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PubMed1996

Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: influence of nociceptive assay.

Several genetic mouse models of opiate sensitivity have been identified or produced in an attempt to investigate mechanisms underlying individual variation in responses to opiate drugs like morphine. The major models in use presently are the DBA/2 (DBA) versus C57BL/6 (C57) inbred strains, the recombinantly inbred CXBK strain, and mouse lines selectively bred for high- and low-magnitude antinociception after swim stress (HA and LA lines, respectively) or levorphanol administration (HAR and LAR lines, respectively). The hot-plate test, an assay of acute, thermal nociception, was used in the selection of the HA/LA and HAR/LAR lines, and has largely been used to characterize the differential opiate sensitivity of the DBA (high) and C57 (low) strains and the deficient sensitivity of the CXBK strain. There exist, however, many other nociceptive assays used with murine subjects; the most common are the tail-flick/withdrawal test, the acetic acid abdominal constriction test and the formalin test. In the present experiment, baseline nociceptive sensitivities and morphine antinociceptive dose-response relationships (0.1-10 mg/kg i.p. or s.c.) were investigated in mice of all four genetic models and in all four major nociceptive assays, with identical parameters. Results indicate a high degree of dissociation between different genetic models, which suggests that these strains differ in their nociceptive and antinociceptive sensitivities due to the effects of very different genetic and physiological mechanisms. In addition, the present findings suggest that morphine inhibits different modalities of nociception via separate mechanisms that can be genetically dissociated and independently altered. Strikingly, in HA/LA and HAR/LAR mice, we find that an inverse relationship exists with respect to morphine antinociceptive sensitivity in the hot-plate and acetic acid abdominal constriction tests, respectively.

Analgesia↗
PubMed1999

Ecological character displacement in quantitative genetic models.

We study, both analytically and numerically, models of ecological character displacement for two species that compete for the same set of food sources. These models include quantitative genetics and Lotka-Volterra type competition and are symmetric with respect to the two species. We allow for various shapes of the carrying capacity and the competition function, and we discuss under what general conditions large character displacement can occur. While some of these conditions, like genetic rigidity, or flat and truncated carrying capacity curves, were known before, we also find that slow dynamics of the genetic variance, steep slopes in the interaction function and carrying capacities that are not truncated can lead to large displacements. We interpret these conditions biologically and also give new insights into models which have been previously investigated.

Animals↗
PubMed1993

Genetic models of arterial hypertension--role of tubular ion transport.

The description of pathogenetic mechanisms underlying different genetic models of essential hypertension is a useful way of illustrating the logical sequence needed to dissect a complex phenotypic condition such as hypertension. The abnormalities in renal function observed in spontaneously hypertensive rats of the Okamoto strain and Milan strain will be emphasized. The description may proceed "downward" from alterations that affect the whole body function to cellular and subcellular levels. However, the identification in the Milan strain rats of a point mutation in the gene coding for adducin, a skeletal protein able to modulate transepithelial sodium transport, provides the opportunity to reconstruct, in an "upward" direction, the sequence of events leading from the single point mutation to the final complex phenotype of essential hypertension.

Animals↗
PubMed2005

Genetic models of human cancer as a multistep process. Paradigm models of colorectal cancer, breast cancer, and chronic myelogenous and acute lymphoblastic leukaemia.

Tumour formations arise as a consequence of alterations in the control of cell proliferation as well as with disorders in interactions between cells and their environment that result in invasion and metastasis. Recent advances in understanding the genetic basis of malignant diseases have been dominated by research in colorectal cancer. Genetic alterations of several proto-oncogenes and tumor-suppressor genes (e.g. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, hyperexpression of c-MYC and RB genes), as well as other genomic alterations, appear at characteristic stages of tumor development and are observed in most neoplasms. Generally, the normal cell has multiple independent mechanisms that regulate its growth and differentiation potential, and several separate events would, therefore, be needed to override these control mechanisms, as well as induce the other aspects of the transformed phenotype, like metastasis. These signals may be either positive or negative, and the acquisition of tumorigenicity results from genetic changes that affect these control points following a multistep mode. Statistics of the frequency of cancer incidence with age in humans indicate that for the genesis of e.g. lung carcinoma, five or six steps are required. Other types of cancers, such as leukemias and sarcomas, probably require quite a different number of rate-limiting changes. One of the best characterized tumours to provide a genetic model is colorectal tumorigenesis. Mutations implicated in breast cancer tumorigenicity are also studied and used as a genetic model in the literature worldwide. Finally, activation of c-abl in chronic myelogenous leukaemia (CML) and acute lymphoblastic leukaemia could also be presented as an example, which provides probably the strongest evidence for the role of proto-oncogenes in human malignancy process.

