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At least 973 records · Page 54Linked to original sources
PubMed1993

Genetic differences between the standard Ames tester strains TA100 and TA98.

The standard Ames tester strains of Salmonella typhimurium are separated by many steps in their pedigree, some involving mutagen treatments, and contain independently isolated uvrB-bio-gal deletions and rfa mutations. In this work the araD531 mutation was introduced into the Ames tester strains TA100 and TA98. The responsiveness of the resulting strains (BA15 and BA14) to a number of chemical mutagens was then assessed by monitoring the induction of forward mutations to L-arabinose resistance (Ara test). Here we have shown that these two strains of the Ames test differ greatly in their responses to mutagens, in ways that are not associated with the mutagenic specificities of the original his mutations. In general, the genetic background of strain TA100 appears to be more sensitive to the killing effects of chemicals than that of TA98. The greatest differences were found with nifurtimox (NFX) and its analogue, compound 1K. The Ara test responded to the mutagenic effects of these two nitrofurans when carried out in the genetic background of strain TA98 but not in that of TA100. A higher sensitivity to the lethal effects of NFX and 1K together with the greater nitro-reduction capability of strain TA100 as compared with TA98 might explain the differences. In conclusion, our results indicate that the standard Ames S. typhimurium tester strains are not isogenic and that genetic differences at loci other than his might be significant for mutagenicity testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Arabinose↗
PubMed1988

Nonselective enrichment for yeast adenine mutants by flow cytometry.

The expression of certain adenine biosynthetic mutations in the yeast Saccharomyces cerevisiae results in a red colony color. This phenomenon has historically provided an ideal genetic marker for the study of mutation, recombination, and aneuploidy in lower eukaryotes by classical genetic analysis. In this paper, it is reported that cells carrying ade1 and/or ade2 mutations exhibit primary fluorescence. Based on this observation, the nonselective enrichment of yeast cultures for viable adenine mutants by using the fluorescence-activated cell sorter has been achieved. The advantages of this approach over conventional genetic analysis of mutation, recombination, and mitotic chromosomal stability include speed and accuracy in acquiring data for large numbers of clones. By using appropriate strains, the cell sorter has been used for the isolation of both forward mutations and chromosomal loss events in S. cerevisiae. The resolving power of this system and its noninvasiveness can easily be extended to more complex organisms, including mammalian cells, in which analogous metabolic mutants are available.

Adenine↗
PubMed2001

Identification of rad27 mutations that confer differential defects in mutation avoidance, repeat tract instability, and flap cleavage.

In eukaryotes, the nuclease activity of Rad27p (Fen1p) is thought to play a critical role in lagging-strand DNA replication by removing ribonucleotides present at the 5' ends of Okazaki fragments. Genetic analysis of Saccharomyces cerevisiae also has identified a role for Rad27p in mutation avoidance. rad27Delta mutants display both a repeat tract instability phenotype and a high rate of forward mutations to canavanine resistance that result primarily from duplications of DNA sequences that are flanked by direct repeats. These observations suggested that Rad27p activities in DNA replication and repair could be altered by mutagenesis and specifically assayed. To test this idea, we analyzed two rad27 alleles, rad27-G67S and rad27-G240D, that were identified in a screen for mutants that displayed repeat tract instability and mutator phenotypes. In chromosome stability assays, rad27-G67S strains displayed a higher frequency of repeat tract instabilities relative to CAN1 duplication events; in contrast, the rad27-G240D strains displayed the opposite phenotype. In biochemical assays, rad27-G67Sp displayed a weak exonuclease activity but significant single- and double-flap endonuclease activities. In contrast, rad27-G240Dp displayed a significant double-flap endonuclease activity but was devoid of exonuclease activity and showed only a weak single-flap endonuclease activity. Based on these observations, we hypothesize that the rad27-G67S mutant phenotypes resulted largely from specific defects in nuclease function that are important for degrading bubble intermediates, which can lead to DNA slippage events. The rad27-G240D mutant phenotypes were more difficult to reconcile to a specific biochemical defect, suggesting a structural role for Rad27p in DNA replication and repair. Since the mutants provide the means to relate nuclease functions in vitro to genetic characteristics in vivo, they are valuable tools for further analyses of the diverse biological roles of Rad27p.

Alleles↗
PubMed1983

Genetic toxicity of dopamine.

