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Disease Models, Animal↗
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Genetic animal models in the study of alcoholism.
Several methods have been applied to the study of the genetic determinants of ethanol (EtOH) sensitivity in animals. The use of inbred strains has indicated that virtually all responses to EtOH have a significant degree of genetic determination. Studies with large batteries of inbred strains have elucidated the common genetic control of several clusters of EtOH-related variables. Studies with Recombinant Inbred strains have identified single genes that may influence EtOH withdrawal severity and EtOH preference drinking. The best developed method has been the use of selective breeding to develop lines of mice or rats differing in EtOH-related behavioral characters. Illustrative examples of potentially important research findings from experiments with LS/SS, P/NP, and WSP/WSR selected lines are discussed. Significant progress has been made in the use of genetic animal models to further our understanding of EtOH-related traits. Several avenues for further research appear to be promising, and specific directions to be pursued are suggested.
Alcoholism↗
Application of a structural model for genetic covariances in international dairy sire evaluations.
A structural model for estimation of genetic covariances in international dairy sire evaluations was compared with a standard multiple-trait mixed model using milk yield data from 13 environments (Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, Israel, Switzerland and five regions of the United States). Data consisted of 2,885,117 first-lactation records from daughters of 17,867 Holstein sires. Parameters of the structural model for genetic covariances included an intercept and measures of genetic, management, and climate similarity. Genetic similarity was defined as the ratio between the number of daughters of common bulls used in a given pair of regions and the total number of daughters of all bulls. The measure of management similarity was the ratio between the absolute value of the difference in average milk yield between two regions and the sum of these averages. Climate similarity was a function of the difference in heat indices between pairs of regions. Results showed that the structural model for the genetic covariances gave more precise estimates of the latter than the standard multivariate analysis because the number of parameters to be estimated in the genetic covariance matrix was reduced from 91 to 16. A comparison of the two models using a deviance information criterion (a measure of quality of fit) showed a slight superiority for the structural model. For the latter, the posterior means of the genetic correlations between environments ranged between 0.63 and 0.98.
Analysis of Variance↗
A two-susceptibility-allele model for genetic diseases and associated marker loci: differences and similarities to a one-s-allele model.
A model for genetic diseases and associated markers is defined where two distinct susceptibility alleles are possible, each associated with a different marker allele. Marker genotype distributions in a disease population are then expressed in terms of haplotype frequencies and penetrance parameters. It is shown that, if the heterozygote with two different disease alleles has a higher penetrance than the two disease homogzygotes, the observed to 'Hardy-Weinberg-expected' ratio of associated marker genotypes (the alpha/beta ratio of Falk, Mendell & Rubinstein, 1983) will always be greater than or equal to one. When all disease penetrances are equal, the model becomes indistinguishable from a recessive one-s-allele model with alpha/beta = 1. Application of these observations to several data sets for insulin dependent diabetes mellitus suggests the possibility that different marker genotype distributions in different samples may be due to different penetrances of the disease genotypes in the samples. If a particular environment causes the heterozygote disease genotype (with two different disease alleles) to have the highest penetrance, the marker genotype distribution would be compatible with the 2-s-allele model. In other environments where the three disease genotypes have essentially equal penetrances, the marker distribution would be compatible with the 1-s-allele model.
Alleles↗
[Heterosis and genetic correlation analysis of rice (Oryza sativa L.) grain weight development under different environmental conditions].
Two sets of test materials were derived from diallel cross among nine different types of selected rice varieties (lines). Based on the experimental data at different development stages of early and late rice, the estimation of heterosis and genetic correlation of rice grain weight at some development stages (0-->t) or at some special development phases (t--1-->t) was conducted by using additive-dominant genetic model and developmental genetic model for quantitative traits. The results indicated that the heterosis over mid-parent value based on population mean was not significant at 5% level at the early stages (1-12 d), and turned to positively significant as the development process proceeded in early rice. The heterobeltiosis based on population mean appeared to be small negative during the entire courses of grain filling. The heterosis over mid-parent based on population mean appeared to be positively significant at the early and middle grain filling stages (1-18 d), but became insignificant at the late stages (19-28 d) in late rice. The heterobeltiosis based on population mean appeared to be positively significant at the early grain filling stages (1-12 d), but turned to be significantly negative as the development process proceeded in late rice. It also indicated that the heterosis of grain weight development was beneficial to improve the quality of grain filling in late rice, compared to that in early rice. The genetic correlation between the grain weights per se at different stages and the final grain weight was mainly controlled by dominant effects, and became closer with the development process in the early rice, while by additive effects in the late rice. It's suggested that indirect selection of final grain weight throughout the process of grain filling would be more effective in late rice.
Edible Grain↗
Genetic versus phenotypic models of selection: can genetics be neglected in a long-term perspective?
