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PubMedDate not supplied

[DRD4 polymorphism and the association with mental disorders].

The dopamine D4 receptor (DRD4) is the most important gene in psychiatric genetics since its involvement in the physiology of behavior, pharmacology response and psychopathology. DRD4's sequence gene present some polymorphism such as in the exon 3 constituted from 2 to 10 copies of repetitive sequences of 48 base pair (bp), from class variable number tandem repeats (VNTR). An additional genetic variant in the exon 1 presents polymorphisms to 12 bp VNTR, and the variation -521 C by T of the promoter region. The -521 T allele can reduce the efficiency of the gene expression in comparison with the C allele. The DRD4 gene codes a protein transmembranal of 7 domains, distributed in front cortex, striatum, hypothalamus and hippocampus. This review discusses the biological significance of DRD4 gene and its perspective with emphasis on the impact of association studies in some illness mental and behavioral traits. The DRD4 polymorphism has been studied in association with illnesses like schizophrenia, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive with tics, bipolar manic-depressive disorder, in addition behavioral traits such as novelty seeking. The DRD4 gene is a genetic marker that could play a role in etiology of different mental illness, and behavioral traits, and its polymorphism can be used in association studies, epigenetic and pharmacogenomic analysis for help to understand the genetics basis of both mental disorders and traits.

Humans↗
PubMed1996

Use of a fluorescent-PCR reaction to detect genomic sequence copy number and transcriptional abundance.

We present a fluorescent-PCR-based technique to assay genomic sequence copy number and transcriptional abundance. This technique relies on the ability to follow fluorescent PCR progressively in real time during the exponential phase of the reaction so that quantitative PCR is accomplished. We demonstrated the ability of this technique to quantitate both known deletions and amplifications of loci that have been measured previously by other methods, and to measure transcriptional abundance. Using an efficient variant of the fluorescent-PCR technology, we can monitor transcription semiquantitatively. The ability to detect all amplifications and deletions at any single copy locus by PCR makes this the technique of choice to assay genomic sequence copy number anomalies in birth defects and cancers. The ability to detect variations in transcript abundance enables this technique to fashion a time and tissue analysis of transcription.

Chromosome Aberrations↗
PubMed2005

Variation in 16S-23S rRNA intergenic spacer regions in Photobacterium damselae: a mosaic-like structure.

Phenotypically, Photobacterium damselae subsp. piscicida and P. damselae subsp. damselae are easily distinguished. However, their 16S rRNA gene sequences are identical, and attempts to discriminate these two subspecies by molecular tools are hampered by their high level of DNA-DNA similarity. The 16S-23S rRNA internal transcribed spacers (ITS) were sequenced in two strains of Photobacterium damselae subsp. piscicida and two strains of P. damselae subsp. damselae to determine the level of molecular diversity in this DNA region. A total of 17 different ITS variants, ranging from 803 to 296 bp were found, some of which were subspecies or strain specific. The largest ITS contained four tRNA genes (tDNAs) coding for tRNA(Glu(UUC)), tRNA(Lys(UUU)), tRNA(Val(UAC)), and tRNA(Ala(GGC)). Five amplicons contained tRNA(Glu(UUC)) combined with two additional tRNA genes, including tRNA(Lys(UUU)), tRNA(Val(UAC)), or tRNA(Ala(UGC)). Five amplicons contained tRNA(Ile(GAU)) and tRNA(Ala(UGC)). Two amplicons contained tRNA(Glu(UUC)) and tRNA(Ala(UGC)). Two different isoacceptor tRNA(Ala) genes (GGC and UGC anticodons) were found. The five smallest amplicons contained no tRNA genes. The tRNA-gene combinations tRNA(Glu(UUC))-tRNA(Val(UAC))-tRNA(Ala(UGC)) and tRNA(Glu(UUC))-tRNA(Ala(UGC)) have not been previously reported in bacterial ITS regions. The number of copies of the ribosomal operon (rrn) in the P. damselae chromosome ranged from at least 9 to 12. For ITS variants coexisting in two strains of different subspecies or in strains of the same subspecies, nucleotide substitution percentages ranged from 0 to 2%. The main source of variation between ITS variants was due to different combinations of DNA sequence blocks, constituting a mosaic-like structure.