The genetic toxicity of dopamine was studied in a battery of test systems including DNA single-strand break analysis in cultured human skin fibroblasts, the Salmonella/mammalian-microsome mutagenicity test, sister-chromatid exchange analysis in human lymphocytes, the mouse-lymphoma forward mutation assay, the sex-linked recessive lethal test in Drosophila melanogaster and the micronucleus test in mouse and rat. Dopamine at concentrations of 50-300 micrograms/ml induced DNA strand breaks in human fibroblasts. It also gave a positive response in the mouse-lymphoma forward mutation assay, where a dose-dependent increase in the frequency of mutant cells was observed in the presence of dopamine, 94-750 micrograms/ml. All other tests showed no response to dopamine. The dopamine-induced DNA strand breaks in human fibroblasts were inhibited by superoxide dismutase or dithiothreitol. Furthermore, dopamine caused nicking of circular Col El DNA and bound to calf thymus DNA in vitro. It is suggested that this genetic activity of dopamine in vitro relates to oxidation of dopamine and the generation of reactive oxygen radicals, semiquinones and quinones. It is unlikely that similar reactions would occur and cause genotoxic activity of dopamine in vivo.

Animals↗
PubMed2000

A new look at the challenging world of tandem repeats.

Recent research has shown a correlation between some genetic diseases and genomic sequences tandemly repeated a variable and excessive number of times. The excessive number of tandem repeats is usually caused by a progressive expansion, generally considered as purely harmful. We put forward a number of hypotheses: the main one is that the number of repeats has normally a specific significance, and that there exist purposive mechanisms having as a primary function the management of tandem repeats length; such a function is generally useful and only rarely may it become harmful, because of some malfunctioning. These hypotheses are suggested by plausibility arguments, and are supported by a number of recent experimental results. They could provide a simple and unifying explanation of many pathological and non-pathological phenomena replacing many ad hoc assumptions. We finally propose to call the study of the above tandem repeat managing mechanisms 'dynamical genetics'.

Aging↗
PubMed1997

Glimpses into the balance between immunity and self-tolerance.

The need to maintain self-tolerance is at odds with the need to draw upon antibody and T cell receptor diversity to fight infection. Advances in genetic manipulation of the mouse have at last brought into view the clonal selection mechanisms that underpin self-tolerance, confirming in general terms the notion of clonal deletion and clonal anergy put forward by Burnet and Nossal. The image that has emerged, however, is much more sophisticated than could have been imagined, revealing that self-reactive clones are deleted or held back in a remarkable series of culling checkpoints placed at many steps along the pathway to antibody production. These checkpoints act in concert to balance the nature and size of the holes in the repertoire generated by self-tolerance against the need to draw upon as many clones as possible for immunity to infection. Spontaneous and induced mutations in the mouse, such as Fas, PTP1C and CD45 mutations, have just begun to yield a few glimpses into the molecular circuitry underpinning these cellular checkpoints. Much more extensive genetic analysis, made possible by the genome project, will be needed to illuminate the details of those circuits and the factors that lead them to fail in autoimmune disease.

Animals↗
PubMed1979

Genetic control of lysine permeases in Saccharomycopsis lipolytica.

In order to obtain strains of Saccharomycopsis lipolytica impaired in the active transport of L-lysine, mutants resistant to a mixture of L-canavanine, L-4-5-transdehydrolysine and L-S-amino ethylcysteine, taken either all three or two by two, were isolated. These compounds were shown previously to be competitive inhibitors of L-lysine uptake. The resistance patterns and excretion capacity of the mutants were established. All mutants behaved as monogenic. Recombination tests indicated that four genes at least were involved. All mutants were impaired in both high and low affinity L-lysine transport systems. Several hypotheses on the functions of these genes are put forward and discussed.

Ascomycota↗
PubMed2006

Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer--a plan to move forward.

This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.

Biomarkers, Tumor↗
PubMed1980

Genetic and biochemical evidence for hexokinase PII as a key enzyme involved in carbon catabolite repression in yeast.

Mutants with reduced hexokinase activity previously isolated as resistant to carbon catabolite repression of invertase and maltase (Zimmermann and Scheel, 1977) were allele tested with mutant strains of Lobo and Maitra (1977) which had defects in one or several of the genes coding for glucokinase and the two unspecific hexokinases. It could be demonstrated, that the mutation abolishing carbon catabolite repression had occurred in a gene allelic to the structural gene of hexokinase PII. Moreover, the defective mutant allele for hexokinase PII isolated by Lobo and Maitra (1977) was also defective in carbon catabolite repression. Neither glucokinase nor hexokinase PI showed any effect on this regulatory system. Biochemical analysis in crude extracts also showed altered kinetic properties of hexokinases in the hex1 mutants. The results directly support the hypothesis previously put forward, that one of the hexokinases is not only active as a catalytic, but also as a regulatory protein.

Crosses, Genetic↗
PubMed2002

Lack of prion protein expression results in a neuronal phenotype sensitive to stress.

