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PubMed2007

Nested, non-parametric, correlative analysis of microarrays for heterogenous phenotype characterization.

We present a non-parametric approach for qualitatively selecting candidate genes to characterize several criteria that are nested among genes selected on the basis of their individual, similar effects upon an array-wide closeness measure. In this setting, a goal is to obtain a reliable characterization of phenotypes, based on very high-dimensional data from a few samples. As opposed to a distance-based approach, the proposed measure defines closeness based on gene signal profiles (functionals) rather than on isolated (numerical) differences in each gene between samples. By using such a measure to characterize intensity differences, we effectively separate biological from artifactual variation in expression, due to tissue effects or signal calibration. Based on this measure, we successively examine the significance of the following: a set of similarly behaved genes relative to all arrayed genes, a set of candidate genes relative to similarly behaved genes, individual candidate genes relative to non-candidates, and the direction, as over- or under-expressed, of candidate genes. In each setting, sample pairs are the units of analysis, with U-statistics the theoretical framework. We illustrate the method on a microarray experiment, where the goal is to select sets of genes that characterize a type of skin cancer and its histological subtypes.

Genetic Heterogeneity↗
PubMed1982

Degranulation of rat cerebellum induces selective variations in gene expression.

Selective variations in the composition of poly(A)-containing mRNA were found to be induced in the rat cerebellum by X-irradiation. mRNA populations prepared from normal and X-irradiated rat cerebella at different stages of their development displayed equal efficiencies when translated in vitro in reticulocyte lysates. Specific differences were revealed, however, when the labeled translation products of both mRNA preparations were subjected to two-dimensional gel electrophoresis followed by fluorography of the dried gels. Of more than 100 polypeptide products, several showed marked intensity differences, indicating changes in the abundance of their directing mRNA species. These differences appear both in developing and in mature cerebellar mRNA, and the extent of modification in mRNA is much higher than the consequent changes in the composition of proteins in the irradiated cerebellum. The degranulation-induced modifications in levels of specific cerebellar mRNA species can be used to identify proteins whose biosynthesis depends on the presence of interneurons.

Animals↗
PubMed2003

DNA-Rag protein interactions in the control of selective D gene utilization in the TCR beta locus.

Ordered assembly of Ag receptor genes by VDJ recombination is a key determinant of successful lymphocyte differentiation and function. Control of gene rearrangement has been traditionally viewed as a result of complex reorganization of the nucleochromatin mediated by several nuclear factors. Selective recombination of the variable (V) genes to the diversity (D), but not joining (J), gene segments within the TCRbeta locus has been shown to be controlled by recombination signal (RS) sequences that flank the gene segments. Through ex vivo and in vitro recombination assays, we demonstrate that the Rag proteins can discriminate between the RS of the D and J genes and enforce selective D gene incorporation into the TCRbeta variable domain in the absence of other nuclear factors or chromatin structure. DNA binding studies indicate that discrimination is not simply caused by higher affinity binding of the Rag proteins to the isolated 12RS of the D as opposed to the J genes. Furthermore, we also demonstrate that the 12RS within the TCRbeta locus is functionally inferior to the consensus 12RS. We propose that selective gene segment usage is controlled at the level of differential assembly and/or stability of synaptic RS complexes, and that evolutionary "deterioration" of the RS motifs may have been important to allow the VDJ recombinase to exert autonomous control over gene segment use during gene rearrangement.

Antibody Diversity↗
PubMed1995

Non-locus-specific polygenes giving responses to selection for gene conversion frequencies in Ascobolus immersus.

Selection for higher and lower meiotic conversion frequencies was investigated in the fungus Ascobolus immersus. Strains carrying the same known gene conversion control factors, which have major effects on conversion frequencies at their specific target locus, sometimes gave significant differences in conversion frequency. Selection for high or low conversion frequencies at the w1-78 site was practiced for five generations, giving significant responses in both directions. These responses were due to polygenes, or genes of minor effect, not to new conversion control factors of major effect. Crosses of selected strains to strains with other mutations showed that the genes' effects were not specific to w1-78, but could affect conversion frequencies of another mutation, w1-3C1, at that locus and of two other loci, w-BHj and w9, which are unlinked to w1 or to each other. The proportional changes in gene conversion frequency due to selection varied according to the locus and site involved and according to the conversion control factor alleles present. There were differences of > or = 277% in conversion frequency between "high" and "low" strains. Selection for conversion frequency had little effect on other features of conversion, such as the frequency of postmeiotic segregation or the relative frequencies of conversion to mutant or wild type.

