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At least 37 records · Page 2Linked to original sources
PubMed1976

Suppression of polarity of insertion mutations in the gal operon and N mutations in bacteriophage lambda.

Bacterial mutations (psuA and psu) known for their ability to suppress the polarity on nonsense mutations are shown to suppress the polarity of certain insertion mutations in the gal operon. The short insertion, IS1 (800 nucleotide pairs), is about 15 to 50% suppressed, whereas longer insertions, IS2 (1,400 nucleotide pairs), and IS3 (1,200 nucleotide pairs), are not. Some of the polarity suppressor mutations (psu-1, psu-2, and psu-3) are at least partially permissive for N-gene mutations (N7 and N53) of bacteriophage lambda, suggesting a relationship between natural and mutational polar signals. That this relationship may be complex is indicated by the fact that other suppressor mutations, effective in suppressing nonsense or insertion polarity, fail entirely to permit the growth of lambda N mutants.

Cell-Free System↗
PubMed2025

TSC angiofibroma and ungual fibroma have different mutation signatures, with recurrent mutations in KMT2C.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome characterized by tumors affecting multiple tissues, including skin, due to inactivating TSC1/TSC2 variants. Genome-wide profiling of somatic mutations in a unique collection of angiofibroma (FAF) and ungual fibroma (UF) TSC skin tumors was performed. METHODS: Genome sequencing was performed on 9 samples, comprising 4 FAF and 5 UF, along with 6 matched normal samples from 6 individuals with TSC. RESULTS: TSC-FAF and TSC-UF skin tumors have different mutation signatures, with a predominance of UV-related single-nucleotide variant (SNV; SBS7a and SBS7b) and dinucleotide variant (DNV; DBS1) signatures in FAF, and aging-related SNV (SBS1 and SBS5) signatures in UF. We also identified a novel DNV signature for TSC-UF, with frequent TG>CA and TT>GG substitutions. Furthermore, 3 inactivating somatic mutations in KMT2C were observed in 2 of 4 TSC-FAF and 5 mutations in other cancer genes. CONCLUSION: The distinct SNV mutation signatures seen in TSC-FAF and UF indicate that they develop through distinct pathogenic mechanisms, UV-induced mutagenesis in FAF, and aging-related mutagenesis in UF. The mechanism of the novel DNV signature in UFs merits further investigation. Our observation on the occurrence of KMT2C mutations suggests that KMT2C inactivation contributes to the pathogenesis of TSC-FAF.

Humans↗
PubMed2024

ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

Humans↗
PubMed1979

Failure of caffeine to influence induced mutation frequencies and the independence of cell killing and mutation induction in V79 Chinese hamster cells.

Using V79 Chinese hamster cells and a replating assay, no effect of caffeine post-treatment on spontaneous or UV- or EMS-induced mutation frequencies to 8-azaguanine resistance was demonstrable. However, considerable potentiation of cell killing was observed. Previous reports that caffeine enhances induced mutation frequencies are explained by an artefact in the situ method used; a similar artefact may also explain the cumulative in situ mutation dose-response curves. Furthermore, the relationship between mutation induction and dose has been shown to be qualitatively distinct from that between cell killing and dose. These differences suggest that cell killing and mutation induction are mediated via independent mechanisms and that pre-mutational lesions may be qualitatively distinct from pre-lethal lesions.

Animals↗
PubMed1976

Immunogenetic analysis of H-2 mutations. V. Serological analysis of mutations H-2da, H-2ra, and H-2ka1.

