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PubMed2005

STin2 variant and family history of suicide as significant predictors of suicide completion in major depression.

BACKGROUND: Suicide is the most serious outcome of major depression, yet not all depressed patients will commit suicide. Genes, along with other factors, might account for this difference. Serotonergic alterations have been observed in suicide and depression and impulsive-aggressive behaviors. Therefore, we aimed to identify predictors of suicide, considering genetic variation at the serotonin transporter (5-HTT) gene. METHODS: We investigated the 5-HTT gene-linked polymorphic region (5-HTTLPR) and intron 2 (STin2) variants of this gene and their relationship to behavioral and clinical risk factors for suicide in a sample of depressed suicides (n =106) and depressed control subjects (n =152), diagnosed by means of proxy-based interviews. RESULTS: We found a significant association of suicide completion with having at least one copy of the STin2 10 allele [chi(2)(1) = 10.833, p = .002]. No differences were found for the 5-HTTLPR variable number of tandem repeats. After controlling for behavioral and clinical risk factors for suicide, the STin2 variant remained a significant predictor of suicide in major depression when jointly considered with a family history of suicide (odds ratio 5.560, 95% confidence interval 1.057-29.247). CONCLUSIONS: The STin2 locus might account, at least in part, for the observed familial aggregation of suicidal behavior. These results should be further explored in families where clustering of suicidal behavior is observed.

Adolescent↗
PubMed2005

Analysis of chromosome 7 in adult and pediatric ependymomas using chromogenic in situ hybridization.

Few studies have yielded reliable data that distinguish between ependymal neoplasms based on molecular genetic attributes. The present study utilizes chromogenic in situ hybridization (CISH), a relatively recent hybridization technique, to retrospectively examine chromosome 7-copy number in pediatric and adult ependymomas. Of the 27 hybridizations, polysomy of chromosome 7 was detected in 10 out of 15 (66%) adult ependymomas, and in only three out of 12 (25%) pediatric lesions. All myxopapillary ependymomas showed polysomy. The remaining tumors were diploid. The authors conclude that (1) there are distinct genetic subsets of ependymoma, in particular, increases in copy number of chromosome 7 are almost exclusively found in myxopapillary ependymoma, and that (2) CISH is a rapid and sensitive method of stratifying morphological variants of ependymoma and potentially other central nervous system (CNS) tumors. These results encourage further investigations with CISH on a larger scale to determine its merit as an ancillary diagnostic and prognostic tool.

Adult↗
PubMed1990

A retroposon in the 5' flank of a Trypanosoma brucei VSG gene lacks insertional terminal repeats.

A retroposon-like repeated sequence, ingi, occurs in high copy number in the genome of Trypanosoma brucei brucei. An ingi is present in the 5' flank of the 5C gene, an intrachromosomal IsTat 1.5 variant surface glycoprotein (VSG) gene family member. The 5' end of the ingi is located 22 bp upstream of the putative VSG start codon and the ingi open reading frame is in the opposite orientation to that of the VSG gene. The termini of the ingi are not flanked by a short repeat sequence and there are no sequences upstream of the ingi insertion which are homologous to the 5' flanking sequence of other 5 VSG gene family members. Thus, it appears that recombination and/or gene conversion between two ingi sequences may have eliminated the original 5C gene flanking sequence. Similar events may also have occurred with all but one previously reported ingi.

Amino Acid Sequence↗
PubMed1995

PCR amplification of intergenic spacers in the ribosomal DNA of Drosophila melanogaster reveals high levels of turnover in length and copy-number of spacers in geographically separated populations.

A recently described PCR-based method for the analysis of intergenic spacer (IGS) length variation in the ribosomal (r) DNA of Drosophila melanogaster was used to analyse the distribution of IGS length variants in the rDNA of a number of recently collected D. melanogaster populations. One group of populations, from Europe and North Africa, was shown to have low intrapopulation IGS length variation following maintenance of massed populations in the laboratory for an extended period. However, a greater degree of IGS profile variability was detected at a number of levels in the majority of laboratory-maintained isofemale lines from two of these populations plus a second group of populations which were collected more recently from the eastern coast of Australia; all of which were immediately divided into isofemale lines following collection. Interestingly, PCR analysis of pooled DNA extracts from 30 individuals of either sex showed almost identical PCR profiles from each of the Australian populations. These preliminary results are discussed with regard to the possible combinations of forces (natural selection, neutral drift and genomic molecular drive) on the patterns of IGS length variation.