Alleles↗
PubMed2003

Development of the liver- and lobe-selective nonviral gene transfer following the instillation of naked plasmid DNA using catheter on the liver surface in mice.

PURPOSE: The present study has undertaken the liver- and lobe-selective nonviral gene transfer following the instillation of naked plasmid DNA (pDNA) using catheter on the liver surface in mice. METHODS: The polyethernylon catheter was inserted intraperitoneally through the abdominal wall and was retained on the surface of the liver right and left medial lobes. pDNA was administered through the catheter to the liver right and left medial lobes. RESULTS: The luciferase levels produced in the applied liver lobes at 6 h after liver surface instillation of pDNA were significantly higher than those produced in other liver lobes and other tissues assayed, and ranged from approximately 5 folds higher in other lobes to 20-30 folds higher in other tissues. Following liver surface instillation of pDNA at a time from 2 to 24 h or at a volume from 15 to 60 microl, the gene expressions of the applied liver lobes were always significantly higher than those of other liver lobes and other tissues. CONCLUSION: We have demonstrated the liver- and lobe-selective gene transfection following the instillation of naked pDNA using catheter on the liver surface in mice.

Animals↗
PubMedDate not supplied

A selective amplifier gene for tamoxifen-inducible expansion of hematopoietic cells.

BACKGROUND: We have developed a novel system for expansion of gene-modified hematopoietic stem/progenitor cells to overcome the low efficiency of current gene transfer methodology. This system involves 'selective amplifier genes', that encode fusion proteins between the granulocyte colony-stimulating factor receptor (GCR) and the hormone-binding domain of estrogen receptor (ER). Hematopoietic progenitors expressing the chimeras showed estrogen-responsive growth in a controllable manner. However, endogenous estrogen may activate the fusion proteins in vivo, depending on the hormonal status of the subjects. METHODS: We replaced ER with a mutant receptor (TmR) which specifically binds to 4-hydroxytamoxifen (Tm), to overcome limitations with wild-type ER. Interleukin-3 (IL-3)-dependent Ba/F3 cells and hematopoietic progenitor cells transduced with the resultant fusion proteins (GCRTmR and delta GCRTmR) were examined for ligand-inducible growth. RESULTS: GCRTmR- and delta GCRTmR-expressing Ba/F3 showed IL-3-independent growth in response to Tm, while the cells were unresponsive to estrogen at concentrations up to 10(-7)-10(-6) M. Furthermore, murine bone marrow cells transduced with GCRTmR and delta GCRTmR formed colonies in methyl-cellulose medium in response to Tm, while virtually no colonies appeared with 10(-7) M estrogen or without cytokines. CONCLUSIONS: These results suggest that influences of the endogenous estrogen can be almost eliminated by using the GCRTmR/Tm or delta GCRTmR/Tm system to expand gene-modified hematopoietic stem/progenitor cells.

Animals↗
PubMed2005

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas.

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (> or =50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors.

Adenoma↗
PubMed1995

Use of haloacetate dehalogenase genes as selection markers for Escherichia coli and Pseudomonas vectors.

The haloacetate dehalogenase gene, dehH2, cloned from Moraxella sp. strain B could be used a selection marker gene for vectors in Escherichia coli and Pseudomonas putida. Haloacetates, especially iodoacetate, inhibit the growth of some microorganisms. The dehH2 gene introduced into the cells conferred iodoacetate resistance on them. Therefore, E. coli and P. putida transformed with vectors marked with dehH2 could be easily selected on plates containing iodoacetate.

Acetates↗
PubMed1999

Development of a modified selective amplifier gene for hematopoietic stem cell gene therapy.

We have proposed a novel concept, ie selective expansion of transduced cells, to overcome the low efficiency of gene transfer into hematopoietic stem cells. Previously, a fusion gene encoding a chimeric receptor (DeltaGCRER) between the mouse granulocyte colony-stimulating factor receptor (G-CSFR) and the hormone-binding domain of rat estrogen receptor was constructed as a 'selective amplifier gene'. Although the chimeric gene conferred estrogen-inducible proliferation on the transduced Ba/F3 cells, it also mediated differentiation of the retrovirally transduced 32D cells upon estrogen treatment. Since only a growth signal is required for our purpose, we further modified the DeltaGCRER gene to attenuate its differentiation signal. Based on the observation that tyrosine-703 in wild-type G-CSFR plays a pivotal role in transmitting the differentiation signal, phenylalanine was substituted for this residue in DeltaGCRER. When the resultant selective amplifier gene (DeltaY703F-GCRER gene) was expressed in 32D cells, sustained growth was supported by estrogen, while differentiation was suppressed. These cells ceased to grow upon estrogen withdrawal and differentiated with G-CSF treatment. The present findings suggested that DeltaY703F-GCRER may have desirable properties as a selective amplifier for hematopoietic stem cell expansion and gene therapy.

