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PubMed2001

Identifying marker genes in transcription profiling data using a mixture of feature relevance experts.

Transcription profiling experiments permit the expression levels of many genes to be measured simultaneously. Given profiling data from two types of samples, genes that most distinguish the samples (marker genes) are good candidates for subsequent in-depth experimental studies and developing decision support systems for diagnosis, prognosis, and monitoring. This work proposes a mixture of feature relevance experts as a method for identifying marker genes and illustrates the idea using published data from samples labeled as acute lymphoblastic and myeloid leukemia (ALL, AML). A feature relevance expert implements an algorithm that calculates how well a gene distinguishes samples, reorders genes according to this relevance measure, and uses a supervised learning method [here, support vector machines (SVMs)] to determine the generalization performances of different nested gene subsets. The mixture of three feature relevance experts examined implement two existing and one novel feature relevance measures. For each expert, a gene subset consisting of the top 50 genes distinguished ALL from AML samples as completely as all 7,070 genes. The 125 genes at the union of the top 50s are plausible markers for a prototype decision support system. Chromosomal aberration and other data support the prediction that the three genes at the intersection of the top 50s, cystatin C, azurocidin, and adipsin, are good targets for investigating the basic biology of ALL/AML. The same data were employed to identify markers that distinguish samples based on their labels of T cell/B cell, peripheral blood/bone marrow, and male/female. Selenoprotein W may discriminate T cells from B cells. Results from analysis of transcription profiling data from tumor/nontumor colon adenocarcinoma samples support the general utility of the aforementioned approach. Theoretical issues such as choosing SVM kernels and their parameters, training and evaluating feature relevance experts, and the impact of potentially mislabeled samples on marker identification (feature selection) are discussed.

Acute Disease↗

PubMed1990

A transcribed gene in an intron of the human factor VIII gene.

We have identified a CpG island contained within the largest factor VIII intron. This island is associated with a 1.8-kb transcript and, unlike factor VIII, is produced abundantly in a wide variety of cell types. The nested gene is oriented in a direction opposite to that of factor VIII and contains no intervening sequences. A cDNA of 1739 bases was isolated from a human liver library and found to have a GC-rich, long open reading frame. Two computer-assisted methods (Fickett TESTCODE and Staden-McLachlan codon usage) predict that the gene codes for a protein. Two other copies of this gene are located within 1.1 Mb of the factor VIII gene. Northern blot analysis of RNA isolated from hemophilia patients deleted for factor VIII sequences has shown that both the intron gene and at least one other copy of the gene are transcribed. A homologous, transcribed sequence is also present in mice.

Amino Acid Sequence↗

PubMed1993

Chromosomal mapping of the human CNP gene using a meiotic crossover DNA panel, PCR, and allele-specific probes.

The human 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) gene is located on chromosome 17, as determined by PCR of somatic cell hybrid DNA panels and confirmed using a mouse-human hybrid containing only human chromosome 17. A polymorphic site (C, T) was previously described at nucleotide 1215 within the most 3' intron of the gene. Nested PCR primer pairs were designed to amplify across this site, and PCR products were hybridized to end-labeled allele-specific probes. To localize further the CNP gene within chromosome 17, a two-step strategy was used. First, dot blots containing DNA from the parents of 10 three-generation families were screened to identify the potentially informative families. Second, 53 members of four selected families were typed at this locus. Previous studies had shown that the 29 siblings present in these four families carry a total of 84 meiotic breakpoints on chromosome 17. Based on the genotypes observed in these 29 siblings, the human CNP gene was localized to a fragment on 17q bounded by THRA1 (thyroid receptor A1) and NGFR (nerve growth factor receptor), a genetic distance of approximately 6 cM.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗

PubMed2002

Historical development of the concept of the gene.

The classical view of the gene prevailing during the 1910s and 1930s comprehended the gene as the indivisible unit of genetic transmission, genetic recombination, gene mutation and gene function. The discovery of intragenic recombination in the early 1940s led to the neoclassical concept of the gene, which prevailed until the 1970s. In this view the gene or cistron, as it was now called, was divided into its constituent parts, the mutons and recons, materially identified as nucleotides. Each cistron was believed to be responsible for the synthesis of one single mRNA and concurrently for one single polypeptide. The discoveries of DNA technology, beginning in the early 1970s, have led to the second revolution in the concept of the gene in which none of the classical or neoclassical criteria for the definition of the gene hold strictly true. These are the discoveries concerning gene repetition and overlapping, movable genes, complex promoters, multiple polyadenylation sites, polyprotein genes, editing of the primary transcript, pseudogenes and gene nesting. Thus, despite the fact that our comprehension of the structure and organization of the genetic material has greatly increased, we are left with a rather abstract, open and general concept of the gene. This article discusses past and present contemplations of genes, genomes, genotypes and phenotypes as well as the most recent advances of the study of the organization of genomes.

