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PubMed1986

Conservation and diversity in the class I genes of the major histocompatibility complex: sequence analysis of a Tlab gene and comparison with a Tlac gene.

The thymus leukemia (TL) antigens, encoded by class I genes in the Tla subregion of the major histocompatibility complex (MHC), are cell surface molecules expressed on thymocytes of certain strains of mice and on certain T-cell leukemias. In order to study the fine structure and interrelationships of genes of the Tla subregion, a Tla-specific probe was isolated from the TL-encoding T13c gene of BALB/c mice (Tlac haplotype). The probe hybridized with two Tla genes in the Tlac haplotype (T13c and T3c) and with only one in the Tlab haplotype (T3b). Examination of this subset of Tla genes (T3b, T3c, and T13c) by restriction enzyme analysis and oligonucleotide hybridization studies confirmed that T3b is the allele of T3c and that T3c and T13c may have arisen by duplication. The T3b gene, while not transcribed in the tissues of the TL- strain C57BL6, was shown to be transcriptionally active in the TL-expressing leukemic cell line ERLD derived from that strain. The T3b gene was cloned and its complete DNA sequence was determined. These data permit complete comparison of two Tla-region genes, T3b and its homologue T13c, and allow us to conclude that these genes show extraordinarily high sequence conservation, in contrast to alleles of the H-2K- and H-2D-region genes. Comparison of T3b with other class I sequences in the H-2 and Qa subregions suggests that the T3-subset genes are the most divergent from other class I genes.

Alleles↗
PubMed1991

Analysis of the tdh gene cloned from a tdh gene- and trh gene-positive strain of Vibrio parahaemolyticus.

A variant of the gene (tdh) encoding thermostable direct hemolysin (TDH) was cloned from the chromosome of Vibrio parahaemolyticus AQ3860, which gave positive results in the hybridization tests with the tdh gene probe and the trh (tdh-related hemolysin) gene probe and showed a low level of reaction in an enzyme-linked immunosorbent assay for TDH. Nucleotide sequence analysis of the cloned gene (tdh5) provided no evidence that tdh5 is evolutionally closer to the trh gene than the other tdh genes. The tdh5 gene was flanked by 40 base-pair sequences constituting perfect inverted repeats, which may suggest association of the tdh5 gene with insertion sequence-like structure. These results suggest that the tdh5 gene and the trh gene were not originally produced by gene duplication in AQ3860 but rather that one of the two genes moved into AQ3860 from an external source.

Animals↗
PubMed1999

Cloning and sequencing of the genes downstream of the wbf gene cluster of Vibrio cholerae serogroup O139 and analysis of the junction genes in other serogroups.

The DNA sequence of the O-antigen biosynthesis cluster (wbf) of a recently emergent pathogen, Vibrio cholerae serogroup O139, has been determined. Here we report the sequence of the genes downstream of the O139 wbfX gene and analysis of the genes flanking the wbf gene cluster in other serogroups. The gene downstream of wbfX, designated rjg (right junction gene), is predicted to be not required for O-antigen biosynthesis but appears to be a hot spot for DNA rearrangements. Several variants of the rjg gene (three different insertions and a deletion) have been found in other serogroups. DNA dot blot analysis of 106 V. cholerae strains showed the presence of the left and right junction genes, gmhD and rjg, respectively, in all strains. Further, these genes mapped to a single I-CeuI fragment in all 21 strains analyzed by pulsed-field gel electrophoresis, indicating a close linkage. The insertion sequence element IS1358, found in both O1 and O139 wb* regions, is present in 61% of the strains tested; interestingly, where present, it is predominantly linked to the wb* region. These results indicated a cassette-like organization of the wb* region, with the conserved genes (gmhD and rjg) flanking the divergent, serogroup-specific wb* genes and IS1358. A similar organization of the wb* region in other serogroups raises the possibility of the emergence of new pathogens by homologous recombination via the junction genes.

Amino Acid Sequence↗
PubMed1986

Rearrangement and expression of T-cell antigen receptor genes in human T-lymphocyte tumor lines and normal human T-cell clones: evidence for allelic exclusion of Ti beta gene expression and preferential use of a J beta 2 gene segment.

