Acetylation pharmacogenetics: profiles of arylamine pharmacology and toxicology in a genetic mouse model.
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Acetylation↗
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Results for “Models, Genetic”
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Toward a model for the molecular genetics of carcinogenesis in rats.
Cultured rat embryo cells are resistant to neoplastic transformation by chemical carcinogens unless they are extensively subcultured or infected with a murine leukemia virus (MuLV) first. We found that, in normal cultured cells, MuLV activates expression of rat genes that are the progenitors of sarcoma virus genes, but not those of endogenous "leukemia" virus. Elevated levels of sarcoma virus-related RNA in normal cells infected with MuLV were indistinguishable from the levels in cells transformed spontaneously or by a carcinogen or a sarcoma virus. Because of previous reports that some carcinomas in rats also contain elevated levels of sarcoma virus-related RNA, we believe these events can be explained by a molecular genetic model which may be generally valid for initiation of carcinogenesis. The basic elements of the model are: transcriptional activation of all the multiple copies of normal rat progenitors of sarcoma virus genes is required before cellular transformation can be initiated, and initiation occurs when a spontaneous or induced mutation in any one active copy of these same genes generates a dominant transforming function.
Animals↗
Using the quantitative genetic threshold model for inferences between and within species.
Sewall Wright's threshold model has been used in modelling discrete traits that may have a continuous trait underlying them, but it has proven difficult to make efficient statistical inferences with it. The availability of Markov chain Monte Carlo (MCMC) methods makes possible likelihood and Bayesian inference using this model. This paper discusses prospects for the use of the threshold model in morphological systematics to model the evolution of discrete all-or-none traits. There the threshold model has the advantage over 0/1 Markov process models in that it not only accommodates polymorphism within species, but can also allow for correlated evolution of traits with far fewer parameters that need to be inferred. The MCMC importance sampling methods needed to evaluate likelihood ratios for the threshold model are introduced and described in some detail.
Bayes Theorem↗
Evaluation of the role of nuclear factor-kappaB signaling in liver injury using genetic animal models.
Most chronic liver diseases are not sufficiently treatable at present and very often progress to liver fibrosis and liver cirrhosis. Several recent studies have suggested that cytokines and cytokine-activated inflammatory signaling pathways might play an important role in the mediation of liver injury. Although pro-inflammatory signaling pathways such as nuclear factor (NF)-kappaB have evolved primarily for host defense to infections, they appear to be involved in the pathogenesis of inflammatory diseases and may mediate liver injury in response to a variety of agents and pathogens. Herein is summarized briefly some recent findings concerning the role of NF-kappaB in different models of liver injury based on transgenic and knockout animal technology.
Animals↗
Discovery of a spontaneous genetic mouse model of preeclampsia.
Preeclampsia remains a leading cause of maternal and fetal morbidity and mortality but has an unknown etiology. Women with elevated baseline blood pressure have an increased risk of this disorder. We hypothesized that BPH/5 mice, an inbred mouse strain with mildly elevated blood pressure, would develop a pregnancy-induced hypertensive syndrome. Nonpregnant female BPH/5 and C57BL/6 mice underwent thoracic aortic implantation of telemeters. After 7 days of recovery and 5 days of baseline mean arterial blood pressure (MAP) recording, strain-matched timed matings were carried out. MAP was recorded continuously during pregnancy and for 1 week after birth. In separate mice in metabolic cages, urinary protein was tracked, followed by renal histological analysis. Before pregnancy, the BPH/5 strain had elevated baseline MAP compared with the C57BL/6 strain, but both strains had similar total urinary protein levels and renal histology. MAP remained stable in both groups during the first 2 weeks of pregnancy. However, at the start of the last trimester, MAP began to rise further in the BPH/5 mice; it rose to peak levels just before delivery and returned to prepregnancy levels by 2 days after delivery. This was accompanied by late-gestational proteinuria and progressive glomerulosclerosis. No changes were observed in the C57BL/6 group except for a small decrease in MAP at mid gestation. The BPH/5 group delivered significantly smaller litters despite normal numbers of fetuses early in gestation, and longitudinal ultrasound studies documented fetal demise before the onset of hypertension and renal disease. This is the first report of an animal model that spontaneously develops a syndrome that bears close resemblance to preeclampsia, and it should have an impact on our understanding of the pathophysiology of this disorder.
