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PubMed1993

The genetics of aging in the yeast Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae possesses a finite life span similar in many attributes and implications to that of higher eukaryotes. Here, the measure of the life span is the number of generations or divisions the yeast cell has undergone. The yeast cell is the organism, simplifying many aspects of aging research. Most importantly, the genetics of yeast is highly-developed and readily applicable to the dissection of longevity. Two candidate longevity genes have already been identified and are being characterized. Others will follow through the utilization of both the primary phenotype and the secondary phenotypes associated with aging in yeast. An ontogenetic theory of longevity that follows from the evolutionary biology of aging is put forward in this article. This theory has at its foundation the asymmetric reproduction of cells and organisms, and it makes specific predictions regarding the genetics, molecular mechanisms, and phenotypic features of longevity and senescence, including these: GTP-binding proteins will frequently be involved in determining longevity, asymmetric cell division will be often encountered during embryogenesis while binary fission will be more characteristic of somatic cell division, tumor cells of somatic origin will not be totipotent, and organisms that reproduce symmetrically will not have intrinsic limits to their longevity.

Aging↗
PubMedDate not supplied

Adverse drug reaction reporting and retrospective phenotyping for oxidation polymorphism.

A genetically determined impairment in the ability to oxidase sparteine and debrisoquine also affects the oxidation of several other drugs. This impairment in oxidation may result in accumulation of the associated drugs and in an increased susceptibility to adverse reactions from these drugs. Dunedin houses the New Zealand national centre for the collation and study of adverse drug reactions. Included among the reporting schemes is an intensified monitoring system for newly released drugs, in which physicians report all clinical events occurring during treatment with the drugs under surveillance. The centre thus has available extensive records of names and addresses of prescribers and patients who have been reported as experiencing an adverse event while receiving drug therapy. We investigated the association between genetically poor oxidation of sparteine and adverse reactions to drugs selected as possibly sharing the sparteine/debrisoquine oxidation pathway; these included perhexiline, metoprolol, debrisoquine, piroxicam, mianserin and nifedipine. A kit containing instructions, a sparteine capsule and a container for urine collection was sent to physicians who reported adverse reactions or events to one of the above drugs for forwarding to the patient. It appeared possible, after assays of returned urine for sparteine and its metabolites, that adverse reactions to nifedipine were associated with genetically poor oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Debrisoquin↗
PubMed2005

Beneficence, determinism and justice: an engagement with the argument for the genetic selection of intelligence.

In 2001, Julian Savulescu wrote an article entitled 'Procreative Beneficence: Why We Should Select the Best Children', in which he argued for the genetic selection of intelligence in children. That article contributes to a debate on whether genetic research on intelligence should be undertaken at all and, if so, should intelligence selection be available to potential parents. As such, the question of intelligence selection relates to wider issues concerning the genetic determinism of behavioural traits, i.e. alcoholism. This article is designed as an engagement in the intelligence selection debate using an analysis of Savulescu's arguments to raise a series of problematic issues in relation to the ethics of parental selection of intelligence. These problematic issues relate to wider assumptions that are made in order to put forward intelligence selection as a viable ethical option. Such assumptions are more generic in character, but still relate to Savulescu's article, concerning issues of genetic determinism, private allocation and inequality, and, finally, individual versus aggregate justice. The conclusion focuses on what the implications are for the question of agency, especially if intelligence selection is allowed.

Beneficence↗
PubMed1999

Limitations in the use of race in the study of disease causation.

Tremendous variation exists in the rates of many chronic diseases across racial groups. However, serious technical and conceptual limitations hamper the ability of racial comparisons to illuminate the causative pathways. First, race is confounded by social class, which is complex, and like other confounders of race, may not be measured with equal validity across racial groups. Second, statistical "adjustments" for race effects can be misleading since residual confounding may be misconstrued as a genetic effect. Third, the biologic concept of race tempts us to ignore the context dependency of genetic expression. When trying to detect genetic effects, both the environmental and genetic contributions must be measured and potential gene-environment interactions accounted for. Unfortunately, this process is beyond our current technical capabilities. To move forward on the problem of prostate cancer and other diseases distinguished by marked ethnic differentials, investigators need a more comprehensive understanding of the factors that mediate the apparent effect of race combined with valid measures of those factors, as well as novel strategies that can help overcome the technical and interpretive limitations of statistical adjustment. Finally, the "grand" theories of race-based genetic susceptibility must be replaced with rigorous criteria to determine when a trait can be ascribed to some genetic origin.