Genetics↗

PubMed1996

Characterization of the genes, including that encoding the viral proteinase, contained in BamHI restriction fragment 9 of the pseudorabies virus genome.

We describe the nucleotide sequence, transcription pattern and open reading frames (ORFs) located on BamHI restriction fragment 9 (0.406-0.435 map units) in the unique long segment of the pseudorabies virus (PRV) genome. The fragment contains three nested genes with a common 3' end. The 5' ends of the corresponding 0.9, 1.7 and 3.3 kb mRNAs have been mapped. Fragment BamHI-9 contains three complete ORFs, ORF1, ORF2 and ORF2.5. ORF1, which is within the 3.3 kb transcript, encodes a protein with an apparent molecular mass of 60 kDa which is homologous to the product of the herpes simplex virus type 1 UL25 gene. The 1.7 kb mRNA contains ORF2, whose product is homologous to the herpesvirus proteinases, while the 0.9 kb transcript contains ORF2.5, which probably encodes the assembly protein precursor. ORF2 was identified as the PRV proteinase gene following expression in E. coli, using the product of ORF2.5 as the substrate protein.

Amino Acid Sequence↗

PubMed2005

Unexpected detection of simian SA11-human reassortant strains of rotavirus G3P[8] genotype from diarrhea epidemic among tribal children of Western India.

This investigation is in continuation with the earlier studies on diarrhea epidemic due to rotavirus, that occurred at Jawhar western India, among tribal children during Dec 2000-Jan 2001 published by National Institute of Virology, Pune. Three rotavirus strains were isolated in cell culture from fecal specimens of affected children. Monoclonal antibody ELISA and RT-PCR typed the isolates as G3P [8]. Two isolates agglutinated guinea pig erythrocytes thereby indicating their animal origin. Antiserum against simian G3, SA11 neutralized both the isolates largely than antiserum against human G3 (YO). Nucleotide sequencing of VP7 gene, nested PCR product of three isolates, and two original fecal specimens showed 100% identity with both simian G3, SA11 prototype and ROSVP7, SA11 strains whereas, lower identity (82%) with human G3 (YO) strain. Partial sequence analysis of the VP4 gene of fecal specimen FS-006964 & isolate I-006964 showed 99% identity with G1P[8] strain, while 80% identity with simian G3P[2], SA11 strain. Thus, the strains appeared to be reassortants between human and simian origin. Serological studies further supported the identity of the causative agent as simian G3, SA11 like strains. Neutralizing antibody titers at very low level against simian G3, SA11 as well as human G3 (YO) strains among the population at Jawhar suggested an overall lack of immunity against the virus. Seroconversion against simian G3, SA11 was shown by six out of seven child patients. Thus, simian G3, SA11 like strains are claimed for the first time as etiological agents of diarrhea in humans.

Child↗

PubMed2005

[The incidence rate of hepatitis B virus surface gene variants in Korean children with immunoprophylaxis failure of perinatal infection].

BACKGROUND/AIMS: Perinatal infection with hepatitis B virus (HBV) may occur despite immunoprophylaxis. One of the important mechanisms for perinatal prophylaxis failure, might include HBV surface gene variants. Therefore, we screened Korean children, in whom perinatal prophylaxis failed, for HBV surface gene variants. METHODS: Thirty-one children with perinatal HBV prophylaxis failure were selected. To amplify the major hydrophilic region of the HBV surface gene, nested PCR with primers targeted to nucleotides 237 to 706 was performed, and then sequencing was done. RESULTS: All cases were shown to be PCR positive for HBV-DNA and genotype C. Nine out of 31 (29%) with perinatal prophylaxis failure had a nucleotide substitution at the major hydrophilic region of the gene; but only two cases (6.5%) had an amino acid substitution. One case was infected by wild type and variants of I126S, and the other by wild type and S114A+I126S, respectively. CONCLUSIONS: In Korea, compared to the previous studies of other nations, gene surface variants such as G145R do not appear to play an important role in perinatal immunoprophylaxis failure.

Child↗

PubMed1998

Nested primers improve sensitivity in the detection of Helicobacter pylori by the polymerase chain reaction.