The H-2 and Ia antigenic composition of strain pairs B10.D2 (H-2d) and M504 (H-2da). A.CA (H-2f) and M506 (H-2fa), and CBA (H-2k) and M523 (H-2ka) was compared by testing their cells against a battery of oligospecific antisera, by performing absorption analysis, and by cross-immunization. The two strains of each pair are congenric and differ in taht the second strain of the pair carries a mutation that occurred in the H-2 haplotype of the first strain. The Ia composition of each mutant haplotype was found to be the same as that of the haplotype from which the mutant was derived. Several differences in the serologically detectable H-2 antigens were found. The H-2d and H-2da haplotypes were found to differ in that the latter lost at least one and gained another antigen. The affected antigens were demonstrated to be classic H-2 antigens controlled by the H-2D locus. The H-2t and H-2fa haplotypes were found to differ in that antigens 26, 37, and 39, controlled by the latter, bound their respective antibodies less firmly than those controlled by the former haplotype. Since all three antigens are coded for by the H-2K locus, since no change was found in the D-region controlled antigens, and since the H-2fa mutation maps in the K end, we conclude that most likely the mutation occurred in the K region. The H-2k and H-2ka haplotypes were found to differ in that the latter lost one antigen encoded by the H-2Kk allele. This mutation, therefore, must have occurred in the H-2K locus. The data tip the scale of evidence in favor of the interpretation that each of the H-2 mutations occurred in a single region, either K or D. No evidence for a second mutation within any of the other H-2 regions was found.

Animals↗
PubMed1978

Isolation of an Escherichia coli K-12 dnaE mutation as a mutator.

Using a papillation method, a large number of Escherichia coli K-12 mutator mutations have been isolated. Only one of these (out of 1,250) mutator mutations has proved to be conditionally lethal at high temperatures. In vivo complementation tests indicated that this mutation, dnaE9, lies in dnaE, the structural gene for DNA polymerase III. The dnaE9 polymerase was not thermolabile in vitro; however, it showed a slow decline in specific activity in vivo at the nonpermissive temperature. Cultures of this mutant exhibited a comparably slow shutoff of DNA synthesis on shift to a nonpermissive temperature. dnaE9 showed temperature-sensitive mutator activity, which is not dependent on recA.

Chromosome Mapping↗
PubMed1979

Nuclear mutations in Saccharomyces cerevisiae which increase the spontaneous mutation frequency in mitochondrial DNA.

Fourteen mutants have been identified in which the frequency of spontaneous mutations in mitochondrial DNA is increased. As well as increasing the frequency of mutations to resistance to erythromycin, oligomycin and spiramycin, all the mutants also show changes in the frequency of spontaneous petite induction. None of the mutants has any effect on the frequency of spontaneous nuclear mutations. Nine of the mutants are in one complementation group and five are in another. The phenotype of both groups is caused by a single nuclear mutation.

Cell Nucleus↗
PubMed1978

The ratio of de novo unbalanced translocation to 47, trisomy 21 Down syndrome. A new method for human mutation surveillance and an apparent recent change in mutation rate resulting in human interchange trisomies in one jurisdiction.

The Down syndrome phenotype may be associated with, among other genotypes, an unbalanced Robertsonian translocation producing an "interchange trisomy" with 46 chromosomes, or 47, trisomy 21. Translocations, like specificlocus point mutations, result from a direct change in structural chromosome elements. In contrast 47, trisomy 21 results from meiotic non-disjunction. Mutation rates for interchange trisomies may be followed indirectly by determining the ratio of instances of Down syndrome associated with a new translocation mutation to those produced by 47, trisomy 21, which accounts for the bulk of the Down syndrome phenotype. This genotypic ratio can be analyzed in data from cytogenetic laboratories, clinics, and chromosome registries and does not depend upon intensive chromosome screening of newborn populations. A similar approach can be adopted to follow trends in Patau syndrome. The genotypic ratio, stratified by maternal age, may in addition, provide a sentinel index for changes in human specific-locus mutations and perhaps other adverse health consequences. Analysis of data from the New York State-North-eastern chromosome registry revealed a two- to three-fold increase in the genotypic ratio for both Down syndrome and Patau syndrome for individuals born in 1973, 1974 and 1975 compared to those born in earlier years.

Down Syndrome↗
PubMed1979

Suppression of a deletion mutation in the glutamine amidotransferase region of the Salmonella typhimurium trpD gene by mutations in pheA and tyrA.