Breast Neoplasms↗
PubMed2005

Study of androgen receptor functions by genetic models.

Androgens exert most of their biological activities through binding to the androgen receptor (AR). The AR belongs to the nuclear receptor superfamily and acts as a ligand-inducible transcriptional factor. AR dysfunction causes a diverse range of clinical conditions, such as testicular mutation (Tfm) syndrome, prostate cancer, and spinal and bulbar muscular atrophy (SBMA). However, the molecular basis of the AR function underlying these AR-related disorders remains largely unknown due to the lack of stable genetic models. Here we review recent results of our studies into genetic models of the loss of AR function in mice and the gain of AR function in Drosophila.

Animals↗
PubMed2001

Genetic models of hypertension in experimental animals.

Genetic animal models are central to ongoing efforts to elucidate the pathophysiology and genetic basis of hypertension. The rat is the leading species in experimental hypertension. Several rat models of hypertension are available for research, including inbred strains, congenic lines, transgenic animals and recombinant inbred strains. Each of these models has been designed to express different phenotypes, including spontaneous hypertension, salt sensitivity, stress sensitivity and susceptibility to end-organ damage. All these models have been extremely useful in the search for the physiological mechanisms that underlie hypertension, but some of them have been specifically designed for detecting the hypertension genes. This latter task is extremely complex in spontaneous hypertension, but genetic animal models may simplify the task by enabling to focus on specific phenotypes. Despite intensive efforts over nearly 3 decades, the genetic basis of hypertension has not been unveiled so far in the rat or in other species. Recent dense mapping of the rat genome, the development of new strategies and technologies in molecular genetics including differential gene expression, expressed sequence tags and DNA biochips render hope that the formidable task of identification of new candidate genes in hypertension will move another major step forward. Once these genes are identified, their function and role in hypertension will have to be determined, utilizing functional genomic strategies and bioinformatics. Finally, the findings in genetic animal models of hypertension will have to be extrapolated to humans by homology and syntenic mapping strategies.

Animals↗
PubMed1987

A genetical model for emergenesis: in memory of Laurence H. Snyder, 1901-86.

When a phenotype is determined by a specific gene combination of several loci, it is called an emergenic trait. Such a trait, although genetically controlled, does not usually run in families, since the specific gene combination can hardly be preserved in the process of reproduction. The present paper suggests a concrete genetical model to account for the phenomenon that there is little resemblance between siblings and parent-child pairs with respect to this trait. The genetical model is multiple homozygosis for all loci involved in the gene configuration. The properties of such a trait in a random mating population for all families, as well as for the segregating families only, are investigated. Some of the difficulties in estimating the genetical parameters on the basis of empirical data are also discussed.

Genetics, Behavioral↗
PubMed2025

A single-locus quantitative genetic model incorporating DNA methylation.

We describe a single-locus quantitative genetic model that incorporates effects due to DNA methylation. Extending Fisher's decomposition of the genotypic value, we distinguish two quantities to predict an individual's phenotypic or genetic values: the "basic genetic value" and the "expressed genetic value". We show how these quantities relate to the concept of breeding value and derive their corresponding formulas, along with those for phenotypic variance and covariance between relatives. The resulting parameters are influenced by several factors, including the population distribution of DNA methylation levels, the functional relationship between methylation and phenotype, the magnitudes of genetic and methylation effects, and allele frequencies. We show that under the conditions modeled, the presence of DNA methylation does not bias estimated breeding values.

DNA Methylation↗
PubMed2001

Behavior genetic modeling of human fertility: findings from a contemporary Danish Twin Study.

Behavior genetic designs and analysis can be used to address issues of central importance to demography. We use this methodology to document genetic influence on human fertility. Our data come from Danish twin pairs born from 1953 to 1959, measured on age at first attempt to get pregnant (FirstTry) and number of children (NumCh). Behavior genetic models were fitted using structural equation modeling and DF analysis. A consistent medium-level additive genetic influence was found for NumCh, equal across genders; a stronger genetic influence was identified for FirstTry, greater for females than for males. A bivariate analysis indicated significant shared genetic variance between NumCh and FirstTry.

Adult↗
PubMed2003

Integrative physiology and functional genomics of epithelial function in a genetic model organism.

