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At least 19 recordsLinked to original sources
PubMed1977

Induction of gene mutations and gene conversions by vinyl chloride metabolites in yeast.

Chloroethylene oxide and 2-chloroacetaldehyde, two metabolites of vinyl chloride, and 2-chloroethanol, a putative metabolic intermediate, were assayed for their genetic activity in the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae. Chloroethylene oxide was found to be the most effective in inducing forward mutations in Sch. pombe and gene conversions in S. cerevisiae, increasing the mutation and conversion frequencies 340 and 50 times, respectively, over those of the controls. In either the presence or the absence of mouse liver microsomes, 2-chloroacetaldehyde showed only feeble genetic activity, and 2-chloroethanol was completely inactive in both yeast strains. In contrast to vinyl chloride, 2-chloroacetaldehyde did not induce forward mutations in Sch. pombe inthe host-mediated assay in mice. The results strongly support the hypothesis that chloroethylene oxide is one of the principal mutagenic agents formed from vinyl chloride in the presence of mouse liver enzymes.

Acetaldehyde↗
PubMed1979

[Comparative study of mutator-gene prv and several other mutator-genes of Escherichia coli K-12].

Mutations prv1, prv2 and mutR34, increasing frequencies of intragenic recombinations, are found not to complement and therefore to be alleles of one gene. Checking for the influence of mutator genes mutS3, mutT1 and uvrE502 on the intragenic recombination in conjugational crossings has shown that mutators mutS3 and uvrE502 increase the frequency of intragenic recombinations while mutT1 does not change it. None of the examined mutator genes influence the conjugational frequencies of recombination. A supplementary analysis for the mutability of the mutant prv1 has been carried out. The prv1 mutation can induce mutations of the frameshift type. Mutations uvrA6, recB21, recC22 and lexA produce no influence on the display of a mutator effect of the prv1 mutation.

Conjugation, Genetic↗
PubMed2024

Predictive modeling of gene mutations for the survival outcomes of epithelial ovarian cancer patients.

Epithelial ovarian cancer (EOC) has a low overall survival rate, largely due to frequent recurrence and acquiring resistance to platinum-based chemotherapy. EOC with homologous recombination (HR) deficiency has increased sensitivity to platinum-based chemotherapy because platinum-induced DNA damage cannot be repaired. Mutations in genes involved in the HR pathway are thought to be strongly correlated with favorable response to treatment. Patients with these mutations have better prognosis and an improved survival rate. On the other hand, mutations in non-HR genes in EOC are associated with increased chemoresistance and poorer prognosis. For this reason, accurate predictions in response to treatment and overall survival remain challenging. Thus, analyses of 360 EOC cases on NCI's The Cancer Genome Atlas (TCGA) program were conducted to identify novel gene mutation signatures that were strongly correlated with overall survival. We found that a considerable portion of EOC cases exhibited multiple and overlapping mutations in a panel of 31 genes. Using logistical regression modeling on mutational profiles and patient survival data from TCGA, we determined whether specific sets of deleterious gene mutations in EOC patients had impacts on patient survival. Our results showed that six genes that were strongly correlated with an increased survival time are BRCA1, NBN, BRIP1, RAD50, PTEN, and PMS2. In addition, our analysis shows that six genes that were strongly correlated with a decreased survival time are FANCE, FOXM1, KRAS, FANCD2, TTN, and CSMD3. Furthermore, Kaplan-Meier survival analysis of 360 patients stratified by these positive and negative gene mutation signatures corroborated that our regression model outperformed the conventional HR genes-based classification and prediction of survival outcomes. Collectively, our findings suggest that EOC exhibits unique mutation signatures beyond HR gene mutations. Our approach can identify a novel panel of gene mutations that helps improve the prediction of treatment outcomes and overall survival for EOC patients.

Humans↗
PubMed1975

Mutator genes and selection for the mutation rate in bacteria.

Gene frequencies in populations of haploid, asexual organisms are described by linear recurrence equations. Several models in which the mutation rate is controlled by one locus and the fitness is controlled at one or more other loci are developed. It is shown that good approximations can be introduced to give explicit solutions for the course of selection in these models. It is shown that a strong non-equilibrium selection for mutator genes is possible even when the presence of such a gene decreases the fitness of an individual. Experiments that corroborate these conclusions are discussed along with the effects of population size that determine the applicability of these results to natural populations.

