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PubMed2004

Ecologically relevant stress resistance: from microarrays and quantitative trait loci to candidate genes - a research plan and preliminary results using Drosophila as a model organism and climatic and genetic stress as model stresses.

We aim at studying adaptation to genetic and environmental stress and its evolutionary implications at different levels of biological organization. Stress influences cellular processes, individual physiology, genetic variation at the population level, and the process of natural selection. To investigate these highly connected levels of stress effects, it is advisable - if not critical - to integrate approaches from ecology, evolution, physiology, molecular biology and genetics. To investigate the mechanisms of stress resistance, how resistance evolves, and what factors contribute to and constrain its evolution, we use the well-defined model systems of Drosophila species, representing both cosmopolitan species such as D. melanogaster with a known genome map, and more specialized and ecologically well described species such as the cactophilic D. buzzatii. Various climate-related stresses are used as model stresses including desiccation, starvation, cold and heat. Genetic stress or genetic load is modelled by studying the consequences of inbreeding, the accumulation of (slightly) deleterious mutations, hybridization or the loss of genetic variability. We present here a research plan and preliminary results combining various approaches: molecular techniques such as microarrays, quantitative trait loci (QTL) analyses, quantitative PCR, ELISA or Western blotting are combined with population studies of resistance to climatic and genetic stress in natural populations collected across climatic gradients as well as in selection lines maintained in the laboratory.

Adaptation, Physiological↗
PubMed1993

Enzymology in vivo using NMR and molecular genetics.

Models of metabolic flux regulation are frequently based on an extrapolation of the kinetic properties of enzymes measured in vitro to the intact cell. Such an extrapolation assumes a detailed knowledge of the intracellular environment of these enzymes in terms of their free substrate and effector concentrations and possible interactions with other cellular macromolecules, which may modify their kinetic properties. There is a considerable incentive, therefore, to study the properties of enzymes directly in vivo. We have been using non-invasive NMR techniques, in conjunction with molecular genetic manipulation of enzyme levels, to study the kinetic properties of individual enzymes in vivo. We have also developed a novel labelling strategy which has allowed us to monitor, by NMR, the ligand binding properties and mobilities of enzymes in the intact cell. This technique may also allow us to measure the diffusion coefficients of these proteins in the cell. These studies should give new insight into the properties of enzymes in vivo.

Animals↗
PubMed1991

Multitrait animal model with genetic groups.

Genetic groups of unknown parents are extended to the multitrait animal model. Computationally feasible mixed model equations are obtained. A strategy to include genetic groups for missing data is proposed. Canonical and triangular transformations can be applied to the multitrait animal model with groups if the transformations can be applied to the same model without groups. Formulations for REML estimation with groups are derived, and the results are almost as feasible as REML estimation without groups. A numerical example is given to illustrate computations of REML formulations.

Algorithms↗
PubMed2001

A genetic rat model of cholinergic hypersensitivity: implications for chemical intolerance, chronic fatigue, and asthma.

The fact that only some individuals exposed to environmental chemicals develop chemical intolerance raises the possibility that genetic factors could be contributing factors. The present communication summarizes evidence from a genetic animal model of cholinergic supersensitivity that suggests that an abnormal cholinergic system could be one predisposing genetic factor. The Flinders Sensitive Line (FSL) rats were established by selective breeding for increased responses to an organophosphate. It was subsequently found that these FSL rats were also more sensitive to direct-acting muscarinic agonists and had elevated muscarinic receptors compared to the selectively bred parallel group, the Flinders Resistant Line (FRL) rats, or randomly bred control rats. Increased sensitivity to cholinergic agents has also been observed in several human populations, including individuals suffering from chemical intolerance. Indeed, the FSL rats exhibit certain behavioral characteristics such as abnormal sleep, activity, and appetite that are similar to those reported in these human populations. In addition, the FSL rats have been reported to exhibit increased sensitivity to a variety of other chemical agents. Peripheral tissues, such as intestinal and airway smooth muscle, appear to be more sensitive to both cholinergic agonists and an antigen, ovalbumin. Hypothermia, a centrally mediated response, is more pronounced in the FSL rats after nicotine and alcohol, as well as agents that are selective for the dopaminergic and serotonergic systems. In some cases, the increased sensitivity has been detected in the absence of any changes in the receptors with which the drugs interact (dopamine receptors), while receptor changes have been seen in other cases (nicotine receptors). Therefore, there may be multiple mechanisms underlying the multiple chemical sensitivity-chemical intolerance of the FSL rats. An elucidation of these mechanisms may provide useful clues to those involved in chemical intolerance in humans.

