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At least 811 records · Page 45Linked to original sources
PubMed2002

Polymorphisms of the DNA repair gene XRCC1 and the frequency of somatic mutations at the glycophorin A locus in newborns.

Two DNA polymorphisms in the XRCC1 gene, a microsatellite repeat region in the 3' un-translated region (3'UTR) of the gene and a G-->A substitution resulting in an Arg to Gln amino acid change in codon 399, were examined in 189 newborns who had previously been studied for glycophorin A (GPA) N0 and NN variant frequencies (Vfs) in cord blood erythrocytes. The GPA analysis had revealed that 14 of the 189 had extreme NN Vfs ranging from 40 x 10(-6) to 1787 x 10(-6). Mean Vfs for the remaining 175 were N0=(4.8+/-2.80)x10(-6) and NN=(2.62+/-2.01)x10(-6). Seven alleles of a polymorphic tandem [AC](n) region of the XRCC1 gene were identified. No association between [AC](n) genotype and either N0 or NN Vfs was found amongst the group of 175 nor was the distribution of genotypes unusual for the group of 14 with extreme NN Vfs. Analysis of the 399Gln polymorphism revealed that for the group of 175, 36.0% were Arg/Arg, 49.7% Arg/Gln and 14.3% Gln/Gln and genotype had no influence on N0 and NN Vfs. However, the distribution of genotypes was significantly different in the group of 14 with extreme NN Vfs, 14.3% being Arg/Arg, 42.8% Arg/Gln and 42.8% Gln/Gln. The 14 newborns with extreme NN Vfs may represent a sub-group with an unidentified genotoxic exposure and/or predisposition to gene-duplication mutations or alternatively the high values could have arisen by increased clonal expansion of haemopoietic precursor cells carrying NN mutations. Our results suggest that carriers of the Gln/Gln genotype are over represented in this group but the role that the genotype has in the derivation of high NN Vfs remains to be resolved.

Base Sequence↗
PubMed2003

High gradient magnetic cell sorting and internal standardisation substantially improve the assay for somatic mutations at the glycophorin A (GPA) locus.

In the MACS-BR6 version of the GPA assay [Int. J. Radiat. Res. 70 (1996) 131] variant red blood cells (RBC) are isolated from 5 x 10(8) normal RBC by magnetic cell separation (MACS) before detection and quantification by immunolabelling and flow cytometry as in the classical BR6 assay. In the present work it is described how the MACS-BR6 assay is improved by internal standardisation with FITC-labelled RBC. This modification of the assay has the advantage that (i) the analysis of variants is not disturbed by the overwhelming number of normal RBC that (ii) the precision of the assay is improved and finally that (iii) a sufficient number of variants is available for further investigations. Tn positive RBC behave in MACS like variants. It is demonstrated that in normal individuals Tn cells (frequency: approximately 2 x 10(-8)) do not disturb the assay.

Adult↗
PubMed1997

On the origin of spontaneous somatic mutations and sectored plaques detected in transgenic mice.

The use of transgenic mice with bacterial genes that can be readily recovered and analysed for mutation has made it possible to measure mutant frequencies in many tissues. The mutations are detected by packaging the murine DNA into lambda phage and then growing these phage on a bacterial lawn under conditions such that the mutants are distinguishable from nonmutants. In the lacI mouse assay, the mutant plaques are blue whereas the nonmutant plaques are clear. The mutations detected in the lacI Big Blue Mouse are, in principle, a mixture of mutations that arose in the mouse (in vivo mutations), mutations that arose in the bacterium from lesions pre-existing in the murine DNA (ex vivo mutations), and mutations that arose during growth of the phage on the bacteria (in vitro mutations). It has been suggested that plaque morphology can be used to visually distinguish in vivo mutations (which would be seen as wholly blue plaques) from ex vivo mutations (which would produce blue and white sectored plaques) and in vitro mutations (which would produce sectored or pin-point plaques). We show here that this is not the case: ex vivo mutations produce plaques that are a homogeneous blue. By superinfection of bacteria with mutant and nonmutant phage and by in vitro mutagenesis, we found that blue plaques may contain large proportions of nonmutant phage. None of the mutant plaques seen after in vitro mutagenesis were sectored but most contained nonmutant phage. In addition, we show that most spontaneous mutations from the small intestine, which has a higher than normal mutant frequency, arose in vivo, since 17 of 17 mutants were homogeneous mutants. Sectored plaques must arise in some way other than by ex vivo mutation, like perhaps by the confluence of a mutant and nonmutant plaque.