Game theoretical concepts in evolutionary biology have been criticized by populations geneticists, because they neglect such crucial aspects as the mating system or the mode of inheritance. In fact, the dynamics of natural selection does not necessarily lead to a fitness maximum or an ESS if genetic constraints are taken into account. Yet, it may be premature to conclude that game theoretical concepts do not have a dynamical justification. The new paradigm of long-term evolution postulates that genetic constraints, which may be dominant in a short-term perspective, will in the long run disappear in the face of the ongoing influx of mutations. Two basic results (see Hammerstein; this issue) seem to reconcile the dynamical approach of long-term population genetics with the static approach of evolutionary game theory: (1) only populations at local fitness optima (Nash strategies) can be long-term stable; and (2) in monomorphic populations, evolutionary stability is necessary and sufficient to ensure long-term dynamic stability. The present paper has a double purpose. On the one hand, it is demonstrated by fairly general arguments that the scope of the results mentioned above extends to non-linear frequency dependent selection, to multiple loci, and to quite general mating systems. On the other hand, some limitations of the theory of long-term evolution will also be stressed: (1) there is little hope for a game theoretical characterization of stability in polymorphic populations; (2) many interesting systems do not admit long-term stable equilibria; and (3) even if a long-term stable equilibrium exists, it is not at all clear whether and how it is attainable by a series of gene substitution events.
Biological Evolution↗
Guess LOD approach: sufficient conditions for robustness.
Analysis of genetic linkage between a disease and a marker locus requires specifying a genetic model describing both the inheritance pattern and the gene frequencies of the marker and trait loci. Misspecification of the genetic model is likely for etiologically complex diseases. In previous work we have shown through analytic studies that misspecifying the genetic model for disease inheritance does not lead to excess false-positive evidence for genetic linkage provided the genetic marker alleles of all pedigree members are known, or can be inferred without bias from the data. Here, under various selection or ascertainment schemes we extend these previous results to situations in which the genetic model for the marker locus may be incorrect. We provide sufficient conditions for the asymptotic unbiased estimation of the recombination fraction under the null hypothesis of no linkage, and also conditions for the limiting distribution of the likelihood ratio test for no linkage to be chi-squared. Through simulation studies we document some situations under which asymptotic bias can result when the genetic model is misspecified. Among those situations under which an excess of false-positive evidence for genetic linkage can be generated, the most common is failure to provide accurate estimates of the marker allele frequencies. We show that in most cases false-positive evidence for genetic linkage is unlikely to result solely from the misspecification of the genetic model for disease or trait inheritance.
Genetic Linkage↗
Genetic mouse models of Alzheimer's disease.
In the current minireview, we focus on genetic mouse models of Alzheimer's disease (AD). Because various excellent, up-to-date reviews, special issues, and reliable websites are already dedicated to the genetics of Alzheimer's disease in general and of animal models in particular, this review is not meant to be comprehensive. Rather, we aim to steer the Alzheimer's novice through the recent mouse literature on AD. Special attention will be paid to genetic models that have been tested behaviorally.
Alzheimer Disease↗
Genetic analysis of milk production traits of polish black and white cattle using large-scale random regression test-day models.
Genetic parameters for milk, fat, and protein yield and persistency in the first 3 lactations of Polish Black and White cattle were estimated. A multiple-lactation model was applied with random herd-test-day effect, fixed regressions for herd-year and age-season of calving, and random regressions for the additive genetic and permanent environmental effects. Three data sets with slightly different edits on minimal number of days in milk and the size of herd-year class were used. Each subset included more than 0.5 million test-day records and more than 58,000 cows. Estimates of covariance components and genetic parameters for each trait were obtained by Bayesian methods using the Gibbs sampler. Due to the large size and a good structure of the data, no differences in estimates were found when additional criteria for record selection were applied. More than 95% of the genetic variance for all traits and lactations was explained by the first 2 principal components, which were associated with the mean yield and lactation persistency. Heritabilities of 305-d milk yield in the first 3 lactations (0.18, 0.16, 0.17) were lower than those for fat (0.12, 0.11, 0.12) and protein (0.13, 0.14, 0.15). Estimates of daily heritabilities increased in general with days in milk for all traits and lactations, with no apparent abnormalities at the beginning or end of lactation. Genetic correlations between yields in different lactations ranged from 0.74 (fat yield in lactations 1 and 3) to 0.89 (milk yield in lactations 2 and 3). Persistency of lactation was defined as the linear regression coefficient of the lactation curve. Heritability of persistency increased with lactation number for all traits and genetic correlations between persistency in different lactations were smaller than those for 305d yield. Persistency was not genetically correlated with the total yield in lactation.
Animals↗
Agrobacterium T-DNA integration: molecules and models.