Animals↗
PubMed2002

Possible roles for products of polymorphic MHC and linked olfactory receptor genes during selection processes in reproduction.

PROBLEM: Polymorphic genes of the human major histocompatibility complex [MHC; human leukocyte antigen (HLA)] are probably important in determining resistance to parasites and avoidance of inbreeding. We investigated whether HLA-associated sexual selection could also involve HLA-linked olfactory receptor (OR) genes, which might not only participate in olfaction-guided mate choice, but also in selection processes within the testis. METHOD OF STUDY: The testicular expression status of HLA class I molecules (by immunohistology) and HLA-linked OR genes (by transcriptional analysis) was determined. RESULTS: Various HLA class I heavy chains, but not beta2-microglobulin (beta2m), were expressed, mainly at the spermatocyte I stage. Of 17 HLA-linked OR genes analyzed, eight were found to be transcribed in the testis. They exhibited varying numbers of 5'- or 3'-non-coding exons as well as differential splicing. CONCLUSIONS: We suggest that testis-expressed polymorphic HLA and OR proteins are functionally connected and serve the selection of spermatozoa, enabling them to distinguish 'self from 'non-self [the sperm-receptor-selection (SRS) hypothesis].

Epithelium↗
PubMed2006

Feature selection using Haar wavelet power spectrum.

BACKGROUND: Feature selection is an approach to overcome the 'curse of dimensionality' in complex researches like disease classification using microarrays. Statistical methods are utilized more in this domain. Most of them do not fit for a wide range of datasets. The transform oriented signal processing domains are not probed much when other fields like image and video processing utilize them well. Wavelets, one of such techniques, have the potential to be utilized in feature selection method. The aim of this paper is to assess the capability of Haar wavelet power spectrum in the problem of clustering and gene selection based on expression data in the context of disease classification and to propose a method based on Haar wavelet power spectrum. RESULTS: Haar wavelet power spectra of genes were analysed and it was observed to be different in different diagnostic categories. This difference in trend and magnitude of the spectrum may be utilized in gene selection. Most of the genes selected by earlier complex methods were selected by the very simple present method. Each earlier works proved only few genes are quite enough to approach the classification problem 1. Hence the present method may be tried in conjunction with other classification methods. The technique was applied without removing the noise in data to validate the robustness of the method against the noise or outliers in the data. No special software or complex implementation is needed. The qualities of the genes selected by the present method were analysed through their gene expression data. Most of them were observed to be related to solve the classification issue since they were dominant in the diagnostic category of the dataset for which they were selected as features. CONCLUSION: In the present paper, the problem of feature selection of microarray gene expression data was considered. We analyzed the wavelet power spectrum of genes and proposed a clustering and feature selection method useful for classification based on Haar wavelet power spectrum. Application of this technique in this area is novel, simple, and faster than other methods, fit for a wide range of data types. The results are encouraging and throw light into the possibility of using this technique for problem domains like disease classification, gene network identification and personalized drug design.

Artificial Intelligence↗
PubMed1984

Synthesis of an ochre suppressor tRNA gene and expression in mammalian cells.

We have used site-specific mutagenesis to change the anticodon of a Xenopus laevis tyrosine tRNA gene so that it would recognize ochre codons. This tRNA gene is expressed when amplified in monkey cells as part of a SV40 recombinant and efficiently suppresses termination at both the ochre codon separating the adenovirus 2 hexon gene from a 23-kd downstream gene and the ochre codon at the end of the NS1 gene of influenza virus A/Tex/1/68. Termination at an amber codon of a NS1 gene of another influenza virus strain was not suppressed by the (Su+) ochre gene suggesting that in mammalian cells amber codons are not recognized by ochre suppressor tRNAs. Finally, microinjection into mammalian cells of both (Su+) ochre tRNA genes and selectible genes containing ochre nonsense mutations gives rise to colonies under selective conditions. We conclude that it should be possible to isolate a wide assortment of mammalian cell lines with ochre suppressor activity.

