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PubMed2006

A nonparametric likelihood ratio test to identify differentially expressed genes from microarray data.

Microarray experiments contribute significantly to the progress in disease treatment by enabling a precise and early diagnosis. One of the major objectives of microarray experiments is to identify differentially expressed genes under various conditions. The statistical methods currently used to analyse microarray data are inadequate, mainly due to the lack of understanding of the distribution of microarray data. We present a nonparametric likelihood ratio (NPLR) test to identify differentially expressed genes using microarray data. The NPLR test is highly robust against extreme values and does not assume the distribution of the parent population. Simulation studies show that the NPLR test is more powerful than some of the commonly used methods, such as the two-sample t-test, the Mann-Whitney U-test and significance analysis of microarrays (SAM). When applied to microarray data, we found that the NPLR test identifies more differentially expressed genes than its competitors. The asymptotic distribution of the NPLR test statistic and the p-value function is presented. The application of the NPLR method is shown, using both synthetic and real-life data. The biological significance of some of the genes detected only by the NPLR method is discussed.

Algorithms↗
PubMed2002

Ku is important for telomere maintenance, but not for differential expression of telomeric VSG genes, in African trypanosomes.

Trypanosome antigenic variation, involving differential expression of variant surface glycoprotein (VSG) genes, has a strong association with telomeres and with DNA recombination. All expressed VSGs are telomeric, and differential activation involves recombination into the telomeric environment or silencing/activation of subtelomeric promoters. A number of pathogen contingency gene systems associated with immune evasion involve telomeric loci, which has prompted speculation that chromosome ends provide conditions conducive for the operation of rapid gene switching mechanisms. Ku is a protein associated with eukaryotic telomeres that is directly involved in DNA recombination and in gene silencing. We have tested the hypothesis that Ku in trypanosomes is centrally involved in differential VSG expression. We show, via the generation of null mutants, that trypanosome Ku is closely involved in telomere length maintenance, more so for a transcriptionally active than an inactive telomere, but exhibits no detectable influence on DNA double strand break repair. The absence of Ku and the consequent great shortening of telomeres had no detectable influence either on the rate of VSG switching or on the silencing of the telomeric promoters of the VSG subset that is expressed in the tsetse fly.

Amino Acid Sequence↗
PubMed2005

Identification of differentially expressed genes in the developing mouse inferior colliculus.

Although injured neurons of inferior colliculus (IC) display a robust axonal outgrowth through a lesion site at postnatal day six (P6) in vitro, and are capable to re-innervate their target cells, injured neurons from P10 IC are unable to regenerate their axons across the lesion site. This axonal regenerative failure has been attributed to an increase of expression of inhibitory molecules in endogenous tissue, during development. As a first step to identify such inhibitory molecules, the present study reports the isolation of molecules differentially expressed in the IC during development. A two-directional (forward and backward) suppression subtractive hybridization (SSH) was performed on IC tissue between P6 and P10 stages. One hundred cDNAs from P6 (P6-P10) and 200 cDNAs from P10 (P10-P6)-subtracted libraries were randomly sequenced. A dot-blot screening of sequenced cDNAs revealed the differential expression for the majority of these cDNAs at their respective developmental stage. Then, the analysis of sequenced clones showed that P6 library was highly enriched in molecules expressed early in the development, such as GAP43 or vimentin proteins. By contrast, the P10 library contained mostly molecules expressed at later stages of development in the central nervous system, such as myelin-related proteins. Our results show that SSH is a suitable method for identifying differentially expressed genes in the developing IC. In addition, these results provide a foundation for further studies dealing with molecules involved in the IC development before and at the onset of hearing, some of which being probably involved in the axonal outgrowth mechanism.

Animals↗
PubMed2006

Identification of differentially expressed proteins during larval molting of Helicoverpa armigera.

