is possible that another susceptibility gene, linked to these DRB1 alleles, exists within the MHC region. We screened the TNFA, TNFB, HSP70-1 and Hum70t genes around the class III region, as well as the HLA-DMA and -DMB genes in the class II region, for genetic polymorphism in sarcoidosis. None of these genes suggested a susceptibility to sarcoidosis. These studies support the thesis that one of the major genetic factors controlling the development of sarcoidosis is located within the DRB1 locus in the HLA class II region.

Cytokines↗
PubMed1990

The b mating-type locus of Ustilago maydis contains variable and constant regions.

The b locus of the phytopathogenic fungus Ustilago maydis encodes a multiallelic recognition function that controls the ability of the fungus to form a dikaryon and complete the sexual stage of the life cycle. The b locus has at least 25 alleles and any combination of two different alleles, brought together by mating between haploid cells, allows the fungus to cause disease and undergo sexual development within the plant. An open reading frame of 410 amino acids has been shown to specify a polypeptide responsible for the activity of the b1 allele, and comparisons of the predicted amino acid sequences for 6 b alleles allowed identification of variable and constant regions within the coding region of the gene. Haploid strains carrying a null mutation at the b locus, created by gene disruption, are viable but fail to interact with formerly compatible strains to give an infectious dikaryon. Analysis of mutants carrying a null allele indicated that the products of different alleles of the b locus combine to form a new regulatory activity and that this activity directly or indirectly turns on the pathway leading to sexual development and pathogenesis.

Alleles↗
PubMed2001

Steroid-induced plasticity in the sexually dimorphic vasotocinergic innervation of the avian brain: behavioral implications.

Vasotocin (VT, the antidiuretic hormone of birds) is synthesized by diencephalic magnocellular neurons projecting to the neurohypophysis. In addition, in male quail and in other oscine and non-oscine birds, a sexually dimorphic group of VT-immunoreactive (ir) parvocellular neurons is located in a region homologous to the mammalian nucleus of the stria terminalis, pars medialis (BSTm) and in the medial preoptic nucleus (POM). These cells are not visible in females. VT-ir fibers are present in many diencephalic and extradiencephalic locations. Quantitative morphometric analyses demonstrate that, in quail, these elements are expressed in a sexually dimorphic manner (males>females) in regions involved in the control of different aspects of reproduction: i.e., the POM (copulatory behavior), the lateral septum (secretion of gonadotropin-releasing hormone [GnRH]), the nucleus intercollicularis (control of vocalizations), and the locus coeruleus (the main noradrenergic center of the avian brain). In many of these regions, VT-ir fibers are closely related to aromatase-ir, GnRH-ir, or estrogen receptor-expressing neurons. This dimorphism has an organizational nature: administration of estradiol-benzoate to quail embryos (a treatment that abolishes male sexual behavior) results in a dramatic decrease of the VT-immunoreactivity in all sexually dimorphic regions of the male quail brain. Conversely, the inhibition of estradiol (E2) synthesis during embryonic life (a treatment that stimulates the expression of male copulatory behavior in adult testosterone (T)-treated females) results in a male-like distribution of VT-ir cells and fibers. Castration markedly decreases the immunoreactivity in both the VT-immunopositive elements of the BSTm and the innervation of the SL and POM, whereas T-replacement therapy restores the VT immunoreactivity to a level typical of intact birds. These changes reflect modifications of VT mRNA concentrations (and probably synthesis) as demonstrated by in situ hybridization and they are paralleled by similar changes in male copulatory behavior (absent in castrated male quail, fully expressed in CX+T males). The aromatization of T into estradiol (E2) also controls VT expression and, in parallel limits the activation of male sexual behavior by T. In castrated male quail, the restoration by T of the VT immunoreactivity in POM, BSTm and lateral septum could be fully mimicked by a treatment with E2, but the androgen 5alpha-dihydrotestosterone (DHT) had absolutely no effect on the VT immunoreactivity in these conditions. At the doses used in this study, DHT also did not synergize with E2 to enhance the density of VT immunoreactive structures. Systemic or i.c.v. injections of VT markedly inhibit the expression of all aspects of male sexual behavior. VT, presumably, does not simply represent one step in the biochemical cascade of events that is induced by T in the brain and leads to the expression of male sexual behavior. Androgens and estrogens presumably affect reproductive behavior both directly, by acting on steroid-sensitive neurons in the preoptic area, and indirectly, by modulating peptidergic (specifically vasotocinergic) inputs to this and other areas. The respective contribution of these two types of actions and their interaction deserves further analysis.