Base Sequence↗
PubMedDate not supplied

[Detection of intragenomic polymorphism in the LR2 region of human intergenic ribosomal spacer].

It is a common point of view today that tandem ribosomal genes are subject to concerted evolution, a process that promotes homogeneity among the many copies through the mechanisms of unequal homologous exchange and gene conversion. These mechanisms can lead to opposite results: they can correct and eliminate new variants and they also can promote the spread of new gene variants throughout individual gene clusters among homologous and non homologous chromosomes. A number of experiments performed to decide which of these mechanisms is more important have yielded contradictory answers to this question. In this work we have cloned and partially sequenced 36 PCR-amplified copies of the human rIGS segment 22763-23523 apart from the transcription start point, obtained from the individual genome. This segment is enriched by (G)n and (AG)n clusters and enters into 2kb LR2 element of the human rIGS. Comparative analysis showed that absolutely identical sequences are absent among 36 inserts sequenced. The 26 clones differed only on a number of repeating elements in the paralogous (G)n and (AG)n clusters. The last ten clones differed not only on a number of cluster repeating elements, but contained insertions and deletions of distinct sizes, which do not correspond to the human rIGS polymorphism variants described earlier.

Base Sequence↗
PubMed2003

Genesis of variants of Vibrio cholerae O1 biotype El Tor: role of the CTXphi array and its position in the genome.

The gene encoding cholera toxin, the principal virulence factor of Vibrio cholerae, is encoded by a filamentous, lysogenic bacteriophage known as CTXphi. The genome of V. cholerae, the host for CTXphi, consists of two chromosomes, one large and one small. Here, it is shown that localization and array of CTX prophage DNA in either the large or small chromosome of V. cholerae is likely to be one of the reasons for the emergence of O1 biotype El Tor variants isolated just before and after the V. cholerae O139 cholera outbreak in 1992. Analyses of the organization of the CTX region of the genome of pre-O139 El Tor strains revealed that these strains carry two distinct CTX prophages integrated in the small chromosome in tandem: CTX(ET), the prophage having a conserved NotI site in its repeat sequence segment which seems to be specific for the El Tor strains so far examined, followed by CTX(calc)-like genome, the prophage found in recent O139 clinical isolates from Calcutta. In sharp contrast, in post-O139 El Tor strains only one copy of the CTX(ET) prophage was found to be integrated in the large chromosome. To the authors' knowledge, the presence of CTX prophage in the small chromosome of O1 El Tor strains has not been reported previously. It is also shown that the difference in the CTX copy number and the position of the bacteriophage on the genomes of pre- and post-O139 El Tor strains have an effect on cholera toxin production. While a pre-O139 strain produced maximum cholera toxin in yeast extract/peptone medium at 30 degrees C, a post-O139 El Tor strain showed maximal yield at 37 degrees C, indicating differential regulation of cholera toxin between the strains. It appears from this study that the variation in the integration site of the CTX prophage, its copy number and the presence of diverse phage genomes in V. cholerae O1 biotype El Tor may be strategically important for generating variants with subtle phenotypic modulations of virulence factor production in this longest-ruling seventh pandemic strain.

Bacteriophages↗
PubMed1982

pIJ101, a multi-copy broad host-range Streptomyces plasmid: functional analysis and development of DNA cloning vectors.