Insect molting involves many molecular processes, such as protein degradation and protein synthesis in the epidermis. Various proteins have been implicated in these processes. The differentially expressed proteins during larval molting of Helicoverpa armigera were investigated using two-dimensional electrophoresis (2-D-PAGE) and matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry (MALTI-TOF-MS). Four larval tissues sampled during molting and feeding were examined. Seventy-seven differentially expressed proteins were identified in these tissues, including 20 proteins from the fifth-molting epidermis (fifth instar molting to sixth instar), 36 proteins from the fifth-molting hemolymph, and 21 from the fifth-molting fat bodies. No obviously different spots were identified from the fifth-molting midgut under these experimental conditions. After application of MALTI-TOF-MS and similarity analysis comparing results to a Drosophila protein database, 30 proteins were identified: 10 proteins from the fifth-molting epidermis, 11 proteins from the hemolymph, and 9 proteins from fat bodies. These proteins were separated into 5 groups according to their probable functions, such as enzymes, regulators, protein hydrolases, receptors, and proteins with unknown functions. These differentially expressed proteins were proposed to be involved in the Helicoverpa molting cascade.

Animals↗
PubMed1996

Differential expression of dipeptidyl peptidase IV (CD26) and thyroid peroxidase in neoplastic thyroid tissues.

This paper reports the results of research to examine the possibility of using the differential expression of two enzymes, dipeptidyl peptidase IV (DPPIV/CD26, EC: 3.4.14.5) and thyroid peroxidase (TPO, EC: 1.11.1.7), as histochemical markers histopathologically to diagnose thyroid carcinomas. The research is based on previous reports that DPPIV/CD26 is overexpressed in differentiated thyroid carcinoma tissues, and that TPO activity is very low in thyroid carcinoma tissues. Differential expression of the two enzymes in 32 thyroid tissues of various thyroid diseases was studied by Northern blot analysis and histochemical analysis. On Northern blot analyses, all 14 differentiated thyroid carcinomas (11 papillary carcinomas and 3 follicular carcinomas) overexpressed DPPIV/CD26 mRNA, whereas all 17 benign thyroid tissues (4 normal thyroid tissues, 4 Graves' diseases, 2 adenomatous goiters and 7 follicular adenomas) showed faint mRNA expression of DPPIV/CD26. All 17 benign thyroid tissues expressed high levels of TPO mRNA, whereas all 11 papillary carcinomas strongly underexpressed TPO mRNA. Histochemically, all 17 benign tissues were DPPIV/CD26 negative and strongly TPO positive, while all 11 papillary carcinomas were strongly DPPIV/CD26 positive and TPO negative. Two of 3 follicular carcinomas were histochemically positive for the two enzymes. A medullary carcinoma did not show any mRNA expression of either enzyme. These results suggest that the differential expression of these two enzymes can be applied to study the thyroid tumorigenesis.

Adenocarcinoma, Follicular↗
PubMed1997

Differentially expressed genes in androgen-dependent and -independent prostate carcinomas.

Differential gene expression between androgen-dependent (LNCaP-FGC) and androgen-independent (LNCaP-LNO) prostate cancer cells has been investigated using RNA arbitrarily primed and differential display PCR of mRNA. Four differentially expressed cDNA transcripts were identified, of which differential expression was confirmed by Northern blot analysis. Sequence analysis revealed two unknown (JC19 and GC79) and two known genes [B-cell translocation gene 1 and UDP-glucuronosyltransferase 2B15 (UGT2B15)]. JC19, GC79, and B-cell translocation gene 1 were more highly expressed in LNCaP-FGC cells compared with LNCaP-LNO cells, whereas UGT2B15 was only expressed in LNCaP-LNO cells. Androgens and 1,25-dihydroxyvitamin D3 were able to down-regulate UGT2B15 mRNA in LNCaP-LNO cells. For GC79 mRNA, down-regulation was only observed with androgens in LNCaP-FGC cells. Expression of JC19 mRNA was studied using a panel of human prostate cancer xenografts. In androgen-dependent xenografts, expression of JC19 mRNA was much higher compared with androgen-independent xenografts, in which significant expression was hardly detectable. The mRNA expression pattern in the xenografts is in good agreement with that observed in the cell culture system. In conclusion, the differential display technique used in the present study allows analysis of gene expression in vitro and in vivo and can be used for the identification of important genes involved in androgen-independent prostate cancer development.

Androgens↗
PubMed2004

Tests for finding complex patterns of differential expression in cancers: towards individualized medicine.