To investigate potential routes of spread of infection by the polymerase chain reaction (PCR) it is important that the technique is effective in the types of specimen to be investigated. To establish the limits of detection of Helicobacter pylori by PCR in clinical material from the gastric mucosa, faeces, dental plaque and oral rinses, samples were seeded with known numbers of bacteria. DNA extraction was followed by amplification with primers from the urease C gene. Nested primers were used to amplify the PCR product which was detected using a digoxigenin-labelled probe. Faeces or plaque inhibited the single reaction 10(2)-10(6) fold. A second amplification using nested primers and probing increased the sensitivity to a level similar to that obtained with pure culture. This method is potentially useful with less likelihood of false negative results when trying to detect H. pylori by PCR in highly contaminated, clinical material.

DNA Primers↗

PubMed2004

Increased expression of Drosophila tetraspanin, Tsp68C, suppresses the abnormal proliferation of ytr-deficient and Ras/Raf-activated hemocytes.

Tetraspanins are evolutionary conserved transmembrane proteins thought to facilitate cell proliferation, movement or fusion by acting as organizers of different signaling events. Despite their prevalence and conservation, their specific role and functions remain largely elusive, as their redundancy in various organisms has hindered loss of function studies. Here, we take a gain of function approach to study Drosophila tetraspanin Tsp68C and its effect on larval hemocytes. We recently characterized a lethal mutation in ytr, a conserved gene that encodes a nuclear arginine-rich protein of unknown function, which is accompanied by abnormal differentiation and proliferation of the larval hematopoietic tissue in flies. A hemolectin (hml)-Gal4 construct carried by hml-Gal4 transgenic flies was sufficient by itself to abrogate the hematopoietic defects in ytr mutant larvae. This rescue correlated with the overexpression of tsp68C, a tetraspanin gene nested in the hml promoter. The suppression of abnormal proliferation by the hml-Gal4 construct was not restricted to ytr-deficient hemocytes, but was also observed in hemocytes expressing the oncogenic forms of Raf or Ras proteins. However, it had no effect on overproliferation mediated by a constitutively active form of Jak. New hml-Gal4 lines, in which the tsp68C gene was silenced or deleted from the promoter, no longer rescued the hematopoietic defect in ytr mutants nor suppressed the activated Raf-induced overproliferation. Therefore, change in tetraspanin Tsp68C expression has a strong suppressor effect on abnormal proliferation and differentiation of hemocytes in the context of specific lesions, such as overactivation of the Ras/Raf/MAPK pathway.

Amino Acid Sequence↗

PubMed1988

Differential premature termination of transcription as a proposed mechanism for the regulation of coronavirus gene expression.

We propose that the different subgenomic mRNA levels of coronaviruses are controlled through differential premature termination of transcription, and are modulated by the relative strength of transcriptional initiation/blockage events. We present the complete set of sequences covering the leader encoding and intergenic regions of the MHV-A59 strain. A computer-assisted analysis of the two now complete sets of these sequences of strain IBV-M42 and MHV-A59 shows that, in contrast to the previous theory, differences amongst stabilities of intermolecular base-pairings between the leader and the intergenic regions are not sufficient to determine the mRNA gradients in both MHV and IBV infected cells. Neither can the accessibility of the interacting regions on the leader and the negative stranded genome, as revealed by secondary structure analysis, explain the mRNA levels. The nested gene organisation itself, on the other hand, could be responsible for observed mRNA levels gradually increasing with gene order. Relatively slow new initiation events at intergenic regions are proposed to block elongation of passing transcripts which, via temporary pausing, can cause premature termination of transcription. This effects longer transcripts more than shorter ones.

Base Composition↗

PubMed1992

Unusual organizational features of the Drosophila Gart locus are not conserved within Diptera.

The Drosophila Gart locus consists of two genes. One gene encodes three enzymes in the de novo purine nucleotide biosynthesis pathway [glycinamide ribonucleotide synthetase (GARS), aminoimidazole ribonucleotide synthetase (AIRS), and glycinamide ribonucleotide transformylase (GART)]. The second gene lies within an intron of the purine gene and encodes a cuticle protein. To investigate the evolution of the Gart locus, the Chironomus tentans homolog was cloned by screening a genomic DNA library with a polymerase chain reaction product. This study shows that the interesting structural features of this locus conserved in two distant Drosophila species are not found in the Chironomus homolog. These features include the cuticle protein gene nested within an intron and the existence of an alternative transcript to yield a monofunctional enzyme. In addition, the extremely rapid divergence of coding sequence seen for members of the tandemly duplicated AIRS domain in Drosophila is found to be much less rapid in Chironomus.

Acyltransferases↗

PubMed1996

Genomic PCR detects tumor cells in peripheral blood from patients with myxoid liposarcoma.