Causality↗
PubMed1998

Analysis of mutagens with single cell gel electrophoresis, flow cytometry, and forward mutation assays in an isolated clone of Chinese hamster ovary cells.

We investigated the induction of DNA strand breaks in the single cell gel electrophoresis (SCGE or comet) assay with whole cell clastogenicity measured with flow cytometric analysis in cells from an isolated clone of the Chinese hamster ovary (CHO) AS52 cell line. Under identical treatment conditions the responses were compared with forward mutation at gpt using 2-acetoxyacetylaminofluorene (2AAAF), ultraviolet radiation (UV) and ethyl methanesulfonate (EMS). Cytotoxicity for each agent was evaluated in the SCGE and forward mutation assays. Forward mutation was 4-10-fold more sensitive than DNA strand breaks detected in the SCGE assay. For 2AAAF and EMS, the kinetics of the induction of genetic damage were similar for the three assays, although there were differences in sensitivity. With UV, the induction kinetics of gpt mutation differed from that expressed by SCGE and flow cytometric analysis. With the chemical mutagens 2AAAF and EMS, there was a high correlation between the SCGE assay and forward mutation and also between the SCGE assay and flow cytometry. There was no significant correlation between flow cytometry and forward mutation. With UV, only the SCGE assay and flow cytometry were correlated. Agent-specific variations in the intragenomic distribution of DNA damage for each mutagen was measured in the SCGE assay.

Acetoxyacetylaminofluorene↗
PubMed2006

New roles for model genetic organisms in understanding and treating human disease: report from the 2006 Genetics Society of America meeting.

Fundamental biological knowledge and the technology to acquire it have been immeasurably advanced by past efforts to understand and manipulate the genomes of model organisms. Has the utility of bacteria, yeast, worms, flies, mice, plants, and other models now peaked and are humans poised to become the model organism of the future? The Genetics Society of America recently convened its 2006 meeting entitled "Genetic Analysis: Model Organisms to Human Biology" to examine the future role of genetic research. (Because of time limitations, the meeting was unable to cover the substantial contributions and future potential of research on model prokaryotic organisms.) In fact, the potential of model-organism-based studies has grown substantially in recent years. The genomics revolution has revealed an underlying unity between the cells and tissues of eukaryotic organisms from yeast to humans. No uniquely human biological mechanisms have yet come to light. This common evolutionary heritage makes it possible to use genetically tractable organisms to model important aspects of human medical disorders such as cancer, birth defects, neurological dysfunction, reproductive failure, malnutrition, and aging in systems amenable to rapid and powerful experimentation. Applying model systems in this way will allow us to identify common genes, proteins, and processes that underlie human medical conditions. It will allow us to systematically decipher the gene-gene and gene-environment interactions that influence complex multigenic disorders. Above all, disease models have the potential to address a growing gap between our ability to collect human genetic data and to productively interpret and apply it. If model organism research is supported with these goals in mind, we can look forward to diagnosing and treating human disease using information from multiple systems and to a medical science built on the unified history of life on earth.

Animals↗
PubMed1994

[Is there a genetic component in bronchial hyperreactivity in the human species?].

Whether a hereditary, genetic component of human non allergenic bronchial hyperresponsiveness exists in man is controversial. Therefore, the "Dutch hypothesis" that bronchial hyperresponsiveness is a risk factor of asthma and chronic bronchitis has not been validated by hard data, although it was put forward more than two decades ago. In some inbred strains of mice and rats, bronchial hyperresponsiveness to acetylcholine or serotonin is transmitted as a Mendelian monogenic trait or a polygenic one. Genetic studies of human bronchial hyperresponsiveness are difficult, if only because it is an ill-defined phenotype, and because acquired, inflammation-related bronchial hyperresponsiveness is at the forefront in airway diseases such as asthma. Studies of concordance in mono- and dizygotic twins, of distribution in the general population, and of familial inheritance suggest transmission from generation to generation of human bronchial hyperresponsiveness. This only applies to bronchial response to cholinergic agents because of the small number of studies done with other bronchial challenges. Furthermore, there is no agreement on the mode of transmission of this specific type of bronchial hyperresponsiveness. One hopes that combining genetic epidemiology with molecular genetics in the forthcoming years will result in a better understanding of genetic risk factors of human bronchial hyperresponsiveness.