BACKGROUND: Microarray studies in cancer compare expression levels between two or more sample groups on thousands of genes. Data analysis follows a population-level approach (e.g., comparison of sample means) to identify differentially expressed genes. This leads to the discovery of 'population-level' markers, i.e., genes with the expression patterns A > B and B > A. We introduce the PPST test that identifies genes where a significantly large subset of cases exhibit expression values beyond upper and lower thresholds observed in the control samples. RESULTS: Interestingly, the test identifies A > B and B < A pattern genes that are missed by population-level approaches, such as the t-test, and many genes that exhibit both significant overexpression and significant underexpression in statistically significantly large subsets of cancer patients (ABA pattern genes). These patterns tend to show distributions that are unique to individual genes, and are aptly visualized in a 'gene expression pattern grid'. The low degree of among-gene correlations in these genes suggests unique underlying genomic pathologies and high degree of unique tumor-specific differential expression. We compare the PPST and the ABA test to the parametric and non-parametric t-test by analyzing two independently published data sets from studies of progression in astrocytoma. CONCLUSIONS: The PPST test resulted findings similar to the nonparametric t-test with higher self-consistency. These tests and the gene expression pattern grid may be useful for the identification of therapeutic targets and diagnostic or prognostic markers that are present only in subsets of cancer patients, and provide a more complete portrait of differential expression in cancer.

Delivery of Health Care↗
PubMed2006

Is HLA class II profile relevant for the study of large-scale differentially expressed genes in type 1 diabetes mellitus patients?

We have previously identified 30 differentially expressed genes when comparing recently diagnosed type 1 diabetes mellitus (DM-1) patients and controls paired for sex, age, and ethnic background. In this article we performed the hierarchical clustering of these genes taking into account the human-leukocyte-antigen (HLA)-DRB1/DQB1 profile. The dendrogram obtained using the Cluster program grouped patients and controls into three clusters, one including individuals with no susceptibility alleles, another including individuals with at least three susceptibility alleles, and a third intermingling susceptibility/protective alleles. In addition to other variables, the results of the present article suggest that the major histocompatibility complex (MHC) class II profile may be of relevance for the study of a large-scale differentially expressed genes.

Algorithms↗
PubMed2004

Identifying differentially expressed genes from microarray experiments via statistic synthesis.

MOTIVATION: A common objective of microarray experiments is the detection of differential gene expression between samples obtained under different conditions. The task of identifying differentially expressed genes consists of two aspects: ranking and selection. Numerous statistics have been proposed to rank genes in order of evidence for differential expression. However, no one statistic is universally optimal and there is seldom any basis or guidance that can direct toward a particular statistic of choice. RESULTS: Our new approach, which addresses both ranking and selection of differentially expressed genes, integrates differing statistics via a distance synthesis scheme. Using a set of (Affymetrix) spike-in datasets, in which differentially expressed genes are known, we demonstrate that our method compares favorably with the best individual statistics, while achieving robustness properties lacked by the individual statistics. We further evaluate performance on one other microarray study.

Algorithms↗
PubMed2006

A Laplace mixture model for identification of differential expression in microarray experiments.

Microarrays have become an important tool for studying the molecular basis of complex disease traits and fundamental biological processes. A common purpose of microarray experiments is the detection of genes that are differentially expressed under two conditions, such as treatment versus control or wild type versus knockout. We introduce a Laplace mixture model as a long-tailed alternative to the normal distribution when identifying differentially expressed genes in microarray experiments, and provide an extension to asymmetric over- or underexpression. This model permits greater flexibility than models in current use as it has the potential, at least with sufficient data, to accommodate both whole genome and restricted coverage arrays. We also propose likelihood approaches to hyperparameter estimation which are equally applicable in the Normal mixture case. The Laplace model appears to give some improvement in fit to data, though simulation studies show that our method performs similarly to several other statistical approaches to the problem of identification of differential expression.

Arabidopsis↗
PubMed1996

Identification by differential display of annexin-VI, a gene differentially expressed during melanoma progression.