The prion protein is a highly conserved glycoprotein expressed most highly in the synapse. Evidence has recently been put forward to suggest that the prion protein is an antioxidant. However, the functional importance of the prion protein has been disputed; it is claimed that mice genetically ablated to lack prion protein expression are normal and have no specific phenotype. We have reexamined the phenotype of prion protein knockout mice and found that there are multiple biochemical changes in the mice, including increased levels of nuclear factor NF-kappaB and Mn superoxide dismutase, COX-IV decreased levels of Cu/Zn superoxide dismutase activity, decreased p53, and altered melatonin levels. Additionally, cultured cells from these mice are more sensitive to a range of insults, all linked to increased neuronal sensitivity to oxidative stress. These results imply that prion protein knockout mice are more sensitive to oxidative stress and have an altered phenotype that must be taken into account when considering the additional effects of increased levels of proteins such as Doppel. The implication of these results is that the consequence of genetic ablation of genes must include biochemical analysis as well as analyses of possible developmental and behavioral changes.

Animals↗
PubMed1991

The induction of forward and reverse specific-locus mutations and dominant cataract mutations in spermatogonia of treated strain DBA/2 mice by ethylnitrosourea.

The mutagenic effectiveness of ethylnitrosurea (ENU) was assessed in treated spermatogonia of DBA/2 mice. In a total of 17,515 offspring examined following 160 mg ENU/kg body weight treatment of parental males, 26 forward specific-locus mutations, 2 reverse specific-locus mutations and 9 dominant cataract mutations were recovered. ENU increased the mutation rate to all 3 genetic endpoints. However, ENU was less effective in treated DBA/2 mice than in the standard experimental protocol employing treated hybrid (102 X C3H)F1 male mice. This observed difference for a direct-acting mutagen such as ENU may result from differences in the detoxification of ENU or from differences in the DNA-repair capabilities of strain DBA/2. The first documented reverse mutation of the b allele is reported. The reversion was shown to be due to an AT to GC transition. To date, in addition to the reverse mutation of the b allele, 5 independent ENU-induced mutations recovered in germ cells of the mouse have been molecularly characterized and all have been shown to be base substitutions at an AT site. This is in contrast to the expected mechanism of ENU mutation induction due to O6-ethylguanine adduct formation which results in a GC to AT base-pair substitution and emphasizes the complexities of mutagenesis in germ cells of mammals.

Alleles↗
PubMed2006

Modeling the effect of inbreeding among founders in linkage analysis.

In this paper, we present a unified mathematical model for linkage analysis that allows for inbreeding among founders in all families. The identical by descent (IBD) configuration of each pedigree is modeled as a Markov process containing two parameters; the inverse inbreeding and kinship coefficient and a rate parameter proportional to the inverse expected length of chromosome segments shared IBD by two different founder haplotypes. We use hidden Markov models and define a forward-backward algorithm for computing the conditional IBD-distribution given marker data, thereby extending the multipoint method of Lander and Green [1987. Construction of multilocus genetic maps in humans, Proc. Natl. Acad. Sci. USA 84, 2363-2367] to situations where founders are inbred. Our methodology is valid for arbitrary pedigree structures. Simulation and theoretical approximations for nonparametric linkage (NPL) analysis based on affected sib pairs reveal that NPL scores are inflated and type 1 errors increased when the inbreeding coefficient or rate parameter is underestimated. When the parents are genotyped, we present a general way of modifying the score function to drastically reduce this effect.

Algorithms↗
PubMed2002

Comparison between radiological and artificial neural network diagnosis in clinical screening.

The imaging protocol of the UK multicentre magnetic resonance imaging study for screening in women at genetic risk of breast cancer aims to assist in detecting and diagnosing malignant breast lesions. In this paper, we evaluate a three-layer, feed-forward, backpropagation neural network as an artificial radiological classifier using receiver operating characteristic (ROC) curve analysis and compare the results with those obtained using a proposed radiological scoring system for the study which currently supplements the radiologist's clinical opinion, in comparison with histological diagnosis. Based on the 76 symptomatic cases evaluated, descriptive features scored by radiologists showed considerable overlap between benign and malignant, although some features such as irregular contours and heterogeneous enhancement were more often associated with malignant pathology. In this preliminary evaluation, ROC analysis showed that the proposed scoring scheme did not perform well, indicating further refinement is required. When all 23 features were used in the neural network, its performance was poorer than that of the scoring scheme. When only ten features were used, limited to descriptors of enhancement characteristics, the neural network performed similar to the scoring scheme. This comparison shows that the neural network approach to clinical diagnosis has considerable potential and warrants further development.

Breast Neoplasms↗
PubMed1999

[Advances in cancer research. Cancer research and clinical oncology in the 21st century].

It is my great pleasure to congradulate the Japanese Journal of Cancer and Chemotherapy on its 25 th anniversary. During this period, great progress has been made in cancer research, mainly owing to the advances in technology in molecular biology. Recently, not only researchers, but lay people as well have come to understand that cancer is mainly a genetic disease. Advances in the human genome project, DNA chip technology and gene technology; including gene targeting and cloning techniques, will enable us to accelerate progress forward the final goal of cancer research in the coming century. Major changes are coming in both cancer research and clinical oncology, which will completely transform the human social environment.