The gene encoding the beta chain of the human T-cell receptor for antigen is composed of variable (V), diversity (D), joining (J), and constant (C) gene segments which undergo specific rearrangements during T-lymphocyte ontogeny. Southern blot analyses of seven human T-cell tumor lines and normal human T-lymphocyte clones revealed that most of these T-cell lines rearrange their Ti beta genes differently. The T-cell tumor line HPB-MLT rearranges and transcribes both of its Ti beta genes. Cloning and sequencing of the Ti beta cDNAs corresponding to these rearrangements revealed that one of the rearranged Ti beta genes is defective, while the other is functional and corresponds to the Ti beta protein expressed on the surface of these cells. Thus, this cell line displays a pattern of allelic exclusion of Ti beta gene expression. A comparison of four C beta 2-containing Ti beta cDNAs from three different cell lines revealed that three of the four utilize the same J beta 2.5 gene segment joined to different D beta and V beta genes, suggesting that there may be preferential use of this J gene during J beta 2 rearrangements. Hybridization analyses with probes for the alpha and beta genes of the T-cell receptor and the T-cell-specific T gamma gene revealed that HPB-MLT cells appear to express approximately equivalent amounts of RNA corresponding to each of the rearranged Ti alpha and Ti beta genes. However, they express a much lower level of T gamma RNA.

Alleles↗
PubMed1993

Gene transfer of herpes simplex virus type I thymidine kinase gene as a drug sensitivity gene into human lung cancer cell lines using retroviral vectors.

One of the recent strategies for gene therapy as a cancer control is the targeted introduction of a drug-sensitivity gene into tumor cells. We investigated the gene transfer of herpes simplex virus type I thymidine kinase (HSV-TK) gene as a drug-sensitivity gene into human lung cancer cell lines. We used a recombinant retroviral vector derived from Moloney murine leukemia virus (MuLV) as one of potential vectors for gene therapy. The amphotropic retroviral vector consisted of the HSV-TK gene and the neomycin-resistant gene under Rous sarcoma virus (RSV) promoter control. The antiherpes drugs, acyclovir (ACV) and ganciclovir (GCV), were chosen for testing the activity of HSV-TK that was transferred into human lung cancer cell lines. ACV and GCV are nucleoside analogs specifically converted by HSV-TK to a toxic form capable of inhibiting DNA synthesis. The cytotoxicity was determined by using a tetrazolium-based colorimetric assay (MTT assay). The results obtained from our experiments demonstrated that the retroviral vector-mediated HSV-TK gene transfer leads to ACV- and GCV-dependent cytotoxicity in human lung cancer cell lines, which were both small cell carcinoma and non-small cell carcinoma established from human specimens. These findings suggest that the gene transfer of HSV-TK gene into tumor cells would be one of the models for the use of gene therapy to control lung cancer.

Drug Resistance, Microbial↗
PubMed2002

[Genetic variations in plasminogen activator inhibitor-1 gene and beta fibrinogen gene associated with glomerular microthrombosis in lupus nephritis and the gene dosage effect].