To identify genes involved in the melanocyte to malignant melanoma conversion, we have applied differential display to the comparison of syngeneic murine B16F10 (metastatic melanoma) and Melan-a-immortalized melanocyte cell lines. Approximately 7000 bands were analyzed, revealing approximately 80 to be differentially displayed. Reverse Northern blotting and subsequent Northern blotting confirmed the reproducible differential expression of four transcripts. Three B16F10-specific bands encode novel genes or partially sequenced cDNAs of unknown function. One Melan-a-specific band was found to be identical to the 3' end region of the mouse Annexin VI mRNA and shown to have a reduced message expression in B16F10 relative to Melan-a. Differential expression was confirmed at the protein level with Western blotting using a rabbit polyclonal antiserum. Immunohistochemistry of human melanoma specimens with this antiserum revealed a decrease or loss of Annexin VI expression as melanomas progressed from a benign to a more malignant phenotype. Our results provide further evidence for a potential role of Annexin VI in tumor suppression.

Animals↗
PubMed2000

Protein-tyrosine phosphatases in the vessel wall: differential expression after acute arterial injury.

Many protein-tyrosine phosphatases (PTPases) have now been identified, but little is known about PTPase expression and regulation in vascular tissue and in vascular disease. Polymerase chain reaction (PCR) amplification and cDNA fingerprinting of PTPase catalytic domains, combined with random sequencing of PCR product libraries, identified 18 (8 receptor-like and 10 cytosolic) PTPases in the rat carotid artery and revealed differential expression of 5 of these PTPases during neointima formation after balloon catheter injury. In situ hybridization was used to localize mRNA expression in vessel cross sections for the 5 differentially expressed PTPases. This revealed that for 3 PTPases (SHP1, CD45, and PTPbeta), differential transcript abundance was due to appearance/loss of the cell types by which they were expressed (leukocytes for SHP1 and CD45, endothelial cells for PTPbeta). However, mRNA expression of 2 PTPases (PTPL1 and PTP1B) was specifically upregulated by proliferating and migrating smooth muscle cells (SMCs) in characteristic temporal and regional patterns in response to vessel damage. Quantitative PCR analysis showed that PTP1B and PTPL1 were induced approximately 30-fold and approximately 60-fold, respectively, by 2 weeks after injury in the damaged vessels compared with the uninjured vessels. PTP1B was rapidly upregulated in the media after vessel injury and remained highly expressed in the developing neointima. By contrast, PTPL1 expression did not increase dramatically until the SMCs had migrated into the intima. The differential expression of PTP1B and PTPL1 by SMCs after injury suggests roles for these PTPases in the regulation of vessel wall remodeling.

Animals↗
PubMed1998

Differential expression of progestin receptor isoforms in the hypothalamus, pituitary, and endometrium of rhesus macaques.

The progestin receptor exists in at least two isoforms: a long form (PR-B) and a short form (PR-A), which can be separated and detected with Western blot analysis. It has been suggested from in vitro transfection experiments that differential expression of the two isoforms may provide one mechanism for tissue specific actions of progesterone (P). However, more information from in vivo experimentation is needed. It has been reported that P down-regulates the expression of PR in the endometrium and pituitary of E primed macaques. However, PR protein and PR messenger RNA expression in the hypothalamus is maintained with P treatment of E-primed macaques. Thus, there is tissue-specific regulation of PR by its cognate ligand in the nonhuman primate. To gain insight into the tissue-specific regulation of PR by P, we questioned whether differential expression of the isoforms of PR exists in the endometrium, pituitary, and hypothalamus of rhesus monkeys. The expression of PR-A and PR-B was examined after E (28-30 days) and E + P (14 days E + 14 days E + P) treatment in the primate endometrium, pituitary, and hypothalamus. After E or E + P treatment, the levels of PR-A were 5 times higher than PR-B in the endometrium. PR-A was 1.6-fold higher than PR-B in the pituitary. In the hypothalamus, the ratio of A to B ranged from less than 1 (B exceeds A) to unity (A and B equimolar). There was no difference in the ratio of A to B between E-treated and E + P-treated groups in any tissue examined. These observations (a) provide further support of the hypothesis that differential expression of the isoforms of PR may subserve the tissue specific actions of P and (b) also suggest that P does not differentially affect the expression of the isoforms of its cognate receptor in the endometrium, pituitary, or hypothalamus.

