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At least 199 records · Page 11Linked to original sources
PubMed1980

Segregation analysis of schizophrenia under a mixed genetic model.

Family data were collected on a multi-ethnic cohort of hospitalized schizophrenics in Hawaii in 1942. Results showed that prevalence rates for Orientals were significantly higher (p less than 0.001) than rates for Caucasians, Polynesians and others. Complex segregation analysis using a generalized mixed genetic model was performed on 507 sibships collected under both complete and incomplete selection. Likelihood ratio tests between the generalized model and two subhypotheses of a major gene effect and a polygenic effect revealed that neither subhypotheses could be rejected at the 5% level of significance. While neither hypothesis could be adequately supported by the likelihood ratio test, certain aspects of the findings suggest a preference for the multifactorial model in explaining the inheritance of schizophrenia in these data.

Asian People↗
PubMed2001

Perfect simulation from population genetic models with selection.

We consider using the ancestral selection graph (ASG) to simulate samples from population genetic models with selection. Currently the use of the ASG to simulate samples is limited. This is because the computational requirement for simulating samples increases exponentially with the selection rate and also due to needing to simulate a sample of size one from the population at equilibrium. For the only case where the distribution of a sample of size one is known, that of parent-independent mutations, more efficient simulation algorithms exist. We will show that by applying the idea of coupling from the past to the ASG, samples can be simulated from a general K-allele model without knowledge of the distribution of a sample of size one. Furthermore, the computation involved in generating such samples appears to be less than that of simulating the ASG until its ultimate ancestor. In particular, in the case of genic selection with parent-independent mutations, the computational requirement increases only quadratically with the selection rate. The algorithm is demonstrated by simulating samples at a microsatellite locus.

Algorithms↗
PubMed2005

Mouse genetic models for aneuploidy induction in germ cells.

Rodents have been successfully used as models to identify risks of chemical exposures or age to aneuploidy induction in germ cells, which may be transmitted to the progeny. For this administration in vivo as well as exposures to in vitro maturing germ cells have been useful. Genetic models involving mice with structural chromosomal rearrangements and transgenic animals have the potential to model conditions predisposing to aneuploidy in one or both sexes, and in this way to identify potential targets for aneugens and gender-effects. The review provides an overview of mouse genetic models for aneuploidy induction in mammalian germ cells and discusses perspectives for combining genetic with experimental approaches in aneuploidy research.

Aneuploidy↗
PubMed2003

Androgen receptor functions from reverse genetic models.

The androgen receptor (AR) is a ligand-dependent transcription factor involved in the regulation of many different physiological processes. AR dysfunction causes a diverse range of clinical conditions, including testicular feminization mutation (Tfm) syndrome, prostate cancer, and motor neuron disease (Kennedy's disease). However, due to lack of genetic models, the molecular basis of the AR in these disorders remains largely unknown. Using a conditional targeting technique based on the Cre-loxP system, we successfully generated null AR mutant (ARKO) mice. ARKO males exhibited normal healthy growth, but showed typical Tfm abnormalities. Hormonal assay of ARKO males revealed that while serum androgen levels were very low, estrogen levels were normal. Another hallmark of ARKO males was late-onset obesity, with marked accumulation of white adipose tissue. To clarify the role of human AR (hAR) mutants with expanded polyQ stretches as observed in neurodegenerative disease, we also established a Drosophila model in which either wild-type or polyQ-expanded hAR were ectopically expressed. Although no overt phenotype was detected in adult fly-eye neurons expressing mutant hAR, the ingestion of androgen caused marked neurodegeneration.

Animals↗
PubMed2006

Genetic model for the chronic activation of skeletal muscle AMP-activated protein kinase leads to glycogen accumulation.

