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PubMed2003

Understanding the molecular responses to hypoxia using Drosophila as a genetic model.

We have previously discovered that Drosophila melanogaster could recover from extended periods of anoxia (0% oxygen) with no apparent consequential injuries. We have since employed forward and reverse genetic approaches to decipher the molecular basis for anoxia tolerance. In so doing, we have identified several independent mutant lines that demonstrated increased sensitivity to anoxia. Characterization of one of these mutants resulted in the identification of a dADAR gene that plays a role in the sensitivity to low levels of oxygen. We have also used microarrays to study all known Drosophila genes, the expression of which may be altered by hyoxia. Microarrays experiments have generated a large body of information that is being currently analyzed. We believe that these undertakings will provide insight into the genetic mechanisms of hypoxia tolerance and ischemic injuries.

Adenosine Deaminase↗
PubMed2002

Mouse genetic models for prepulse inhibition: an early review.

Prepulse inhibition (PPI) is the phenomenon in which a weak prepulse stimulus attenuates the response to a subsequent startling stimulus. Patients with schizophrenia and some other neuropsychiatric disorders have impaired PPI. Impaired PPI in these patient populations is thought to reflect dysfunctional sensorimotor gating mechanisms. Recently, various inbred mouse strains and genetically modified mouse lines have been examined to investigate the potential genetic basis of sensorimotor gating. This review provides a synopsis of the use of mouse models to explore genetic and neurochemical influences on PPI. Studies describing the PPI responses of various inbred strains of mice, mice with genetic mutations, and mice treated with various drugs prior to July 2001 are reviewed. The continuous nature of the distribution of PPI responses among inbred strains of mice indicates that PPI is a polygenic trait. Findings from spontaneous and gene-targeted mutants suggest that mutant mice are important tools for dissecting and studying the role of single genes and their products, and chromosomal regions in regulating PPI. Pharmacological studies of PPI have typically confirmed effects in mice that are similar to those reported previously in rats, with some important exceptions. The use of mice to study PPI is increasing at a dramatic rate and is helping to increase our understanding of the biological basis for sensorimotor gating.

Animals↗
PubMed2001

Modeling genetic networks and their evolution: a complex dynamical systems perspective.

After finishing the sequence of the human genome, a functional understanding of genome dynamics is the next major step on the agenda of the biosciences. New approaches, such as microarray techniques, and new methods of bioinformatics provide powerful tools aiming in this direction. In the last few years, important parts of genome organization and dynamics in a number of model organisms have been determined. However, an integrated view of gene regulation on a genomic scale is still lacking. Here, genome function is discussed from a complex dynamical systems perspective: which dynamical properties can a large genomic system exhibit in principle, given the local mechanisms governing the small subsystems that we know today? Models of artificial genetic networks are used to explore dynamical principles and possible emergent dynamical phenomena in networks of genetic switches. One observes evolution of robustness and dynamical self-organization in large networks of artificial regulators that are based on the dynamic mechanism of transcriptional regulators as observed in biological gene regulation. Possible biological observables and ways of experimental testing of global phenomena in genome function and dynamics are discussed. Models of artificial genetic networks provide a tool to address questions in genome dynamics and their evolution and allow simulation studies in evolutionary genomics.

Biological Evolution↗
PubMed1999

Alcoholism as a complex trait: comparison of genetic models and role of epidemiological risk factors.

A genetic component for alcoholism appears likely, but the genes involved have yet to be identified. The mode of inheritance is probably more complex than for traditional mendelian disorders. In particular, there are marked differences in alcoholism by gender, parent-of-origin effects, ethnicity, and other epidemiological factors. We investigated the evidence for the presence of susceptibility genes for alcohol dependence in the Collaborative Study on the Genetics of Alcoholism data set.

Adolescent↗
PubMed2000

Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat.

