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Results for “gene expression variability”

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PubMed1994

Somatic diversification in the heavy chain variable region genes expressed by human autoantibodies bearing a lupus-associated nephritogenic anti-DNA idiotype.

Monoclonal anti-DNA antibodies bearing a lupus nephritis-associated idiotype were derived from five patients with systemic lupus erythematosus (SLE). Genes encoding their heavy (H)-chain variable (VH) regions were cloned and sequenced. When compared with their closest VH germ-line gene relatives, these sequences exhibit a number of silent (S) and replacement (R) substitutions. The ratios of R/S mutations were much higher in the complementarity-determining regions (CDRs) of the antibodies than in the framework regions. Molecular amplification of genomic VH genes and Southern hybridization with somatic CDR2-specific oligonucleotide probes showed that the configuration of the VH genes corresponding to VH sequences in the nephritogenic antibodies is not present in the patient's own germ-line DNA, implying that the B-cell clones underwent somatic mutation in vivo. These findings, together with the characteristics of the diversity and junctional gene elements utilized to form the antibody, indicate that these autoantibodies have been driven through somatic selection processes reminiscent of those that govern antibody responses triggered by exogenous stimuli.

Amino Acid Sequence↗
PubMed2000

Variability in gene expression patterns of Ewing tumor cell lines differing in EWS-FLI1 fusion type.

Type 1 and type 2 EWS-FLI1 fusion products result from variation in breakpoint locations arising from the t(11;22)(q24;q12) recurrent chromosomal translocation in Ewing's sarcoma family tumors (EFT). Previously, studies from our institution (updated in the present communication at a median follow-up of more than 6 years) and others suggested a prognostic difference for EFT patients with localized disease depending on the type of EWS-FLI1 fusion present in the tumor. It has been suggested that the observed clinical discrepancies result from different transactivation potentials of the various EWS-FLI1 fusion proteins. In an attempt to identify genes whose expression levels are differentially modulated by structurally different EWS-FLI1 transcription factors, we have used two related PCR-based subtractive approaches, cDNA representational difference analysis (cDNA-RDA) and linker-capture subtraction (LCS) to compare transcript representations in cDNA pools of type 1 versus type 2 EFT cell lines. About 800 clones obtained by the two approaches were analyzed by dot blot hybridization to cDNA pools. Eighty-six clones showing the highest variability in signal intensities on the dot blots were further hybridized to individual EFT cell line RNAs on Northern blots, and four of them were additionally studied by real-time quantitative PCR (RTQ-PCR). Although interindividual variations in gene expression patterns in the range of one- to several-fold were observed, no correlation to specific EWS-FLI1 fusion types could be identified. Among the genes differentially expressed in individual EFT cell lines are several previously implicated in tumor growth, invasion, and metastasis. Although our data may have revealed candidate genes whose composite expression pattern may be relevant for the biology of individual EFT, they do not support a role of distinct EWS-FLI1 fusion types for EFT prognosis based on different transactivation potentials.

Blotting, Northern↗
PubMed2006

Varicella-Zoster virus gene expression at variable periods following death in a rat model of ganglionic infection.

We used a rat model of Varicella-Zoster virus (VZV) ganglionic infection, which mirrors some of the features of VZV latency in humans, to determine the temporal pattern of expression of a VZV immediate-early gene (63) and a VZV late gene (40) at 0, 24 and 48 h after death of the animal. The immediate-early VZV gene 63 is known to be abundantly expressed during human ganglionic latency, while the late VZV gene 40 is not expressed during human latency. Using both RNA in situ hybridisation (ISH) and nested RT-PCR, it was found that at all time points in both thoracic and lumbar ganglia, the number of ganglia positive for VZV gene 63 was higher than for gene 40. The expression of gene 40 did not increase with time postmortem (pm) These results provide indirect support for the hypothesis that patterns of expression of VZV genes detected in human tissue at even 48 h pm reflect the pattern of expression during human ganglionic latency.