Animals↗
PubMed2005

Maturation of the hypothalamic arcuate agouti-related protein system during postnatal development in the mouse.

The hypothalamic arcuate nucleus (Arc) and its neurons expressing agouti-related protein (AgRP) are key components of the forebrain circuitry involved in long-term regulation of energy homeostasis, including conveying leptin signaling to other hypothalamic and extrahypothalamic regions. In the present work, we investigated the postnatal development (P0, P5, P10, P15, and P21) of this system (AgRP transcript and peptide) in the mouse brain using in situ hybridization and immunohistochemistry. At all stages, AgRP mRNA expression was detected exclusively in the Arc. At P0, AgRP mRNA levels were low, and only a few AgRP-immunoreactive fibers were present reaching, rostrally, the bed nucleus of the stria terminalis and, caudally, the dorsal raphe nucleus. During the following period (P5-P21), the levels of AgRP mRNA gradually increased in the Arc along with a parallel increase in the AgRP fiber density in the hypothalamic regions responsible for control of appetite, including the paraventricular nucleus, as well as in extrahypothalamic regions, including locus coeruleus. These data provide evidence that, in the mouse, the maturation of the AgRP Arc system occurs mainly during the first three postnatal weeks. Together with the existing data on the physiology of appetite and body weight, our data suggest that the first three postnatal weeks in the mouse represents a critical period for the formation of brain mechanisms underlying appetite control via peripheral hormones.

Aging↗
PubMed2005

Association between the DRD2 A1 allele and opium addiction in the Iranian population.

Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of certain neuropsychiatric disorders such as drug abuse. It has been shown that the dopamine D2 receptor (DRD2) gene dysfunction is associated with multi-drug addiction. Addiction to opium is the most common form of drug abuse in Iran. We studied the allelic association between DRD2 Taq I A polymorphism in 100 opium-dependent Iranian patients and 130 unrelated controls. A 310 bp (base pair) region surrounding Taq I site at the DRD2 locus was amplified by polymerase chain reaction (PCR) and the PCR product was incubated with Taq I restriction enzyme. The A1 allele remained intact while the A2 allele was cut. Significant association was observed between A1 allele and addiction in the patients group (P < 0.0001). Moreover, the frequency of A1A1 genotype was significantly higher in opium users than controls (P < 0.0001). Our result indicates that DRD2 might be involved in the pathophysiology of opium addiction.

Adult↗
PubMed2007

Association study between the TNXB locus and schizophrenia in a Japanese population.

The chromosome 6p21-24 region, which contains the human leukocyte antigen (HLA) region, has been suggested as an important locus for a susceptibility gene for schizophrenia. Recently, a significant association between schizophrenia and the TNXB locus, located immediately telomeric of the NOTCH4 locus in the HLA region, was observed. Few studies have further investigated the region in schizophrenia. In the present study, we investigated the region in a Japanese population. Subjects included 241 patients with schizophrenia and 290 controls. Twenty-six single nucleotide polymorphisms (SNPs) and the corresponding haplotypes were analyzed. As a result, exactly the same SNPs in the TNXB locus (rs1009382 and rs204887) as in the previous study were associated with schizophrenia (P = 0.034 and 0.034, respectively, uncorrected). A SNP (rs2071287) in the NOTCH4 locus and haplotype around it were also suggested to associate with the disease, consistent with another previous study (P = 0.041 and permutation P = 0.024, respectively, uncorrected). Although these associations became insignificant after Bonferroni correction, the findings might provide support for the association of the TNXB locus or its adjacent region of the NOTCH4 locus with schizophrenia.

Adult↗
PubMed1991

The equine major plasma serpin multigene family: partial characterization including sequence of the reactive-site regions.