Animals↗
PubMed1983

Amplification of adenosine deaminase gene sequences in deoxycoformycin-resistant rat hepatoma cells.

Deoxycoformycin-resistant rat hepatoma cells exhibit up to a 2000-fold increase in adenosine deaminase activity compared to the sensitive parental cells. The increased enzyme activity in these cells is accompanied by similar increases in 1) the amount of adenosine deaminase protein, 2) the relative rate of adenosine deaminase synthesis in vivo, and 3) adenosine deaminase mRNA activity. To further investigate the mechanism(s) responsible for the overproduction of adenosine deaminase in these cells, we have isolated a recombinant plasmid containing a 1.4-kilobase insert complementary to at least part of the adenosine deaminase mRNA. Using this cDNA as a specific hybridization probe, all deoxycoformycin-resistant variants were shown to have increased amounts of adenosine deaminase mRNA and gene sequences. The relative increase in the level of mRNA and gene copy number was similar to the relative increase in enzyme activity for most resistant cell lines. However, the degree of adenosine deaminase gene amplification in one deoxycoformycin-resistant cell line (6-10-200) was 3-4-fold less than the relative increase in adenosine deaminase mRNA. These results indicate that the increased adenosine deaminase activity in deoxycoformycin-resistant rat hepatoma cells is due in large part, but not exclusively, to gene amplification.

Adenosine Deaminase↗
PubMed2007

The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors.

A lesser-recognized form of human herpesvirus 6 (HHV-6) persistence is integration of the viral genome in a host chromosome and high viral copy numbers in blood or sera are characteristic of this phenomenon. A cross-sectional study was performed to determine the frequency of high HHV-6 viral loads in whole blood (>6 log(10) copies/ml) in a population of blood donors in London, UK. Blood samples from 500 anonymized blood donors were collected from one donation center, DNA extracted, and quantitative realtime PCR used to measure viral load. Four samples (0.8%) were found to have high viral copy numbers of HHV-6 (median 6.7 log(10) copies/ml; range 6.5- 6.9 log(10) copies/ml). Cellular DNA was also quantitated using qRT-PCR for beta-globin. By comparing these two results, we calculated that there were between two and five copies of HHV-6 present per cell in these four donors. The median viral load detected in plasma from the four individuals was 3.8 log(10) copies/ml (range 3.5-4.0 log(10) copies/ml). All samples were HHV-6 variant B. In addition, a retrospective analysis of all diagnostic blood samples performed for HHV-6 in our center showed a prevalence of 2.9% of high viral loads characteristic of integration. In conclusion, high viral copy numbers of HHV-6, representing a population of viral integration, is detected in 0.8% of UK blood donors. The presence of high HHV-6 viral loads in healthy normal individuals reiterates the need to consider the confounding effect of HHV-6 viral integration in any laboratory diagnosis of HHV-6 infection.

Blood Donors↗
PubMed2006

Comparison of four Taura syndrome virus (TSV) isolates in oral challenge studies with Litopenaeus vannamei unselected or selected for resistance to TSV.

Taura syndrome virus (TSV) infection in TSV-resistant (TSR) and TSV-susceptible (Kona) Litopenaeus vannamei (also called Penaeus vannamei) was investigated using histology, in situ hybridization (ISH), conventional reverse transcription polymerase chain reaction (RT-PCR) assays, and SYBR-Green real-time RT-PCR analysis. The shrimp were challenged by feeding with minced tissues of L. vannamei infected with 4 genotypic variants of TSV (Bz01, Th04, UsHi94, and Ve05). Survival probabilities of TSR shrimp were higher than those for Kona shrimp with all 4 variants. Th04, UsHi94, and Ve05 gave no Taura syndrome lesions with TSR shrimp. In contrast, TSR shrimp challenged with Bz01 and Kona shrimp with all 4 TSV variants exhibited severe necrosis of cuticular epithelial cells and lymphoid organ spheroids, indicative of acute and chronic phases of TSV infection, respectively. TSV was not detected by RT-PCR in TSR shrimp infected with Th04, UsHi94, and Ve05, or in Kona shrimp infected with Ve05 but was detected in TSR shrimp infected with Bz01 and in Kona shrimp infected with Bz01, Th04, and UsHi94. Real-time RT-PCR revealed that mean TSV copy numbers in TSR shrimp infected with Bz01, Th04, and UsHi94 were significantly (p < 0.0005) lower than those in Kona shrimp. In contrast, mean TSV copy numbers in TSR and Kona shrimp infected with Ve05 were not significantly different (p > 0.4). The results show that TSR L. vannamei are susceptible to infection but give high survival rates following challenge by all 4 variants of TSV.

