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Results for “gene expression variability”

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PubMed2004

Interlaboratory evaluation of rat hepatic gene expression changes induced by methapyrilene.

Several studies using microarrays have shown that changes in gene expression provide information about the mechanism of toxicity induced by xenobiotic agents. Nevertheless, the issue of whether gene expression profiles are reproducible across different laboratories remains to be determined. To address this question, several members of the Hepatotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute evaluated the liver gene expression profiles of rats treated with methapyrilene (MP). Animals were treated at one facility, and RNA was distributed to five different sites for gene expression analysis. A preliminary evaluation of the number of modulated genes uncovered striking differences between the five different sites. However, additional data analysis demonstrated that these differences had an effect on the absolute gene expression results but not on the outcome of the study. For all users, unsupervised algorithms showed that gene expression allows the distinction of the high dose of MP from controls and low dose. In addition, the use of a supervised analysis method (support vector machines) made it possible to correctly classify samples. In conclusion, the results show that, despite some variability, robust gene expression changes were consistent between sites. In addition, key expression changes related to the mechanism of MP-induced hepatotoxicity were identified. These results provide critical information regarding the consistency of microarray results across different laboratories and shed light on the strengths and limitations of expression profiling in drug safety analysis.

Animals↗
PubMed1998

A plant transformation vector with a minimal T-DNA II. Irregular integration patterns of the T-DNA in the plant genome.

A minimal T-DNA binary vector was used for Agrobacterium-mediated transfer of a chimeric T4 lysozyme gene located next to the left border, and transgenic potato plants which expressed T4 lysozyme protein were identified and further analysed. Frequent rearrangements of T4 lysozyme transgenes were detected. A vector derivative containing two matrix associated regions (MARs) flanking its multiple cloning site was constructed. In transgenic potato plants, reduced variability in gene expression due to position effects was detected. When either the donor vector contained MAR sequences, or when vector pPCV701 which contains a pBR322 fragment next to the left border were used, only relatively few rearrangements were observed. However, when the T4 lysozyme gene was driven by a CaMV 35S promoter modified by multiplied enhancer region carrying either 2 or 4 elements, frequent rearrangements were again obtained.

Blotting, Southern↗
PubMed1984

Müllerian anomalies and renal agenesis: autosomal dominant urogenital adysplasia.

We report two families in which müllerian anomalies or renal agenesis appeared to be caused by an autosomal dominant gene that produces unilateral or bilateral renal agenesis and a spectrum of müllerian anomalies. This single gene disorder may account for the high incidence of müllerian anomalies observed in females with bilateral renal agenesis and the increased frequency of renal anomalies in patients with müllerian malformations. The range of müllerian anomalies in this disorder includes bicornuate uterus, uterus didelphys, Rokitansky- Kuster -Hauser syndrome (vaginal atresia with or without absence of the uterus), and total müllerian aplasia. Gene expression is not sex limited. Affected males can have bilateral or unilateral renal agenesis, and possibly may have unilateral or bilateral absence of the vas deferens or seminal vesicles. We suggest that autosomal dominant urogenital adysplasia is common, but underdiagnosed because of the deceptive variability in gene expression. In addition, reduced gene penetrance and reduced biologic fitness from lethal renal anomalies or genital tract anomalies may obscure the autosomal dominant nature of this disorder in most families.

Adult↗
PubMed1989

Variation in enzymatic transient gene expression assays.

We examined causes for high variability in data from enzymatic transient gene expression assays. Our results strongly suggest that variation in transfection efficiency is the major cause of data variation and can seriously compromise valid interpretation of data. We compared averaging data from multiple transfections and cotransfection of a second reporter gene as methods for correcting for variation in transfection efficiency. We found that transfection efficiency can be so highly variable that neither method necessarily overcomes the resulting bias in data. Depending upon the degree in variation in transfection efficiency, a combination of the two methods may be advisable. The need to normalize data for transfection efficiency is dependent upon the difference in strengths of promoters being tested and the relative variability of the transfection method used. We also show that the level of reporter gene expression between transfection experiments performed on different days can vary by more than 10-fold.

Animals↗
PubMed1981

[Recurrent familial neuropathy: report of one family].