Streptomyces lividans ISP 5434 contains four small high copy number plasmids: pIJ101 (8.9 kb), pIJ102 (4.0 kb), pIJ103 (3.9 kb) and pIJ104 (4.9 kb). The three smaller species appear to be naturally occurring deletion variants of pIJ101. pIJ101 and its in vivo and in vitro derivatives were studied after transformation into S. lividans 66. pIJ101 was found to be self-transmissible by conjugation, to elicit "lethal zygosis" and to promote chromosomal recombination at high frequency in both S. lividans 66 and S. coelicolor A3(2). A restriction endonuclease cleavage map of pIJ101 was constructed for 11 endonucleases; sites for five others were lacking. Many variants of pIJ101 were constructed in vitro by inserting DNA fragments determining resistance to neomycin, thiostrepton or viomycin, and having BamHI termini, into MboI or BclI sites on the plasmid, sometimes with deletion of segments of plasmid DNA. The physical maps of these plasmids were related to their phenotypes in respect of lethal zygosis and transfer properties. In vivo recombination tests between pairs of variant plasmids were also done. These physical and genetic studies indicated that determinants of conjugal transfer occupy less than 2.1 kb of the plasmid. A second segment is required for spread of the plasmid within a plasmid-free culture to produce the normal lethal zygosis phenotype: insertion of foreign DNA in this region caused a marked reduction in the diameter of lethal zygosis zones. The minimum replicon was deduced to be 2.1 kb or less in size; adjacent to this region is a 0.5 kb segment which may be required for stable inheritance of the plasmid. The copy number of several derivatives of pIJ101 in S. lividans 66 was between 40 and 300 per chromosome and appeared to vary with the age or physiological state of the culture. pIJ101 derivatives have a wide host range within the genus Streptomyces: 13 out of 18 strains, of diverse species, were successfully transformed. Knowledge of dispensable DNA segments and the availability of restriction sites for the insertion of DNA, deduced from the properties of plasmids carrying the E. coli plasmid pACYC184 introduced at various sites, was used in the construction of several derivatives of pIJ101 suitable as DNA cloning vectors. These were mostly designed to be non-conjugative and to carry pairs of resistance genes for selection. They include a bifunctional shuttle vector for E. coli and Streptomyces; a Streptomyces viomycin resistance gene of this plasmid is expressed in both hosts.

Chromosome Deletion↗
PubMed2006

Prevalent mutations in prostate cancer.

Quantitative and structural genetic alterations cause the development and progression of prostate cancer. A number of genes have been implicated in prostate cancer by genetic alterations and functional consequences of the genetic alterations. These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function. More genes relevant to prostate cancer remain to be identified in each of these gene groups. For the genes that have been identified, most need additional genetic, functional, and/or biochemical examination. Identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer.

Animals↗
PubMed2005

Cloning of bradykinin precursor cDNAs from skin of Bombina maxima reveals novel bombinakinin M antagonists and a bradykinin potential peptide.

Bombinakinin M (DLPKINRKGP-bradykinin) is a bradykinin-related peptide purified from skin secretions of the frog Bombina maxima. As previously reported, its biosynthesis is characterized by a tandem repeats with various copy numbers of the peptide and sometimes co-expressed with other structure-function distinguishable peptides. At present study, two novel cDNAs encoding bombinakinin M and its variants were cloned from a cDNA library from the skin of the frog. The encoded two precursor proteins are common in that each contains three repeats of a novel 16-amino acid peptide unit and one copy of kinestatin at their N- and C-terminal parts, respectively. They differ in that the first precursor contains two copies of bombinakinin M and the second one contains one copy of a novel bombinakinin M variant. Bombinakinin M was found to elicit concentration-dependent contractile effects on guinea pig ileum, with an EC50 value of 4 nM that is four times higher than that of bradykinin (1 nM). Interestingly, the synthetic peptide (DYTIRTRLH-amide), as deduced from the 16-amino acid peptide repeats in the newly cloned cDNAs, possessed weak inhibitory activity on the contractile effects of bombinakinin M, but not on that of bradykinin. Furthermore, the newly identified bombinakinin M variant (DLSKMSFLHG-Ile1-bradykinin), did not show contractile activity on guinea pig ileum, but showed potentiation effect on the myotropic activity of bradykinin. In a molar ratio of 1:58, it augmented the activity of bradykinin up to two-fold.