OBJECTIVE: To explore the relationship of plasminogen activator inhibitor-1 (PAI-1) gene -675 4G/5G and beta fibrinogen gene -455 G/A variations to glomerular microthrombosis(T) in lupus nephritis(LN). METHODS: One hundred and one patients with biopsy proven LN were divided into two groups according to the presence or absence of glomerular microthrombus, i.e. group LN+T(n=46) and group LN-T(n=55). The genotypes of PAI-1 gene and beta fibrinogen gene were profiled by polymerase chain reaction-sequence length polymorphism (PCR-SLP) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) respectively. Clinical baseline data at the time of renal biopsy were collected. Normal controls consisted of 128 unrelated healthy adults. The etiologic fractions (EF) were calculated for estimating the contribution of risk genotypes of the two candidate genes to an increase in susceptibility to glomerular microthrombosis in LN patients. RESULTS: Both the 4G/4G genotype and the 4G allele of PAI-1 gene occurred more frequently in group LN+T (47.83% and 0.685) than in group LN-T (23.64% and 0.507)(P<0.05) and normal controls (28.13% and 0.570) (P<0.05). The PAI-1 4G/4G genotype was significantly associated with microthrombosis (OR=2.96, 95%CI:1.26-6.92). Besides, the prevalence of the genotypes carrying the A allele of beta fibrinogen gene, i.e. G/A and A/A, as well as the prevalence of the A allele per se, was increased in group LN+T (47.83% and 0.261) versus group LN-T (27.27% and 0.145)(P<0.05). LN patients carrying the A allele had a high risk of glomerular thrombosis(OR=2.44, 95%CI:0.98-5.59). In addition, the presence of the PAI-1 4G/4G genotype together with the A allele of the beta fibrinogen gene was found to be a greater risk factor (OR=4.5, 95%CI: 1.34-15.12) for glomerular thrombosis in LN than the 4G/4G genotype or the A allele alone. The pooled EF (45.98%) for the risk genotypes of both PAI-1 gene and beta fibrinogen gene was also higher than that for the risk genotypes of either gene (31.67% and 28.23%). CONCLUSION: The above findings indicated that genetic variations in PAI-1 and beta fibrinogen loci might represent risk factors for glomerular microthrombosis in LN. They may have synergetic impact and present gene dosage effect on the susceptibility to this pathological subphenotype.

Adolescent↗
PubMed2004

DBRF-MEGN method: an algorithm for deducing minimum equivalent gene networks from large-scale gene expression profiles of gene deletion mutants.

MOTIVATION: Large-scale gene expression profiles measured in gene deletion mutants are invaluable sources for identifying gene regulatory networks. Signed directed graph (SDG) is the most common representation of gene networks in genetics and cell biology. However, no practical procedure that deduces SDGs consistent with such profiles has been developed. RESULTS: We developed the DBRF-MEGN (difference-based regulation finding-minimum equivalent gene network) method in which an algorithm deduces the most parsimonious SDGs consistent with expression profiles of gene deletion mutants. Positive (or negative) directed edges representing positive (or negative) gene regulations are deduced by comparing the gene expression level between the wild-type and mutant. The most parsimonious SDGs are deduced using graph theoretical procedures. Compensation for excess removal of edges by restoring a minimum number of edges makes the method applicable to cyclic gene networks. Use of independent groups of edges greatly reduces the computational cost, thus making the method applicable to large-scale expression profiles. We confirmed the applicability of our method by applying it to the gene expression profiles of 265 Saccharomyces cerevisiae deletion mutants, and we confirmed our method's validity by comparing the pheromone response pathway, general amino acid control system, and copper and iron homeostasis system deduced by our method with those reported in the literature. Interpretation of the gene network deduced from the S. cerevisiae expression profiles by using our method led to the prediction of 132 transcriptional targets and modulators of transcriptional activity of 18 transcriptional regulators. AVAILABILITY: The software is available on request.

Algorithms↗
PubMed2001

Two C or not two C: recurrent disruption of Zn-ribbons, gene duplication, lineage-specific gene loss, and horizontal gene transfer in evolution of bacterial ribosomal proteins.

BACKGROUND: Ribosomal proteins are encoded in all genomes of cellular life forms and are, generally, well conserved during evolution. In prokaryotes, the genes for most ribosomal proteins are clustered in several highly conserved operons, which ensures efficient co-regulation of their expression. Duplications of ribosomal-protein genes are infrequent, and given their coordinated expression and functioning, it is generally assumed that ribosomal-protein genes are unlikely to undergo horizontal transfer. However, with the accumulation of numerous complete genome sequences of prokaryotes, several paralogous pairs of ribosomal protein genes have been identified. Here we analyze all such cases and attempt to reconstruct the evolutionary history of these ribosomal proteins. RESULTS: Complete bacterial genomes were searched for duplications of ribosomal proteins. Ribosomal proteins L36, L33, L31, S14 are each duplicated in several bacterial genomes and ribosomal proteins L11, L28, L7/L12, S1, S15, S18 are so far duplicated in only one genome each. Sequence analysis of the four ribosomal proteins, for which paralogs were detected in several genomes, two of the ribosomal proteins duplicated in one genome (L28 and S18), and the ribosomal protein L32 showed that each of them comes in two distinct versions. One form contains a predicted metal-binding Zn-ribbon that consists of four conserved cysteines (in some cases replaced by histidines), whereas, in the second form, these metal-chelating residues are completely or partially replaced. Typically, genomes containing paralogous genes for these ribosomal proteins encode both versions, designated C+ and C-, respectively. Analysis of phylogenetic trees for these seven ribosomal proteins, combined with comparison of genomic contexts for the respective genes, indicates that in most, if not all cases, their evolution involved a duplication of the ancestral C+ form early in bacterial evolution, with subsequent alternative loss of the C+ and C- forms in different lineages. Additionally, evidence was obtained for a role of horizontal gene transfer in the evolution of these ribosomal proteins, with multiple cases of gene displacement 'in situ', that is, without a change of the gene order in the recipient genome. CONCLUSIONS: A more complex picture of evolution of bacterial ribosomal proteins than previously suspected is emerging from these results, with major contributions of lineage-specific gene loss and horizontal gene transfer. The recurrent theme of emergence and disruption of Zn-ribbons in bacterial ribosomal proteins awaits a functional interpretation.