Animals↗
PubMed1987

Hereditary bovine syndactyly: diagnosis in bovine fetuses.

Diagnostic guidelines were established for progeny testing of hereditary bovine syndactyly. Through the use of superovulation and embryo transfer, 139 fetuses were recovered at 50 to 77 days gestation. Normal (+/+, +/sy) and syndactylous (sy/sy) anatomy of Holstein fetuses was defined, and the accuracy of macroscopic versus microscopic limb diagnosis was assessed. Chondrification and ossification differences between normal (+/+, +/sy) and syndactylous (sy/sy) fetuses were only age-related. Normal (+/+, +/sy) fetal limbs differed from normal (+/+, +/sy) adult bovine limbs in two ways. Fetal metacarpal and metatarsal III and IV bones were not fused, and fetal metacarpal and metatarsal II and V bones often extended up to three-fourths the length of metacarpal and metatarsal III and IV bones. In syndactylous (sy/sy) fetuses, synostosis asymmetries occurred within and between fetal limbs, and between fetuses, representing variable gene expressivity. Synostosis pattern within limbs did not correspond with those of the adult bovine; the second phalangeal pair was synostotic most frequently in the fetus, followed by the first, and then the third pair. Synostosis patterns between fetal limbs agreed with those of the adult; there was a right-left and front-rear limb gradient. Partial synostoses occurred sporadically in all three paired phalanges. Those of the first and third pair always involved the tip closest to the second phalangeal pair. A unique example of variable gene expressivity occurred in one syndactylous fetus. Both front limbs were syndactylous, while both rear limbs were normal grossly. Microscopically the right rear limb was normal while the left rear limb consisted of closely apposed phalangeal blastemata without coalescence.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Restricted Ig variable region gene expression among Ly-1+ B cell lymphomas.

The majority of the characterized Ly-1+ B cell lymphomas of B10.H-2aH-4bp/Wts origin (the CH series) bear surface Ig related by Ag specificity or idiotype or both. To determine the genetic basis for these structural similarities, we have sequenced the VH and VL region genes expressed by 10 CH lymphomas, and have compared their VH and V kappa gene rearrangements by Southern blot analysis to one another and to those of four other CH lymphomas. Sequence analysis identified only five different VH, and seven different VL genes, and indicated that these V genes are essentially unmutated. CH lymphomas which express the identical VH gene share at least one idiotope. Thus, the basis for shared idiotype and specificity is due in most cases to the use of the same V gene. This restriction in V gene expression is not due to the preferential use of V genes of any particular VH family or VL group, as the expressed V genes belong to four different VH families and four V kappa groups, and include V lambda 1 and V lambda 2. We hypothesize that Ag selection accounts for the restriction in V gene usage among CH lymphomas.

Animals↗
PubMed1989

Relationship of variable region genes expressed by a human B cell lymphoma secreting pathologic anti-Pr2 erythrocyte autoantibodies.

To study the biology of cold agglutinin disease we previously established EBV-transformed B cell clones isolated from a patient with splenic lymphoma of an early plasmacytic cell type and immune hemolysis due to an anti-Pr2 cold agglutinin. These clones had an aberrant chromosomal marker identical to the patient's B cell lymphoma and each secreted IgMk anti-Pr2 similar to the pathologic autoantibody in the serum of the patient. In this study, we have further investigated the Pr2-specific autoimmune response through nucleotide sequencing of VH and VL region genes. We have shown that the seven clones share the same VDJ/VJ gene segments and junctional elements confirming their clonal origin. The VH sequences were 88% homologous to a VHI germline gene while the VL sequences were 97% homologous to a VkIII germline gene. Only 4 somatic mutations (3 silent and 1 conservative) were found in greater than 5,000 bp sequenced, suggesting that a low mutation rate existed. Based on a tumor mass of 10(12) cells and a minimum of 40 divisions, we estimated the somatic mutation rate to be 4.45 x 10(-5) m/bp/d. This somatic mutation rate is similar to those estimated for acute lymphocytic leukemia (pre-B cell) and chronic lymphocytic leukemia (intermediate B cell), but significantly lower than the mutation frequency in follicular lymphomas (activated B cell). We propose that the difference in somatic mutation frequency of a B cell tumor may be related to the stage of B cell differentiation. In addition, the low mutation frequency observed in the Pr2-specific B cell tumor may also reflect, in part, selection by autoantigen to conserve sIg structure and specificity.

