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At least 793 records · Page 44Linked to original sources
PubMed1986

Amplification and deletion of the amyE+-tmrB+ gene region in a Bacillus subtilis recombinant-phage genome by the tmrA7 mutation.

A 22.4-kilobase DNA fragment containing the tmrA7-amyR2-amyE+-tmrB+-aroI+ region of the Bacillus subtilis N7 chromosomal DNA was cloned into a recombinant B. subtilis bacteriophage, p11-AA248. The amyE+-tmrB+ gene region, approximately 12.6 kilobases, in the phage genome was amplified in a tunicamycin-resistant (Tmr) Amy+ AroI+ transductant of B. subtilis by p11-AA248. On the other hand, the amyE+-tmrB+ region in the genomes of 80 to 90% of the phage particles was deleted when the phages were induced from the Tmr Amy+ AroI+ transductants by treatment with 1.0 micrograms of mitomycin C per ml. From analyses of the physical maps and DNA nucleotide sequences in the junction region of the deleted phage genome and the parental DNA fragments, it is suggested that the deletion occurred within a direct repeat sequence composed of 18 base pairs. The endpoints of the amplified gene region seemed to be closely related to both terminal regions of the deleted DNA.

Bacillus subtilis↗
PubMed1989

Overexpression of the yeast transcriptional activator ADR1 induces mutation of the mitochondrial genome.

It was previously observed that increased dosages of the ADR1 gene, which encodes a yeast transcriptional activator required for alcohol dehydrogenase II (ADH II) expression, cause a decreased rate of growth in medium containing ethanol as the carbon source. Here we show that observed reduction in growth rate is mediated by the ADR1 protein which, when overexpressed, increases the frequency of cytoplasmic petites. Unlike previously characterized mutations known to potentiate petite formation, the ADR1 effect is dominant, with the petite frequency rising concomitantly with increasing ADR1 dosage. The ability of ADR1 to increase the frequency of mitochondrial mutation is correlated with its ability to activate ADH II transcription but is independent of the level of ADH II being expressed. Based on restoration tests using characterized mit- strains, ADR1 appears to cause non-specific deletions within the mitochondrial genome to produce rho- petites. Pedigree analysis of ADR1-overproducing strains indicates that only daughter cells become petite. This pattern is analogous to that observed for petite induction by growth at elevated temperature and by treatment with the acridine dye euflavine. One strain resistant to ADR1-induced petite formation displayed cross-resistance to petite mutation by growth at elevated temperature and euflavine treatment, yet was susceptible to petite induction by ethidium bromide. These results suggest that ADR1 overexpression disrupts the fidelity of mitochondrial DNA replication or repair.

Acriflavine↗
PubMed2000

Increased rates of genomic deletions generated by mutations in the yeast gene encoding DNA polymerase delta or by decreases in the cellular levels of DNA polymerase delta.

In Saccharomyces cerevisiae, POL3 encodes the catalytic subunit of DNA polymerase delta. While yeast POL3 mutant strains that lack the proofreading exonuclease activity of the polymerase have a strong mutator phenotype, little is known regarding the role of other Pol3p domains in mutation avoidance. We identified a number of pol3 mutations in regions outside of the exonuclease domain that have a mutator phenotype, substantially elevating the frequency of deletions. These deletions appear to reflect an increased frequency of DNA polymerase slippage. In addition, we demonstrate that reduction in the level of wild-type DNA polymerase results in a similar mutator phenotype. Lowered levels of DNA polymerase also result in increased sensitivity to the DNA-damaging agent methyl methane sulfonate. We conclude that both the quantity and the quality of DNA polymerase delta is important in ensuring genome stability.

DNA Polymerase III↗
PubMed1995

Genomic structure, expression and mutational analysis of the P15 (MTS2) gene.

The P15 gene (MTS2) encodes a cyclin-dependent kinase (CDK) inhibitor with considerable sequence identity and biochemical similarity to the CDK inhibitor p16. It is closely linked to the P16 gene (MTS1) and is homozygously deleted in many tumor cell lines. These features suggest that p15 may be a tumor suppressor. We have determined the genomic structure of P15 and examined its pattern of mRNA expression. In addition, we have shown that ectopic expression of p15 inhibits growth of tumor-derived cell lines. We have also searched for P15 mutations in tumor cell lines and in 9p21-linked melanoma kindreds. Other than the previously described homozygous deletions, no mutations of P15 were found. Collectively, these observations suggest a role for p15 in growth regulation, but a limited role for p15 in tumor progression.