Myxoid liposarcoma (MLS) is the most common subtype of liposarcoma. The cytogenetic hallmark of MLS is the pathognomonic t(12;16)(q13;p11), present in more than 85% of cases. The translocation leads to the fusion of the CHOP and FUS genes at 12q13 and 16p11, respectively, and the generation of a FUS/CHOP hybrid protein. The presence of a tumor-specific chimeric gene makes it possible to identify MLS cells by polymerase chain reaction (PCR). We have analyzed peripheral blood samples obtained during a 10-year period at diagnosis of primary and/or recurrent disease in 19 MLS patients with t(12;16) and in one MLS patient with t(12;22;20), resulting in the fusion of the CHOP and EWS genes. Nested PCR on genomic DNA from blood samples amplified FUS/CHOP hybrid fragments in three patients and EWS/CHOP in the patient with t(12;22;20). There was no obvious association between PCR findings and clinical outcome, but larger series are needed to draw any firm conclusions.

Adult↗

PubMed1986

Relationship of prevalence of non-insulin-dependent diabetes mellitus to Amerindian admixture in the Mexican Americans of San Antonio, Texas.

A genetic and epidemiological survey of non-insulin-dependent diabetes mellitus (NIDDM) was conducted among the Mexican Americans residing in three socioeconomically distinct areas of San Antonio, Texas: a low socioeconomic (SES) traditional area (barrio), a middle SES, ethnically balanced area (transitional), and a high SES, predominantly Anglo area (suburb). Seventeen polymorphic markers were used to relate the prevalences of NIDDM with the extent of Amerindian ancestry of 1,237 Mexican Americans of these three residential areas. While only the RH and haptoglobin loci showed evidence of association with NIDDM, an admixture analysis of the combined allele frequency data revealed a pattern of decreasing NIDDM prevalence with increasing socioeconomic status (as approximated by neighborhood of residence) and a parallel decrease in Amerindian ancestry. The rank-order correlation between NIDDM prevalence and Amerindian admixture is 0.943 (P less than .001) for the crude prevalence rate and 0.829 (P less than .02) for the age-adjusted rate. Nested gene diversity analysis revealed that the heterogeneity of allele frequencies is more pronounced when individuals were classified by their NIDDM disease status as compared to the classification by neighborhood. Estimation of Amerindian ancestry of each individual did not reveal any significant change in the shape of the distributions of individual admixture proportions in diabetics as compared to the controls. Nevertheless, the results suggest that genetic factors partially explain the differences in NIDDM prevalence observed between the Mexican American and Anglo populations in the southwestern United States.

Adult↗

PubMed1998

A second family with nonsyndromic sensorineural hearing loss linked to Xp21.2: refinement of the DFN4 locus within DMD.

X-linked inherited hearing impairment is a group of heterogeneous disorders accounting for less than 2% of hereditary hearing loss. DFN4, a sex-linked hearing impairment associated with profound sensorineural hearing loss, has been previously mapped to Xp21.2, a region containing the DMD locus. We have identified a family from Turkey with deafness in which the disease maps to and refines the DFN4 locus. In contrast to the previous family, the crossover points are entirely within the DMD locus. Two-point lod score analysis for the markers DXS 997, DXS 1214, and DXS 1219 showed a lod score of 2. 59. 5' and 3' crossovers were between DMD 44 and DXS 1219 and between DXS 1214 and DXS 985, respectively, suggesting that DFN4 is either an allele of DMD or a mutation in a DMD nested gene. The restriction of the DFN4 locus to DMD suggests that dystrophin may play an important role in hearing.

Chromosome Mapping↗

PubMed1998

Nucleotide sequence and infectivity of a full-length cDNA clone of panicum mosaic virus.

The sequence of an infectious cDNA clone of panicum mosaic virus (PMV) showed that the single-stranded RNA genome is 4326 nucleotides (nt) and a single highly abundant subgenomic (sg) RNA of 1475 nt was synthesized during PMV infection of pearl millet plants and protoplasts. Computer comparisons revealed strong similarities between the predicted amino acid sequences of the p48 and p112 open reading frames (ORFs) and replicase proteins of members of the Tombusviridae. The sgRNA has the potential to encode five proteins. Three small ORFs, p8, p8-FS, and/or p6.6 have similarity to ORFs of carmo-, necro-, and machlomoviruses thought to be involved in virus spread in plants. The sgRNA also has the potential to encode a 26-kDa capsid protein and a 15-kDa nested gene (p15) of unknown function. PMV transcripts also supported replication and movement of SPMV, the satellite virus. Genome organization, physicochemical properties, and biological features indicate that PMV is a member of the Tombusviridae family. However, PMV differs sufficiently from previously described members to warrant its placement in a new genus provisionally designated Panicovirus.