Amino Acid Sequence↗
PubMed1996

Evidence for a major gene for type II diabetes and linkage analyses with selected candidate genes in Mexican-Americans.

We have carried out two independent family studies in low-income Mexican-Americans from San Antonio, Texas. In the first study, probands were ascertained at random without regard to any medical condition (658 examined individuals from 50 families), and in the second study, probands were subjects with type II diabetes identified in a prior epidemiological survey (523 examined individuals from 29 families). Pedigrees ranging in size from 2 to 45 family members (median 11) in the first study and from 2 to 50 family members (median 12) in the second study were examined. Diabetes was diagnosed according to World Health Organization criteria. In both sets of families, segregation analyses revealed support for a major gene with an autosomal dominant mode of inheritance influencing early age of onset of diabetes. Non-Mendelian inheritance was rejected in both data sets. Individuals with the early age of onset allele had a mean age of diabetes onset of 51 years in the first data set and 60 years in the second data set. In the first data set, the major gene accounted for approximately 70% of the phenotypic variance in age of onset of diabetes, and there were no residual family effects once the major gene effect was taken into account. In the second data set, the major gene accounted for approximately 50% of the phenotypic variance, and residual family effects were statistically significant. Linkage analyses were performed with 11 candidate genes, and tight linkage with diabetes was rejected for Rh blood group, glucose transporter 2, fatty acid-binding protein, tumor necrosis factor beta, glucokinase, and lipoprotein lipase. A logarithm of odds (LOD) score of 0.92 at a recombination fraction of 0.05 was observed for insulin receptor substrate 1. This LOD score corresponds to a chi2 of 4.24 (P = 0.039).

Alleles↗
PubMed2005

Feature selection and classification for microarray data analysis: evolutionary methods for identifying predictive genes.

BACKGROUND: In the clinical context, samples assayed by microarray are often classified by cell line or tumour type and it is of interest to discover a set of genes that can be used as class predictors. The leukemia dataset of Golub et al. 1 and the NCI60 dataset of Ross et al. 2 present multiclass classification problems where three tumour types and nine cell lines respectively must be identified. We apply an evolutionary algorithm to identify the near-optimal set of predictive genes that classify the data. We also examine the initial gene selection step whereby the most informative genes are selected from the genes assayed. RESULTS: In the absence of feature selection, classification accuracy on the training data is typically good, but not replicated on the testing data. Gene selection using the RankGene software 3 is shown to significantly improve performance on the testing data. Further, we show that the choice of feature selection criteria can have a significant effect on accuracy. The evolutionary algorithm is shown to perform stably across the space of possible parameter settings - indicating the robustness of the approach. We assess performance using a low variance estimation technique, and present an analysis of the genes most often selected as predictors. CONCLUSION: The computational methods we have developed perform robustly and accurately, and yield results in accord with clinical knowledge: A Z-score analysis of the genes most frequently selected identifies genes known to discriminate AML and Pre-T ALL leukemia. This study also confirms that significantly different sets of genes are found to be most discriminatory as the sample classes are refined.

Algorithms↗
PubMed1990

The immunoglobulin lambda-like gene cluster (14.1, 16.1 and F lambda 1) contains gene(s) selectively expressed in pre-B cells and is the human counterpart of the mouse lambda 5 gene.

A human immunoglobulin (Ig)-related gene, covering approximately 8 kb, was isolated from a cosmid genomic library, by hybridization with a C lambda probe and with a lambda-like probe. This gene was identified as 14.1 It belongs to the human lambda-like cluster which is composed of three genes (14.1, 16.1 and F lambda 1) that do not rearrange. Sequence data indicate that 14.1 is organized similarly to the mouse lambda 5 gene. It contains three exons with lengths of 69, 38, and 106 codons as compared with 65, 38, and 106 for exons 1, 2, and 3 of mouse lambda 5, respectively. The corresponding homology values were 61, 66 and 75.5%. Using a 14.1 specific probe containing exon 1, we showed that this gene was selectively expressed in human pre-B cell lines. It is likely to encode a 213-amino acid lambda-like light chain that would associate with mu chains and play an important role in the early steps of B cell differentiation.

Amino Acid Sequence↗
PubMed1997

High-efficiency transformation of Arabidopsis thaliana with a selectable marker gene regulated by the T-DNA 1' promoter.