Base Sequence↗
PubMed2002

P53 mutations in colorectal cancer assessed in both genomic DNA and cDNA as compared to the presence of p53 LOH.

Mutations in p53 is a most common genetic alteration in human cancer and has been related to outcome, also in colorectal cancer. However, published results are not unanimous on this point without clear-cut explanations. Different analytical methods have been applied which could explain some discrepancies. Another factor of importance may be the source of nucleic acids used for identification of sequence alterations. Therefore we compared mutations in exons 7 and 8 of p53 found in genomic DNA, with mutations in cDNA from the same patients and evaluated to what extent LOH and mutations in p53 occurred simultaneously, which are prerequisites for a complete loss of p53 function according to the classic concept. cDNA and genomic DNA from tumor tissue from 123 patients were used. Thirty-four mutations were found in both tumor cDNA and genomic DNA. Twenty missense mutations were the same in both cDNA and genomic DNA. Two missense mutations, one 1 bp deletion and one nonsense mutation were only found in genomic DNA, while nine missense mutations and one 9 bp deletion were found in cDNA only. Statistical analysis showed no significant difference among mutations in cDNA and genomic DNA (p=1.00). Only 2 patients (5%) had both LOH and mutations in exons 2-11 of p53. One patient had LOH without p53 mutation, while 18 patients (44%) showed p53 mutation without LOH and 20 patients (49%) had wt p53 without LOH. Forty-four patients (52%) were non-informative for LOH of the entire cohort consisting of 85 patients. Our findings suggest that different results reported on the role mutated p53 may have in colorectal cancer are probably not explained by the source of nucleic acids (RNA vs DNA) for sequence determinations. Rather, unknown information about simultaneous but different presence of p53 LOH in previously published reports is more likely. However, an unexpectedly infrequent occurrence (5-10%) of complete and isolated p53 ablation (LOH + mutation) would demand considerably larger patient populations (1500-2000 patients) than ever published for relating p53 function to survival in patients with colorectal cancer. Therefore, the role of p53 dysfunction in progression of colorectal cancer remains uncertain.

Adult↗
PubMed2000

Deleterious mutations and the evolution of sex.

It has been suggested that sexual reproduction is maintained because it reduces the load imposed by recurrent deleterious mutations. If rates of deleterious mutation per diploid genome per generation (U) exceed 1, and mutations interact synergistically, then sexuals can overcome their inherent twofold disadvantage. We have tested this hypothesis by estimating genomic point mutation rates for protein-coding genes in a range of animal taxa. We find a positive linear relationship between U and generation time. In species with short generation times, U is predicted to be far below 1, suggesting that sex is not maintained by its capacity to purge the genome of deleterious mutations.

Animals↗
PubMed2006

Different mutations in the genome-linked protein VPg of potato virus Y confer virulence on the pvr2(3) resistance in pepper.

Five different amino acid substitutions in the VPg of Potato virus Y were shown to be independently responsible for virulence toward pvr2(3) resistance gene of pepper. A consequence of these multiple mutations toward virulence involving single nucleotide substitutions is a particularly high frequency of resistance breaking (37% of inoculated plants from the first inoculation) and suggests a potentially low durability of pvr2(3) resistance. These five mutants were observed with significantly different frequencies, one of them being overrepresented. Genetic drift alone could not explain the observed distribution of virulent mutants. More plausible scenarios were obtained by taking into account either the relative substitution rates, the relative fitness of the mutants in pvr2(3) pepper plants, or both.

Amino Acid Substitution↗
PubMed2002

Mutations in bacteriophage T4 genome.

Bacteriophage (phage) T4 belonging to T-even phages is one of the best known phages with a completely deciphered genome sequence. As a model of living systems, T4 phage has many technical advantages. It can be very easily grown in large quantities, manipulated by classical genetics, and engineered by site-directed mutagenesis. Many substances have been first tested for mutagenicity in T-even phages. The results of these tests were very often applicable to higher organisms due to similar mechanisms of mutagenesis. T4 phage is also important in phage therapy, which represents an alternative treatment of bacterial infections since the bacterial resistance to antibiotics has become a serious medical problem. The site-directed mutagenesis is a method that enables to introduce mutations which can influence phage affinity to bacteria and can be a practical technique for enriching phage collections and for widening specificity of phages for new bacterial strains now insensitive to phage therapy.