Alleles↗
PubMed2026

Metagenomic Deep Sequencing Identifies Gene Mutations Associated with Chemotherapeutic Resistance in Vitreoretinal Lymphoma.

PURPOSE: To identify gene mutations associated with chemotherapeutic resistance in patients with vitreoretinal lymphoma (VRL) using metagenomic deep sequencing (MDS) of intraocular specimens. METHODS: Patients with VRL confirmed by cytopathology and immunohistochemistry, flow cytometry, and/or polymerase chain reaction for MYD88, were included. Intraocular specimens underwent MDS of the host genome. Gene mutations were identified and cross-referenced with the Catalogue of Somatic Mutations in Cancer database to determine associations with chemotherapeutic resistance. RESULTS: Forty-nine patients with VRL underwent MDS, with six specimens from four patients revealing eight gene mutations associated with chemotherapeutic resistance. Four specimens from three patients harbored mutations associated with methotrexate resistance, the mainstay of VRL treatment. In one patient, serial sampling from the initial vitrectomy and two subsequent recurrences revealed distinct resistance-associated mutations at each time point. Despite multi-agent therapy including rituximab, consolidation regimens, and lenalidomide, this patient ultimately succumbed to the disease, whereas the other three patients remained in long-term remission. CONCLUSIONS: Our findings demonstrated that specific gene mutations associated with chemotherapeutic resistance may be harbored by VRL. The detection of different resistance mutations at sequential time points in one patient may reflect clonal selection, treatment pressure, or variable detection sensitivity. The ability to easily sample ocular fluid and detect different mutations associated with tumor recurrence or persistence may provide insights into tumor pathogenesis and could inform prognosis and influence treatment decisions. These findings establish a foundation for developing targeted PCR assays for identified resistance genes, which could transform clinical practice in VRL.

Chemotherapeutic resistance-associated mutations↗
PubMed1975

Induction of gene mutations and chromosomal aberrations by simian virus 40 in cultured mammalian cells.

Induction of gene mutations by SV40 was studied in aneuploid human and Chinese hamster cells. In Chinese hamster cells SV40-induced chromosome aberrations were also studied. SV40 penetrated into the cells of both lines and induced synthesis of the T antigen. The efficiency of infection in Chinese hamster cells was tested additionally by their ability to form colonies in medium lacking the serum growth factor. The maximal number of cells with serum growth factor independence was observed on the first day after infection. When hamster cells had been maintained in "factor-free medium" for the first two passages after infection a sub-line was isolated, which synthesized T antigen 60 days after exposure to SV40. This was considered to be an indirect proof of the integration of viral genome into host chromosome. A significant increase in the frequency of chromosomal aberrations was detected in SV40-infected Chinese hamster cells. It was observed on the first and second days after treatment. The most numberous were the chromosome and chromatid breaks, which were distributed randomly in 5 morphological groups according to the chromosome length. SV40-induced mutations of resistance to 8-AG and 6-MP in human and Chinese hamster cells respectively were detected, when cells were plated in selective medium one to five days after infection. Induction was detected in all the 4 experiments with human cells and in 9 out of 11 experiments with Chinese hamster cells. Induction was highly significant according to the Wilcoxon test (P greater than 0.99), when the results of all experiments carried out in human and Chinese hamster cells were summarized. Resistance was stable after prolonged cultivation of 13 isolated clones under non-selective conditions. It is suggested that viral genome integration, gene mutations and chromosomal aberrations may have common molecular mechanisms. The role of gene mutations in virus-induced carcinogenesis is discussed.

Aneuploidy↗
PubMed1979

An assay for histocompatibility gene mutations in mice.

A method used for detecting histocompatibility gene mutations by tailskin graft tests in mice is described. Advantages and disadvantages are found for this assay system. The results of published work point to some interesting features of the H-gene mutational event, but also leave many questions yet to be answered.