The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbred strain of rats that display many of the characteristics of human absence epilepsy. In these rats, reciprocal thalamocortical projections play a critical role in the generation of spike-and-wave discharges that characterize absence seizures. When compared to those of the non-epileptic control strain, juvenile animals of the GAERS strain reportedly possess higher-amplitude T-type calcium currents in neurons of the thalamic reticular nucleus (nRt). We hypothesized that differences in calcium currents seen between GAERS and controls result from differences in expression of genes for low-voltage-activated calcium channels. Quantitative in situ hybridization was used to compare expression of alpha1G, alpha1H, alpha1I, and alpha1E calcium channel subunit mRNAs from adult and juvenile animals of the two strains. We found higher levels of alpha1H mRNA expression in nRt neurons of juvenile animals (34.9+/-2. 3 vs. 28.4+/-1.8 grains/10(3) pixels, p<0.05), perhaps accounting in part for earlier reports of elevated T-type current amplitude in those cells. In adult GAERS animals, we found elevated levels of alpha1G mRNA in neurons of the ventral posterior thalamic relay nuclei (64.8+/-3.5 vs. 53.5+/-1.7 grains/10(3) pixels, p<0.05), as well as higher levels of alpha1H mRNA in nRt neurons (32.6+/-0.8 vs. 28.2+/-1.6 grains/10(3) pixels, p<0.05). These results suggest that the epileptic phenotype apparent in adult GAERS may result in part from these significant, albeit small ( approximately 15-25%), elevations in T-type calcium channel mRNA levels.

Aging↗
PubMed2000

CGS 21680 exerts marked antidystonic effects in a genetic model of paroxysmal dyskinesia.

The effect of the adenosine A(2A) receptor agonist CGS 21680 (2-carboxyethyl)phenylethylamino]-5'-N-ethylcarbonyamido-ade nosine) on severity of dystonia was examined in genetically dystonic hamsters which exhibit attacks of dystonic and choreoathetotic disturbances in response to mild stress. CGS 21680 significantly reduced the severity of dystonia (0.5, 1.0 and 2.0 mg/kg i.p.). The marked antidystonic effects of CGS 21680 in the hamster model suggest that this compound may represent an interesting candidate for the therapy of paroxysmal dystonia. Furthermore, the present data indicate that the precipitating effect of caffeine in patients with paroxysmal dystonia is probably due to its adenosine receptor antagonistic action.

Adenosine↗
PubMed2003

5-HT1A receptor knockout mouse as a genetic model of anxiety.

Low levels of the serotonin(1A) (5-HT(1A)) receptor have been repeatedly found in mood and anxiety disorders. Stress often exacerbates psychiatric disease and can also reduce 5-HT(1A) receptor levels. When receptor deficiency was produced in mice by genetic knockout, an anxiety-like phenotype was observed. Anxiety in mice is defined as a high level of avoidance of novel and unfamiliar environment and increased fear reaction. Other aspects of anxiety such as autonomic activation, increased stress responsiveness, and neuroendocrine abnormalities have also been described in receptor knockout mice. These data indicate that 5-HT(1A) receptor knockout mice represent a genetic animal model of anxiety with both construct and face validities. Although the core phenotype of anxiety can be reproduced in knockout mice in various inbred and outbred backgrounds, abnormalities in 5-HT dynamics and resistance to the anxiolitic drug diazepam have been seen in one but not on other genetic backgrounds. This indicates that while the development of anxiety is an invariable consequence of receptor deficit, other features induced by receptor loss are strongly modulated by other gene(s). Strain-dependent variability within the core phenotype does not diminish the value of 5-HT(1A) receptor knockout mice as a model of anxiety. Indeed, it is consistent with the manifestation of anxiety in genetically heterogeneous human population.

Animals↗
PubMed1985

Sympathetic factors in the cardiovascular complications of hypertension: evidence in genetic models for hypertension, stroke and atherosclerosis.

The role of the nervous system in the pathogenesis of cardiovascular complications in hypertension has been clarified to a great extent in genetic rat models for hypertension, stroke and atherosclerosis, especially in the evolution of cardiovascular hypertrophy in hypertension, the most common process related to the pathogenesis and complications of hypertension, in the development of stroke, one of the most common sequelae of hypertension itself and in the pathogenesis of atherosclerotic vascular diseases, the most usual cause of myocardial infarction.

Animals↗
PubMed2003

Exact moment calculations for genetic models with migration, mutation, and drift.