Classically, biologists try to understand their complex systems by simplifying them to a level where the problem is tractable, typically moving from whole animal and organ-level biology to the immensely powerful "cellular" and "molecular" approaches. However, the limitations of this reductionist approach are becoming apparent, leading to calls for a new, "integrative" physiology. Rather than use the term as a rallying cry for classical organismal physiology, we have defined it as the study of how gene products integrate into the function of whole tissues and intact organisms. From this viewpoint, the convergence between integrative physiology and functional genomics becomes clear; both seek to understand gene function in an organismal context, and both draw heavily on transgenics and genetics in genetic models to achieve their goal. This convergence between historically divergent fields provides powerful leverage to those physiologists who can phrase their research questions in a particular way. In particular, the use of appropriate genetic model organisms provides a wealth of technologies (of which microarrays and knock-outs are but two) that allow a new precision in physiological analysis. We illustrate this approach with an epithelial model system, the Malpighian (renal) tubule of Drosophila melanogaster. With the use of the beautiful genetic tools and extensive genomic resources characteristic of this genetic model, it has been possible to gain unique insights into the structure, function, and control of epithelia.

Animals↗
PubMed1989

A quantitative genetic model for growth, shape, reaction norms, and other infinite-dimensional characters.

Infinite-dimensional characters are those in which the phenotype of an individual is described by a function, rather than by a finite set of measurements. Examples include growth trajectories, morphological shapes, and norms of reaction. Methods are presented here that allow individual phenotypes, population means, and patterns of variance and covariance to be quantified for infinite-dimensional characters. A quantitative-genetic model is developed, and the recursion equation for the evolution of the population mean phenotype of an infinite-dimensional character is derived. The infinite-dimensional method offers three advantages over conventional finite-dimensional methods when applied to this kind of trait: (1) it describes the trait at all points rather than at a finite number of landmarks, (2) it eliminates errors in predicting the evolutionary response to selection made by conventional methods because they neglect the effects of selection on some parts of the trait, and (3) it estimates parameters of interest more efficiently.

Analysis of Variance↗
PubMed1995

A genetic model of malignant phase hypertension in rats.

A genetic model of malignant phase hypertension in rats is described which closely parallels the natural history of untreated human malignant phase hypertension. Although the factors initiating transition from essential hypertension to the accelerated phase in humans remain unknown, we report the characteristics of a genetically determined and reproducible phenotype which was found to result from a cross between hypertensive transgenic Ren-2 rats and normotensive Sprague-Dawley (Edinburgh) rats. Male F1 hybrids developed malignant phase hypertension with a penetrance of 73.5% (95% confidence limits 65.7 to 81.3%) by 100 days of age. Phenotypic features included an accelerated rise in blood pressure, fibrinoid necrosis, activation of the renal renin-angiotensin system and microangiopathic hemolytic anemia. In an analytical cross no significant difference in blood pressure was observed between malignant phase and non-malignant phase animals prior to transition, implying that a factor in addition to hypertension appears necessary for inducing transition to the malignant phase phenotype. Segregation of the malignant phenotype suggested that susceptibility is determined by at most two genetic loci.

Alleles↗
PubMed2006

Global and focal aspects of absence epilepsy: the contribution of genetic models.

The cortico-reticular theory of absence epilepsy explains the origin of the bilateral generalized spike-wave discharges (SWDs) characterizing absence seizures via a subcortical pacemaker that is responsible for both normal sleep spindles and pathological SWDs. This pacemaker is the reticular thalamic nucleus (RTN); it produces spontaneous oscillations together with thalamic relay cells and the cortex in an assembled thalamo-cortico-thalamic network. Recently, Meeren et al. [2002. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. Journal of Neuroscience 22, 1480-1495.] proposed a focal theory of absence epilepsy based on experimental findings in the WAG/Rij rat, a genetic model of absence epilepsy: the somatosensory cortex contains a focus that initiates a cascade of events that ultimately leads to the occurrence of the bilateral and generalized SWDs if the state of the thalamo-cortical circuitry is favorable. Pharmacological, neurochemical, and neurophysiological data are presented and reviewed here that suggest SWDs might emerge from spontaneous oscillating neurons in the somatosensory cortex during both wakefulness and drowsiness. There is evidence for a variety of neurobiological changes, including a deficient global (parvalbumin) and local GABA-ergic (neurophysiological) system in the neocortex, which may explain why specifically the perioral region of the somatosensory cortex is hyperexcitable and the initiation site of 10Hz oscillations. The neuronal cortical and subcortical circuitry that produces SWDs is part of a large oscillatory system involved in generating cerebral rhythms associated with vibrissal movements. It needs to be established whether similar or comparable pathophysiological processes are also present in humans. Our hypothesis can be readily tested in other models and in humans considering that it is very specific and can be subjected to experimental verification.

