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At least 145 records · Page 8Linked to original sources
PubMed1985

A genetic model for age at onset in Huntington disease.

Although numerous investigators have confirmed excess paternal transmission among juvenile-onset cases of Huntington disease (HD), there are conflicting reports that the late-onset form is inherited more often from the mother than from the father. Results from a survey of age at onset and age at death in 569 patients corroborate earlier findings of delayed onset of HD among offspring of affected mothers at both ends of the onset-age spectrum: 23 of 28 juvenile-onset offspring had affected fathers, and there were 1.6 times more late-onset offspring born to affected mothers than to affected fathers. These patterns, together with data that link age-at-onset variability to familial longevity trends, suggest a model where age at onset is governed, generally, by a set of independently inherited aging genes, but expression of the HD gene may be significantly delayed in individuals who possess a particular maternally transmitted factor.

Adolescent↗
PubMed1995

Beta-cell mass depletion precedes the onset of hyperglycaemia in the GK rat, a genetic model of non-insulin-dependent diabetes mellitus.

It is unclear whether reported histopathological changes in the endocrine pancreas of the GK rat (a spontaneous model of non-insulin-dependent diabetes) are related to the pathogenesis of hyperglycaemia or occur secondarily to metabolic alterations. We found that total pancreatic insulin stores in GK rats from the Paris colony were depleted by 62% (p < 0.01) in adult (4-month-old) overtly hyperglycaemic animals compared to those of normal Wistar control rats, and that beta-cell mass in GK pancreata was decreased to a similar extent (51%, p < 0.05). This indicates that decreased in vivo and in vitro insulin secretory response to glucose in GK rats could be due not only to impaired stimulus-secretion coupling for glucose in their beta cells but also to a reduced number of beta cells. Reduced total beta-cell mass in adult GK rats was associated with a noticeable alteration in the architecture of a subpopulation of islets: only large islets displayed signs of disorganization of the mantle-core relationship due to prominent fibrosis, with clusters of beta cells widely separated by strands of connective tissue. Our study also provides a first record of the pathophysiologic changes occurring in the GK rat from the neonatal period. Four-day-old GK pups demonstrated normal basal glycaemia compared to Wistar rats of the same age. GK islets displayed a well-preserved architecture, with normal staining of beta cells and no fibrosis. However, their total pancreatic insulin stores and total beta-cell mass were significantly lower [59% (p < 0.01) and 64% (p < 0.05) respectively] than those of controls. These data indicate that a reduction in islet tissue clearly predates the onset of diabetes (hyperglycaemia). Therefore, a reduction of total beta-cell mass should be considered as a primary feature in the pathological sequence leading to diabetes in GK rats, at least in those originating from the Paris colony.

Animals↗
PubMed2006

Seascape genetics: a coupled oceanographic-genetic model predicts population structure of Caribbean corals.

Population genetics is a powerful tool for measuring important larval connections between marine populations [1-4]. Similarly, oceanographic models based on environmental data can simulate particle movements in ocean currents and make quantitative estimates of larval connections between populations possible [5-9]. However, these two powerful approaches have remained disconnected because no general models currently provide a means of directly comparing dispersal predictions with empirical genetic data (except, see [10]). In addition, previous genetic models have considered relatively simple dispersal scenarios that are often unrealistic for marine larvae [11-15], and recent landscape genetic models have yet to be applied in a marine context [16-20]. We have developed a genetic model that uses connectivity estimates from oceanographic models to predict genetic patterns resulting from larval dispersal in a Caribbean coral. We then compare the predictions to empirical data for threatened staghorn corals. Our coupled oceanographic-genetic model predicts many of the patterns observed in this and other empirical datasets; such patterns include the isolation of the Bahamas and an east-west divergence near Puerto Rico [3, 21-23]. This new approach provides both a valuable tool for predicting genetic structure in marine populations and a means of explicitly testing these predictions with empirical data.

Animals↗
PubMed2003

Use of max and min scores for trend tests for association when the genetic model is unknown.