Amino Acid Sequence↗

PubMed2004

Findings in an independent sample support an association between bipolar affective disorder and the G72/G30 locus on chromosome 13q33.

Markers near the nested genes G72 and G30 on chromosome 13q33 have been implicated in the etiology of schizophrenia and, recently, bipolar affective disorder (BPAD). Hattori et al (2003) reported that single-nucleotide polymorphisms (SNPs) near the G72/G30 locus were associated with BPAD in a sample of 22 pedigrees, and that SNP haplotypes were associated in a second, larger sample of triads. The present study attempts to replicate this finding in an independent case-control sample. Six SNPs near the G72/G30 locus, including the most strongly associated markers in the previous study, were tested in 139 cases and 113 ethnically matched controls. Significant association was detected between BPAD and two adjacent SNPs (smallest P=0.007; global P=0.024). Haplotype analysis produced additional support for association (smallest P=0.004; global P=0.004). Analysis of 31 unlinked microsatellite markers detected no population stratification in the cases or controls studied. Although the associated alleles and haplotypes differ from those previously reported, these new results provide further evidence, in an independent sample, for an association between BPAD and genetic variation in the vicinity of the genes G72 and G30.

Bipolar Disorder↗

PubMed2003

Polymerase chain reaction-based diagnosis of infection with Cryptosporidium in children with primary immunodeficiencies.

BACKGROUND: Patients with deficient cell-mediated immunity are prone to chronic biliary tract infection with Cryptosporidium, which can lead to the development of sclerosing cholangitis and acute cryptosporidiosis after bone marrow transplantation (BMT). The organism is very difficult to detect during asymptomatic periods. METHODS: PCR techniques were compared with standard microscopy for detecting the organism in such patients. Amplification targets were two fragments of the 18S ribosomal RNA gene (unnested) and part of the Cryptosporidium oocyst wall protein gene (nested and unnested). Twenty eight-patients with primary immunodeficiencies were studied including: CD40 ligand deficiency (13); undefined combined immunodeficiency (10); major histocompatibility complex II deficiency (2); and other defects (3). Samples analyzed included stool, bile and liver tissue. RESULTS: Of 25 patients tested prospectively, Cryptosporidium could be detected by PCR but not by microscopy in 12, only 3 of whom had a known history of infection. Five of this group had sclerosing cholangitis. Nine of the PCR-positive patients subsequently underwent BMT and 5 developed acute posttransplant diarrhea and cholangiopathy associated with Cryptosporidium excretion. Of the 13 PCR-negative patients, 3 had cholangiopathy (sclerosing cholangitis in 1 and minor changes in 2). Four of these underwent BMT and none developed cryptosporidiosis. In 3 patients, studied only after developing post-BMT cholangiopathy and diarrhea, Cryptosporidium was detected by PCR but not by microscopy. Genotyping and sequencing showed multiple types of Cryptosporidium in approximately one-third of positive cases. CONCLUSIONS: These results indicate that PCR-based procedures are more sensitive than microscopy for detecting Cryptosporidium in patients with immunodeficiencies.

Adolescent↗

PubMed2002

[Rapid identification of human testis spermatocyte apoptosis-related gene, TSARG2, by nested PCR and draft human genome searching].

Cloning apoptosis-related novel genes is a key to further understanding of apoptosis mechanism and the biology process of germ cells, and is of momentous significance on clarifying physiological and pathological process of spermatogenesis. To rapidly attain human novel gene full-length cDNA sequence, the gene-specific primers and the vector-specific primers were designed for nested PCR, and draft human genome searching was performed to rapidly identify the TSARG2 (GenBank accession number AY040204) 5' end from a human testis cDNA library, by using a cDNA fragment (GenBank accession number BE644542) as an electronic probe, which was significantly changed in cryptorchidism and represented a novel gene. Furthermore, a mouse homologue of this gene was identified (GenBank accession number AF395083) by lab on-line. TSARG2 with a 1 233 bp length was composed of 6 exons and spanned about 115 kb of genomic DNA, The putative protein encoded by this gene was 305 amino acid with a theoretical molecular weight of 34 751 dalton and did not share significant homology with any known protein in databases. TSARG2 was expressed in many tissues and mapped to chromosome 4q33-34.1 by database analyses. Therefore, we propose that nested-PCR and draft human genome searching are rapid, sensitive, accurate and efficient method for isolating gene 5' end, even full-length gene from cDNA library.

Amino Acid Sequence↗