Agglutinins↗
PubMed2004

Genetics of atrioventricular conduction disease in humans.

Atrioventricular (AV) conduction disease (block) describes impairment of the electrical continuity between the atria and ventricles. Classification of AV block has utilized biophysical characteristics, usually the extent (first, second, or third degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is unknown. In young patients, AV block may result from injury or be the major cardiac manifestation of neuromuscular disease. However, in some cases, AV block has unknown or idiopathic cause. In such cases, familial clustering has been noted and published pedigrees show autosomal dominant inheritance; associated heart disease is common (e.g., congenital heart malformation, cardiomyopathy). The latter finding is not surprising given the common origin of working myocytes and specialized conduction system elements. Using genetic models incorporating reduced penetrance (disease absence in some individuals with disease gene), variable expressivity (individuals with disease gene have different phenotypes), and genetic heterogeneity (similar phenotypes, different genetic cause), molecular genetic causes of AV block are being identified. Mutations identified in genes with diverse functions (transcription, excitability, and energy homeostasis) for the first time provide the means to assess risk and offer insight into the molecular basis of this important clinical condition previously defined only by biophysical characteristics.

Animals↗
PubMed2004

Modeling gene expression from microarray expression data with state-space equations.

We describe a new method to model gene expression from time-course gene expression data. The modelling is in terms of state-space descriptions of linear systems. A cell can be considered to be a system where the behaviours (responses) of the cell depend completely on the current internal state plus any external inputs. The gene expression levels in the cell provide information about the behaviours of the cell. In previously proposed methods, genes were viewed as internal state variables of a cellular system and their expression levels were the values of the intemal state variables. This viewpoint has suffered from the underestimation of the model parameters. Instead, we view genes as the observation variables, whose expression values depend on the current intemal state variables and any external input. Factor analysis is used to identify the internal state variables, and Bayesian Information Criterion (BIC) is used to determine the number of the internal state variables. By building dynamic equations of the internal state variables and the relationships between the internal state variables and the observation variables (gene expression profiles), we get state-space descriptions of gene expression model. In the present method, model parameters may be unambiguously identified from time-course gene expression data. We apply the method to two time-course gene expression datasets to illustrate it.

Algorithms↗
PubMed1991

Expression of immunoglobulin genes in common variable immunodeficiency.

Five common variable immunodeficiency (CVI) patients were analyzed for expression of immunoglobulin (Ig) genes. In the pokeweed mitogen (PWM)-induced Ig-production assay, the combination of T and B cells showed that all patients' T cells had normal helper functions and all patients' B cells had profound defects. The defective B-cell maturation stages based on their Ig gene expression patterns were variable. One of five patients showed normal mu-chain gene expression and nearly normal IgM production, but neither IgG nor IgA production, which suggested that this patient's B-cell defects might lie on a mu- to gamma or mu- to alpha class-switch stage. B cells in another patient showed low mu-chain gene expression and low IgM production, but an Ig enhancer region, which is an important region for expression of Ig genes, was intact. Thus, this patient might have a transacting factor defect which interacts with the Ig enhancer region. The other three patients showed no mu-chain gene expression and no IgM production. Thus, their B-cell defects lay on the B-cell maturation stage, similar to X-linked agammaglobulinemia. These results showed that primary B-cell defects in CVI occurred at several B-cell differentiation stages, which could be recognized by expression of Ig genes.

Adult↗
PubMed1997

Maternal immunoglobulins have no effect on the rate of maturation of the B cell compartment of the offspring.