Prototrophic revertants of a trpD deletion mutant that lacks the glutamine amidotransferase domain of the bifunctional component II subunit of the anthranilate synthetase-phosphoribosyltransferase complex have been found to arise by the occurrence of sublethal missense mutations in either the pheA or tyrA loci. Such suppressor mutations were obtained directly by mutation of the wild-type pheA gene as well as indirectly by partial reversion of a variety of nonleaky pheA and tyrA mutations. The suppressor strains have only a portion of the normal level of the pheA or tyrA enzyme activity and thus experience a partial limitation in the synthesis of phenylalanine or tyrosine. This limitation leads to a relaxation of end-product regulation of the phenylalanine- or tyrosine-specific enzymes of the common aromatic pathway and to the overproduction of the branch point intermediate, chorismic acid, which is one of the substrates of the anthranilate synthetase reaction. It is proposed that the high intracellular level of chorismic acid acts to elevate the non-physiological NH3-dependent anthranilate synthetase activity of the component I subunit, thereby eliminating the need for the glutamine amidotransferase activity of the component II subunit. Consistent with this is the finding that phenylalanine and tyrosine are specific inhibitors of growth of the pheA and tyrA suppressor strains, respectively, causing a shutdown of the overproduction of chorismic acid by reestablishing normal end-product control of the common pathway.

Anthranilate Phosphoribosyltransferase↗
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↗
PubMed2026

Co-mutation Based Genetic Networks to Infer Temporal Mutation Dynamics in Ancient Human Mitochondrial Genomes.

The evolutionary history of Homo sapiens is marked by complex interactions between environmental, cultural, and genetic factors. To investigate the molecular signatures of these processes, we analyzed ancient mitochondrial DNA (mtDNA) across temporal and geographic contexts using principles of co-occurrence of minor alleles defined as co-mutation, through spatiotemporal co-mutation networks of variable sites. Haplogroup-based assessments of variable sites revealed a major transition from foraging to agrarian lifestyles during the Copper-Bronze Age. Genetic network analyses demonstrated that COX and CYB loci exhibited distinct temporal dynamics, with their interactions modulated by NADH dehydrogenase genes in a geological age-dependent manner. To complement the network approach, we constructed phylogeny-based gene interaction networks and assessed polymorphism-to-divergence from chimpanzee ratios. The tree-based networks displayed topologies consistent with co-mutation analyses but showed reduced gene-gene connectivity. Polymorphism/divergence analysis further indicated that the CYB gene has been under long-term purifying selection, whereas ATP6, COX, and NADH dehydrogenase genes experienced episodic purifying selection aligned with distinct historical phases. Collectively, our findings demonstrate that network-based analysis of ancient mtDNA provides insights into early human lifestyle transitions and haplogroup diversification, contributing to the evolutionary foundations of modern human populations.

Ancient humans↗
PubMed1978

Mutation in continuous cultures of Schizosaccharomyces pombe II. Effect of amino acid starvation on mutational response and DNA concentration.

In agreement with the results obtained in Escherichia coli by other workers and our own previous data, the kinetics with which spontaneous mutations to resistance to the 12,13-epoxytrichothecene trichodermin accumulate in a lysine auxotroph of Schizosaccharomyces pombe are dependent upon the nutrilite used to limit the growth of the population. Under conditions of glucose-limitation mutation accumulation is proportional to generation time, while under lysine-limitation it becomes proportional to chronological time. In contrast to observations made in bacterial system, however, no significant change in the DNA content per cell is noted in slow growing cultures grown under amino acid starvation. These findings help to eliminate some of the theories put forward to explain the differential mutational responses observed under different growth limiting regimes.

Ascomycota↗
PubMed1976

Mutations in Escherichia coli that relieve catabolite repression of tryptophanase synthesis. Mutations distant from the tryptophanase gene.