Animals↗
The cell cycle of early mammalian embryos: lessons from genetic mouse models.
Genes coding for cell cycle components predicted to be essential for its regulation have been shown to be dispensable in mice, at the whole organism level. Such studies have highlighted the extraordinary plasticity of the embryonic cell cycle and suggest that many aspects of in vivo cell cycle regulation remain to be discovered. Here, we discuss the particularities of the mouse early embryonic cell cycle and review the mutations that result in cell cycle defects during mouse early embryogenesis, including deficiencies for genes of the cyclin family (cyclin A2 and B1), genes involved in cell cycle checkpoints (Mad2, Bub3, Chk1, Atr), genes involved in ubiquitin and ubiquitin-like pathways (Uba3, Ubc9, Cul1, Cul3, Apc2, Apc10, Csn2) as well as genes the function of which had not been previously ascribed to cell cycle regulation (Cdc2P1, E4F and Omcg1).
Animals↗
[A genetically defined model for testing teratogenicity in vivo].
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Abnormalities, Drug-Induced↗
Genetic animal models of epilepsy.
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Animals↗
On the inheritance of abdominal aortic aneurysm.
To determine the mode of inheritance of abdominal aortic aneurysm, data on first-degree relatives of 91 probands were collected. Results of segregation analysis performed on these data are reported. Many models, including nongenetic and genetic models, were compared using likelihood methods. The nongenetic model was rejected; statistically significant evidence in favor of a genetic model was found. Among the many genetic models compared, the most parsimonious genetic model was that susceptibility to abdominal aortic aneurysm is determined by a recessive gene at an autosomal diallelic major locus. A multifactorial component in addition to the major locus does not increase the likelihood of the data significantly.
Adult↗
The Prague Hypertensive Rat: a new model of genetic hypertension.
Several animal models of genetic hypertension have been developed but not all of them possess a closely related control strain. Therefore, a new model based on Wistar rats is described in which both hypertensive and normotensive lines were bred from a single parental pair. Several basic data on the two lines (called the Prague Hypertensive Rat, PHR, and the Prague Normotensive Rat, PNR) are given. PNR had a longer survival compared with PHR. At the age of 7 weeks, systolic blood pressure was 161 +/- 14 mmHg in PHR males and 109 +/- 9 mmHg in PNR males. Its further increase with age was very slow in PNR but very steep in PHR. Typical left ventricular cardiac hypertrophy developed in PHR in which cardiac output was not significantly different from that of PNR but total peripheral resistance was higher. Kidney weight was also greater in PHR than in PNR. There was no difference in basic renal functions except of proteinuria which was higher in PHR than in PNR. No differences were observed in extracellular and interstitial fluid volumes whereas plasma and blood volumes were slightly but significantly greater in PHR than in PNR suggesting a shift of extracellular fluid towards the intravascular compartment. This hypertensive model the parameters of which resemble to those of human essential hypertension should be especially suitable for cross-transplantation studies.
Animals↗
Dissection of behavior and psychiatric disorders using the mouse as a model.
Mouse genetic models have played an important role in the elucidation of molecular pathways underlying human disease. This approach is becoming an increasingly popular way to study the genetic underpinning of psychiatric disorders. Genes within candidate regions for susceptibility to psychiatric illness can be evaluated through the phenotypic assessment of mutants mapped to the corresponding regions in the mouse genome. Alternatively, one can search for mouse mutants displaying characteristics that might correspond to physiological and behavioral markers of a psychiatric disorder, sometimes referred to as endophenotypes. Mice with anomalies in these traits can be generated by targeted mutagenesis in known genes (gene-based mutagenesis or reverse genetics), or can be identified among progeny of mice in a random mutagenesis screen (phenotype-based mutagenesis or forward genetics). In this review, we discuss recently generated behavioral mutants in the mouse. We also give an overview of several robust and commonly used behavioral phenotypes, their relevance to human disease and lessons learned from recent successes in mouse behavioral genetics.