Genetic transformation mediated by Agrobacterium involves the transfer of a DNA molecule (T-DNA) from the bacterium to the eukaryotic host cell, and its integration into the host genome. Whereas extensive work has revealed the biological mechanisms governing the production, Agrobacterium-to-plant cell transport and nuclear import of the Agrobacterium T-DNA, the integration step remains largely unexplored, although several different T-DNA integration mechanisms have been suggested. Recent genetic and functional studies have revealed the importance of host proteins involved in DNA repair and maintenance for T-DNA integration. In this article, we review our understanding of the specific function of these proteins and propose a detailed model for integration.
Active Transport, Cell Nucleus↗
Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism.
The present article summarizes some comparative studies of the Fawn-Hooded (FH) rat, a potential animal model of ethanol preference, and the Flinders Sensitive Line (FSL) rat, a potential animal model of depression. Both FH and FSL rats exhibit high degrees of immobility in the forced swim test and have difficulty learning a two-way active avoidance task. However, there were no differences between the FH and FSL rats in the elevated plus maze. Studies of ethanol preference indicated high rates of ethanol intake (greater than 4 g/kg) and preference (greater than 50%) in the FH rats, but low rates of ethanol intake (less than 1.1 g/kg) and preference (less than 20%) in FSL rats. It is concluded that the FSL rats exhibit behaviors consistent with their being an animal model of depression, whereas the FH rats exhibit features consistent with their being an animal model of both depression and alcoholism. Psychopharmacological challenges indicated that both FSL and FH rats were more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist. However, FSL rats were also more sensitive to serotonergic agonists, and some of the present results and other investigators have reported serotonergic subsensitivity in the FH rats. Thus, FSL rats exhibit both cholinergic and serotonergic supersensitivity, whereas FH rats exhibit cholinergic supersensitivity but normal or reduced serotonergic sensitivity. Progeny from a genetic cross between FH and FSL rats exhibit cholinergic supersensitivity and have high ethanol preference scores. These data are consistent with genetic models suggesting that ethanol preference may be influenced by dominant genes, whereas cholinergic sensitivity may be influenced by recessive genes.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Parametric estimation in a genetic mixture model with application to nuclear family data.
The apparent conflict between the biometrician and Mendelian genetics has been recently resolved by the introduction of a genetic mixed model to analyze continuous traits measured on human families and to elucidate the mechanism of underlying major genes. The mixed model formulated by Elston and Stewart (1971, Human Heredity 21, 523-542), extended by Morton and MacLean (1974, American Journal of Human Genetics 26, 489-503), and reviewed, with further extensions, by Boyle and Elston (1979, Biometrics 35, 55-68) has become an extremely useful tool of wide applicability in the field of genetic epidemiology. This model allows for segregation at a major locus, a polygenic effect, and a sibling environmental variation. The main concern of this paper is with estimating the model parameters by the method of maximum likelihood. The expectation-maximization (EM) algorithm is developed to derive the estimates iteratively. An approximation of the information matrix when using the EM algorithm is given. We illustrate the methodology by fitting the model to the arterial blood pressure data collected by Miall and Oldham (1955, Clinical Science 14, 459-487).
Biometry↗
Two different putative genetic animal models of childhood depression.
BACKGROUND: In an attempt to model childhood depression, we examined whether existing genetic animal models of depression in adult rats are also valid in prepubertal rats. METHODS: Two different "depressed" rat lines were studied: the Flinders Sensitive Line (FSL) and their controls, Sprague-Dawley (SD); and the Wistar Kyoto (WKY) line and their controls, Wistar. We hypothesized that male prepubertal FSL and WKY rats would show increased swim test immobility and different patterns of social play and of basal plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) compared with control rats. RESULTS: Prepubertal FSL and WKY rats exhibited significantly longer duration of immobility than control rats in the swim test. The FSL rats demonstrated significantly higher levels of social play behaviors and lower levels of corticosterone and ACTH compared with SD control rats, whereas WKY rats demonstrated significantly lower levels of social play behaviors and higher plasma levels of corticosterone and ACTH compared with Wistar control rats. CONCLUSIONS: The results might suggest that prepubertal FSL and WKY rats are both putative genetic animal models of childhood depression, exhibiting separate patterns and symptoms of childhood depression.
Adrenocorticotropic Hormone↗
Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression.