The AMP-activated protein kinase (AMPK) is an important metabolic sensor/effector that coordinates many of the changes in mammalian tissues during variations in energy availability. We have sought to create an in vivo genetic model of chronic AMPK activation, selecting murine skeletal muscle as a representative tissue where AMPK plays important roles. Muscle-selective expression of a mutant noncatalytic gamma1 subunit (R70Qgamma) of AMPK activates AMPK and increases muscle glycogen content. The increase in glycogen content requires the presence of the endogenous AMPK catalytic alpha-subunit, since the offspring of cross-breeding of these mice with mice expressing a dominant negative AMPKalpha subunit have normal glycogen content. In R70Qgamma1-expressing mice, there is a small, but significant, increase in muscle glycogen synthase (GSY) activity associated with an increase in the muscle expression of the liver isoform GSY2. The increase in glycogen content is accompanied, as might be expected, by an increase in exercise capacity. Transgene expression of this mutant AMPKgamma1 subunit may provide a useful model for the chronic activation of AMPK in other tissues to clarify its multiple roles in the regulation of metabolism and other physiological processes.

AMP-Activated Protein Kinases↗
PubMed1999

A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder.

Inherited defects in the degradation of glycosphingolipids (GSLs) cause a group of severe diseases known as GSL storage disorders. There are currently no effective treatments for the majority of these disorders. We have explored a new treatment paradigm, substrate deprivation therapy, by constructing a genetic model in mice. Sandhoff's disease mice, which abnormally accumulate GSLs, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span. However, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results support the validity of the substrate deprivation therapy and also highlight some limitations.

Animals↗
PubMed2002

Evolutionary genetic models of the ovarian time bomb hypothesis for the evolution of genomic imprinting.

At a small number of loci in eutherian mammals, only one of the two copies of a gene is expressed; the other is silenced. Such loci are said to be "imprinted," with some having the maternally inherited allele inactivated and others showing paternal inactivation. Several hypotheses have been proposed to explain how such a genetic system could evolve in the face of the selective advantages of diploidy. In this study, we examine the "ovarian time bomb" hypothesis, which proposes that imprinting arose through selection for reduced risk of ovarian trophoblastic disease in females. We present three evolutionary genetic models that incorporate both this selection pressure and the effect of deleterious mutations to elucidate the conditions under which imprinting could evolve. Our findings suggest that the ovarian time bomb hypothesis can explain why some growth-enhancing genes active in early embryogenesis [e.g., mouse insulin-like growth factor 2 (Igf2)] have evolved to be maternally rather than paternally inactive and why the opposite imprinting status has evolved at some growth-inhibiting loci [e.g., mouse insulin-like growth factor 2 receptor (Igf2r)].

Animals↗
PubMed1989

A population genetical model for sequence evolution under multiple types of mutation.

DNA sequencing and restriction mapping provide us with information on DNA sequence evolution within populations, from which the phylogenetic relationships among the sequences can be inferred. Mutations such as base substitutions, deletions, insertions and transposable element insertions can be identified in each sequence. Theoretical study of this type of sequence evolution has been initiated recently. In this paper, population genetical models for sequence evolution under multiple types of mutation are developed. Models of infinite population size with neutral mutation, infinite population size with deleterious mutation and finite population size with neutral mutation are considered.

Base Sequence↗
PubMed1999

ACE inhibition induces regression of proteinuria and halts progression of renal damage in a genetic model of progressive nephropathy.

Experimental data consistently indicate that renal disease progression is fully prevented in proteinuric glomerulopathies by long-enough angiotensin-converting enzyme (ACE) inhibition therapy. Whether regression of established proteinuria to normal can be achieved is, however, ill defined. The current study was designed with the aim to clarify whether ACE inhibition may induce regression of established proteinuria and renal structural damage in MWF rats, a genetic model of progressive proteinuria and renal injury. Animals treated with the ACE inhibitor lisinopril from 20 weeks of age (time when proteinuria is already important) and age-matched untreated rats were followed for 10 weeks. ACE inhibition normalized systolic blood pressure and progressively reduced proteinuria (from 172 +/- 79 to 81 +/- 23 mg/24 hours). In these animals, a highly significant correlation was obtained between baseline proteinuria and antiproteinuric response. At variance in untreated rats, proteinuria showed a marked increase in the 10-week follow-up period (from 165 +/- 57 to 325 +/- 86 mg/24 hours). Lisinopril prevented the progression of renal damage, as documented by a significantly lower incidence of glomeruli affected by sclerotic lesions (P < 0.01) than in untreated animals after the 10-week study period. Kidney tissue damage was comparable in lisinopril-treated rats and in untreated animals at 20 weeks of age, indicating that structural changes were arrested by the treatment. Thus, in proteinuric MWF rats, late-onset ACE inhibition normalized blood pressure, effectively and progressively restored high protein excretion rate toward normal values, and arrested progression of tissue damage.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Population genetics models of common diseases.