Using properties of moment stationarity we develop exact expressions for the mean and covariance of allele frequencies at a single locus for a set of populations subject to drift, mutation, and migration. Some general results can be obtained even for arbitrary mutation and migration matrices, for example: (1) Under quite general conditions, the mean vector depends only on mutation rates, not on migration rates or the number of populations. (2) Allele frequencies covary among all pairs of populations connected by migration. As a result, the drift, mutation, migration process is not ergodic when any finite number of populations is exchanging genes. In addition, we provide closed-form expressions for the mean and covariance of allele frequencies in Wright's finite-island model of migration under several simple models of mutation, and we show that the correlation in allele frequencies among populations can be very large for realistic rates of mutation unless an enormous number of populations are exchanging genes. As a result, the traditional diffusion approximation provides a poor approximation of the stationary distribution of allele frequencies among populations. Finally, we discuss some implications of our results for measures of population structure based on Wright's F-statistics.

Gene Frequency↗
PubMed2006

Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best?

Given that natural selection is so powerful at optimizing complex adaptations, why does it seem unable to eliminate genes (susceptibility alleles) that predispose to common, harmful, heritable mental disorders, such as schizophrenia or bipolar disorder? We assess three leading explanations for this apparent paradox from evolutionary genetic theory: (1) ancestral neutrality (susceptibility alleles were not harmful among ancestors), (2) balancing selection (susceptibility alleles sometimes increased fitness), and (3) polygenic mutation-selection balance (mental disorders reflect the inevitable mutational load on the thousands of genes underlying human behavior). The first two explanations are commonly assumed in psychiatric genetics and Darwinian psychiatry, while mutation-selection has often been discounted. All three models can explain persistent genetic variance in some traits under some conditions, but the first two have serious problems in explaining human mental disorders. Ancestral neutrality fails to explain low mental disorder frequencies and requires implausibly small selection coefficients against mental disorders given the data on the reproductive costs and impairment of mental disorders. Balancing selection (including spatio-temporal variation in selection, heterozygote advantage, antagonistic pleiotropy, and frequency-dependent selection) tends to favor environmentally contingent adaptations (which would show no heritability) or high-frequency alleles (which psychiatric genetics would have already found). Only polygenic mutation-selection balance seems consistent with the data on mental disorder prevalence rates, fitness costs, the likely rarity of susceptibility alleles, and the increased risks of mental disorders with brain trauma, inbreeding, and paternal age. This evolutionary genetic framework for mental disorders has wide-ranging implications for psychology, psychiatry, behavior genetics, molecular genetics, and evolutionary approaches to studying human behavior.

Adaptation, Physiological↗
PubMed2005

Rethinking genetic models of asthma: the role of environmental modifiers.

Asthma is a common, chronic disease with a complex etiology. To date, more than 35 genes have been associated with asthma or related phenotypes in multiple populations, but none of them has been shown to contribute to risk in all populations studied. We suggest that genetic susceptibility is both context dependent and developmentally regulated, and that ignoring the environmental context will miss many important associations and clues to pathogenesis. We define 'environment' broadly to include the in utero environment, maternal affection status and sex, and propose that epigenetic mechanisms are the link between our genes and our environment.

Asthma↗
PubMed2005

Modelling genetic networks with noisy and varied experimental data: the circadian clock in Arabidopsis thaliana.

Circadian clocks in all organisms include feedback loops that generate rhythmic expression of key genes. We model the first such loop proposed for the clock of Arabidopsis thaliana, the experimental model species for circadian timing in higher plants. As for many biological systems, there are no experimental values for the parameters in our model, and the data available for parameter fitting is noisy and varied. To tackle this we constructed a cost function, which quantifies the agreement between our model and various key experimental features. We then undertook an efficient global search of parameter space, to test whether the proposed circuit can fit the experimental data. Using this approach we show that circadian clock models can function well with low cooperativity in transcriptional regulation, whereas high cooperativity has been a feature of previous (hand-fitted) clock models in other species. Our optimized solution for the Arabidopsis clock model fits several, but not all, of the key experimental features. We test the predicted effects of well-characterized mutations in the clock circuit and show the phases of the circadian cycle where additional components that are yet to be identified experimentally must be present to complete the circadian feedback loop.

Arabidopsis↗
PubMed2000

Genetic modeling of abnormal photosensitivity in families with polymorphic light eruption and actinic prurigo.