Animals↗
PubMed1992

Population genetic models of genomic imprinting.

The phenomenon of genomic imprinting has recently excited much interest among experimental biologists. The population genetic consequences of imprinting, however, have remained largely unexplored. Several population genetic models are presented and the following conclusions drawn: (i) systems with genomic imprinting need not behave similarly to otherwise identical systems without imprinting; (ii) nevertheless, many of the models investigated can be shown to be formally equivalent to models without imprinting; (iii) consequently, imprinting often cannot be discovered by following allele frequency changes or examining equilibrium values; (iv) the formal equivalences fail to preserve some well known properties. For example, for populations incorporating genomic imprinting, parameter values exist that cause these populations to behave like populations without imprinting, but with heterozygote advantage, even though no such advantage is present in these imprinting populations. We call this last phenomenon "pseudoheterosis." The imprinting systems that fail to be formally equivalent to nonimprinting systems are those in which males and females are not equivalent, i.e., two-sex viability systems and sex-chromosome inactivation.

Dosage Compensation, Genetic↗
PubMed1979

Schizophrenia: a study of genetic models.

The likelihoods of observing 25 four-generational families of schizophrenics comprising 1,333 individuals have been calculated on the basis of 12 different genetic models and one control 'sporadic' model. The control model gave a log10 likelihood (L), of -240.92. Five of the genetic models were definitely excluded as incompatible with certain pedigrees. The three models with the highest likelihoods were: one locus, the heterozygote having a 10% probability of being classified schizophrenic (L: -220.05); two interacting loci (L:-219.46); and four polygenes (L:-216.87).

Alleles↗
PubMed2006

A genetic model for determining MSH2 and MLH1 carrier probabilities based on family history and tumor microsatellite instability.

Mutation-predicting models can be useful when deciding on the genetic testing of individuals at risk and in determining the cost effectiveness of screening strategies at the population level. The aim of this study was to evaluate the performance of a newly developed genetic model that incorporates tumor microsatellite instability (MSI) information, called the AIFEG model, and in predicting the presence of mutations in MSH2 and MLH1 in probands with suspected hereditary non-polyposis colorectal cancer. The AIFEG model is based on published estimates of mutation frequencies and cancer penetrances in carriers and non-carriers and employs the program MLINK of the FASTLINK package to calculate the proband's carrier probability. Model performance is evaluated in a series of 219 families screened for mutations in both MSH2 and MLH1, in which 68 disease-causing mutations were identified. Predictions are first obtained using family history only and then converted into posterior probabilities using information on MSI. This improves predictions substantially. Using a probability threshold of 10% for mutation analysis, the AIFEG model applied to our series has 100% sensitivity and 71% specificity.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Gene-environment interactions in complex diseases: genetic models and methods for QTL mapping in multiple half-sib populations.

An interval quantitative trait locus (QTL) mapping method for complex polygenic diseases (as binary traits) showing QTL by environment interactions (QEI) was developed for outbred populations on a within-family basis. The main objectives, within the above context, were to investigate selection of genetic models and to compare liability or generalized interval mapping (GIM) and linear regression interval mapping (RIM) methods. Two different genetic models were used: one with main QTL and QEI effects (QEI model) and the other with only a main QTL effect (QTL model). Over 30 types of binary disease data as well as six types of continuous data were simulated and analysed by RIM and GIM. Using table values for significance testing, results show that RIM had an increased false detection rate (FDR) for testing interactions which was attributable to scale effects on the binary scale. GIM did not suffer from a high FDR for testing interactions. The use of empirical thresholds, which effectively means higher thresholds for RIM for testing interactions, could repair this increased FDR for RIM, but such empirical thresholds would have to be derived for each case because the amount of FDR depends on the incidence on the binary scale. RIM still suffered from higher biases (15-100% over- or under-estimation of true values) and high standard errors in QTL variance and location estimates than GIM for QEI models. Hence GIM is recommended for disease QTL mapping with QEI. In the presence of QEI, the model including QEI has more power (20-80% increase) to detect the QTL when the average QTL effect is small (in a situation where the model with a main QTL only is not too powerful). Top-down model selection is proposed in which a full test for QEI is conducted first and then the model is subsequently simplified. Methods and results will be applicable to human, plant and animal QTL mapping experiments.

Animals↗