Bacterial Proteins↗
PubMed2003

The Caenorhabditis elegans spalt-like gene sem-4 restricts touch cell fate by repressing the selector Hox gene egl-5 and the effector gene mec-3.

Members of the spalt (sal) gene family encode zinc-finger proteins that are putative tumor suppressors and regulate anteroposterior (AP) patterning, cellular identity, and, possibly, cell cycle progression. The mechanism through which sal genes carry out these functions is unclear. The Caenorhabditis elegans sal gene sem-4 controls the fate of several different cell types, including neurons, muscle and hypodermis. Mutation of sem-4 transforms particular tail neurons into touch-neuron-like cells. In wild-type C. elegans, six touch receptor neurons mediate the response of the worm to gentle touch. All six touch neurons normally express the LIM homeobox gene mec-3. A subset, the two PLM cells, also express the Hox gene egl-5, an Abdominal-B homolog, which we find is required for correct mec-3 expression in these cells. The abnormal touch-neuron-like-cells in sem-4 animals express mec-3; we show that a subset also express egl-5. We report: (1) that ectopic expression of sem-4 in normal touch cells represses mec-3 expression and reduces touch cell function; (2) that egl-5 expression is required for both the fate of normal PLM touch neurons in wild-type animals and the fate of a subset of abnormal touch neurons in sem-4 animals, and (3) that SEM-4 specifically binds a shared motif in the mec-3 and egl-5 promoters that mediates repression of these genes in cells in the tail. We conclude that sem-4 represses egl-5 and mec-3 through direct interaction with regulatory sequences in the promoters of these genes, that sem-4 indirectly modulates mec-3 expression through its repression of egl-5 and that this negative regulation is required for proper determination of neuronal fates. We suggest that the mechanism and targets of regulation by sem-4 are conserved throughout the sal gene family: other sal genes might regulate patterning and cellular identity through direct repression of Hox selector genes and effector genes.

Animals↗
PubMed2004

Linkage of the beta-like omega-globin gene to alpha-like globin genes in an Australian marsupial supports the chromosome duplication model for separation of globin gene clusters.

The structure, function, and evolutionary history of globin genes have been the subject of extensive investigation over a period of more than 40 years, yet new globin genes with highly specialized functions are still being discovered and much remains uncertain about their evolutionary history. Here we investigate the molecular evolution of the beta-globin gene family in a marsupial species, the tammar wallaby, Macropus eugenii. We report the complete DNA sequences of two beta-like globin genes and show by phylogenetic analyses that one of these genes is orthologous to embryonically expressed epsilon-globin genes of marsupials and eutherians and the other is orthologous to adult expressed beta-globin genes of marsupials and eutherians. We show that the tammar wallaby contains a third functional beta-like globin gene, omega-globin, which forms part of the alpha-globin gene cluster. The position of omega-globin on the 3' side of the alpha-globin cluster and its ancient phylogenetic history fit the criteria, originally proposed by Jeffreys et al. (1980), of a "fossil" beta-globin gene and suggest that an ancient chromosome or genome duplication preceded the evolution of unlinked clusters of alpha- and beta-globin genes in mammals and avians. In eutherian mammals, such as humans and mice, omega-globin has been silenced or translocated away from the alpha-globin locus, while in marsupials omega-globin is coordinately expressed with the adult alpha-globin gene just prior to birth to produce a functional hemoglobin (alpha2 omega2).