Animals↗
Pathology of idiopathic dystonia: findings from genetic animal models.
Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions. In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain. The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia. Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia. Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are describe. This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt(sz)), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease. Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder. Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.
Animals↗
Validation and discovery in Markov models of genetics data.
Markov models provide a natural framework for modeling cellular and molecular level changes over time. Kalbfleisch and Lawless propose using a Chi-squared statistic for assessing the appropriateness of assuming a first-order, homogeneous Markov process. While this statistic provides a global test of the Markov assumption, it does not permit identification of individual departures. We consider two approaches for discovering specific departures from the Markov assumption. First, we propose a diagnostic that tests whether the number of observed transitions out of a given state at a given time point is different than expected. Second, we construct statistics based on the number of observations in each state at each time point. In both cases, we construct multiple correlated statistics and testing is achieved through simulations. These approaches are applied to HIV genetics sequences measured over time.
Journal Article↗
Estimating two-stage models for genetic influences on alcohol, tobacco or drug use initiation and dependence vulnerability in twin and family data.
Genetic research on risk of alcohol, tobacco or drug dependence must make allowance for the partial overlap of risk-factors for initiation of use, and risk-factors for dependence or other outcomes in users. Except in the extreme cases where genetic and environmental risk-factors for initiation and dependence overlap completely or are uncorrelated, there is no consensus about how best to estimate the magnitude of genetic or environmental correlations between Initiation and Dependence in twin and family data. We explore by computer simulation the biases to estimates of genetic and environmental parameters caused by model misspecification when Initiation can only be defined as a binary variable. For plausible simulated parameter values, the two-stage genetic models that we consider yield estimates of genetic and environmental variances for Dependence that, although biased, are not very discrepant from the true values. However, estimates of genetic (or environmental) correlations between Initiation and Dependence may be seriously biased, and may differ markedly under different two-stage models. Such estimates may have little credibility unless external data favor selection of one particular model. These problems can be avoided if Initiation can be assessed as a multiple-category variable (e.g. never versus early-onset versus later onset user), with at least two categories measurable in users at risk for dependence. Under these conditions, under certain distributional assumptions, recovery of simulated genetic and environmental correlations becomes possible. Illustrative application of the model to Australian twin data on smoking confirmed substantial heritability of smoking persistence (42%) with minimal overlap with genetic influences on initiation.
Australia↗
Co-recessive inheritance: a model for DNA repair, genetic disease and carcinogenesis.
A genetic model for some cases of excision-deficient xeroderma pigmentosum (XP) is proposed in which the trait (i.e., XP) is expressed if and only if the individual is homozygous or hemizygous for defective alleles at more than one of a specific set of loci. The model might also apply in some cases of certain other diseases associated with defective DNA repair. The model accounts for several paradoxical aspects of XP, including the large number of complementation groups despite the biochemically limited DNA-repair defect, the co-existence of XP and Cockayne's syndrome in two different complementation groups of XP, siblings with markedly different degrees of severity of XP in one family and transmission of the disease in an X-linked manner in another, the existence of some individuals who appear to have the DNA-repair defect but not clinical XP, and the seeming paradox of a disease associated with a marked defect in a DNA-repair mechanism but not associated with an obvious increase in incidence of internal cancer. The model predicts that a large proportion of the general population is a carrier of one or more of these defective genes for DNA-repair mechanisms. Such genes may be important in the etiology of much of human cancer.
Chromosome Mapping↗
Alcohol and genetics: new models.