Actinic prurigo and polymorphic light eruption are two of the so-called idiopathic photodermatoses, resulting from abnormal cutaneous responses to ultraviolet radiation (photosensitivity). Whereas they are clinically distinct in most cases, there are sufficient similarities between them to suggest they may be related conditions. To take this further, we examined the prevalence of polymorphic light eruption in families ascertained through actinic prurigo probands, as evidence of a shared pathogenesis. We then determined the heritability of photosensitivity in 420 individuals from families ascertained through polymorphic light eruption and actinic prurigo probands using segregation analysis. Across 58 pedigrees the prevalence of photosensitivity in first-degree relatives was 20.9% compared with a population prevalence of 13.6%, giving a relative risk of 1.5 (confidence interval 1.15-2.0) and providing evidence of clustering within families. The prevalence of photosensitivity (predominantly polymorphic light eruption) in relatives of actinic prurigo probands was 23.7%, with a relative risk of 1.74 (confidence interval 1.24-2.36). Modeling for polymorphic light eruption across all pedigrees revealed a strong genetic component with polymorphic light eruption showing a dominant mixed mode of inheritance. The model parameters estimate that 72% of the U.K. population carry a low penetrance polymorphic light eruption susceptibility allele, but that among this highly prevalent genotype only 24% of susceptible females and 13% of susceptible males will have polymorphic light eruption. Expression of polymorphic light eruption in genetically susceptible individuals (intergenotype variance) is determined in large part by a polygenic component, with an important additional environmental component. In summary, this study provides clear evidence that polymorphic light eruption is an inherited condition. It also suggests that polymorphic light eruption and actinic prurigo share a common genetic background, supporting the view that actinic prurigo may represent a human leukocyte antigen-restricted subset of polymorphic light eruption.

Family Health↗
PubMed1989

Estimation of genetic model parameters: variables correlated with a quantitative phenotype exhibiting major locus inheritance.

A major locus that is detected through its effect on one phenotype (a primary trait) may also affect other quantitative phenotypes or qualitative disease endpoints (secondary traits). The pattern of effects of the major locus on a set of primary and secondary traits suggests candidate defects for the mutant allele. The effects are directly estimable when "measured genotypes" or a tightly linked marker allow unambiguous assignment of major locus genotypes. When genotypes assignments are ambiguous for a major locus detected through its effect on a quantitative primary trait, we propose estimators using genotypic probabilities. Making certain reasonable assumptions, we demonstrate asymptotic unbiasedness of these genotypic probability estimators of the genotypic means and variances for either the quantitative primary or secondary traits, of the covariances between quantitative primary and secondary traits, and of prevalences for the secondary qualitative traits. An important application of genotypic probability estimators is to define an effect of a major locus that cannot be detected upon analysis of the variable; for example, major locus effects may be defined for hypertension or blood pressure as secondary traits, but not detected as primary traits.

Alleles↗
PubMed2003

Zebrafish: a genetic model for vertebrate organogenesis and human disorders.

Mutations may be tolerated without noticeable effect or may present with a specific phenotype that reveals information about the function of the mutated gene. This information is an inexhaustible source for understanding biology and let us ask particular questions about the molecular mechanisms of development, degeneration and disease. The zebrafish (Danio rerio) has been proven to be instrumental in the genetic analysis of spontaneous and induced mutations and has provided invaluable clues to the elucidation of complex molecular processes in vertebrate biology. Since completion of the two large-scale mutagenesis screens carried out at the Max-Planck Institute in Tuebingen and at the Massachusetts General Hospital in Boston, many of the recovered mutations have been cloned and the function of the mutated genes studied. Special interest laid in the analysis of mutations affecting structures and organ systems characteristic for vertebrates such as the notochord, neural crest, heart, vasculature, blood and kidney. This review updates our knowledge of heart, vessel, blood and kidney organogenesis in zebrafish and extrapolates our insights to human disorders by assessing common genetic pathways.

Animals↗
PubMed1988

A new method to test genetic models in HLA associated diseases: the MASC method.

We propose a new method to analyse data on HLA associated diseases. The method uses the simultaneous information on the marker associations and segregation with the disease. It may also take into account the differential risk of being affected for specific relatives of a patient as well as the differential HLA haplotype sharing according to the marker genotype of the patient. It is based on the principle of minimization of a sum of independent chi-squares. It allows us to test the goodness-of-fit of various models in an easy and economical way. The method is applied to a sample of 269 French IDDM patients and their relatives leading to the rejection of models with one locus closely linked to HLA with two and three alleles.

Alleles↗