Amino Acid Sequence↗
PubMed2005

Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.

Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis--with the pedigree disequilibrium test and the family-based association test--and for genotypic and haplotypic association analysis--with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.

Autistic Disorder↗
PubMed1996

Regulatable promoters for use in gene therapy applications: modification of the 5'-flanking region of the CFTR gene with multiple cAMP response elements to support basal, low-level gene expression that can be upregulated by exogenous agents that raise intracellular levels of cAMP.

This study focuses on the design, construction, and evaluation of a chimeric promoter for gene therapy applications where it is desirable to have low-level basal expression of the newly transferred gene, which can be induced to higher levels of expression by the administration of pharmacologic agents that can be safely used locally and/or systemically in humans. To achieve this, a chimeric promoter was constructed using fragments of the 5'-flanking region of the human cystic fibrosis transmembrane conductance regulator (CFTR) gene, and multiple tandem repeats of the consensus sequence and flanking elements of the cAMP response element (CRE), promoter sequences that support increased transcription in response to elevations in intracellular cAMP levels. Preliminary studies using plasmid vectors demonstrated that: (i) the 5'-flanking sequences from the CFTR gene have low promoter activity in the human airway epithelial cell lines; (ii) chimeras using -718 bp fragment from the 5'-flanking sequence of CFTR gene as the base, with the addition of 4-10 units of a 25-bp sequence containing the CRE consensus sequence, were all inducible by a rise in intracellular cAMP, with the chimera having eight CRE repeats the most responsive; and (iii) a CF126(CRE8) chjimera, consisting of the -126 bp fragment from the 5'-flanking region of CFTR gene together with eight CRE repeats, yielded low-level basal activity but maximal upregulation by cAMP, resulting in expression of the reporter gene that was 51-58% of an RSV-LTR control. On the basis of these observations, replication-deficient adenoviral vectors containing the CF126(CRE8) chimera and the luciferase reporter gene [AdCF126(CRE8).Luc] or the Escherichia coli lacZ (beta-Gal) reporter gene [AdCF126(CRE8). beta gal] were constructed. In several human airway epithelial cell lines, the AdCF126 (CRE). Luc vector provided low basal activity, but was significantly upregulated by agents that increase cAMP levels. Intranasal administration of the beta-Gal-expressing AdCF126(CRE8) beta gal vector into C57B1/6 mice demonstrated cAMP-induced upregulation of the reporter gene in airway epithelial cells. Quantification of the inducibility of the basal promoter activity in the airway epithelium using the AdCF126(CRE8). Luc vector demonstrated an 11-fold upregulation of the basal promoter activity in the lung with the administration of a phosphodiesterase inhibitor and a cAMP analog. These observations demonstrate the feasibility of using a chimeric promoter comprised of a minimal fragment of the CFTR 5'-flanking region, together with added multiple CRE, to control genes delivered in vivo. Importantly, because there are many drugs used in humans that raise cAMP, the concept of using a cAMP-regulatable promoter may also be a useful approach to enhance the safety, efficacy, and feasibility of a variety of human gene therapy strategies.

Animals↗
PubMed1993

Chromosomal assignment of human and rat hypertension candidate genes: type 1 angiotensin II receptor genes and the SA gene.

OBJECTIVE: The chromosomal location of candidate genes for a disease, especially if the disease is multifactorial, is an important datum. The objective of the present study was to determine the chromosomal location of candidate hypertensinogenic genes, both in humans and in the rat, a species widely used for animal models of human hypertension. The type 1 angiotensin II receptor (AT1) genes are obvious hypertension candidate genes, whereas the SA gene has recently been shown to cosegregate with hypertension in the rat. DESIGN: The chromosomal location of the relevant genes was determined using somatic cell hybrids segregating either human chromosomes or rat chromosomes. The presence of the human or rat genes was determined by the Southern blot method, using rat probes. RESULTS: A single AT1 gene (AT1) was detected in the human genome, and was assigned to chromosome 3, whereas two non-syntenic genes were detected in the rat genome, corresponding to the previously identified A and B subtypes. They were assigned to the rat chromosome 17 (At1a) and 2 (AT1b). The Sa gene was assigned to human chromosome 16 and rat chromosome 1, disclosing a new synteny group retained on rat chromosome 1 and human chromosome 16. CONCLUSIONS: These chromosomal assignments should be useful for linkage analyses of genes controlling blood pressure. The genes that we studied, and the chromosomes that we identified, deserve special attention in such linkage analyses.