Animals↗
PubMed1975

Transcription termination factor rho activity is altered in Escherichia coli with suA gene mutations.

Rho factor has been purified from a strain of E. coli containing the Su78 mutation in the suA gene and assayed in another strain with an amber mutation in the suA gene. The rho from the Su78 mutant strain is present in normal amounts but has altered termination function; it does not terminate transcription at some sites that are recognized effectively by the rho factor from the isogenic wild-type strain. Rho in cells with an amber mutation in the suA gene has been assayed by its RNA-dependent ATPase activity. Extracts of cells of this strain have only 9% as much of this rho activity as extracts of cells of the isogenic wild-type strain. These results suggest that rho is the product of the suA gene. Since mutations in the suA gene are known to decrease polar effects of mutations in other genes, it is also suggested that rho factor is at least partially responsible for polar effects.

Bacterial Proteins↗
PubMed1975

Further characterization of a non-essential mutator gene in Escherichia coli K-12.

The properties of mutR, a mutator closely linked to thyA, have been further characterized. We have found that the mutator gene is carried on a specialized transducing phage (lambdapcI857 thyA) generated by the excision of lambdacI857 integrated at a secondary attachment site between lysA and thyA. We present three lines of evidence indicating that mutR is a nonessential gene. (i) Deletions of the mutator can be found amoung survivors of heat induction of lambdacI857 when the phage is integrated between lysA and thyA. (ii) Mutations in mutR can be induced with the frameshift mutagen ICR-191. (iii) An amber mutant in mutR has been found. Viable strains could be made by combining the mutator with polB, polA polR, ligts7, and uvrA mutations. The mutator was still able to increase the spontaneous mutation frequency in these genetic backgrounds. When the reversion patterns of a series of well-characterized trpA mutations were analyzed, the results suggested that mutR is more efficient at causing transitions than transversion mutations.

Base Sequence↗
PubMed2026

YAP1 induces hepatocellular carcinoma via DNA demethylation rather than by canonical driver gene mutations.

Large-scale genome sequencing analyses have identified driver gene mutations (DGMs) in most cancers as well as their associated tumorigenic mechanisms. However, a small fraction of cancers are not positive for these canonical DGMs, leaving the mechanisms underpinning their formation a mystery. We hypothesized that canonical DGM-negative cancers might be driven by activation of the transcriptional coactivator YAP1 that led to the induction of epigenetic changes. To test this theory, we established a mouse mosaic model of hepatocellular carcinoma (HCC) in which we induced YAP1-TEAD activation in a few hepatocytes. Whole-exome sequencing did not identify canonical DGMs in HCCs, but bisulfite sequencing revealed widespread DNA demethylation leading to the transcriptional activation of multiple oncogenes. Knockdown of the DNA demethylation-promoting gene, Tet1, attenuated HCC formation in these mice. Single-cell spatial transcriptomics identified a Tet1-high subpopulation of HCC cells that interacted with other hepatic cell types. Our mechanistic mouse data align with the observation that YAP1-TEAD-TET1-associated signatures were also elevated in hepatocytes from patients with Fontan-associated liver disease (FALD), a condition associated with the development of HCCs with lower frequencies of canonical DGMs. Our study suggests that the YAP1-TEAD-TET1 axis promotes canonical DGM-negative HCC development, and provides new insights into the molecular processes involved.

Animals↗
PubMed2022

Comparison on Major Gene Mutations Related to Rifampicin and Isoniazid Resistance between Beijing and Non-Beijing Strains of Mycobacterium tuberculosis: A Systematic Review and Bayesian Meta-Analysis.