Analysis of Variance↗
PubMed1996

Size and genomic location of the pMGA multigene family of Mycoplasma gallisepticum.

The pMGA multigene family encodes variant copies of the cell surface haemagglutinin of Mycoplasma gallisepticum. Quantitative Southern blotting, using an oligonucleotide probe complementary to a region conserved in the leader sequence of all known pMGA genes, was used to estimate the number of members of the family in the genome of seven strains of M. gallisepticum. The number of copies estimated to be present in the genome varied from 32 in strain F to 70 in strain R, indicating that the pMGA gene family may be second in size only to the tRNA family among prokaryotes. If all members of the pMGA family are of similar length to those which have been characterized, a minimum of 79 kb (7.7%) of the genome of strain S6, 82 kb (8.2%) of PG31 and 168 kb (16%) of the genome of strain R is dedicated to encoding variants of the same haemagglutinin. The GAA repeat motif identified in the intergenic region between all characterized pMGA genes appeared to be a feature common to most, if not all, pMGA genes, and furthermore probably exclusive to them. The genomic locations of members of the pMGA family were determined by PFGE and Southern blot hybridization of M. gallisepticum strain S6. The hybridizing regions were localized to four separate regions on the chromosome. The pMGA genes are likely to be predominantly arranged as tandem repeats within these regions, similar to the restricted regions for which the genomic sequence has been determined.

Antigenic Variation↗
PubMed2004

Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers.

OBJECTIVE: Case control studies in adults suggest that defective alleles in the gene that codes for the hepatic cytochrome P450 2A6 (CYP2A6) protect against nicotine dependence (ND) and higher levels of cigarette consumption. These two hypotheses were tested in young adolescents. DESIGN: Self reports of tobacco use and ND symptoms were collected every 3-4 months in a prospective study of 1293 grade 7 students from a convenience sample of 10 schools. SUBJECTS: 281 smokers with genetic data were analysed; those who were not already tobacco dependent and who had inhaled (n = 228) were followed 29.9 months on average, until they became dependent or were censored. MAIN OUTCOME MEASURES: The association between metabolic activity, represented by CYP2A6 genotype, and conversion to dependence was analysed using Cox's proportional hazards model. RESULTS: During follow up 67 subjects (29.4%) became dependent. Relative to CYP2A6*1/*1, having 1-2 copies of the inactive CYP2A6*2 or *4 variant was a strong risk factor for developing dependence (hazard ratio 2.8, 95% confidence 1.3 to 6.3). Subjects with 1-2 partially inactive CYP2A6*9 or *12 variants were not at increased risk. Mean past-week cigarette consumption at the end of follow up (controlling for age, sex, and number of months since first inhalation) among dependent subjects was 29.1 among normal inactivators, compared to 17.2, and 12.7 among slower (1-2 copies of *9 or *12), and slowest (1-2 copies of *2 or *4) inactivators, respectively (p = 0.09). CONCLUSION: Adolescents with 1-2 copies of CYP2A6*2 or *4 are at substantially increased risk of becoming dependent but smoke less once dependent. Genetic risk for ND may need to be considered in the conceptualisation of tobacco control programmes for adolescents.

Adolescent↗
PubMed1993

Variant mitochondrial plasmids of broad bean arose by recombination and are controlled by the nuclear genome.

Various cytoplasms of broad bean contain three mitochondrial plasmids (mtp1, 2 and 3), previously described. In cytoplasm 350 we have observed several additional mitochondrial plasmids, varying in number and in identity according to the nuclear background. Replacement of the nucleus by backcrossing led to the appearance or disappearance of additional plasmids, indicating that the nuclear genome controls either the creation or the copy level of mitochondrial plasmids. Analysis of eight variant additional plasmids (mtp4-11) suggests that they all result from a double recombination event between mtp1 and mtp2. In all cases, one recombination point was located within a 276-bp sequence, identical in both plasmids. For 7 plasmids, the region in which the second recombination event occurred could be narrowed down to a short stretch containing imperfect tandem repeats of a 31-bp motif. The largest sequence shared by the recombination regions was hexanucleotide GCGACG.