Animals↗
PubMed1999

Somatic mutation in the mammary gland: influence of time and estrus.

A critical factor in the quantitation of mutation induction in vivo is the time interval between treatment and sampling. In order to study mutagenesis in the mammary epithelium, the cell type in which breast cancer arises, we have measured the manifestation time, the minimum time required for the maximum mutant frequency to be achieved, in this tissue. The F1 LacZ transgenic mice (Muta MousexSWR) were treated with N-ethyl-N-nitrosourea (ENU) at 50 mg/kg for five consecutive days and then sampled at 1, 2, 4, 6, 9, or 12 weeks after the last treatment. The LacZ- mutant frequency reached a maximum at 4 weeks post-treatment and did not vary significantly thereafter. Dlb-1- mutations in the small intestine reached a maximum at 2 weeks after treatment and did not vary significantly thereafter. Since the stage of estrus cycle during carcinogen exposure influences the mammary tumor incidence and latency, it was expected that it would also affect mutation induction. To test this, F1 LacZ mice in the estrus or di-estrus stage were treated with an acute dose of 250 mg/kg ENU and sampled 10-13 weeks post-treatment. No statistical difference between the two groups was found, indicating that the effect of estrus on carcinogenesis is not due to variation in the sensitivity of the stage of the mammary gland to mutation.

Animals↗
PubMed1994

Antigen diversity in the bacterium B. hermsii through "somatic" mutations in rearranged vmp genes.

B. hermsii counters host immunity with multiphasic antigenic variation. This is conferred by interplasmidic and intraplasmidic rearrangements of vmp genes. In several independent events, activation of a silent vmp gene through intraplasmidic deletions but not interplasmidic recombinations was followed by the appearance at its 5' end of multiple mutations that were not present in the silent gene. The prevalence of mutant alleles in postwitch populations increased during infections. Differences between the silent and expressed genes were at the same nucleotides at which vmp pseudogenes differed, suggesting these were templates for postswitch gene conversions. The mechanism of this bacterium to generate diversity, namely, intramolecular deletions followed by mutations in the rearranged gene, mirrors the strategy used by vertebrate hosts to eliminate it.

Animals↗
PubMed1999

Motif-specific probes identify individual genes and detect somatic mutations.

This report describes the correlation between motif-specific hybridization and nucleotide sequence as an approach to the identification of individual human V(H) genes using motif-specific oligonucleotide probes, complementary to specific motifs within individual V(H) genes. The sensitivity of the hybridization and post washing processes permits discrimination of single nucleotide differences between probe and target. This feature is used both to identify individual genes, as well as to detect mutations in genes by sequential hybridization with multiple probes. In addition to the general strategy, specific details are provided for the identification of 12 V(H)3 genes and 14 V(H)4 genes.

Base Sequence↗
PubMed2000

Lipid peroxidation status, somatic mutations and micronuclei in peripheral lymphocytes: a case observation on a possible interrelationship.

A controlled dietary study was conducted in healthy female volunteers and reported elsewhere [1]. In a subset of samples four different biomarkers were analyzed: plasma malondialdehyde (MDA) levels and urinary 8-isoprostaglandin-F(2alpha) were measured as markers for lipid peroxidation. The frequency of hprt (hypoxanthine guanine phosphoribosyl transferase) mutants and micronuclei in peripheral blood lymphocytes were analyzed as indicators of genotoxic effects. One of the ten individuals showed extremely high background levels in all of the four endpoints measured. This case observation raises the possibility that life style factors and dietary habits affect the level of DNA reactive lipid peroxidation products, which in turn increase mutagenic and cytogenetic effects. A possible association between these biomarkers, particularly in relation to dietary fat intake and antioxidant status, should now be studied in a larger trial.