The number and frequency of susceptibility alleles for common diseases are important factors to consider in the efficient design of disease association studies. These quantities are the results of the joint effects of mutation, genetic drift and selection. Hence, population genetics models, informed by empirical knowledge about patterns of disease variation, can be used to make predictions about the allelic architecture of common disease susceptibility and to gain an overall understanding about the evolutionary origins of such diseases. Equilibrium models and empirical studies suggest a role for both rare and common variants. In addition, increasing evidence points to changes in selective pressures on susceptibility genes for common diseases; these findings are likely to form the basis for further modeling studies.

Genetic Predisposition to Disease↗
PubMed2006

Regulation of ovulation rate in mammals: contribution of sheep genetic models.

Ovarian folliculogenesis in mammals from the constitution of primordial follicles up to ovulation is a reasonably well understood mechanism. Nevertheless, underlying mechanisms that determine the number of ovulating follicles were enigmatic until the identification of the fecundity genes affecting ovulation rate in sheep, bone morphogenetic protein-15 (BMP-15), growth and differentiation factor-9 (GDF-9) and BMP receptor-1B (BMPR-1B). In this review, we focus on the use of these sheep genetic models for understanding the role of the BMP system as an intra-ovarian regulator of follicular growth and maturation, and finally, ovulation rate.

Animals↗
PubMed1976

Genetic models for the analysis of data from the families of identical twins.

Genetic models are described which exploit the unique relationships that exist within the families of identical twins to obtain weighted least squares estimates of additive, dominance and epistatic components of genetic variance as well as estimates of the contributions of X-linked genes, maternal effects and three sources of environmental variation. Since all of the relationships required to achieve a resolution of these variance components are contained within each family unit, the model would appear to be superior to previous approaches to the analysis of quantitative traits in man.

Biometry↗
PubMed2002

Evaluation of Lewis and SHR rat strains as a genetic model for the study of anxiety and pain.

The study of inbred strains of rodents that differ for specific behaviours can help us to understand the biological mechanisms underlying complex psychological traits. Lewis (LEW) and SHR inbred rat strains, for example, have been recently proposed as a genetic model for the study of anxiety. Our goal was to characterise two Brazilian substrains of LEW and SHR rats, that have never been compared before, behaviourally and/or pharmacologically, in order to evaluate their potential contribution to studies on anxiety and pain. Male and female LEW and SHR rats were submitted after 8 weeks of age to five anxiety/emotionality tests: the open field (7 or 260 lux), the elevated plus-maze, the elevated T-maze and the black/white box. Rats of all groups were also submitted to the formalin test of nociception and measurement of blood pressure. Significant strain differences (P<0.05) were observed in both sexes for all indices of anxiety and also for measures of pain and blood pressure. SHRs, compared with LEWs, explored more the aversive environments of all anxiety tests, showed less nociceptive responses and were hypertensive. All differences in experimental anxiety parameters agree with previous differences reported between two French LEW and SHR substrains, suggesting that LEWs are more anxious than SHRs, thus consolidating these strains as a useful genetic model for the study of anxiety and pain. The possible involvement of tachykinergic mechanisms is discussed.

Animals↗
PubMed2002

The role of NOS in heart failure: lessons from murine genetic models.