Base Sequence↗
PubMed2001

Stability and DNA-binding properties of the omega regulator protein from the broad-host range Streptococcus pyogenes plasmid pSM19035.

At the transcriptional level, the pSM19035-encoded omega protein coordinates the expression of proteins required for control of copy number and maintenance of plasmids. Using circular dichroism, fluorescence spectroscopy, ultracentrifugation and an electrophoretic mobility shift assay, the wild-type omega protein and a variant with a C-terminal hexa-histidine tag (omega-H(6)) were characterized. The omega protein is mainly alpha-helical (42%), occurs as homodimer in solution, unfolds thermally with half transition temperatures, T(m), between approximately 43 and approximately 78 degrees C depending on the ionic strength of the buffer, and binds PcopS-DNA with high affinity. The omega-H(6) protein has a modified conformation with lower alpha-helix content (29%), lower thermal stability, and strongly reduced affinity to PcopS-DNA.

Bacterial Proteins↗
PubMed2000

Type 2 cytokine gene activation and its relationship to extent of disease in patients with tuberculosis.

The extent of type 2 cytokine gene expression in patients with pulmonary tuberculosis (TB) was studied by use of quantitative nested reverse-transcription polymerase chain reaction on freshly isolated peripheral blood mononuclear cells. Interleukin (IL)-4 and IL-13 mRNA expression was significantly greater in patients-median mRNA copy numbers were 1.7 and 1.1 log10 higher, respectively-than in matched tuberculin-positive control subjects. Significant correlations with radiologic extent of disease and serum IgE levels supported the biologic significance of these results. Interferon-gamma mRNA copy numbers exceeded those of type 2 cytokines but were only marginally lower in patients than in control subjects. Gene expression of an IL-4 splice variant (IL-4delta2) was bimodally distributed in both patient and control groups. Patients with greater IL-4delta2 expression also expressed more IL-4 mRNA and had more extensive disease. Type 2 cytokines are associated with immunopathologic changes in TB patients but could be a cause or consequence of disease.

Adolescent↗
PubMed1991

Expression of catalase and myeloperoxidase genes in hydrogen peroxide-resistant HL-60 cells.

We studied the expression of catalase and myeloperoxidase genes in the hydrogen peroxide-resistant variants of human myeloid leukemia HL-60 cells HP50-2 and HP100-1. Southern blot hybridization with catalase and myeloperoxidase cDNA probes indicated that the copy number of the catalase gene in HP50-2 and HP100-1 cells was two and eight times, respectively, higher than that in HL-60 cells, whereas the copy number of the myeloperoxidase gene was the same. The amplified catalase and c-myc genes in HP100-1 cells were not decreased by treatment of the cells with inhibitors of poly(ADP-Ribose) polymerase, such as nicotinamide and benzamide. RNA blot hybridization with cDNA probes indicated that the content of catalase mRNA in HP50-2 and HP100-1 cells was four and 16 times higher, respectively, than that in HL-60 cells. By contrast, the content of myeloperoxidase mRNA in HP50-2 and HP100-1 cells was only a few percent of that in HL-60 cells. Furthermore, fluorescent in situ hybridization of a catalase cDNA probe to chromosomes indicated that the catalase gene in HP100-1 was amplified in the p13 region of a derivative chromosome 11. These results indicate that the increased synthesis of catalase in these resistant cells is mainly due to increased expression of the catalase gene, and that the lack of myeloperoxidase synthesis in these cells is due to the absence of its mRNA.

Catalase↗
PubMed1983

Plasmid marker rescue transformation in Bacillus subtilis.