Adult↗
PubMed1999

Methyl bromide causes DNA methylation in rats and mice but fails to induce somatic mutations in lambda lacZ transgenic mice.

Following single or multiple oral treatments of rats or lambda lacZ transgenic mice with methyl bromide, methylated DNA adducts (N7- and/or O6-methylguanine) were found at comparable levels in various tissues, including among others the glandular stomach, the forestomach and the liver. Multiple rat treatment resulted in substantial decreases in the repair enzyme O6-alkylguanine-DNA alkyltransferase which were probably due in part to direct interaction of the enzyme with methyl bromide. However, no induction of mutagenesis in the lacZ transgene could be detected in any tissue 14 days after single treatments of up to 50 mg/kg or after multiple treatments of as many as 10 daily treatments of 25 mg/kg MeBr.

Animals↗
PubMed1999

Induction of somatic mutations but not methylated DNA adducts in lambdalacZ transgenic mice by dichlorvos.

In order to examine the in vivo genotoxic activity of dichlorvos, lambdalacZ transgenic mice (Muta Mouse) were treated i.p. with single (4.4 or 11 mg/kg) or multiple (5 x 11 mg/kg) doses of this agent and sacrificed 4 h or 14 days post-treatment for DNA adduct measurement or mutant frequency analysis, respectively. Neither methylated DNA adducts nor an increase in mutant frequency were detected in the bone marrow, white blood cells, liver, spleen, lung, brain and sperm cells after the single doses. However, following multiple dosing a statistically significant 3-fold increase in mutant frequency was observed in the liver, while a non-statistically significant increase was observed in the bone marrow. In contrast, dimethylsulphate, a model methylating agent, gave rise to detectable DNA adducts but no increase in mutant frequency following i.p. administration of single (30 mg/kg) or multiple (10 x 6 mg/kg) doses.

Animals↗
PubMed2000

Somatic mutations of beta-catenin play a crucial role in the tumorigenesis of sporadic hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant hepatic tumor during early childhood. Its molecular pathogenesis is still poorly understood. Mutations of adenomatous polyposis coli (APC) gene have been identified in sporadic cases and in individuals associated with familial adenomatous polyposis syndrome. beta-catenin is a key element in the cadherin-mediated cell adhesion system and Wnt/wingless pathway, and is controlled by APC. APC affects the degradation of beta-catenin by its NH(2)-terminal phosphorylation on the serine/threonine residues of exon 3. Mutations of these phosphorylation sites are primary targets for activating mutations in several types of human cancer and lead to nuclear accumulation of beta-catenin protein. In this study, we examined nine patients with HB using immunohistochemistry and direct DNA sequencing. All nine cases showed predominant nuclear expression of beta-catenin. Eight cases (89%) showed mutations involving exon 3 of the beta-catenin gene, including five with deletions and three with missense mutations. All five deletions were in-frame deletions without frameshift. The very high frequency of mutations in the beta-catenin gene suggests that beta-catenin mutations are crucial in the tumorigenesis of HB.

Amino Acid Sequence↗
PubMed2002

Somatic mutations at STR loci--a reason for three-allele pattern and mosaicism.

Two families are analysed in which one of the parents exhibited a three-allele pattern at the ACTBP2 locus. Since the alleles were obviously segregated independently to the children, a generalised mosaicism must be assumed involving at least two tissues in one of them and at least four tissues in the other one. The intensity of the PCR amplified alleles in both three-allele individuals indicate an occurrence in a very early embryonic stage. Occurrence was most probably due to a single step mutation in both cases. Forensic implications would include paternity testing as well as stain analysis.

Alleles↗