Acetylcholine↗
PubMed2004

Using hierarchical modeling in genetic association studies with multiple markers: application to a case-control study of bladder cancer.

BACKGROUND: Genetic association studies are generating much information, usually in the form of single nucleotide polymorphisms in candidate genes. Analyzing such data is challenging, and raises issues of multiple comparisons and potential false-positive associations. Using data from a case-control study of bladder cancer, we showed how to use hierarchical modeling in genetic epidemiologic studies with multiple markers to control overestimation of effects and potential false-positive associations. METHODS: The data were first analyzed with the conventional approach of estimating each main effect individually. We subsequently employed hierarchical modeling by adding a second stage (prior) model that incorporated information on the potential function of the genes. We used an empirical-Bayes approach, estimating the residual effects of the genes from the data. When the residual effect was set to zero, we instead used a semi-Bayes approach, in which they were pre-specified. We also explored the impact of using different second-stage design matrices. Finally, we used two approaches for assessing gene-environment interactions. The first approach added product terms into the first-stage model. The second approach used three indicators for subjects exposed to gene-only, environment-only, and both genetic and environmental factors. RESULTS: By pre-specifying the prior second-stage covariates, the estimates were shrunk to the mean of each pathway. The conventional model detected a number of positive associations, which were reduced with the hierarchical model. For example, the odds ratio for myeloperoxidase (G/G, G/A) genotype changed from 3.17 [95% confidence interval (CI), 1.32-7.59] to 1.64 (95% CI, 0.81-3.34). A similar phenomenon was observed for the gene-environment interactions. The odds ratio for the gene-environment interaction between tobacco smoking and N-acetyltransferase 1 fast genotype was 2.74 (95% CI, 0.68-11.0) from the conventional analysis and 1.24 (95% CI, 0.80-1.93) from the hierarchical model. CONCLUSION: Adding a second-stage hierarchical modeling can reduce the likelihood of false positive via shrinkage toward the prior mean, improve the risk estimation by increasing the precision, and, therefore, represents an alternative to conventional methods for genetic association studies.

Arylamine N-Acetyltransferase↗
PubMed2005

Predictors of physical health: toward an integrated model of genetic and environmental antecedents.

People in higher-income groups tend to experience better physical health, yet this does not appear to be the direct result of access to medical care. This has prompted a search for psychological factors more likely to be present in high-income environments that might help to explain the relationship. Physical health has been associated with a number of such psychological measures including positive affect and well-being, negative affect and neuroticism, positive social relationships, and perceived control. Building from recent findings of moderation of genetic variance in physical health by income and perceived control, we explore the genetic and environmental relationships among all these variables in a nationwide U.S. twin sample. These relationships suggest possible mechanisms by which psychological characteristics, behaviors, physical health, and environmental circumstances could be influenced by common groups of genes with varying degrees of activity in different environments. We discuss the implications of such mechanisms for differential expression of genetic variation in the population and suggest ways in which consideration of such effects can inform gerontology research.

Causality↗
PubMed1979

Some models of genetic selection.

This paper begins with a description of the classical theory of viability selection in which probabilities that individuals of various genotypes survive are in proportions that do not change with time and are independent of population structure. Salient features of viability selection with one and two loci are reviewed. This theory is intimately connected with the usual theory of mass selection in quantitative genetics. It is well known that the mean of the relative viabilities does not necessarily increase if there is viability selection at more than one locus. It also turns out that if there is selection for fecundity with one locus, the mean fecundity may steadily decrease or oscillate rather than increase. This and the fact that a Hardy-Weinberg structure may no longer exist at any stage of life may have a bearing on predicting progress from artificial selection on reproductive characters. Classical viability selection theory does not completely describe natural selection. Other possibilities are discussed. Among these is the density and frequency dependent selection induced when the population lives in a limited habitat. Implications in quantitative genetics are discussed.