Nitric Oxide Synthases (NOSs) are a group of related proteins that produce nitric oxide (NO). In mammals, there are three known members of this gene family: nNOS (NOS1), iNOS (NOS2) and eNOS (NOS3). Each has been disrupted by targeted gene ablation in mice and the corresponding phenotypes examined. These mice have allowed an examination of the contribution of each NOS in a variety of experimental models and continue to provided insights into the patho-physiological role of NOS and NO. With increasing sophistication, murine transgenic approaches continue to offer a wealth of information, and invaluable tools to further study the NOS system. The focus of this review will be an examination of the tools available, and the insights gained from studies done on murine NOS genetic models in the context of heart failure.

Animals↗
PubMed1986

Genetic modelling in schizophrenia according to HLA typing.

Studying families of schizophrenic patients, we observed that the risk of developing the overt form of the illness could be enhanced by some factors. Among these various factors we focused our attention on a biological variable, namely the presence or the absence of particular HLA antigens: partitioning our schizophrenic patients according to their HLA structure (i.e. those with HLA-A1 or CRAG-A1 antigens and those with HLA-non-CRAG-A1 antigens, respectively), revealed different illness distribution in the two groups. From a genetic point of view, this finding suggests the presence of heterogeneity in the hypothetical liability system related to schizophrenia and we evaluated the heterogeneity hypothesis by applying alternative genetic models to our data, trying to detect more biologically homogeneous subgroups of the disease.

Adolescent↗
PubMedDate not supplied

What can genetic models tell us about behavioral plasticity?

Biological diversity and learning have played an essential interactive role in the evolution of species, as intra-specific individual differences have exerted a buffering effect towards environmental changes, and learning ability per se has allowed their maintenance. By exploiting biological diversity individuals with defective learning and memory have been produced that allow the study of the neural substrates of encoding mechanisms, as has been done in studies from Drosophila to rodents. Various aspects of this neurogenetic approach are reviewed and pitfalls are indicated. It is clear that genetic models need to be implemented by an integrated multidisciplinary top-down approach based on behavioral, electrophysiological, histochemical, immunocytochemical and neurochemical techniques. Examples are presented from some animal models that illustrate how a systems level analysis of the neural substrates of information processing can be carried out using such an integrated scheme.

Animals↗
PubMed2006

Organophosphorus insecticides chlorpyrifos and diazinon and oxidative stress in neuronal cells in a genetic model of glutathione deficiency.

Over the past several years evidence has been accumulating from in vivo animal studies, observations in humans, and in vitro studies, that organophosphorus (OP) insecticides may induce oxidative stress. Such effects may contribute to some of the toxic manifestations of OPs, particularly upon chronic or developmental exposures. The aim of this study was to investigate the role of oxidative stress in the neurotoxicity of two commonly used OPs, chlorpyrifos (CPF) and diazinon (DZ), their oxygen analogs (CPO and DZO), and their "inactive" metabolites (TCP and IMP), in neuronal cells from a genetic model of glutathione deficiency. Cerebellar granule neurons from wild type mice (Gclm +/+) and mice lacking the modifier subunit of glutamate cysteine ligase (Gclm -/-), the first and limiting step in the synthesis of glutathione (GSH), were utilized. The latter display very low levels of GSH and are more susceptible to the toxicity of agents that increase oxidative stress. CPO and DZO were the most cytotoxic compounds, followed by CPF and DZ, while TCP and IMP displayed lower toxicity. Toxicity was significantly higher (10- to 25-fold) in neurons from Gclm (-/-) mice, and was antagonized by various antioxidants. Depletion of GSH from Gclm (+/+) neurons significantly increased their sensitivity to OP toxicity. OPs increased intracellular levels of reactive oxygen species and lipid peroxidation and in both cases the effects were greater in neurons from Gclm (-/-) mice. OPs did not alter intracellular levels of GSH, but significantly increased those of oxidized glutathione (GSSG). Cytotoxicity was not antagonized by cholinergic antagonists, but was decreased by the calcium chelator BAPTA-AM. These studies indicate that cytotoxicity of OPs involves generation of reactive oxygen species and is modulated by intracellular GSH, and suggest that it may involve disturbances in intracellular homeostasis of calcium.

Animals↗