To elucidate a general role of maternal immunoglobulins (Ig) on the kinetics of B cell development of the offspring, we studied non-genetic influences of maternal Ig on the developing immune system of B cell-competent mice. These animals were the offsprings of either B cell-deprived microMT or of normal C57BL/6 females. In these mice, we have compared the kinetics of Ig production, the numbers of B cell progenitors, the expression of surface markers specific of the B lineage and the progression of Ig variable gene expression. We show that the absence of maternal Ig has no detectable effect on the kinetics of IgM and IgG production by the offspring's immune system. The number of B cell precursors, the kinetics of generation of B cells and their pattern of surface markers expression is identical in both types of mice. The acquisition of diversity in the B cell repertoire and the changes in the ratios of variable gene family expression are also indistinguishable. We conclude that maternally derived Ig has no influence on the rate of development and maturation of the B cell compartment of the offspring.

Animals↗
PubMed2006

The contributions of normal variation and genetic background to mammalian gene expression.

BACKGROUND: Qualitative and quantitative variability in gene expression represents the substrate for external conditions to exert selective pressures for natural selection. Current technologies allow for some forms of genetic variation, such as DNA mutations and polymorphisms, to be determined accurately on a comprehensive scale. Other components of variability, such as stochastic events in cellular transcriptional and translational processes, are less well characterized. Although potentially important, the relative contributions of genomic versus epigenetic and stochastic factors to variation in gene expression have not been quantified in mammalian species. RESULTS: In this study we compared microarray-based measures of hepatic transcript abundance levels within and between five different strains of Mus musculus. Within each strain 23% to 44% of all genes exhibited statistically significant differences in expression between genetically identical individuals (positive false discovery rate of 10%). Genes functionally associated with cell growth, cytokine activity, amine metabolism, and ubiquitination were enriched in this group. Genetic divergence between individuals of different strains also contributed to transcript abundance level differences, but to a lesser extent than intra-strain variation, with approximately 3% of all genes exhibiting inter-strain expression differences. CONCLUSION: These results indicate that although DNA sequence fixes boundaries for gene expression variability, there remain considerable latitudes of expression within these genome-defined limits that have the potential to influence phenotypes. The extent of normal or expected natural variability in gene expression may provide an additional level of phenotypic opportunity for natural selection.

Animals↗
PubMed1989

Trypanosoma brucei: enrichment by UV of intergenic transcripts from the variable surface glycoprotein gene expression site.

The expression site for the variable surface glycoprotein (VSG) gene AnTat 1.3A of Trypanosoma brucei is 45 kilobases long and encompasses seven expression site-associated genes (ESAGs) (E. Pays, P. Tebabi, A. Pays, H. Coquelet, P. Revelard, D. Salmon, and M. Steinert, Cell 57:835-845, 1989). After UV irradiation, several large transcripts from the putative promoter region were strongly enriched. We report that one such major transcript starts near the poly(A) addition site of the first gene (ESAG 7), spans the intergenic region, and extends to the poly(A) addition site of the second gene (ESAG 6), thus bypassing the normal 3' splice site of the ESAG 6 mRNA. Since this transcript is spliced, we conclude that UV irradiation does not inhibit splicing but stabilizes unstable processing products. This demonstrates that at least some intergenic regions of the VSG gene expression site are continuously transcribed in accordance with a polycistronic transcription model.

Animals↗
PubMed1989

Trypanosoma brucei: posttranscriptional control of the variable surface glycoprotein gene expression site.

The arrest of variable surface glycoprotein (VSG) synthesis is one of the first events accompanying the differentiation of Trypanosoma brucei bloodstream forms into procyclic forms, which are characteristic of the insect vector. This is because of a very fast inhibition of VSG gene transcription which occurs as soon as the temperature is lowered. We report that this effect is probably not controlled at the level of transcription initiation, since the beginning of the VSG gene expression site, about 45 kilobases upstream from the antigen gene, remains transcribed in procyclic forms. The permanent activity of the promoter readily accounts for the systematic reappearance, upon return to the bloodstream form after cyclical transmission, of the antigen type present before passage to the tsetse fly. The abortive transcription of the VSG gene expression site appears linked to RNA processing abnormalities. Such posttranscriptional controls may allow the modulation of gene expression in a genome organized in large multigenic transcription units.