Animals↗
PubMed2002

Involvement of lipopolysaccharide related receptors and nuclear factor kappa B in differential expression of inducible nitric oxide synthase in chicken macrophages from different genetic backgrounds.

Macrophages from Cornell K-strain chickens (B(15)B(15)) are hyper and from GB2 chickens (B(6)B(6)) are hypo-responders to LPS-mediated inducible NOS (iNOS) expression and activity. The molecular mechanism(s) responsible for this differential expression is not yet fully understood. We have previously reported that macrophages from K (iNOS hyper-responder) and GB2 (iNOS hypo-responder) chickens differ in constitutive expression of TLR4 but not in CD14 molecules. The objectives of the current study was to determine if the iNOS differences between K and GB2 macrophages are possibly due to differential expression of LPS-induced TLR4, CD14 and/or nuclear factor kappa B (NF kappa B). The results showed that Sephadex-elicited, adherence purified K macrophages expressed more inducible TLR4 and CD14 receptors (P<0.05) at 6 and 12h post-LPS stimulation than GB2 macrophages as measured by flow cytometry. In addition, pre-incubation of macrophages from a transformed chicken macrophage cell line, MQ-NCSU, with 50 microg/ml anti-CD14 and anti-TLR4 antibodies significantly reduced where as pre-incubation with 100 microg/ml completely blocked LPS-mediated iNOS activity as measured by nitrite levels. Furthermore, the amount of nuclear bound NF kappa B was found to be significantly greater in K than in GB2 macrophages at 3 min post-LPS stimulation. This nuclear localization of NF kappa B as well as iNOS activity was completely inhibited by pretreatment of macrophages with 50 micro M MG132, a proteosome inhibitor, both in K and GB2 macrophages. Taken together, these findings suggest that a differential and perhaps more stronger LPS-mediated signaling via CD14, TLR4 and NF kappa B is responsible for the heightened iNOS gene induction in K-strain (hyper-responder) macrophages than in GB2 (hypo-responder) chickens.

Animals↗
PubMed2006

[Identification of the differentially expressed genes between primary breast cancer and paired lymph node metastasis through combining mRNA differential display and gene microarray].

OBJECTIVE: To identify and clone the genes related to breast cancer metastasis through comparing the mRNA expression profiling between primary breast cancer and paired lymph node metastasis. METHODS: First, primary breast cancer cells and paired lymph node metastasis tissues were used to identify their differentially expressed genes by using mRNA differential display, and fragments of differentially expressed genes were obtained by gel cutting and cloning to pGEM-T vector, then sequencing and blasting with the GenBank for their homologous genes. Then, the obtained genes were validated by using reverse dot blot hybridization and gene microarray. Finally, the mRNA expression levels in the 7 breast cancer cell lines with different metastasis behaviors were detected by real-time RT-PCR. RESULTS: The mRNA expression profiling of the metastatic breast cancers in lymph node was similar to that of their primary cancers. 16 differentially expressed gene fragments were obtained from mRNA differential display; four of them were found to be unknown genes, and had been accepted by the GenBank, with the accession numbers BG518428, BG518429, BM005520, and BM005521. Of the other 12 genes, 8 were known genes, and 4 were genes with known sequences but unknown functions. The kinesin-like DNA binding protein (KNSL4) and dihydropyrimidine dehydrogenase (DYPD) were down-regulated in the metastatic tissues in comparison with the paired primary tissues, which was identified by both radioactivity-labeled reverse dot blot hybridization and fluorescence-labeled gene microarray hybridization. KNSL4 mRNA expression had a down-regulation trend with increasing metastatic ability of breast cancer cell lines. CONCLUSIONS: The gene expression profiling of the lymph node metastasis is almost similar to that of their primary breast cancer, indicating that the metastatic cancer cells in lymph node are the subclone with higher metastasis ability of the primary cancer cells, and that some differentially expressed genes between them may be involved in the change of metastasis phenotype. KNSL4 and DYPD are potential metastasis-related genes, and KNSL4 mRNA expression is correlated with metastasis behaviors of the breast cancer cell lines, suggesting that KNSL4 may play an important role in the metastasis process of breast cancer.