The authors report a case of a family with hereditary compression of peripheral nerves. The disease is traced through five generations. Six members were proved to be affected. 14 patients were examined. The review of the literature and the family studied suggest that the disorder is transmitted by an autosomal dominant gene with variable expressivity.

Adult↗
PubMed1987

The 5' flanking sequence of a Trypanosoma brucei variable surface glycoprotein gene.

The mechanism controlling transcription at several telomeric expression sites for variable surface glycoprotein (VSG) genes in Trypanosoma brucei is unknown. Most VSG genes in expression sites have a region 5' of the gene lacking restriction enzyme sites. This 'barren region' is involved in recombination events which replace the VSG gene with a copy of a different, non-telomeric, VSG gene leading to a switch in VSG expression. Alterations in the barren region have been considered as possible modulators of expression of the adjacent VSG gene in other switching events where no gene replacement occurs. The expressed copy of the ILTat 1.3 VSG gene remains in its expression site, on a 160 kilobase (kb) chromosome, in trypanosomes not expressing the ILTat 1.3 VSG. Here we report the complete sequence of the barren region adjacent to this gene, determined both from trypanosomes expressing the gene and from those that are not. The sequence is identical whether or not the ILTat 1.3 VSG gene is expressed. This confirms that alterations in the barren region are not involved in modulation of expression of the gene, as suggested by restriction enzyme mapping. Sequence data from the 5' flanking region of a second telomeric gene copy on an 80 kb minichromosome, and from the ILTat 1.3 expression site after replacement of the ILTat 1.3 gene by another gene from a minichromosome, provide evidence that telomeric VSG genes on minichromosomes are also flanked by long repeat arrays, and that these arrays are involved in inter-telomeric gene replacements as well as replacements by non-telomeric genes.

Animals↗
PubMed1989

Alterations in the p53 gene and the clonal evolution of the blast crisis of chronic myelocytic leukemia.

Molecular mechanisms responsible for the clinical progression of chronic myelocytic leukemia to its accelerated phase or to blast crisis have not been defined. We found alterations of the p53 gene (p53 is a 53-kDa nuclear protein) including deletions and rearrangements in 8 of 34 patients in blast crisis and 1 of 4 patients in the accelerated phase, but in only 1 of 38 patients in the chronic phase of chronic myelocytic leukemia. Only two other examples of p53 gene alterations were found among 203 patients with hematologic malignancies and solid tumors. Transcripts of the p53 gene were uniformly found in chronic-phase cells, but gene expression was variable in blast crisis, and transcripts were reduced or undetectable in 10 of 16 patients. Heterogeneous alterations in the structure and expression of the p53 gene appear to be relatively frequent in blast crisis and may be involved in the evolution of disease.

Blast Crisis↗
PubMed1992

[Sacrum abnormalities and neural tube closure defect: different manifestations of a same genetic disease?].

The authors report the case of a full-term female infant exhibiting an anterior meningocele, combined with a hemi-sacrum and an anal dysfunction. Both her father and brother had the same although less pronounced abnormalities. The father's sister was anencephalic. This case, together with previously published data, suggests that sacrum malformations and neural tube defects may derive from a unique dominant autosomal gene with variable expressivity.

Female↗
PubMed1997

Identical genetic changes in different histologic components of Wilms' tumors.