Clinical Medicine↗
PubMed2002

Molecular characteristics of Neisseria meningitidis strains isolated in Burkina Faso in 2001.

In the course of an epidemic of meningitis in Burkina Faso in 2001, 27 cerebrospinal fluid samples from patients in 7 districts were forwarded to Norway for isolation and characterization of the causative agents. Neisseria meningitidis was isolated from 13 (48%) samples. The isolates were analysed using serological and genetic methods. Of the 13 strains, 4 were serogroup A, serotype 21:P1.9, sequence type (ST)-5 and belonged to clonal subgroup III, while the remaining 9 strains were serogroup W135, serotype 2a:P1.5,2, ST-11 and belonged to the electrophoretic type-37 complex. PCR analyses revealed meningococcal DNA in 13/14 culture-negative samples. Sequence analysis of the PCR products demonstrated that at least 3 different meningococcal strains were responsible for these 13 cases. Our results show that the W135 strain associated with the 2000 hajj (Muslim pilgrimage) outbreak was a significant cause of disease in Burkina Faso in 2001. Further studies are warranted to determine whether W135 is about to replace serogroup A in sub-Saharan Africa.

Adolescent↗
PubMedDate not supplied

[Role of hereditary factors in the formation of secondary insulin dependence in patients with type II diabetes mellitus].

A total of 389 patients with diabetes mellitus were examined. A genetic analysis has shown a most high possibility of diabetes in the sibs of patients with type II diabetes and secondary insulin dependence. The authors put forward a hypothesis that secondary insulin dependence formation in diabetics with type II condition results from interactions of two gene complexes with a recessive effect, responsible for types I and II diabetes mellitus development. They suggest a model of age-dependent epistasis with an 'insulin-dependence' gene quantitative effect.

Adult↗
PubMed2004

Evolution of a child health profile initiative.

While information technology has proliferated and advanced dramatically in the last 10 years, the application of information technology to health care policy and delivery has not been well coordinated either among public health agencies or between the public and private health sectors. In 1998, the Genetic Services Branch, Division of Services for Children with Special Health Needs, Maternal and Child Health Bureau, Health Resources and Services Administration (HRSA/MCHB) began an initiative to help facilitate assessment and prompt provision of appropriate services to improve the health of children. Twenty-five state public health programs received grants to improve integration of newborn screening and genetic services systems with other maternal and child health systems. All Kids Count--a program of the Public Health Informatics Institute--completed a qualitative assessment of state programs that were funded to develop plans for integration. The results are being translated into a business/policy case addressing the need for integration, a description of essential functions that such systems support, ultimately system requirements, and measures for evaluation. HRSA/MCHB's partnership with All Kids Count continues with a project to develop a community of practice to assist programs in moving their integrated child health information systems forward.

Child↗
PubMed2025

Exploring the shared genetic basis of attention-deficit/hyperactivity disorder and obstructive sleep apnea: A multi-omics analysis.

BACKGROUND: Observational studies have suggested an association between attention-deficit/hyperactivity disorder (ADHD) and obstructive sleep apnea (OSA), but these findings are often inconsistent due to potential biases from medication use, and varying diagnostic criteria. Genetic analyses can help mitigate these confounding factors, providing additional evidence. METHODS: This study evaluated the genetic correlations between ADHD and OSA using Genome-wide association study (GWAS) summary data, applying linkage disequilibrium score regression (LDSC) and SUPER GeNetic cOVariance Analyzer (SUPERGNOVA). Cross-trait association and colocalization analysis identify potential pleiotropic loci. Tissue enrichment analysis and gene-level analysis of shared genes between OSA and ADHD was conducted. Additionally, bidirectional Mendelian randomization was used to assess potential causal relationships. RESULTS: We found significant genetic correlations between ADHD and OSA (rg = 0.309, p = 3.252E-27), and identified 8 novel pleiotropic loci through cross-trait association analysis. Tissue enrichment analysis showed that these shared genes were primarily concentrated in brain tissues, particularly in deep gray matter regions, and were associated with immune and inflammatory pathways. Forward Mendelian Randomization analysis showed that ADHD was significantly associated with the risk of OSA (OR 1.070, 95 % CI 1.013-1.130, p = 0.016), and reverse analysis showed that OSA was significantly associated with the risk of ADHD (OR 1.240, 95 % CI 1.106-1.390, p = 2.213E-4). CONCLUSION: The findings of this study show a significant positive genetic correlation between ADHD and OSA and each is a risk factor for the other. Inflammation in specific brain regions may be the underlying mechanism for their comorbidity.

Humans↗