Alleles↗
PubMed2000

Cerebral protein synthesis in a genetic mouse model of phenylketonuria.

Local rates of cerebral protein synthesis (lCPS(leu)) were measured with the quantitative autoradiographic [1-(14)C]leucine method in a genetic mouse model (Pah(enu2)) of phenylketonuria. As in the human disease, Pah(enu2) mice have a mutation in the gene for phenylalanine hydroxylase. We compared adult homozygous (HMZ) and heterozygous (HTZ) Pah(enu2) mice with the background strain (BTBR). Arterial plasma concentrations of phenylalanine (Phe) were elevated in both HMZ and HTZ mutants by 21 times and 38%, respectively. In the total acid-soluble pool in brain concentrations of Phe were higher and other neutral amino acids lower in HMZ mice compared with either HTZ or BTBR mice indicating a partial saturation of the l-amino acid carrier at the blood brain barrier by the elevated plasma Phe concentrations. In a series of steady-state experiments, the contribution of leucine from the arterial plasma to the tRNA-bound pool in brain was found to be statistically significantly reduced in HMZ mice compared with the other groups, indicating that a greater fraction of leucine in the precursor pool for protein synthesis is derived from protein degradation. We found reductions in lCPS(leu) of about 20% throughout the brain in the HMZ mice compared with the other two groups, but no reductions in brain concentrations of tRNA-bound neutral amino acids. Our results in the mouse model suggest that in untreated phenylketonuria in adults, the partial saturation of the l-amino acid transporter at the blood-brain barrier may not underlie a reduction in cerebral protein synthesis.

Animals↗
PubMed1999

How inbreeding and outbreeding influence the risk of extinction--a genetically explicit model.

We have developed a stochastic model to explore the common effect which genetics and demography have on the extinction risk of endangered populations. The dynamics is formulated as a MARKOVian birth and death process (in continuous time), whereby selection acts through different mortalities of each genotype. With the help of this model we are able to show how inbreeding and outbreeding can influence the genetic variability and the survival of a population. Whether inbreeding or outbreeding takes place depends on the specific mating system. In our model we consider positive assortative as well as disassortative mating. In the case of additive fitness we show that inbreeding reduces the extinction risk and the genetic variability.

Animals↗
PubMed2000

Stability and change in genetic and environmental influences on hand-grip strength in older male twins.

The aim of this study was to investigate aging-related changes in the contribution of genetic and environmental influences to hand-grip strength in late adulthood. Subjects in this study are 152 intact twin pairs (77 monozygotic and 75 dizygotic pairs) from the National Heart, Lung, and Blood Institute Twin Study assessed repeatedly for hand-grip strength at mean ages of 63 and 73 yr. Structural equation genetic modeling was used to investigate stability and change in the genetic and environmental components of variance of hand-grip strength in late adulthood. Average decline in strength over the 10 yr of follow-up was -1.05+/-6.8 (SD) kg and was highly significant (P = 0.003). The test-retest correlation between baseline and follow-up grip strength was 0.62 (P<0.001). Bivariate genetic modeling found significant genetic and shared environmental stability in hand-grip strength over the 10 yr of follow-up, with genetic and shared environmental influences accounting for 35 and 48%, respectively, of the test-retest phenotypic correlation. We conclude from these results that stability in hand-grip strength in late adulthood is due primarily to continuity of genetic and familial influences.

Aged↗
PubMedDate not supplied

Brain structure in men remains highly heritable in the seventh and eighth decades of life.