BACKGROUND: In young children and infants, Wilms' tumor is the most common cancer of the kidney. Wilms' tumor exhibits heterogeneous histopathologic features, consisting of rapidly proliferating blastemal and epithelial cells and a stromal component that has heterologous elements (e.g., cartilage, bone, and striated muscle). It is unclear whether the stromal and heterologous components of sporadic Wilms' tumor are neoplastic or should be considered non-neoplastic. PURPOSE: Our purpose was twofold: 1) to selectively analyze the different histologic tissue components of sporadic Wilms' tumors, including blastemal, epithelial, stromal, and heterologous elements, for loss of heterozygosity (LOH) of the WT1 gene and for expression of the WT1 gene and 2) to determine the role of WT1 gene expression in the development of these tissues. METHODS: By use of tissue microdissection techniques, various histologic elements (blastema, stroma, epithelium, and striated muscle) of sporadic Wilms' tumor were obtained from specimens taken from 18 patients. DNA was extracted from the dissected tissue fragments, and DNA solutions were amplified by use of the polymerase chain reaction and the polymorphic genomic markers D11S1392 and D11S904 to detect LOH at the WT1 gene locus (11p13). Three selected specimens with heterologous elements and LOH at 11p13 were analyzed for expression of the WT1 gene by means of the in situ reverse transcription-polymerase chain reaction. RESULTS: Nine (50%) of the 18 specimens showed LOH at the WT1 locus. Although identical WT1 gene deletion was consistently observed in all of the various histologic components of these nine specimens, WT1 gene expression was high in the blastemal and epithelial elements and low in the stromal and heterologous elements. CONCLUSIONS AND IMPLICATIONS: Identical allelic deletion at 11p13 in all components of the sporadic Wilms' tumors examined suggests that the stromal tissue components are neoplastic rather than non-neoplastic. In conjunction with variable WT1 gene expression in the different histologic components, the results raise the possibility that undifferentiated blastemal cells are the precursors of the stromal and heterologous elements. Morphologically benign stromal and heterologous elements may therefore be derived from neoplastic cells. The developmental state of the various tissue components of Wilms' tumor may be attributed to an altered residual WT1 gene that is required for the maturation of blastemal and epithelial cells but that is not required for the maturation of stromal and heterologous elements.

Alleles↗
PubMed1984

The role of duplication in the expression of a variable surface glycoprotein gene of Trypanosoma brucei.

The variable surface glycoprotein (VSG) genes of Trypanosoma brucei have been classified into two groups depending upon whether or not duplication of the genes is observed when they are expressed. We report here the observation of duplication apparently linked to expression of the ILTaT 1.3 gene in the ETaR 1 trypanosome stock. In the ILTaR 1 stock, expression of the ILTaT 1.3 VSG did not involve a new duplication, but instead activation of a preexisting gene copy that had been apparently generated earlier by a duplication event analogous to that directly observed in the ETaR 1 trypanosomes. The results suggest that the well-characterised gene duplications found with other VSG genes are common to all VSG genes but are not directly responsible for controlling expression. All currently available data can be accommodated by a model that assumes that gene duplication and replacement occurs independently of antigenic switching.

Animals↗
PubMed2006

Use of external controls in microarray experiments.

DNA microarray analysis has become the most widely used technique for the study of gene expression patterns on a genomic scale. Microarray analysis is a complex technique involving many steps, and a number of commercial and in-house developed arrays and protocols for data collection and analysis are used in different laboratories. Inclusion of external or spike-in RNA controls allows one to evaluate the variability in gene expression measurements and to facilitate the comparison of data collected using different platforms and protocols. This chapter describes what external controls are, which collections of spike-in controls are available to researchers, and how they are implemented in the laboratory. Applications of external controls in the assessment of microarray performance, normalization strategies, the evaluation of algorithms for gene expression analysis, and the potential to quantify absolute mRNA levels are discussed.

Animals↗
PubMed1993

Differential expression of T cell receptor variable beta genes on CD4+ and CD8+ T cells: influence by sex linked genes?

We examined the expression of seven V alpha or V beta T cell receptor (TCR) segments on human CD4+ and CD8+ T cells. Confirming previously published results, we found a preferential expression of four V segment gene products on CD4+ T cells. One of these markers (V beta 6.7) was constantly expressed on more CD4+ T cells than CD8+ T cells. None of the analyzed blood samples showed a complete deletion of T cells expressing a particular V beta gene segment. In addition, our data provide the first evidence that genes on sex chromosomes may influence the formation of the human T cell repertoire. The ratio of CD4+/CD8+ T cells expressing V beta 12 gene products was always > or = 1 in female donors, whereas approximately 30% male donors exhibited more CD8+V beta 12+ T cells than CD4+V beta 12+ T cells.

Adult↗
PubMed1996

HOXB7 constitutively activates basic fibroblast growth factor in melanomas.