Alcoholism is a complex genetic trait; susceptibility is influenced by multiple genes of small effect. To pursue mechanistic studies, genetic animal models have been used. These models are partial, each addressing one or more of the contributing traits rather than the disease as a whole. Animal studies have modeled alcohol's rewarding effects, the development of tolerance, the pathological consequences to brain systems, and the dependence on alcohol inferred from the presence of withdrawal symptoms when the drug is removed. The classical genetic methods of inbred strain analysis and development and studies of selectively bred lines have been employed for more than 40 years. Recently, such studies have shown that a genetic tendency to experience severe withdrawal is associated with a tendency to avoid self-administration of alcohol. Also recently, attempts to identify the specific genes conferring risk or protection from alcohol's effects have been undertaken. These studies have used mapping techniques based on gene sequence polymorphisms, studies of gene expression differences, and the use of candidate gene targeting such as creation of null mutants. Studies reviewed here have mapped quantitative trait loci (QTL) for many genes affecting alcohol sensitivity, tolerance, reward, and withdrawal severity. The furthest progress in gene mapping has been made toward one withdrawal QTL on mouse chromosome 4. Using multiple congenic strains, the gene conferring increased withdrawal severity has been isolated to a region of less than 1 centiMorgan, containing fewer than 20 genes. A strong candidate gene, coding for a multiple PS095/DLG/Z0-1 (PDZ) binding domain zinc finger protein, cannot be excluded. Although many more such genes will be identified in the near future, their contribution to the mapped phenotype will be shown to be dependent on epistatic interactions with other risk genes, as well as genes in the animal's background. Progress in gene identification will also depend crucially on the precise description of the phenotypes being mapped so that their pleiotropic range of influence on the multi-behavioral phenotypic syndrome can be determined.
Alcoholism↗
Genetic approaches to neurotrauma research: opportunities and potential pitfalls of murine models.
Genetic strategies provide new ways to define the molecular cascades that regulate the responses of the mammalian nervous system to injury. Genetic interventions also provide opportunities to manipulate and control key molecular steps in these cascades, so as to modify the outcome of CNS injury. Most current genetic strategies involve the use of mice, an animal that has not heretofore been used extensively for neurotrauma research. Therefore, one purpose of the present review is to consider how mice respond to neural trauma, focusing especially on recent information that reveals important differences between mice and rats, and between different inbred strains of mice. The second aim of this review is to provide a brief introduction to the opportunities, caveats, and potential pitfalls of studies that use genetically modified animals for neurotrauma research.
Animals↗
Unexpected estimates of variance components with a true model containing genetic competition effects.
Simulation of a model containing genetic competition effects was initiated to determine how well REML could untangle variances due to direct and competition genetic effects and pen effects. A two-generation data set was generated with six unrelated males that were each mated to five unrelated females to produce 300 progeny, from which 30 females (one per mating in previous generation) were mated to six unrelated males to produce 300 more progeny. Progeny were randomly assigned, six per pen, to 50 pens per generation. Parameters were V(g), V(c), C(gc), V(p), and V(e), representing direct and competition genetic variance with covariance, and pen and residual variance. Eight statistical models were used to analyze each of 400 replicates of 16 sets of parameters. Both V(g) and V(e) were fixed at 16.0. Values of C(gc) were -2.0, -1.0, 0.1, 1.0, and 2.0. Values of V(c) were 1.0 and 4.0, and values of V(p) were 0.1, 1.0, and 10.0. With the full model, average estimates resembled true parameters, except that V(p) was consistently overestimated when small (0.1 and 1.0), which in turn slightly changed other estimates. The most unexpected result was overestimation of V(p) when V(c) and Cgc were ignored. Overestimation depended on V(c) and the number of competitors in common between records in a pen. Upward bias was somewhat greater when Cg(c) was positive than when it was negative. For example, with C(gc) = 2, V(c) = 4, and V(p) = 0.1, the mean estimate of V(p) was 20.4 when C(gc) and V(c) were dropped from the model and 15.3 when C(gc) = -2.0. When V(p) was ignored, estimates of both C(gc) and V(c) increased in proportion with V(p). Also V(g) increased more with greater V(p). Another unexpected result occurred when pen was considered fixed. Empirical sampling standard errors of estimates of C(gc) and V(c) were decreased generally by factors of 2 to 30. Based on these results, we conclude a high estimate of pen variance may indicate genetic competition effects are important, and ignoring either the pen or competition effects will bias estimates of other components.
Algorithms↗