Amino Acid Sequence↗
PubMed2001

Correlation of hepatitis B virus load with loss of e antigen and emerging drug-resistant variants during lamivudine therapy.

It remains unclear whether sequential assessment of hepatitis B virus (HBV) load during lamivudine therapy can predict the loss of hepatitis B e antigen or emergence of drug-resistant variants. Therefore, a longitudinal study was carried out in 28 consecutive patients with chronic hepatitis B who started lamivudine therapy for a median of 12 months (range, 6-31). HBV DNA copy numbers were determined at 3-month intervals. From month 6 onward, HBV viral load below the detection limit of the PCR was predictive of the loss of envelope antigen (P = 0.043). Continuously detectable HBV DNA during the first 12 months of treatment indicated emergence of drug-resistant variants (P = 0.034). These data suggest that the goal of lamivudine therapy should be complete suppression of serum HBV DNA.

Administration, Oral↗
PubMed2005

Distribution of saa gene variants in verocytotoxigenic Escherichia coli isolated from cattle and food.

The pathogenesis of verocytotoxigenic Escherichia coli (VTEC) infection in humans is multifactorial, given that verocytotoxins are the principal virulence factor. Most strains causing serious diseases possess the eae gene that encodes the adhesin intimin, but its presence is not essential for virulence as some cases are caused by eae-negative strains. An autoagglutinating adhesin designated Saa was found in some eae-negative strains. This protein varies in size as a consequence of variation in the number of copies of a 37-aa repeat unit in the C-terminal region. Based on these findings, we designed PCR primers to amplify the region coding for these differences to detect saa gene variants present in VTEC strains isolated in Argentina from cattle and meat. The gene saa was detected in 36 (31.6%) eae-negative strains and 5 variants were found. Strains isolated from cattle possessed 4 saa variants, whereas 2 variants were present in isolates from meat. Saa variant 1 predominated (18 strains) and was distributed in strains isolated both from cattle and from meat. Our study revealed the existence of two novel saa variants, termed 4 and 5, which have a higher number of 111-bp repeats than saa genes previously studied.

Adhesins, Bacterial↗
PubMed2006

DLG5 variants contribute to Crohn disease risk in a Canadian population.

Variants in the gene encoding the DLG5 scaffolding protein have been reported to be associated with increased risk of inflammatory bowel disease (IBD) and particularly Crohn's disease (Crohn disease; CD). These findings have not been uniformly replicated in follow-up studies. In this study we genotyped a cohort of 402 Canadian CD and 179 ulcerative colitis (UC) patients and 537 healthy controls for three IBD/CD-associated DLG5 variants. Our data reveal that the common DLG5 haplotype (A), which was previously considered protective for IBD, is associated with modest increases in risk for IBD (P=0.02) and CD (P=0.04). The effects of haplotype copy number on risk for IBD were minor, with the odds ratio (ORs) being 1.37 for the heterozygous risk genotype and 1.7 for the homozygous risk genotype. While we were unable to replicate the proposed association between the DLG5 c.113G>A variant and IBD, an association of IBD (P=0.02) and CD (P=0.04) with the rarer c.4136C>A variant was replicated in this cohort. These associations were restricted to the non-Jewish subjects in this cohort and were not detected in the Ashkenazi Jewish population studied here. Within the non-Jewish group, no associations were detected between the DLG5 variants and specific phenotypic features, such as site of disease, and there was no evidence of epistasis between DLG5 and any of the CD-associated CARD15 or SLC22A4/A5 gene variants. Together, the results indicate a role for DLG5 variants in IBD susceptibility and suggest that further studies are warranted to evaluate this role in different IBD populations and to determine the functional pathways that couple DLG5 variants to IBD.

Adult↗
PubMed2026

Pan-Cancer Quantification of Driver Alteration Transmission Across Molecular Layers Reveals Limited Propagation to Protein Abundance.