Objective: The Beijing strain of Mycobacterium tuberculosis (MTB) is controversially presented as the predominant genotype and is more drug resistant to rifampicin and isoniazid compared to the non-Beijing strain. We aimed to compare the major gene mutations related to rifampicin and isoniazid drug resistance between Beijing and non-Beijing genotypes, and to extract the best evidence using the evidence-based methods for improving the service of TB control programs based on genetics of MTB. Method: Literature was searched in Google Scholar, PubMed and CNKI Database. Data analysis was conducted in R software. The conventional and Bayesian random-effects models were employed for meta-analysis, combining the examinations of publication bias and sensitivity. Results: Of the 8785 strains in the pooled studies, 5225 were identified as Beijing strains and 3560 as non-Beijing strains. The maximum and minimum strain sizes were 876 and 55, respectively. The mutations prevalence of rpoB, katG, inhA and oxyR-ahpC in Beijing strains was 52.40% (2738/5225), 57.88% (2781/4805), 12.75% (454/3562) and 6.26% (108/1724), respectively, and that in non-Beijing strains was 26.12% (930/3560), 28.65% (834/2911), 10.67% (157/1472) and 7.21% (33/458), separately. The pooled posterior value of OR for the mutations of rpoB was 2.72 ((95% confidence interval (CI): 1.90, 3.94) times higher in Beijing than in non-Beijing strains. That value for katG was 3.22 (95% CI: 2.12, 4.90) times. The estimate for inhA was 1.41 (95% CI: 0.97, 2.08) times higher in the non-Beijing than in Beijing strains. That for oxyR-ahpC was 1.46 (95% CI: 0.87, 2.48) times. The principal patterns of the variants for the mutations of the four genes were rpoB S531L, katG S315T, inhA-15C > T and oxyR-ahpC intergenic region. Conclusion: The mutations in rpoB and katG genes in Beijing are significantly more common than that in non-Beijing strains of MTB. We do not have sufficient evidence to support that the prevalence of mutations of inhA and oxyR-ahpC is higher in non-Beijing than in Beijing strains, which provides a reference basis for clinical medication selection.

Isoniazid↗
PubMed1975

[Base pair substitutions induced by Escherichia coli K-12 mutator gene prv].

Using the trpA system of Yanofsky, it is shown that the mutator gene prv of Escherichia coli K-12 induces transitions in both directions (A:T in equilibrium G:C), and not A:T leads to leads to C:G and C:G leads to A:T transversions. The prv1 mutation was found to be recessive in prv+/prv1 merodiploid.

Base Sequence↗
PubMed2026

Seventeen-year follow-up of hypophosphatasia diagnosed in middle-aged siblings harboring a novel intronic and a rare missense ALPL gene mutation.

Hypophosphatasia (HPP) is the rare inborn-error-of-metabolism that features impaired mineralization of the skeleton and teeth due to a deactivating mutation or mutations of the gene ALPL which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). We report 17-year follow-up of twin sisters and a brother referred in middle-age for painful proximal femoral "stress fractures" and then diagnosed with HPP. They reported generalized muscle and bone pain, metatarsal fractures, arthropathy and, since childhood, tooth loss. Their concordant findings were explained by compound heterozygosity in ALPL for a rare maternal missense mutation (c.1403C > T, p.Ala468Val) in exon 12, together with a novel presumably paternal change (c.863-14G > A) predicting a cryptic mRNA splice site in intron 8. Fractures continued during follow-up until one sister received a three-and-one-half-year course of hydroxyapatite-targeted TNSALP supplementation therapy (asfotase alfa) during which substantial improvement occurred in her clinical, biochemical, and functional parameters as well as quality of life. Following subsequent unplanned treatment cessation she suffered significant clinical deterioration, including new fractures and loss of mobility. Her bone histopathology documented osteomalacia. Treatment resumption restored its benefits. Among ten asymptomatic family members evaluated in this four-generation kindred, eight were carriers heterozygous for either ALPL mutation. Those harboring the maternal missense defect manifested mild hypophosphatasemia, suggesting a dominant-negative mutation effect. This experience underscores the importance of in-depth phenotyping and then clinical follow-up to characterize ALPL variant combinations, and for maintaining effective asfotase alfa treatment.

Humans↗
PubMed1977

Evidence for chemically-induced structural gene mutations at the thymidine kinase locus in cultured L5178Y mouse lymphoma cells.