Bacteriophage T4↗
PubMed2006

Indirect mechanisms of genomic instability and the biological significance of mutations at tandem repeat loci.

Radiation induction of genomic instability has two features: induction of untargeted mutation and delayed mutation. These phenomena have been studied mostly in tissue culture cells, but analyses have also been conducted in whole body systems. The study of response in whole body systems frequently applies repeat sequences as markers to detect mutations. These studies have generated conflicting findings. In addition, lack of knowledge of the mechanisms involved in repeat mutation confounds the interpretation of the biological significance of increased rates of repeat mutation. In this review, some of the existing controversies of genomic instability are discussed in relation to the mechanism of repeat mutation. Analyses of published and unpublished studies indicate a mechanistic similarity between radiation-induced genomic instability at repeat loci and dynamic mutations of triplet repeats. Because of their repetitive nature, repeat sequences frequently block progression of replication forks and are consequently resolved by slippage and/or recombination. Irradiation of cells induces S checkpoints and promotes slippage/recombination mediated repeat mutations. Thus, genomic instability at repeat loci might be viewed as a consequence of cellular attempts to restore the stability of replication in the face of the stalled replication fork; this process can occur both spontaneously as well as after exposure to radiation.

Animals↗
PubMed1990

A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations.

Overlapping cDNA clones from the translocation breakpoint region (TBR) gene, recently discovered at the neurofibromatosis type 1 locus and found to be interrupted by deletions and a t(17;22) translocation, have been sequenced. A 4 kb sequence of the transcript of the TBR gene has been compared with sequences of genomic DNA, identifying a number of small exons. Identification of splice junctions and a large open reading frame indicates that the gene is oriented with its 5' end toward the centromere, in opposition to the three known active genes in the region. PCR amplification of a subset of the exons, followed by electrophoresis of denatured product on native gels, identified six variant conformers specific to NF1 patients, indicating base pair changes in the gene. Sequencing revealed that one mutant allele contains a T----C transition changing a leucine to a proline; another NF1 allele harbors a C----T transition changing an arginine to a stop codon. These results establish the TBR gene as the NF1 gene and provide a description of a major segment of the gene.

Amino Acid Sequence↗
PubMed1998

Impact of genomic imprinting on genomic instability and radiation-induced mutation.

PURPOSE: The purpose of this review is to assess the effect of radiation-induced mutation on genes subject to genomic imprinting, and the consequences of this on the understanding of genomic instability. Genomic imprinting is the phenomenon in which one of the two alleles of a gene is expressed or suppressed depending on the gamete from which it was inherited, thus effectively rendering a cell hemizygous for the expression of certain key genes. The consequence of this is that such loci are potentially more likely targets for mutagenesis since one allele is normally inactive. This is not only important in the recognition of a subgroup of target genes for radiation-induced damage, but also raises the possibility of mutations affecting the epigenotype of key tumour suppressor or tumour promoting genes. Such mutations may in principle affect the stability of imprinting and may fall into a novel class of 'epimutation', where the DNA sequence is not affected, but post-transcriptional mechanisms of epigenotype maintenance are stably altered. These novel mechanisms are discussed in relation with radiation-induced genomic instability and the heritability of tumour predisposition from radiation-exposed parents. CONCLUSIONS: As yet there is only circumstantial evidence that the targets for radiation-induced DNA and epigenetic damage are imprinted genes, or genes involved in the maintenance of the epigenotype. However, the potential consequences of such genes being important targets for the generation of genomic instability or other forms of damage are serious and could affect the interpretation of the risks of low dose radiation exposure and of epidemiological data.

Alleles↗
PubMed2005

PRR5 encodes a conserved proline-rich protein predominant in kidney: analysis of genomic organization, expression, and mutation status in breast and colorectal carcinomas.