In case-control studies, the Cochran-Armitage (CA) trend test is powerful for detection of an association between a risk allele and a marker. To apply this test, a score should be assigned to the genotypes based on the genetic model. When the underlying genetic model is unknown, the trend test statistic is a function of the score. In this paper, simple procedures are given to obtain two scores (max and min), which respectively maximize and minimize the CA trend test statistics for genetic associations. These two scores can be used to examine the effect of the choice of scores on the test of no association. When the CA trend test statistic with the max (or min) score is less (or greater) than a prespecified value, the conclusion is clear: we will accept (or reject) the null hypothesis of no association for any scores used. When this value is less than the CA trend test statistic with the max score but greater than the one with the min score, the decision of whether or not to reject the null hypothesis depends on the choice of scores. In this situation, the CA trend test with a prespecified score cannot be used without careful scientific justification of the choice of scores. The use of max and min scoring schemes is applied to a real data set.

Case-Control Studies↗
PubMed1991

Contrasting hemodynamic effects of high oral calcium in genetic models of salt-sensitive hypertension.

Interest in effects of oral calcium (Ca) on blood pressure is now generally focused on salt-induced hypertension. In this study hemodynamic effects of long-term high oral Ca were examined in two different genetic models of salt-sensitive hypertension, stroke-prone spontaneously hypertensive rats (spSHR) and Dahl salt-sensitive (DS) hypertensive rats. High vs low oral Ca (2.0 vs 0.4% Ca, 8-13 rats/diet) significantly (p less than 0.05) attenuated salt-induced hypertension (7% NaCl intake) in female spSHR (mean arterial pressure = 137 vs 175 mmHg) but aggravated such hypertension in female DS rats (141 vs 124 mmHg). Pressor responsiveness to norepinephrine (NE) and angiotensin (A) II were examined in the same rats. High oral Ca decreased pressor responses to graded intravenous injections of NE and AII in spSHR and increased such responses in DS rats. In spSHR, the decreased pressor responsiveness preceded the antihypertensive effect of high oral Ca. In summary, 2.0 vs 0.4% oral Ca produces contrasting effects on blood pressure in two genetic models of salt-sensitive hypertension (stroke-prone SHR and Dahl salt-sensitive rats). These contrasting effects on blood pressure may be related to differential effects of oral Ca on vascular responsiveness to endogenous vasoconstrictors in these two genetic models of salt-sensitive hypertension.

Administration, Oral↗
PubMed1992

Branching process with emigration--a genetic model.

Solution of a genetic improvement problem under the model of assortative mating is proposed. This has been achieved through the technique applied to a branching process incorporating a generation-dependent emigration component. The model explains a population subject to culling against genes governing undesirable characters and this work has been tried for a diploid population with two alleles at a single locus, which may be extended to the multilocus case.

Animals↗
PubMed2001

Zebrafish--an emerging genetic model for the study of cytokines and hematopoiesis in the era of functional genomics.

Now that whole genomes are sequenced, the identification of gene function rather than gene discovery is a major challenge. Saturation mutagenesis and screening for mutant phenotypes are methods that allow sampling of the genome for lesions in genes critical for particular physiological processes. This approach promises to provide new insights into gene function, even for molecularly well-characterized processes such as hematopoiesis and cytokine signaling. Animal models for such genetic approaches have traditionally included Drosophila and the mouse. Recently, the zebrafish (Danio rerio) has emerged as a flexible and informative vertebrate for genetic studies. Zebrafish hematopoiesis has a morphological and molecular complexity closer to that of mammals than does Drosophila, providing scope for recognizing mutant zebrafish phenotypes representing finely tuned lesions in these processes. Compared to mice, zebrafish represent an economical, flexible, and genetically tractable animal model for mutagenesis studies. The structure of the teleost genome creates several phylogenetic issues in assessing zebrafish and piscine orthologues and paralogues of known mammalian genes, here exemplified by a cytokine ligand (interleukin-1beta), kinase receptors (c-kit and c-fins), and a family of intracellular signaling molecules (JAK kinases). Several anemic zebrafish mutants are now genetically characterized, and others present hematopoietic phenotypes that promise novel insights into the regulation of hematopoiesis.

Animals↗
PubMed2002

Minireview: genetic models for the study of gonadotropin actions.