Precision oncology relies primarily on DNA-level alterations for therapeutic decisions, but the extent to which driver mutations propagate to protein abundance has not been systematically evaluated. Here, I developed a regression-based transmission score (TS_R 2) to quantify driver alteration signal propagation across DNA, mRNA, and protein layers. Applying this framework to matched genomic, transcriptomic, proteomic, and phosphoproteomic data from 754 Clinical Proteomic Tumor Analysis Consortium (CPTAC) tumors across seven cancer types, I analyzed 86 driver gene-cancer type pairs, of which 83 were evaluable for the full two-layer transmission score. I employed covariate-adjusted regression for each molecular transition, assessing significance via permutation testing (n = 1000). Mixed-effects modeling then partitioned gene-intrinsic from cancer-type-dependent effects. Only 5 of 83 evaluable pairs (6%) demonstrated high transmission (TS_R 2 > 0.05), with receptor tyrosine kinases (EGFR, FGFR2) exemplifying this class. The primary bottleneck occurred at the mutation-mRNA transition, not mRNA-protein translation. Gene identity accounted for 49% of transmission efficiency variance, nearly double the contribution of cancer type (29%). Copy number alterations transmitted signals 13.8-fold more efficiently than point mutations, and truncating mutations showed higher transmission than missense variants (Wilcoxon p = 0.005). Microsatellite instability attenuated mRNA-protein transmission in UCEC and COAD. These findings demonstrate that many driver alterations show limited propagation to protein abundance. This challenges DNA-only interpretations in precision oncology and provides a framework for integrated functional driver prioritization.

Humans↗
PubMed1995

Genomic organization of an invariant surface glycoprotein gene family of Trypanosoma brucei.

The genomic organization of a gene family for the invariant surface glycoprotein, ISG75 (invariant surface glycoprotein with a molecular mass of 75 kDa), from Trypanosoma brucei is described. In T. brucei strain 427 ISG75 genes are present in tandem arrays at two loci, A and B, containing 5 and 2 copies, respectively. At the 3'-end of locus A, a single gene was identified that encodes a structural isoform of ISG75. This isoform contains a unique amino-terminal domain, whereas the rest of the protein is nearly identical to the polypeptides encoded by the other genes. This isoform is transcribed into a stable mRNA, but the expression of the derived polypeptide was below the detection limit. The ISG75 gene clusters are present on chromosomal bands 9' and 10, supporting the hypothesis of Gottesdiener et al. [25] that these bands contain allelic chromosomes. The total number of ISG75 genes is strain dependent, but at least one copy of the unique isoform is present in every variant tested.

Amino Acid Sequence↗
PubMed2001

Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily.

Cytomegalovirus is the leading cause of congenital viral disease and the most important opportunistic infection in immunocompromised patients. We have used a mouse experimental infection model (MCMV) to study the genetic parameters of host/virus interaction. Susceptibility to infection with MCMV is controlled by Cmv1, a chromosome 6 locus that regulates natural killer (NK) cell activity against virally infected targets. Here, we use a positional cloning strategy to isolate the gene mutated at the Cmv1 locus. Cmv1 maps within a 0.35-cM interval defined by markers D6Ott8 and D6Ott115, which corresponds to a physical distance of 1.6 Mb (refs. 6-8). A transcript map of the region identified 19 genes, including members of the killer cell lectin-like receptor family a (Klra, formerly Ly49; refs. 9-12), which encode inhibitory or activating NK cell receptors that interact with MHC class I molecules. Klra genes have different copy numbers and genomic organization, and are highly polymorphic among inbred strains, making it difficult to distinguish between normal allelic variants and distinct Klra genes, or possible mutations associated with Cmv1. The recombinant inbred strain BXD-8/Ty (BXD-8; ref. 18), derived from Cmv1r C57BL/6 (B6, resistant) and Cmv1s DBA/2 (susceptible), is of particular interest because it is highly susceptible to MCMV infection despite having a B6 haplotype at Cmv1. We determined that MCMV susceptibility in BXD-8 is associated with the deletion of Klra8 (formerly Ly49h).

Animals↗
PubMed1996

Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA.