Angiotensin II↗
PubMed2004

Experimental gene therapy using p21Waf1 gene for esophageal squamous cell carcinoma by gene gun technology.

In our previous study, the proliferation rate of esophageal squamous cell carcinoma cell lines, which poorly expressed p21Waf1, was found to be regulated by p21Waf1 gene transfection using adenovirus vector. In the present study, in order to examine the effect of p21Waf1 gene therapy in esophageal cancer, we used gene gun technology, which proved to be a powerful method to introduce the p21Waf1 gene into esophageal cancer cells. p21Waf1 transfection to KE3 and YES2 cells (weakly expressed p21Waf1 protein cells) showed a high expression of p21Waf1 protein after applying this gene gun technique. In KE3 and YES2 cells, statistical significant growth inhibition was observed after p21Waf1 transfection compared with LacZ transfection (KE3, p=0.0009; YES2, p<0.0001). In in vivo transfection experiments, on day 14, the estimated volume of KE3 tumors subjected to p21Waf1 gene transfection was 95% in comparison with the pretreatment volume on day 0, while the volume of KE3 tumors subjected to LacZ gene therapy increased to 268%. On day 14, the estimated volume of YES2 tumors subjected to either p21Waf1 or LacZ gene therapy increased to 474 and 686%, respectively. In KE3 and YES2 cells, significant growth inhibition was observed after combination therapy using p21Waf1 transfection and anticancer drug 5-fluorouracil (5Fu) compared with 5Fu alone (KE3, p<0.0001; YES2, p<0.0001). In conclusion, p21Waf1 gene therapy using the gene gun technique significantly inhibited the low basal p21Waf1 expressed esophageal cancer cell growth in vitro and in vivo. Furthermore, p21Waf1 transfection strongly enhanced the effect of 5Fu suggesting that p21Waf1 may prove beneficial in chemotherapy combined with gene therapy using gene gun technology in patients with esophageal cancer who have a low level of p21Waf1 expressed tumor.

Animals↗
PubMed1984

The nucleotide sequence of the murine I-E beta b immune response gene: evidence for gene conversion events in class II genes of the major histocompatibility complex.

We have determined the DNA sequence of the murine I-E beta b immune response gene of the major histocompatibility complex (MHC) of the C57BL/10 mouse and compared it with the sequence of allelic I-E and non-allelic I-A genes from the d and k haplotypes. The polymorphic exon sequences which encode the first extracellular globular domain of the E beta domain show approximately 8% nucleotide substitutions between the E beta b and E beta d alleles compared with only approximately 2% substitutions for the intron sequences. This suggests that an active mechanism such as micro gene conversion events drive the accumulation of these mutations in the polymorphic exons. The fact that several of the nucleotide changes are clustered supports this hypothesis. The E beta b and E beta k genes show approximately 2-fold fewer nucleotide substitutions than the E beta d/E beta b pair. The A beta bm12, a mutant I-A beta b gene from the C57BL/6 mouse, has been shown to result from three nucleotide changes clustered in a short region of the beta 1 domain, which suggests that a micro gene conversion event caused this mutation. We show here that the E beta b gene is identical to the non-allelic A beta bm12 DNA sequence in the mutated region and suggest, therefore, that the E beta b gene was the donor sequence for this intergenic transfer of genetic information. Diversity in class II MHC genes appears therefore to be generated, at least in part, by the same mechanism proposed for class I genes: intergenic transfer of short DNA regions between non-allelic genes.

Alleles↗
PubMed1984

The Eb beta gene may have acted as the donor gene in a gene conversion-like event generating the Abm 12 beta mutant.