Asthma↗
PubMed1995

Safety evaluation of pullulanase enzyme preparation derived from Bacillus licheniformis containing the pullulanase gene from Bacillus deramificans.

Pullulanase enzyme is an amylopectin debranching enzyme used in starch hydrolysis. This article describes studies conducted to investigate the safety of a pullulanase enzyme preparation produced by a strain of Bacillus licheniformis that has been transformed by introduction of genetic material from another Bacillus species, B. deramificans. A 4-week dietary toxicity study in rats was conducted in which test animals received pullulanase in the feed at concentrations of 0.2, 1.0, and 5.0%. No adverse treatment-related effects were observed. Lack of genetic toxicity potential was demonstrated by the results of a bacterial mutation assay in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538, in an in vitro histidine forward mutation study in mouse lymphoma cells, and in in vivo mouse bone marrow chromosome aberration and micronucleus assays. The enzyme preparation also has been shown to be a nonirritant in eye and primary dermal irritation tests in rabbits and is nontoxic by inhalation exposure. Finally, the genetically altered B. licheniformis has been demonstrated to be nonpathogenic upon single intraperitoneal injection to rats of both live and killed cells at doses up to 10(11) cells/kg. The results of these studies demonstrate that the enzyme preparation may be considered safe when employed in starch processing.

Animal Feed↗
PubMed2004

The future of human embryonic stem cell research: addressing ethical conflict with responsible scientific research.

Embryonic stem (ES) cells have almost unlimited regenerative capacity and can potentially generate any body tissue. Hence they hold great promise for the cure of degenerative human diseases. But their derivation and the potential for misuse have raised a number of ethical issues. These ethical issues threaten to paralyze pubic funding for ES cell research, leaving experimentation in the hands of the private sector and precluding the public's ability to monitor practices, research alternatives, and effectively address the very ethical issues that are cause for concern in the first place. With new technology being inevitable, and the potential for abuse high, government must stay involved if the public is to play a role in shaping the direction of research. In this essay, I will define levels of ethical conflict that can be delineated by the anticipated advances in technology. From the urgent need to derive new ES cell lines with existing technology, to the most far-reaching goal of deriving genetically identical tissues from an adult patients cells, technology-specific ethical dilemmas can be defined and addressed. This staged approach provides a solid ethical framework for moving forward with ES cell research. Moreover, by anticipating the moral conflicts to come, one can predict the types of scientific advances that could overcome these conflicts, and appropriately direct federal funding toward these goals to offset potentially less responsible research directives that will inevitably go forward via private or foreign funding.

Bioethics↗
PubMed2006

Historical and modern genetics of plant graft hybridization.

Graft hybridization is a type of asexual hybridization in which heritable changes may be induced by grafting. Darwin was the first to put forward the conception of graft hybridization. The existence of graft hybrids has been extensively documented, although there has been a refusal to accept its reality, other than perceiving the phenomenon as involving "simple" chimeras. Graft hybrids can be divided into two categories--chimera graft hybrid (so-called graft chimera) and nonchimera graft hybrid (so-called vegetative hybrid). These differ with respect to grafting methods, characteristics, and mechanisms proposed to underlie the two categories. Graft hybridization is not only a simple and powerful means of plant breeding but also provides striking evidence in favor of Darwin's notions about Pangenesis--a developmental theory of heredity, on the one hand, and a phenomenon that plays a crucial role in revealing the mystery of non-Mendelian inheritance in grafted fruit trees.

Chimera↗
PubMed1972

Kinetic studies on the two common inherited forms of human erythrocyte adenylate kinase.