We constructed an 18-megadalton plasmid (pBD221) carrying resistance determinants for kanamycin, chloramphenicol, and erythromycin, as well as the hisH determinant from the Bacillus licheniformis chromosome. This plasmid has a copy number of about one and can be stably maintained in Bacillus subtilis. Linear fragments of pBD221 DNA were used to transform competent cultures carrying mutant variants of the same plasmid. Rescue transformation did not proceed by recircularization and replication of the donor DNA. Rescue transformation exhibited first-order dependence on DNA concentration, and the concentration dependence curve was virtually identical to the curve obtained with chromosomal DNA. The donor DNA molecular weight dependence of plasmid marker rescue transformation obtained by using restriction fragments was not distinguishable from previously published data obtained by using fractionated sheared chromosomal DNA. Plasmid rescue transformation, like chromosomal transformation, was dependent on the recE, recA, recB, and recD gene products. Plasmid rescue transformation, like chromosomal transformation, proceeded with few exchanges. Linkage data obtained with the plasmid rescue system fit a quantitative model based on studies with chromosomal transformation. We conclude that plasmid marker rescue transformation probably proceeds by a mechanism similar to the mechanism used during the formation of chromosomal transformants and hence may be considered an appropriate general model for the study of transformational recombination.

Anti-Bacterial Agents↗
PubMed2000

Quantitative analysis of human DNA sequences by PCR and solid-phase minisequencing.

Reliable quantification by PCR requires careful experimental design and conditions, often involving sampling of the PCR reactions at different time points or amplifying multiple dilutions of a standard DNA. We describe here an accurate, quantitative and easily automatizable solid-phase method based on competitive PCR. The PCR products are analyzed by solid-phase mini-sequencing after capture of biotinylated PCR products in streptavidin-coated microtiter wells and single-nucleotide extension of a specific detection primer by a radioactively labelled nucleotide. The results are expressed as numeric cpm-values, and the incorporated label expresses the relative amount of sequence variants in the original template mixture. We have applied the method to determination of allele frequencies in pooled DNA samples, of mitochondrial heteroplasmy, of gene copy numbers, and to forensic DNA analysis.

Aspartylglucosaminuria↗
PubMed2001

Solid variant of alveolar rhabdomyosarcoma with unbalanced t(2;13) and hypotetraploidy, without MYCN amplification.

The histological subtype of alveolar rhabdomyosarcoma (AR) is characterised by the cytogenetic translocation t(2;13)(q35;q14) in approximately 70% of cases, a rearrangement rarely present in the embryonal rhabdomyosarcoma (ER) subtype. The MYCN gene is amplified in some cases of AR. We present a young man with an unusual pattern, namely solid variant of AR with hypotetraploidy and the t(2;13) in an unbalanced form. The MYCN gene was not amplified on FISH, but showed increased copy number, consistent with ploidy.

Adult↗
PubMed1998

stevor and rif are Plasmodium falciparum multicopy gene families which potentially encode variant antigens.

Several multicopy gene families have been described in Plasmodium falciparum, including the var genes that code for the variant surface antigen PfEMP1, the stevor family of subtelomeric open reading frames and the rif interspersed repetitive elements. This report documents the chromosomal location of stevor genes, their transcription and characteristics of the deduced protein. On 14 chromosomes, 34 stevor copies were identified from the Dd2 parasite line. Most are in subtelomeric regions within 50 kb of the telomere. stevor genes are located close to var genes and rij. All stevor genes sequenced had two exons: a short exon 1 encoding a start codon and a transmembrane domain; exon 2 encoding for the remainder of the approximately 30 kDa protein and including two more transmembrane segments. A similar structure was found for copies of rif and its predicted protein. In both STEVOR and RIF proteins, a highly polymorphic region is predicted to be a loop on the outer side of the membrane. We propose that stevor and rif are members of a larger superfamily. The number of copies of stevor and rif, their location close to the var genes, their extreme polymorphism and the predicted structure of the proteins suggest that stevor and rif code for variant surface antigens.

Amino Acid Sequence↗
PubMed1980

The organisation of the long range periodicity calf satellite DNA I variants as revealed by restriction enzyme analysis.

The analysis of a large number of restriction sites within the long range periodicity calf satellite DNA I does not reveal a superimposable shorter repeat. Although some restriction sites are present in almost all the 100,000 tandemly arranged copies of the 1460 bp repetition unit, other sites such as Atu CI occur at much lower frequencies. When present they are distributed randomly along the satellite DNA molecules. The missing sites appear to result from random and presumably single base alterations. Digestion with the enzymes Hha I and Kpn I showed another type of variant to exist within the calf satellite DNA I. Unlike Atu CI the distributions of the variants detected by these enzymes are not random and organised on long stretches of satellite DNA. The possible functional significance and evolutionary implication of these results are discussed.

Animals↗