At least two different class II histocompatibility antigens, I-A and I-E, are encoded by the murine major histocompatibility complex. Both types of class II antigens are composed of polypeptide chains called alpha and beta. Class II antigens display extensive genetic polymorphism, the main part of which resides in the NH2-terminal domains of the A alpha, A beta and E beta chains. Recently it was shown that the mutant gene Abm 12 beta differed from the wild-type gene Ab beta by three nucleotide substitutions, which all occur within a stretch of 14 nucleotides. Multiple substitutions of the type found in the Abm 12 beta gene suggest that the mutant arose by a gene conversion-like event. To examine whether the Eb beta gene may have served as the donor gene in the generation of the Abm 12 beta gene, we have isolated and sequenced a cDNA clone corresponding to the Eb beta gene. Comparisons of the Eb beta, the Ab beta and the Abm 12 beta nucleotide sequences revealed that the Eb beta sequence is identical to that of Abm 12 beta in the positions where the latter differs from the Ab beta sequence. This observation is consistent with the notion that the Abm 12 beta mutant gene arose by a gene conversion-like event involving the Eb beta gene.

Alleles↗
PubMed1999

Human ovalbumin serpin evolution: phylogenic analysis, gene organization, and identification of new PI8-related genes suggest that two interchromosomal and several intrachromosomal duplications generated the gene clusters at 18q21-q23 and 6p25.

The human ovalbumin (ov) serpins are associated with tumorigenesis, inflammation, and protection from autolysis by granule proteinases. Their genes are located at 18q21 or 6p25, falling into two structurally very similar but distinct categories depending on the presence or absence of a particular exon. Analysis of ov-serpin gene structure provides an opportunity to elucidate the mechanisms contributing to the formation of the larger serpin gene superfamily. Here we have identified a new gene (PI8L1) at 6p25 that is 72% identical to the 18q21 gene PI8. FISH analysis using the 3' untranslated region of PI8 yielded an additional signal at 18q23, separable from the known 18q21.3 signal by the t(1;18)(p32;q23) chromosomal translocation. The presence of more than one PI8-related gene was confirmed by analysis of human genomic DNA using the same probe. Cloning and analysis of PI8 showed that its intron number and phasing are identical to those of the 6p25 genes PI6, PI9, and ELANH2, and it lacks the interhelical variable loop exon found in other 18q21 genes. PCR analysis demonstrated that PI5 at 18q21 also lacks this exon, indicating that it is organized identically to the 6p25 genes. By contrast, PI10 and megsin have this exon and resemble the other 18q21 genes, PLANH2, SCCA-1, and SCCA-2, in structure. Using these data with an ov-serpin phylogenic tree we have constructed, we propose that the ov-serpin gene clusters arose via interchromosomal duplication of PI5 (or a precursor) to 6p25, followed by duplication at 6p25, and a more recent interchromosomal duplication from 6p25 to 18q to yield PI8.

3' Untranslated Regions↗
PubMed1993

The pea late nodulin gene PsNOD6 is homologous to the early nodulin genes PsENOD3/14 and is expressed after the leghaemoglobin genes.

The pea late nodulin gene PsNOD6 has been cloned and sequenced. PsNOD6 is homologous to the pea early nodulin genes PsNOD3 and PsENOD14. In situ hybridization experiments showed that, like the PsENOD3 and PsENOD14 genes, the PsNOD6 gene is only expressed in the infected cell type. The PsNOD6 gene is first expressed at the transition of the pre-fixation zone II into the interzone II-III (the amyloplast-rich zone preceding the fixation zone III), whereas the early nodulin genes PsENOD3 and PsENOD14 are already induced in the pre-fixation zone II. Thus these nodulin genes encoding homologous proteins are induced at consecutive stages of nodule development. The expression of the late nodulin genes encoding leghaemoglobin precedes the expression of the late nodulin gene PsNOD6. Therefore these late nodulin genes have to be regulated by different mechanisms despite the fact they are expressed in the same cell type. This conclusion is consistent with the fact that PsNOD6 lacks one of the conserved regions occurring in the promoters of all other late nodulin genes studied.

Amino Acid Sequence↗