Mitochondrial DNA (mtDNA) is maternally inherited in mammals. Despite the high genome copy number in mature oocytes (10(5)) and the relatively small number of cell divisions in the female germline, mtDNA sequence variants segregate rapidly between generations. To investigate the molecular basis for this apparent paradox we created lines of heteroplasmic mice carrying two mtDNA genotypes. We show that the pattern of segregation can be explained by random genetic drift occurring in early oogenesis, and that the effective number of segregating units for mtDNA is approximately 200 in mice. These results provide the basis for estimating recurrence risks for mitochondrial disease due to pathogenic mtDNA mutations and for predicting the rate of fixation of neutral mtDNA mutations in maternal lineages.

Animals↗
PubMed2026

Utilization of long-read sequencing for the detection of structural rearrangements with AgileStructure.

MOTIVATION: Changes in genome organisation contribute to genetic disease when they disrupt gene function or regulation. Structural rearrangements may interrupt coding sequence or alter expression through promoter loss or gain, chromatin changes, copy-number variation, or disruption of short-range regulatory elements. Although short-read sequencing excels at detecting small variants, it performs poorly at resolving breakpoints of large rearrangements, especially in repetitive or low-complexity regions. Long-read sequencing overcomes these limitations, but analytical tools have not kept pace, making accurate identification and annotation of large structural variants challenging. RESULTS: We developed AgileStructure, a desktop application for locating and annotating large‑scale genomic rearrangements using aligned long‑read data. The software enables user‑guided exploration of breakpoint‑spanning reads, supporting accurate interpretation of complex events and filling a key gap in current structural variant analysis workflows. AVAILABILITY AND IMPLEMENTATION: Source code, binaries, user guide, and example aligned read data, are available on GitHub: https://github.com/msjimc/AgileStructure. An archived version is also available on Zenodo at https://doi.org/10.5281/zenodo.18610110.

Software↗
PubMed1991

Sequence and expression of potato U2 snRNA genes.

Plant UsnRNA multigene families show a high degree of sequence variation among individual gene members. The potato U2snRNA gene family consists of between twenty-five and forty genes. Four potato U2snRNA gene variants have been isolated. Despite the sequence variation in coding and flanking regions, all maintain the conserved U2snRNA secondary structure and all contain the plant UsnRNA promoter elements: the upstream sequence element (USE) and TATA-like box in the -70 and -30 regions respectively. In RNase A/T1 protection analyses, one of the genes, PotU2-22, protected high levels of full length U2snRNA transcripts in potato leaf, stem, root and tuber RNA. Thus, PotU2-22 or genes with identical coding regions, are highly expressed in these potato organs and therefore represent a major subset of functional U2snRNA genes. Similar expression levels of the PotU2-22 sequence variant were also found in four genetically different potato cultivars and also in tobacco, a species closely related to potato, suggesting conservation of the coding regions of expressed U2snRNA genes. A second gene, PotU2-4, protected very low levels of full length transcripts while a third gene, PotU2-11, was not expressed in the potato organs analysed. The relative expression levels of the gene variants may reflect individual gene differences in, for example, the USE and TATA regulatory elements, or variations in gene copy number.

Animals↗
PubMed1992

Review of the Streptomyces lividans/vector pIJ702 system for gene cloning.

Interest in the biology of the Streptomyces and application of these soil bacteria to production of commercial antibiotics and enzymes has stimulated the development of efficient cloning techniques and a variety of streptomycete plasmid and phage vectors. Streptomyces lividans is routinely employed as a host for gene cloning, largely because this species recognizes a large number of promoters and appears to lack a restriction system. Vector pIJ702 was constructed from a variant of a larger autonomous plasmid and is often used as a cloning vehicle in conjunction with S. lividans. The host range of vector pIJ702 extends beyond Streptomyces spp., and its high copy number has been exploited for the overproduction of cloned gene products. This combination of host and vector has been used successfully to investigate antibiotic biosynthesis, gene structure and expression, and to map various Streptomyces mutants.

Cloning, Molecular↗