L5178Y mouse lymphoma cells normally appear to possess two functional thymidine kinase alleles (TK+/+). TK-deficient (TK-/-) clonal lines can be derived from these cells by treatment with EMS or other mutagens. Mezger-Freed [12] has argued that such stable phenotypic variants do not arise as the result of gene mutations but instead represent epigenetic events such as normally occur during differentiation without any permanent gene alteration. If this be so, then rare TK+/- revertants arising in TK-/- cultures should possess TK enzyme identical with one of those present in the original TK+/+ cells, since only depression of the TK gene is involved. Our studies show that this is not the case. Among the mutant TK enzymes analyzed in vitro (those from parental TK+/- lines, each derived in turn from separate TK-/- lines) differences were found in (1) solubility in saline; (2) solubility in 3 M LiCl; (3) Km's; and (4) ATP-Mg2+ requirements. These findings were incompatible with a non-mutational model for the production of these stable variants and, in conjunction with reversion-rate data, they tended to favor either direct structural gene modifications or mutations affecting the expression of adult and fetal enzymes.

Bromodeoxyuridine↗
PubMed1979

[Antimutagenic effect of alpha-tocopherol on the gene mutation frequency in Salmonella].

The work presents the data on the antimutagenic effect of alpha-tocopherol on the frequency of N-nitroso-N-methyl urea induced gene mutations in Salmonella in vitro and in vivo. In vitro tests have revealed the dependence of decreasing the rate of induced mutations both on combination of treatments with mutagen/antimutagen and on the dose of the mutagen. In vivo tests have demonstrated that the mutagenic effect of alpha-tocopherol depends on the duration of its action on organisms.

Animals↗
PubMed1977

Suppression of gene 49 mutations of bacteriophage T4 by a second mutation in gene X: structure of pseudorevertant DNA.

Mutations in gene 49 of bacteriophage T4 were suppressed by a second mutation in gene X. Mapping studies located gene X between genes 41 and 42. Complementation results indicated that mutations in FdsA gene (a suppressor of gene 49 mutants) were in gene X. The intracellular pseudorevertant DNA was examined for unusual properties which could explain its successful encapsidation. After the in vivo inactivation of a temperature-sensitive gene 32 (DNA unwinding) protein, the intracellular pseudorevertant DNA was converted into DNA pieces of approximately genome size. A similar conversion was observed after in vitro digestion of pseudorevertant DNA with single-strand-specific S1 endonuclease. Appreciable quantities of oligomeric intermediates were not produced during this conversion process. These data indicate that pseudorevertant DNA contains sizable single-stranded gaps and has a conformation similar to that of wild-type DNA. The results further suggest that the suppression of gene 49 mutant abnormal DNA phenotype and the encapsidation defect by a second mutation in gene X is associated with the formation of sizable single-stranded gaps. These studies raise the possibility that single-stranded gaps may be involved directly in the DNA encapsidation process, or may act indirectly as a consequence of their effect on the organization of intracellular DNA.

Coliphages↗
PubMed1975

A structural gene mutation affecting the regulatory subunit of cyclic AMP-dependent protein kinase in mouse lymphoma cells.

Compared to the wild-type parental line of S49 mouse lymphoma cells, intact cells of a mutant line (kin.A) are 10-fold less sensititive to biologic effects of exogenous cyclic adenosine 3':5'-monophophosphate (cAMP), such as induction of cAMP phosphodiesterase, cell cycle-specific growth inhibition, and cytolysis. The cAMP-dependent protein kinase (ATP:protein phosphotransferase; EC 2.7.1.37) activity of kin.A cells exhibits an apparent Ka for activation by cAMP 10-fold greater than that of wild type, and is much more resistant to inactivation by heat. These differences between the wild-type and mutant enzymes persist through a high degree of purification, suggesting a structural alteration in the kin.A holoenzyme. Heterologous reconstitution experiments, using separated R and C subunits of the wild-type and kin.A cAMP-dependent kinases, show that the altered cAMP affinity and thermolability are conferred by the R component of the kin.A enzyme. These results are most consistent with a structural mutation in the kin.A gene coding for the R subunit of cAMP-dependent protein kinase. Evidence for a structural mutation helps to define one mechanism of heritable variation in cultured somatic cells. The phenotype produced by the kin.A structural mutation also greatly strengthens the conslusion that cAMP-dependent protein kinase is essential for cAMP regulation of growth and enzyme induction in intact S49 cells.

Cell Line↗