The midsagittal cross-sectional dimensions of the corpus callosum, the coronal cross-sectional area of the lateral ventricles at the level of the pons, and a three-dimensional estimate of intracranial volume were derived from magnetic resonance brain images obtained from 45 monozygotic and 40 dizygotic male twin pairs aged 68 to 78. Univariate genetic analyses indicated strong genetic influences contributing significantly to the variability of each brain structure. The estimated proportion of genetic variance (i.e. heritability) was 81% for intracranial volume, 79% for the midline cross-sectional area of the corpus callosum, and 79% for lateral ventricle size. There was no evidence that shared environmental influences contributed significantly to twin-pair similarities. We further used bivariate genetic modeling to estimate the genetic and environmental correlation between correlated brain structures. Intracranial volume and corpus callosum area was highly correlated, and this relationship was entirely due to shared genetic effects between these two brain structures. By contrast, the relationship between the height of the corpus callosum and the size of the lateral ventricles was due to both genetic and environmental influences in common. Corresponding genetic and environmental correlations were 0.68 and 0.58, respectively, indicating that more than half of the genetic and environmental influences on these two brain structures were shared. The manner in which the brain responds to the environment with advancing age is highly genetically determined, both for the lateral ventricles, which dilate with aging and disease, and for the corpus callosum, which is deformed in shape by age-related ventricular enlargement, whereas its midline cross-sectional area remains unchanged.

Aged↗
PubMed1993

Choice of optimality criteria for the design of crossbreeding experiments.

Crossbreeding experiments carried out over several generations and analyzed using genetic models including additive, dominance, and epistatic effects deserve careful planning. Designs should be optimized with respect to the specific aim of the experiment. Using an experiment with guinea pigs as an example, designs were optimized for three different criteria: D-optimality, where the determinant of the variance-covariance matrix of all parameters in the genetic model is minimized, DS-optimality, where a specific subset of parameters is of special interest and the respective determinant is minimized, and DA-optimality, where a linear function or a set of linear functions of the parameters in the model is of interest. The linear function used in this particular case relates to the comparison of a composite line of two breeds and a rotational crossbreeding system at equilibrium. The designs produced by a sequential design algorithm depend very much on the optimality criterion. Designs that are optimal for the comparison of composites and rotations are very inefficient for the estimation of the whole set of parameters in the model or the specific subset of special interest in this case. Assuming that the underlying genetic model is correct, composites and rotations at equilibrium may be compared extremely efficiently using only crosses arising in the first three generations of crossbreeding.

Algorithms↗
PubMed2006

Docosahexaenoic acid protects from amyloid and dendritic pathology in an Alzheimer's disease mouse model.

Genetic data argues that Alzheimer's disease (AD) can be initiated by aggregates of a 42 amino acid beta amyloid peptide (Abeta42). The Abeta aggregates, notably small oligomer species, cause a cascade of events including oxidative damage, inflammation, synaptic toxicity and accumulation of intraneuronal inclusions; notably neurofibrillary tangles. Cognitive deficits are likely to begin with a failure of synaptogenesis and synaptic plasticity with dendritic spine loss and dying back of dendritic arbor. This is followed by neuron loss in key areas involved in learning and memory. Significant prevention or delay of clinical onset may be achievable by modifying environmental risk factors that impact the underlying pathogenic pathways. Because low fish intake and low blood levels of the marine lipid, docosahexaenoic acid (DHA) have been associated with increased AD risk we have tested the impact of depleting or supplementing with dietary DHA on AD pathogenesis in transgenic mice bearing a mutant human gene known to cause AD in people. We reported that even with intervention late in life dietary DHA depletion dramatically enhanced oxidative damage and the loss of dendritic markers, while DHA supplementation markedly reduced Abeta42 accumulation and oxidative damage, corrected many synaptic deficits and improved cognitive function. Loss of brain DHA was exacerbated in mice expressing the mutant human AD transgene, this is consistent with evidence for increased oxidative attack on DHA oxidation in AD. Treatment with the curry spice extract curcumin, a polyphenolic antioxidant that inhibits AP aggregation, has been strongly protective in the same mouse model. Many Western diets are typically deficient in DHA and low in polyphenolic antioxidant intake. These and other data argue that increasing dietary intake of both DHA and polyphenolic antioxidants may be useful for AD prevention.

Alzheimer Disease↗