The equine Pi system, which is highly polymorphic and was considered to be controlled by a single locus, has been shown to be controlled by four loci (named Spi 1-4). This system is the equine equivalent of the major human plasma serpin (serine protease inhibitor), human alpha 1 PI. Twenty-two haplotypes of the equine Pi system have been characterized by two-dimensional electrophoresis, resulting in the assignment of pI, Mr, and bovine trypsin and chymotrypsin inhibition characteristics to 109 proteins. These proteins have been analyzed further to determine their relatedness to each other as well as to human alpha 1 PI using immunochemical, structural, and functional criteria. The amino acid sequences of the N termini and reactive-site regions have been determined on proteins from each of the four equine Spi loci. This allowed the designation of the proteins from the Spi 1 locus as being METserpins and the functional equivalents of human alpha 1 PI. The Spi 4 proteins are ARGserpins, and by alignment the Spi 2 proteins are ILEserpins, the first so far described. The P1 residue for the Spi 3 proteins was unable to be determined. The limited peptide and immunopeptide mapping revealed that proteins from all four loci were closely related, but within the four there were two pairs (Spi 1 and 2 and Spi 3 and 4) which were more related. All were probably derived from the same gene that gave rise to human alpha 1 PI.

Amino Acid Sequence↗
PubMed1984

The zeste-white interaction: induction and genetic analysis of a novel class of zeste alleles.

The recovery and analysis of a novel class of zeste mutations is described. z and z do not require two w genes for their expression unless the z gene is present. Analysis of genetic interactions among zeste alleles proved that z mutations are strong antagonists of the z gene product. z is readily reverted by X-rays or by ethylmethane sulphonate to a range of intermediate zeste alleles and thus it is considered to be an insertional mutation. We suggest that z and op mutations arose as a result of insertions in a presumptive control region, and two alternative models for the structure of the zeste locus are evaluated.

Journal Article↗
PubMed1999

Physical mapping of the autoimmune disease susceptibility locus, Bphs: co-localization with a cluster of genes from the TNF receptor superfamily on mouse chromosome 6.

An important approach to understanding complex diseases is to reduce them into well-characterized subphenotypes that are under monogenic control. One such example is Bordetella pertussis toxin-induced histamine sensitization in mice, a subphenotype of experimental allergic encephalomyelitis and experimental allergic orchitis. This subphenotype is controlled by a single locus, Bphs, previously mapped to a 33 cM region on mouse Chromosome (Chr) 6. We achieved considerable reduction of this candidate region and constructed a YAC contig across the refined interval. Our results demonstrate that Bphs is located between D6Mit151 and a newly developed marker, EC108RR, a region containing a small cluster of genes belonging to the TNF receptor superfamily. Sequence and quantitative analysis of the candidate gene, tumor necrosis factor receptor 1 (Tnfr1, p55), indicates that it is unlikely to be Bphs. However, the location of Bphs, together with physiologic effects it shares with Tnfr1 activation, suggest that Bphs may prove to be another member of the TNF receptor superfamily.

Animals↗
PubMed2001

Clonal maintenance of imprinted expression of SNRPN and IPW in normal lymphocytes: correlation with allele-specific methylation of SNRPN intron 1 but not intron 7.

DNA methylation is a heritable and reversible modification to CpG sites in the mammalian genome. Parental allele-specific methylation is hypothesized to be important in the establishment and maintenance of imprinted gene expression; however, dynamic changes in allele-specific patterns have been observed. The upstream regulatory region of the small nuclear riboprotein N gene (SNRPN) is an important imprinting control region (ICR) for establishing and maintaining the methylation imprint in the locus on 15q11-13 associated with Prader-Willi and Angelman syndromes (PWS). To compare directly the role of allele-specific methylation patterns and the maintenance of imprinted expression in the PWS region, clonal populations of normal T lymphocytes were cultured for 22-25 generations. A novel long-range semi-nested polymerase chain reaction (PCR) strategy was utilized in order to span two different methylation sites, and a polymorphism within SNRPN was used so that allele-specific methylation of both sites could be determined. Reverse transcription/PCR followed by polymorphism analysis was also performed in order to determine parental allele-specific transcription. Exclusive paternal expression at both SNRPN and IPW was maintained in all T cell clones and correlated with maternal methylation of the intron 1 NotI site. In contrast, biallelic methylation was observed in all clones at the previously described paternally methylated HpaII site in intron 7. These results demonstrate that the maintenance of paternal expression of SNRPN and IPW correlates with a strict clonal maintenance of allele-specific methylation at the CpG-dense 5' end of SNRPN. Differential maintenance of methylation sites within imprinted genes may depend on the density and chromatin organization of surrounding CpG sites.

Alleles↗