Breast Neoplasms↗
PubMed2002

Differential expression and genetic variation of hepatic messenger RNAs from genetically lean and fat chickens.

Although excessive adiposity has become a major drawback in meat type chicken production, few of the genes involved in this process have been characterized so far. In order to identify putative genes involved in adiposity, we performed differential display analysis of RNAs extracted from the liver of divergently selected lean and fat chickens. Twenty-six differential products were selected and purified by single strand conformation polymorphism gel electrophoresis before sequencing and Northern blot analyses. An orthologous sequence of a mammalian cytochrome P450 2C subfamily member was proven to be differentially expressed in the liver of lean and fat chickens and could play an important role in the regulation of adiposity. In mammals, these genes are involved in detoxification of xenobiotics and metabolism of some important biological compounds. Four other genes were found differentially expressed to a lower extent. Some unidentified products were shown to be lean or fat specific, with sequence polymorphism and liver specific expression, strongly suggesting that the related gene could be directly involved in adiposity. Our data indicate that differential display can evidence genes with differential expression and with sequence polymorphism, making this strategy more accurate for differential analysis of messenger RNAs.

Adipose Tissue↗
PubMedDate not supplied

Programmed cell death in procyclic form Trypanosoma brucei rhodesiense --identification of differentially expressed genes during con A induced death.

Trypanosoma brucei rhodesiense can be induced to undergo apoptosis after stimulation with Con A. As cell death in these parasites is associated with de novo gene expression we have applied a differential display technique, Randomly Amplified Differential Expressed Sequence-Polymerase Chain Reaction (RADES-PCR) to the study of gene expression during Con A induced cell death in these organisms. Twenty-two differentially displayed products have been cloned and sequenced. These represent the first endogenous genes to be identified as implicated in cellular death in trypanosomatids (the most primitive eukaryote in which apoptosis has been described). Evidence for an ancestral death machinery, 'proto-apoptosis' in single celled organisms is discussed.

Animals↗
PubMed2001

Expression profile of nine novel genes differentially expressed in hepatitis B virus-associated hepatocellular carcinomas.

Chronic hepatitis B virus (HBV) infection is known to be one of the major causes in the development of hepatocellular carcinoma (HCC), although the biomolecular mechanism(s) involved remain unclear. To identify the cellular gene(s) involved in HBV-associated hepatocarcinogenesis, we used the mRNA differential display method and examined three paired tumor and nontumor tissues, all of which had chromosomally integrated HBV-DNA through chronic infection. Using 240 different combinations of three one-base anchored oligo-dT primers and 80 arbitrary 13-mers, genes decreased or increased in expression more than twofold between each tumor tissue and its paired nontumor tissue were identified. Twenty-nine known genes and four novel genes were differentially over-expressed in the HCC tumor tissues. In contrast, 27 known genes and five novel genes were under-expressed in those tumor tissues. The nucleotide sequences of the nine novel gene fragments were determined and their expression patterns were examined in 40 HCC samples. HA61T2, PT18, HG63T1, and HG57T1 were preferentially over-expressed in 32 cases (80%, P<0.001), 24 cases (60%), 23 cases (57.5%) and 22 cases (55%) of the 40 tumor tissues, respectively. There was an increased frequency of HG57T1 over-expression in HCC patients with HBV-positive serology and low serum alpha-feto protein (AFP) levels (P<0.05). DNT10, PT8, PT19, ENT25 and HA6T4 were under-expressed in 26 cases (65%), 23 cases (57.5%), 21 cases (53%), 20 cases (50%) and 18 cases (45%) of the 40 tumor samples, respectively. There was a strong correlation of DNT10 under-expression with high serum AFP level in HCC patients, irrespective of HBV serology (P<0.01). HA6T4 was preferentially under-expressed in HCC tumors in patients with HBV-positive serology and high serum AFP levels (P<0.05). Thus, the functional analyses of the known and novel genes identified in this study should prove valuable to further understand the mechanism(s) of hepatocarcinogenesis.

Base Sequence↗