Homeobox (HOX) genes control axial specification during mammalian development and also regulate skin morphogenesis. Although selected HOX genes are variably expressed in leukemias and kidney and colon cancer cell lines, their relationship with the neoplastic phenotype remains unclear. In both normal development and neoplastic transformation, HOX target genes are largely unknown. We investigated the expression and function of HOXB cluster genes in human melanoma. The HOXB7 gene was constitutively expressed in all 25 melanoma cell lines and analyzed under both normal and serum-starved conditions, as well as in in vivo primary and metastatic melanoma cells; conversely, HOXB7 was expressed in proliferating but not quiescent normal melanocytes. Treatment of melanoma cell lines with antisense oligomers targeting HOXB7 mRNA markedly inhibited cell proliferation and specifically abolished expression of basic fibroblast growth factor (bFGF) mRNA. Band shift and cotransfection experiments showed that HOXB7 directly transactivates the hFGF gene through one out of five putative homeodomain binding sites present in its promoter. These novel findings indicate a key role for constitutive HOXB7 expression in melanoma cell proliferation via bFGF. The results also raise the possibility that growth factor genes are critical HOX target genes in other developmental and/or neoplastic cell systems.

Antisense Elements (Genetics)↗
PubMed2005

Monoallelic yet combinatorial expression of variable exons of the protocadherin-alpha gene cluster in single neurons.

Diverse protocadherin-alpha genes (Pcdha, also called cadherin-related neuronal receptor or CNR) are expressed in the vertebrate brain. Their genomic organization involves multiple variable exons and a set of constant exons, similar to the immunoglobulin (Ig) and T-cell receptor (TCR) genes. This diversity can be used to distinguish neurons. Using polymorphisms that distinguish the C57BL/6 and MSM mouse strains, we analyzed the allelic expression of the Pcdha gene cluster in individual neurons. Single-cell analysis of Purkinje cells using multiple RT-PCR reactions showed the monoallelic and combinatorial expression of each variable exon in the Pcdha genes. This report is the first description to our knowledge of the allelic expression of a diversified receptor family in the central nervous system. The allelic and combinatorial expression of distinct variable exons of the Pcdha genes is a potential mechanism for specifying neuron identity in the brain.

Animals↗
PubMedDate not supplied

Induction of drug resistance and protein kinase C genes in A2780 ovarian cancer cells after incubation with antineoplastic agents at sublethal concentrations.

We examined the inducibility of drug resistance (MDR1, MRP1, LRP) and protein kinase C (PKC) isozyme (alpha, epsilon, eta, theta, tau, zeta) corresponding genes in A2780 ovarian cancer cells after a 24-hour treatment with adriamycin (ADR), camptothecin (CAM), etoposide (ETO) or vincristine (VCR). Sublethal concentrations of drugs were used to exclude short-term effects caused by selection. Cell cycle analysis was performed to identify possible correlation between resistance factors, PKC isozymes and proliferation. We found a mostly combined induction of MDR1, LRP, PKC tau and PKC zeta by CAM, ETO and VCR. PKC alpha, epsilon, eta and theta gene expression altered variably. Cell cycle analysis showed that A2780 cells responded with a marked G2/M arrest after a 24-hour treatment with CAM, ETO and VCR but an association between the induction of PKC isozymes corresponding genes and proliferation was not seen. Our analysis points to a possible link between atypical PKC tau/PKC zeta and MDR1/LRP in cytostatic stress response of cancer cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Impact of transcriptional properties on essentiality and evolutionary rate.

We characterized general transcriptional activity and variability of eukaryotic genes from global expression profiles of human, mouse, rat, fly, plants, and yeast. The variability shows a higher degree of divergence between distant species, implying that it is more closely related to phenotypic evolution, than the activity. More specifically, we show that transcriptional variability should be a true indicator of evolutionary rate. If we rule out the effect of translational selection, which seems to operate only in yeast, the apparent slow evolution of highly expressed genes should be attributed to their low variability. Meanwhile, rapidly evolving genes may acquire a high level of transcriptional variability and contribute to phenotypic variations. Essentiality also seems to be correlated with the variability, not the activity. We show that indispensable or highly interactive proteins tend to be present in high abundance to maintain a low variability. Our results challenge the current theory that highly expressed genes are essential and evolve slowly. Transcriptional variability, rather than transcriptional activity, might be a common indicator of essentiality and evolutionary rate, contributing to the correlation between the two variables.

Animals↗