Fertility in both sexes relies on complex physiological and molecular processes with many levels of regulation, and our ability to alter the mammalian genome using transgenic technology has greatly enhanced our understanding of these processes. There are numerous commonalities in human and mouse physiology, and the list of mouse models recapitulating recognized and idiopathic human reproductive defects is growing at an ever-increasing rate. In this review, we focus on genetic models of gonadotropin actions, summarizing features of transgenic mice that phenocopy defects in gonadotropin production and gonadotropin receptor responses seen in patients. In addition, we provide examples of mouse models with genetic alterations influencing pituitary FSH and LH production and their effects. These include: 1) transgenic mice with aberrations in steroid hormone, inhibin, and activin feedback pathways; 2) knockouts that demonstrate specific in vivo functions of pituitary transcription factors; and 3) models with alterations in other pituitary hormones, IGF-1, and leptin signaling pathways, which affect both the central and peripheral endocrine axis. What we have to learn from these and other models will continue to revise our conceptions of physiology, identify new targets for contraception, and improve our tools for understanding, diagnosing, and treating cases of human endocrinopathies and pathologies of the reproductive tissues.

Animals↗
PubMed1985

Handedness, language dominance and aphasia: a genetic model.

A simple two-allele Mendelian model of the genetics of handedness is described and fitted to data in the literature. The model proposes that there are two alleles, D (dextral) and C (chance), the homozygous DD genotype producing only right-handers (directional asymmetry), the homozygous CC genotype producing a racemic mixture of 50% right-handers and 50% left-handers (fluctuating asymmetry), and the heterozygote, DC, being intermediate between the homozygotes and producing 25% left-handers, and 75% right-handers. It is also suggested that the true population incidence of left-handedness is 7.75%, deviations from this figure being due to either criterion shifts or selection biases. The same model is then fitted, by means of a number of minor conceptual extensions, to data from the literature on the relationship of handedness to language dominance, acute and permanent aphasia, and visual processing dominance.

Aphasia↗
PubMed2005

Genomic control for association studies under various genetic models.

Case-control studies are commonly used to study whether a candidate allele and a disease are associated. However, spurious association can arise due to population substructure or cryptic relatedness, which cause the variance of the trend test to increase. Devlin and Roeder derived the appropriate variance inflation factor (VIF) for the trend test and proposed a novel genomic control (GC) approach to estimate VIF and adjust the test statistic. Their results were derived assuming an additive genetic model and the corresponding VIF is independent of the candidate allele frequency. We determine the appropriate VIFs for recessive and dominant models. Unlike the additive test, the VIFs for the optimal tests for these two models depend on the candidate allele frequency. Simulation results show that, when the null loci used to estimate the VIF have allele frequencies similar to that of the candidate gene, the GC tests derived for recessive and dominant models remain optimal. When the underlying genetic model is unknown or the null loci and candidate gene have quite different allele frequencies, the GC tests derived for the recessive or dominant models cannot be used while the GC test derived for the additive model can be.

Biometry↗
PubMed1999

Longevity, genes, and aging: a view provided by a genetic model system.

The genetic analysis of aging in the yeast Saccharomyces cerevisiae has revealed the importance of metabolic capacity, resistance to stress, integrity of gene regulation, and genetic stability for longevity. A balance between these life maintenance processes is sustained by the RAS2 gene, which channels cellular resources among them. This gene cooperates with mitochondria and PHB1 in metabolic adjustments important for longevity. It also modulates stress responses. Transcriptional silencing of heterochromatic regions of the genome is lost during aging, suggesting that gene dysregulation accompanies the aging process. There is evidence that this age change plays a causal role. Aging possesses features of a nonlinear process, and it is likely that application of nonlinear system methodology to aging will be productive.

Aging↗
PubMed2003

The paradox of Prader-Willi syndrome: a genetic model of starvation.

The neurodevelopmental disorder, Prader-Willi syndrome, is generally regarded as a genetic model of obesity. Although the values of some hypothalamic neuropeptides are as expected in obesity, and should result in satiety, we propose that abnormal hypothalamic pathways mean that these are ineffective. We postulate that the body incorrectly interprets the absence of satiation as starvation, and therefore, paradoxically, this syndrome should be redefined as one of starvation that manifests as obesity in a food-rich environment. Also, this syndrome is generally believed to be a contiguous gene disorder, which results from the absence of expression of the paternally derived alleles of maternally imprinted genes on chromosome 15 (15q11-13). We argue, however, that the whole phenotype can be explained by one mechanism and, by implication, the failure of expression of the paternal allele of a single maternally imprinted gene that controls energy balance. We suggest clinical and laboratory approaches to test our hypotheses.

Chromosomes, Human, Pair 15↗