1. The kinetic properties of two genetic variants of human erythrocyte adenylate kinase were studied at limiting concentrations of both ADP and MgADP(-) in the forward direction and at limiting concentrations of both AMP and MgATP(2-) in the reverse direction. 2. Primary reciprocal plots rule out the possibility of a Ping Pong mechanism for both forms of the enzyme. 3. Analysis of the kinetic data by an appropriate computer program gave the following K(m) values for the type 1 enzyme: AMP, 0.33mm+/-0.1; MgATP(2-), 0.95mm+/-0.13; ADP, 0.12mm+/-0.03; MgADP(-), 0.22mm+/-0.04. Values for the type 2 enzyme were: AMP, 0.27mm+/-0.03; MgATP(2-), 0.40mm+/-0.05; ADP, 0.08mm+/-0.07; MgADP(-), 0.20mm+/-0.04. 4. Product inhibition studies were done by studying the reverse reaction. With ADP as product inhibitor competitive inhibition patterns were obtained with AMP and/or MgATP(2-) as variable substrate. Similar results were obtained for product inhibition by MgADP(-) with AMP as variable substrate. The results are consistent with a Rapid Equilibrium Random mechanism. 5. Secondary plots of slope versus product concentration were linear. The data were fitted to the appropriate equation and analysed by computer to give values for the product inhibition constants. 6. Differences between the values of certain kinetic constants for the two forms of the enzyme were observed.

Adenosine Diphosphate↗
PubMed1975

Mutations induced by X-radiation in the yeast Schizosaccharomyces pombe.

Experiments on strains of yeast with different genetic backgrounds were done to evaluate the kinetics of inactivation and mutation induction by X-radiations. A system of forward mutation induction in five loci was used as a specific mutation rate of 0.14-10-minus 8 times locus times rad was evaluated for the wild type. From a comparison of observations with wild type and radiation-sensitive strains, it may be assumed that, in this yeast, mutations are mainly the result of a repair-active process. The range of genotypic and phenotypic influence upon the specific locus mutation rate was evaluated with appropriate biological material and experiments.

Ascomycota↗
PubMed1998

Polymerase chain reaction typing of D21S11 short tandem repeat polymorphism by capillary electrophoresis. Allele frequencies and sequencing data in a population sample from central Italy.

Blood samples were collected from 100 individuals living in Central Italy and analysed for STR locus D21S11 by capillary electrophoresis on an ABI Prism 310 genetic analyzer. For fragment sizing, PCR amplification products, obtained using a 6-FAM 5'-labeled reverse primer and an unlabeled forward primer, were run with an internal size standard labeled with TAMRA dye and typed using the local reciprocal method. An allele ladder consisting of a mix of sequenced amplified products was also prepared. An Italian population database was established. No deviation from Hardy-Weinberg equilibrium was observed. The result of statistical analysis were highly informative (PD = 0.94; mean exclusion change = 0.66). DNA sequencing was performed on a set of representative alleles by Taq cycle sequencing using dye terminator labeling chemistry. A new structural variant was found.

Alleles↗
PubMed2006

Cell cycle checkpoints: the role and evaluation for early diagnosis of senescence, cardiovascular, cancer, and neurodegenerative diseases.

Maintenance of genomic integrity is critical for prevention of a wide variety of adverse cellular effects including apoptosis, cellular senescence, and malignant cell transformation. Under stress conditions and even during an unperturbed cell cycle, checkpoint proteins play the key role in genome maintenance by and mediating cellular response to DNA damage, and represent an essential part of the "cellular stress response proteome". Intact checkpoint signal transduction cascades check the presence of genome damage, trigger cell cycle arrest, and forward the information to the protein core of cell cycle machinery, replication apparatus, repair, and/or apoptotic protein cores. Genetic checkpoint defects lead to syndromes that demonstrate chromosomal instability, increased sensitivity to genotoxic stress, tissue degeneration, developmental retardation, premature aging, and cancer predisposition that is most extensively studied for the ATM-checkpoint mutated in Ataxia telangiectasia. Tissue specific epigenetic control over the function of cell cycle checkpoints can be, further, misregulated by aberrant DNA methylation status. The consequent checkpoint dysregulation may result in tissue specific degenerative processes such as degeneration and calcification of heart aortic valves, diabetic cardiomyopathy, hyperhomocysteinemic cerebrovascular, peripheral vascular and coronary heart diseases, neurodegenerative disorders (Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, glaucoma), and accelerated aging frequently accompanied with cancer. This review focuses on the checkpoints shown to be crucial for unperturbed cell cycle regulation, dysregulation of which might be considered as a potential molecular marker for early diagnosis of and therapy efficiency in neurodegenerative, cardiovascular and cancer diseases. An application of the most potent detection technologies such as "Disease Proteomics and Transcriptomics" also considered here, allows a most specific selection of diagnostic markers.