Loss of heterozygosity on chromosome 22q13.31 is a frequent event during human breast and colorectal carcinogenesis. Herein we characterize a novel gene at chromosome 22q13.31 designated PRR5. Alternative promoter usage and splicing converge to generate five PRR5 transcript variants with maximum mRNA expression in kidney. In vitro transcription/translation demonstrated that the five variants generate three protein isoforms differing in their N-terminal length. Mutational analysis of PRR5 in human breast and colorectal tumors did not reveal somatic mutations. However, mRNA expression analyses revealed PRR5 overexpression in a majority of colorectal tumors but substantial downregulation of PRR5 expression in a subset of breast tumors and reduced expression in two breast cancer cell lines. Treatment with trichostatin A increased PRR5 mRNA levels in BT549 and MDA-MB-231 cells, whereas 5'-aza-2'-deoxycytidine induced expression in MDA-MB-231 cells only. Thus, PRR5 may represent a potential candidate tumor suppressor gene in breast cancer.

Alternative Splicing↗
PubMed1983

Regulation of toxinogenesis in Corynebacterium diphtheriae: mutations in the bacterial genome that alter the effects of iron on toxin production.

Mutants of Corynebacterium diphtheriae C7(beta) that are resistant to the inhibitory effects of iron on toxinogenesis were identified by their ability to form colonies surrounded by toxin-antitoxin halos on agar medium containing both antitoxin and a high concentration of iron. Chromosomal mutations were essential for the altered phenotypes of four independently isolated mutant strains. During growth in deferrated liquid medium containing various amounts of added iron, these mutants differed from wild-type C. diphtheriae C7(beta) in several ways. Their growth rates were slower under low-iron conditions and were stimulated to various degrees under high-iron conditions. The concentrations of iron at which optimal toxin production occurred were higher for the mutants than for wild-type C. diphtheriae C7(beta). Toxin production by the mutants during growth in low-iron medium occurred throughout the period of exponential growth at nearly constant rates that were proportional to the bacterial growth rates. In contrast, toxin production by wild-type C. diphtheriae C7(beta) in similar low-iron cultures occurred predominantly during the late exponential phase, when iron was a growth-limiting nutrient. Additional studies demonstrated that these mutants had severe defects in their transport systems for ferric iron. We propose that the altered regulation of toxinogenesis by iron in our mutants was caused by the severe defects in their iron transport systems. As a consequence, the mutants exhibited a low-iron phenotype during growth under conditions that permitted wild-type C. diphtheriae C7(beta) to exhibit a high-iron phenotype.

Corynebacterium diphtheriae↗
PubMed2001

Detection of simple mutations and polymorphisms in large genomic regions.

We have developed a novel technology that makes it possible to detect simple nucleotide polymorphisms directly within a sample of total genomic DNA. It allows, in a single Southern blot experiment, the determination of sequence identity of genomic regions with a combined length of hundreds of kilobases. This technology does not require PCR amplification of the target DNA regions, but exploits preparative size-fractionation of restriction-digested genomic DNA and a newly discovered property of the mismatch-specific endonuclease CEL I to cleave heteroduplex DNA with a very high specificity and sensitivity. We have used this technique to detect various simple mutations directly in the genomic DNA of isogenic pairs of recombinant Pseudomonas aeruginosa, Escherichia coli and Salmonella isolates. Also, by using a cosmid DNA library and genomic fractions as hybridization probes, we have compared total genomic DNA of two clinical P.aeruginosa clones isolated from the same patient, but exhibiting divergent phenotypes. The mutation scan correctly detected a GA insertion in the quorum-sensing regulator gene rhlR and, in addition, identified a novel intragenomic polymorphism in rrn operons, indicating very high stability of the bacterial genomes under natural non-mutator conditions.

Bacterial Proteins↗
PubMed1999

Genomic characterization of the human peptidyl-prolyl-cis-trans-isomerase, mitochondrial precursor gene: assessment of its role in familial dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common cause of morbidity and mortality, with >30% of cases being inherited. In one family with autosomal dominant familial dilated cardiomyopathy (FDCM), we localized the gene to the region of 10q21-10q23 and have performed candidate positional gene cloning. The peptidyl-prolyl-cis-trans-isomerase, mitochondrial precursor (PPIF: previously known as cyclophilin 3) is a protein that is part of the mitochondrial permeability transition pore, the activation of which is involved in the induction of necrotic and apoptotic cell death. Since it is encoded by a gene located within this FDCM critical region, PPIF was considered a potential candidate gene for FDCM. In order to screen patient genomes for evidence of disease-associated mutations, the genomic organization of this gene was determined. BAC libraries were screened by PCR, using primers designed from the published cDNA sequence, and positive clones were identified. This enabled the gene to be further localized to between the CEPH markers D10S1777 and D10S201. The DNA from a BAC clone was digested and subcloned into pUC18. Following identification of a subclone by whole-cell PCR, the gene was characterized by DNA sequencing; five introns were identified, and the sequences of the intron-exon boundaries were characterized. Additionally, 450 bp of DNA sequence upstream of the published cDNA were obtained and a potential transcription initiation site and promoter sequence were identified. DNA analysis of the entire PPIF coding region (including the intron-exon boundaries) of two affected and one unaffected family member revealed no mutations, therefore excluding this gene as the cause of FDCM in this family.