The effects of acute and chronic stressors on saccharin intake and preference in the hypercholinergic Flinders Sensitive Line (FSL) rat, a putative genetic animal model of depression, were studied and compared to the control Flinders Resistant Line (FRL) rats. Overall, the FRL rats drank significantly less saccharin and water than the FSL rats when compared over a wide range of saccharin concentrations (0.01-5%) under baseline conditions. A 0.02% saccharin concentration was used in subsequent experiments. We observed a significant suppression of saccharin intake/preference at 1 h following a single 5-min exposure to cold swim stress only in FSL rats. There was a tendency to increase saccharin intake in both lines at 1 h following a scrambled foot shock stress. These effects of acute stressors disappeared upon retesting for saccharin consumption/preference 23 h after the stress. Chronic 4-week exposure to unpredictable mild stressors significantly (p < 0.01) decreased saccharin consumption in the FSL rats, but not in the FRL rats. The FSL rats also exhibited a significantly greater decrease in saccharin preference (-24% vs. prestress baseline, as compared to -7% in FRL controls, p < 0.05). In conclusion, FSL rats appear more prone than the FRL rats to chronic, as well as immediate acute, stress-induced anhedonic effects. This outcome further supports the notion that the FSL rat is a useful model of a genetic predisposition to depressive-like reactions.
Animals↗
Angiotensin II subtype-1 receptor antagonists improve hemodynamic and renal changes without affecting glucose metabolisms in genetic rat model of non-insulin-dependent diabetes mellitus.
The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether treatment with an angiotensin II (ANGII) subtype-1 receptor antagonist delays the onset of NIDDM and attenuates diabetic nephropathy in the OLETF rat. OLETF rats fed a regular chow were treated with ANGII subtype-1 receptor antagonists (E4177 or TA606) for 22 weeks. Hemodynamic changes, glucose metabolism, and the effects on diabetic nephropathy were examined. Systolic blood pressure increased in OLETF rats in an age-dependent manner. OLETF rats exhibited increases in plasma concentrations of glucose and insulin and developed glucosuria at the age of 28 weeks. The changes in glucose metabolism were associated with proteinuria and an increase in urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). Morphologic investigation revealed nodular lesions in glomeruli in the OLETF rats. The ANGII receptor antagonist treatment abolished the blood pressure elevation. However, the treatment did not affect plasma glucose and insulin levels and did not significantly reduce glucosuria. Nodular lesions in glomeruli were not improved by the treatment. However, the receptor antagonists significantly reduced proteinuria and urinary NAG excretion. Multivariate analyses revealed that proteinuria was determined by systolic blood pressure, lipid metabolism, and glucose levels in plasma. ANGII subtype-1 antagonism does not improve glucose metabolism in the OLETF rat model of NIDDM, which has abnormalities in the glucose-uptake system. Blood pressure elevation and part of the proteinuria associated with NIDDM depends on the renin-angiotensin system rather than glucose metabolisms per se.
Acetylglucosaminidase↗
Lineage selection and the evolution of multistage carcinogenesis.
A wide array of proto-oncogenes and tumour suppressor genes are involved in the prevention of cancer. Each form of cancer requires mutations in a characteristic group of genes, but no single group controls all cancers. This lack of generality shows that the control of cancer is not an ancient, fixed property of cells. By contrast, it supports a dynamic evolutionary model, whereby genetic controls over unregulated cell growth are recruited independently through evolutionary time in different tissues within different taxa. The complexity of this genetic control can be predicted from a population genetic model of lineage selection driven by the detrimental fitness effects of cancer. Cancer occurs because the genetic control of cell growth is vulnerable to somatic mutations (or 'hits'), particularly in large, continuously dividing tissues. Thus, compared to small rodents, humans must have evolved more complex genetic controls over cell growth in at least some of their tissues because of their greater size and longevity; an expectation relevant to the application of mouse data to humans. Similarly, the 'two-hit' model so successfully applied to retinoblastoma, which originates in a small embryonic tissue, is unlikely to be generally applicable to other human cancers; instead, more complex scenarios are expected to dominate, with complexity depending upon a tissue's size and its pattern of proliferation.
Animals↗
Normal linear models with genetically structured residual variance heterogeneity: a case study.
Normal mixed models with different levels of heterogeneity in the residual variance are fitted to pig litter size data. Exploratory analysis and model assessment is based on examination of various posterior predictive distributions. Comparisons based on Bayes factors and related criteria favour models with a genetically structured residual variance heterogeneity. There is, moreover, strong evidence of a negative correlation between the additive genetic values affecting litter size and those affecting residual variance. The models are also compared according to the purposes for which they might be used, such as prediction of 'future' data, inference about response to selection and ranking candidates for selection. A brief discussion is given of some implications for selection of the genetically structured residual variance model.
Analysis of Variance↗
Angiotensin-Converting Enzyme Inhibition Delays Onset of Glucosuria With Regression of Renal Injuries in Genetic Rat Model of Non-Insulin-Dependent Diabetes Mellitus.
BACKGROUND: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus. METHODS AND RESULTS: Six-week-old OLETF rats were treated with the angiotensin-converting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pressure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glucosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism. CONCLUSIONS: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reductions but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.
Journal Article↗