Two selectable marker genes harbouring the bar coding region but differing in their promoters were compared in an Arabidopsis thaliana transformation assay using in planta infiltration with Agrobacterium tumefaciens. Surprisingly, in four Arabidopsis ecotypes examined, the 1' promoter from the right T-DNA was superior to the most commonly used 35S promoter of cauliflower mosaic virus (CaMV). The ecotype Wassilewskija gave the highest transformation frequencies, with an average of between 5.3 and 6.3% of the seedlings subjected to the selection. This is approximately 30-fold higher than previously reported results. Analysis of T-DNA integration patterns in single transformed plants or pooled populations revealed independent T-DNA integration events in each case. Results show that the 1' promoter is an attractive alternative to the 35S promoter for the generation of T-DNA insertion lines. The 1' promoter may be especially beneficial for the secondary transformation of transgenic strains containing the 35S promoter to exclude homology-mediated gene silencing.

Agrobacterium tumefaciens↗
PubMed2004

A neuroblastoma-selective suicide gene therapy approach using the tyrosine hydroxylase promoter.

In this study, selective expression of therapeutic transgenes was evaluated in neuroblastoma cells. Promoter fragments of the genes for neuron-specific enolase (NSEp), tyrosine hydroxylase (THp), and dopamine-beta-hydroxylase (DBHp) were studied in neuroblastoma and nonneuronal cell lines by transient transfection experiments using fluorescence-activated cell sorting (FACS) analysis of enhanced green fluorescent protein (egfp) and luciferase (luc+) assay. Both reporter gene assays revealed a neuroblastoma-selective expression mediated by NSEp and THp, whereas DBHp was active only in a murine neuroblastoma cell line. Reporter gene expression by NSEp in neuroblastoma cells was markedly higher than expression by THp, but NSEp also showed considerable background activity in nonneuronal cells. THp-driven expression of egfp was 35-fold higher in human neuroblastoma MHH-NB11 compared with nonneuronal HeLa cells. Thus, THp was chosen for a neuroblastoma-selective suicide gene therapy approach using the herpes simplex virus type 1 thymidine kinase (HSV-tk)/ganciclovir (GCV) system. A retrovirus vector that contained an expression cassette of a HSV-tk/egfp fusion gene and THp in antisense orientation was generated. Stably transduced human neuroblastoma cells and nonneuronal cell lines were generated, and HSV-tk/egfp expression was measured by FACS and GCV cytotoxicity assay. There was a 2.2-fold difference in green fluorescence and a 1.4-fold difference in cell killing between the human neuroblastoma MHH-NB11 and HeLa cells after HSV-tk/egfp gene transfer. The overall difference in THp-HSV-tk/egfp-mediated cell killing between neuroblastoma and nonneuronal tumor cell lines was statistically significant (P = 0.001). In conclusion, the present study demonstrated the feasibility of a neuroblastoma-selective gene therapy approach using the THp/HSV-tk/egfp expression cassette.

Animals↗
PubMed1993

Retrovirally transduced Escherichia coli gpt genes combine selectability with chemosensitivity capable of mediating tumor eradication.

"Suicide genes" encoding exceptional sensitivity to chemotherapeutic agents can potentially improve the selectivity of cancer therapy. As a component of a retroviral gene therapy vector, a suicide gene might also improve the safety of gene therapy by permitting the subsequent ablation of transduced cells exhibiting neoplastic or other aberrant behavior. An extra gene, however, cannot easily be added to vectors already carrying a therapeutic gene and a selectable drug resistance marker without compromising gene expression. To circumvent this obstacle, we have investigated a retrovirally transduced Escherichia coli gpt gene on the basis of evidence that it might subserve a dual sensitivity/resistance function. A gpt vector was used to transduce the gene into murine K3T3 sarcoma cells. In vitro, gpt-positive K3T3 clones could be selected on the basis of resistance to a regimen containing mycophenolic acid and xanthine; the same clones were 18 to 86 times as sensitive to 6-thioxanthine (6TX) as their gpt-negative counterparts. In mice, systemic 6TX therapy induced durable regressions in 19/20 gpt-positive K3T3 sarcomas without affecting gpt-negative tumors. These results indicate that selectability and in vivo chemosensitivity can be expressed in the same cell population from a single retrovirally transduced gene and imply the additional possibility of fusing the gpt gene with a therapeutic gene to create vectors expressing three important functions from a single gene.

Animals↗