Cardiomyopathy, Dilated↗
PubMed2003

Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status.

Paraoxonase (PON1) has been termed an environmental response enzyme for its function in the detoxification of organophosphate pesticides, nerve agents and pharmaceuticals such as glucocorticoids and statins, as well as its cardioprotective role in breaking down oxidized LDL. PON1(192) genotype can be predicted with high accuracy from an examination of the two-dimensional plot of paraoxon and diazoxon hydrolysis rates [ 1]. Individuals for whom this functional genomic assay failed to predict PON1(192) genotype, or who had a low PON activity relative to others with the same genotype, were predicted to have genetic alterations that explained the inconsistency. Sequencing of the PON1 region of 23 Caucasian individuals detected a nonsense mutation changing amino acid 194 from a Trp to a stop codon (PON1(Trp194stop)). It was predicted that subjects who genotyped as PON1(192QR) but phenotyped as PON1(192QQ) or PON1(192RR) might carry the protein truncation mutation for which the defective product failed to be detected by the phenotyping assay. Screening of the five discordant subjects resulted in the detection of a single Caucasian carrying the stop codon, and determined its phasing on the PON1(192R) allele. Sequencing confirmed the change and revealed an additional subject with a likely deletion of the 5' end of the PON1 gene. Additional sequencing of 25 subjects with low PON1 activities identified two additional previously undescribed PON1 mutations, which may affect PON1 function: PON1(Pro90Leu) associated with the PON1(192Q) allele and PON1(Asp124missplice) associated with the PON1(192R) allele.

Aryldialkylphosphatase↗
PubMed2000

The fitness effects of spontaneous mutations in Caenorhabditis elegans.

Spontaneous mutation to mildly deleterious alleles has emerged as a potentially unifying component of a variety of observations in evolutionary genetics and molecular evolution. However, the biological significance of hypotheses based on mildly deleterious mutation depends critically on the rate at which new mutations arise and on their average effects. A long-term mutation-accumulation experiment with replicate lines of the nematode Caenorhabditis elegans maintained by single-progeny descent indicates that recurrent spontaneous mutation causes approximately 0.1% decline in fitness per generation, which is about an order of magnitude less than that suggested by previous studies with Drosophila. Two rather different approaches, Bateman-Mukai and maximum likelihood, suggest that this observation, along with the observed rate of increase in the variance of fitness among lines, is consistent with a genomic deleterious mutation rate for fitness of approximately 0.03 per generation and with an average homozygous effect of approximately 12%. The distribution of mutational effects for fitness appears to have a relatively low coefficient of variation, being no more extreme than expected for a negative exponential, and for one composite fitness measure (total progeny production) approaches constancy of effects. These results are derived from assays in a benign environment. At stressful temperatures, estimates of the genomic deleterious mutation rate (for genes expressed at such temperatures) is sixfold lower, whereas those for the average homozygous effect is approximately eightfold higher. Our results are reasonably compatible with existing estimates for flies, when one considers the differences between these species in the number of germ-line cell divisions per generation and the magnitude of transposable element activity.

Animals↗
PubMed1993

Mutations in the 3A genomic region of two cytopathic strains of hepatitis A virus isolated in Italy.

Two strains of hepatitis A virus (HAV) were isolated in cell culture and found to induce a cytopathic effect at early passages. The nucleotide sequences of the 5' non-translated region (5'NTR) and of genes 2B, 2C, 3A and 3B were determined for these strains and found to contain mutations similar to those detected in cell-culture adapted variants of HAV strain HM175. In addition, gene 3A shows a deletion of three aspartic acid residues near the N-terminus of the polypeptide. In combination with variations in the 5'NTR and in genes 2B and 2C, the absence of an aspartic acid residue in position 4 of gene 3A of three cytopathic clones of HM175 suggests a possible role of the 3A protein in determining the cytopathic phenotype.

Aspartic Acid↗