Two mutants are described in which the synthesis of tryptophanase is unusually insensitive to catabolite repression. Neither mutation is linked by transduction to the tryptophane structural gene, neither mutation renders the synthesis of beta-galactosidase insensitive to catabolite repression, and the mutations do not permit tryptophanase to be synthesized in strains deficient in adenyl cyclase. During growth in glucose-minimal medium the mutants maintained a similar intracellular concentration of cyclic AMP to their wild-type parent; but since in the wild type the concentration of cyclic AMP was the same in glycerol-minimal medium as in glucose-minimal medium, it is doubtful whether catabolite repression is mediated by measurable changes in the concentration of this nucleotide.

Adenylyl Cyclases↗
PubMed1975

Immunogenetic analysis of H-2 mutations. III. Genetic mapping and involvement in immune reactions of the H-2ka mutation.

Mutation M523 (H-2ka) occurred spontaneously in strain CBA/CaLacSto and was discovered during routine skin graft testing for genetic homogeneity. By linkage and complementation tests, the mutation was previously mapped in the K end of the H-2 complex. We demonstrate that the mutation occurred in the K region, without affecting the I region in the K end of the complex. The mutant antigens cause rejection of skin grafts, stimulate cells in mixed lymphocyte culture, and function as stimulators as well as targets in cell-mediated lymphocytotoxicity. Yet, they are serologically indistinguishable from the antigens of the original strain and do not induce formation of humoral antibodies upon immunization of the CBA strain. Together with the results obtained on testing of other H-2 mutants, the data strongly support the notion that classical H-2 antigens (i.e., products of the H-2K and H-2D loci) can function as lymphocyte-stimulating determinants, and that I-region differences are not required for the induction of strong cell-mediated lymphocytotoxicity.

Animals↗
PubMed2026

Prognostic impact of age and MDS-associated mutations in NPM1-mutated AML.

Nucleophosmin-1 (NPM1) mutations define a major molecular subtype of acute myeloid leukemia (AML) and is generally associated with favorable prognosis. However, the impact of myelodysplastic syndrome-associated mutations (MDSm+) on patient outcomes within this subgroup remains uncertain. We retrospectively analyzed 271 patients with NPM1-mutated AML from 3 independent cohorts (SWOG, Fred Hutch, and Beat AML) to assess the prognostic significance of MDSm+ and its interaction with age. MDSm+ occurred in 17% of patients, most commonly involving SRSF2 and SF3B1. Although MDSm+ was associated with inferior overall survival (OS) compared with MDSm- in European LeukemiaNet (ELN) 2022 favorable-risk patients (hazard ratio [HR], 2.0; P = .008), this effect was largely driven by worse outcomes in older patients (≥65 years) as older ELN2022 favorable-risk patients had poor OS regardless of the presence of MDSm+ compared with younger patients. After stratification of patients by age, there was not a significant difference between MDSm+ and MDSm- in either younger patients (HR, 0.99; P = .98) or older patients (HR, 1.42; P = .33). These findings indicate that MDSm+ in NPM1 + AML is not independently associated with adverse risk after adjusting for age, and highlight the need for age-adjusted AML risk models.

Journal Article↗
PubMed1979

Mutagenicity tests of diflubenzuron in the micronucleus test in mice, the L5178Y mouse lymphoma forward mutation assay, and the Ames Salmonella reverse mutation test.

Diflubenzuron, one of a new class of pesticides believed to act via inhibition of chitin synthesis in the developing insect cuticle, was tested for possible mutagenic activity using the micronucleus test in mice, the L5178Y mouse lymphoma forward mutation test at the thymidine kinase locus, and the Ames Salmonella/microsome reverse mutation test. No mutagenic effect was found.

Animals↗
PubMed1977

Mutator action by Escherichia coli strains carrying dnaE mutations.

Several newly isolated temperature-sensitive dnaE mutants of Escherichia coli exhibit powerful mutagenic action at permissive temperatures. Mutation rates for the two most active mutants were assayed at four different temperatures and compared to wild-type behavior. Temperature-resistant revertants of the original temperature-sensitive dnaE mutants exhibited lower, nearly normal, mutation rates, but no antimutator strains were found.

Ampicillin↗