Animals↗
PubMedDate not supplied

Transcriptomic characterization of four classes of cell-cell/cell-matrix genes in brains and hearts of wild type and connexin43 null mice.

We have used a highly quantifiable cDNA microarray method to determine the stabilities and expression levels within gene families involved in cell-cell and cell-matrix interactions in neonatal mouse brain and heart. In addition, we have characterized the extent to which deletion of the gap junction protein connexin43 (Cx43) affects these characteristics. Our observations for individual genes revealed a range of differences and variabilities in transcription level among family members; calculation of the genomic patholog (a global measure of gene expression alteration) indicates that these cell interaction genes contribute disproportionately to the overall phenotype. We found significant transcriptomic differences between brain and heart, that deletion of Cx43 considerably decreased gene expression variability and that the average contribution to the pathology of the genes whose encoded proteins are involved in cell-cell or cell-matrix interaction in the Cx43-null mice was about twenty times higher than that of other genes. These findings indicate that gap junction gene expression influences the expression of other genes involved in intercellular and cell-substrate interaction and that expression of these genes is under strong regulatory pressure in the Cx43-null mouse, presumably representing a compensatory response to Cx43 deletion.

Animals↗
PubMed1995

Quantification of cytokine mRNA expression by RT-PCR and electrochemiluminescence.

Variable gene expression constitutes a major mechanism for controlling cell development and cell function. To investigate these changed mRNA levels, a sensitive and quantitative assay is required. We describe a quick and easy method to quantify specific mRNAs by a combination of PCR and an electrochemiluminescent (ECL) detection of the amplified products. Total cellular RNA is reverse-transcribed and amplified with a biotinylated forward primer and a Tris (2,2'-bipyridine) ruthenium (II) (TBR)-labeled reverse primer. The amplification product is captured on streptavidin-coated paramagnetic beads and quantified by ECL detection using the QPCR system 5000. The results can be converted to quantitative values with an external standard curve. This method permits accurate and reliable quantitation of cytokine mRNA expression.

Clone Cells↗
PubMed2005

Modeling prognosis for patients with malignant astrocytic gliomas: quantifying the expression of multiple genetic markers and clinical variables.

The disparate lengths of survival among patients with malignant astrocytic gliomas (anaplastic astrocytomas [AAs] and glioblastoma multiforme [GBM]) cannot be adequately accounted for by clinical variables (patient age, histology, and recurrent status). Using real-time quantitative reverse transcription-polymerase chain reaction, we quantified the expression of four genes that were putative prognostic markers (CDK4, IGFBP2, MMP2, and RPS9) in a set of 43 AAs, 41 GBMs, and seven adjacent normal brain tissues. We previously explicated the expression and prognostic value of PAX6, PTEN, VEGF, and EGFR in these glioma tissues and established a comprehensive prognostic model (Zhou et al., 2003). This study attempts to improve that model by including four additional genetic markers, which exhibited a differential expression (P < 0.001) among tumor grades and between tumor and normal tissues. By including eight log-scaled gene expression variables, three clinical variables, and interaction terms among the eight genes, we established a prognostic model that accounted for two thirds of the variation (R2) in survival for this set of patients. To improve the R2 of the model without compromising its clinical utility, our data demonstrated that incorporating genes from different pathways markedly strengthens the model. Spearman rank correlation analysis of gene expression demonstrated a statistically significant positive correlation (P < 0.01) between the expression of IGFBP2-MMP2 and IGFBP2-VEGF in GBMs, but not in AAs. This finding suggests that the expression of IGFBP2 is associated with pathways activated specifically in GBMs that result in enhancing invasiveness and angiogenesis.

Astrocytoma↗