Animals↗
PubMed2002

Use of randomization testing to detect multiple epistatic QTLs.

Here, we describe a randomization testing strategy for mapping interacting quantitative trait loci (QTLs). In a forward selection strategy, non-interacting QTLs and simultaneously mapped interacting QTL pairs are added to a total genetic model. Simultaneous mapping of epistatic QTLs increases the power of the mapping strategy by allowing detection of interacting QTL pairs where none of the QTL can be detected by their marginal additive and dominance effects. Randomization testing is used to derive empirical significance thresholds for every model selection step in the procedure. A simulation study was used to evaluate the statistical properties of the proposed randomization tests and for which types of epistasis simultaneous mapping of epistatic QTLs adds power. Least squares regression was used for QTL parameter estimation but any other QTL mapping method can be used. A genetic algorithm was used to search for interacting QTL pairs, which makes the proposed strategy feasible for single processor computers. We believe that this method will facilitate the evaluation of the importance at epistatic interaction among QTLs controlling multifactorial traits and disorders.

Algorithms↗
PubMedDate not supplied

Genetic algorithm applied to the selection of factors in principal component-artificial neural networks: application to QSAR study of calcium channel antagonist activity of 1,4-dihydropyridines (nifedipine analogous).

A QSAR algorithm, principal component-genetic algorithm-artificial neural network (PC-GA-ANN), has been applied to a set of newly synthesized calcium channel blockers, which are of special interest because of their role in cardiac diseases. A data set of 124 1,4-dihydropyridines bearing different ester substituents at the C-3 and C-5 positions of the dihydropyridine ring and nitroimidazolyl, phenylimidazolyl, and methylsulfonylimidazolyl groups at the C-4 position with known Ca(2+) channel binding affinities was employed in this study. Ten different sets of descriptors (837 descriptors) were calculated for each molecule. The principal component analysis was used to compress the descriptor groups into principal components. The most significant descriptors of each set were selected and used as input for the ANN. The genetic algorithm (GA) was used for the selection of the best set of extracted principal components. A feed forward artificial neural network with a back-propagation of error algorithm was used to process the nonlinear relationship between the selected principal components and biological activity of the dihydropyridines. A comparison between PC-GA-ANN and routine PC-ANN shows that the first model yields better prediction ability.

Algorithms↗
PubMed1991

Comparison of three forward mutation systems in Saccharomyces cerevisiae for sensitivity to polycyclic and heterocyclic compounds.

Forward mutation to cycloheximide resistance, L-canavanine resistance and DL-alpha-aminoadipic acid resistance in Saccharomyces cerevisiae wild-type strain S7a was tested for sensitivity to nine mutagens in treat-and-plate assays. Eight of these agents, 2-aminofluorene, 2-acetylaminofluorene, benzo[a]pyrene, benzidine, cyclophosphamide, acriflavine, 7,12-dimethylbenz[a]anthracene and 2-aminoanthracene were known or suspected to be difficult to detect whilst one, methyl methanesulphonate, was known to be very active in yeast. Forward mutation to cycloheximide resistance was, overall, the most sensitive system, detecting all nine agents under optimal conditions, although neither benzidine nor benzo[a]pyrene were consistently positive. Mutation to adipic acid resistance occasionally gave responses superior to those at the cycloheximide loci, but mutation to canavanine resistance was never more sensitive than the cycloheximide resistance system. We conclude that forward mutation in strain S7a using both cycloheximide and adipic acid resistance loci is capable of detecting the genetic effects of a range of polycyclic and heterocyclic compounds with greater sensitivity than is seen in other published gene mutation assays with yeast. Although sensitivity is much lower than in bacterial assays, such yeast assays provide a reasonable alternative to bacterial genotoxicity screening for agents such as potent bactericides.

2-Aminoadipic Acid↗
PubMedDate not supplied

Andrological study of two young identical twin bulls.

A study was conducted on two young Italian Holstein bulls obtained by embryonic splitting and, therefore, genetically identical. The andrological evaluation of the subjects revealed a significant difference in semen freezability, valued according to forward motility after thawing (57.34 vs. 46.92; P < 0.01). There was, however, no difference in the quality of fresh semen.

Animals↗