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Results for “Models, Genetic”

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PubMed2001

Likelihoods and simulation methods for a class of nonneutral population genetics models.

Methods for simulating samples and sample statistics, under mutation-selection-drift equilibrium for a class of nonneutral population genetics models, and for evaluating the likelihood surface, in selection and mutation parameters, are developed and applied for observed data. The methods apply to large populations in settings in which selection is weak, in the sense that selection intensities, like mutation rates, are of the order of the inverse of the population size. General diploid selection is allowed, but the approach is currently restricted to models, such as the infinite alleles model and certain K-models, in which the type of a mutant allele does not depend on the type of its progenitor allele. The simulation methods have considerable advantages over available alternatives. No other methods currently seem practicable for approximating likelihood surfaces.

Alleles↗

PubMed2005

Folate supplementation in three genetic models: implications for understanding folate-dependent developmental pathways.

Supplementation of a pregnant mother's diet with folate has been shown to protect the developing embryo from birth defects in humans as well as rodent animal models. Folate supplementation not only reverses a potential nutritional deficiency; folate effectively prevents defects even when the mother's nutritional status is normal. These findings indicate that folate is able to interact with the molecular pathways that control normal embryonic development. Supplementation studies in animals provide the experimental starting point for the identification of such folate-responsive pathways. This review summarizes the progress to date in understanding the folate response in genetic models of birth defects in the mouse.

Animals↗

PubMed2003

A genetic model for a central (septum transversum) congenital diaphragmatic hernia in mice lacking Slit3.

Congenital diaphragmatic hernia (CDH) is a significant cause of pediatric mortality in humans with a heterogeneous and poorly understood etiology. Here we show that mice lacking Slit3 developed a central (septum transversum) CDH. Slit3 encodes a member of the Slit family of guidance molecules and is expressed predominantly in the mesothelium of the diaphragm during embryonic development. In Slit3 null mice, the central tendon region of the diaphragm fails to separate from liver tissue because of abnormalities in morphogenesis. The CDH progresses through continuous growth of the liver into the thoracic cavity. This study establishes the first genetic model for CDH and identifies a previously unsuspected role for Slit3 in regulating the development of the diaphragm.

Animals↗

PubMed2001

Genetic model organisms in the study of N-glycans.

Recently the genomic sequences of three multicellular eukaryotes, Caenorhabditis elegans, Drosophila melanogaster and Arabidopsis thaliana, have been elucidated. A number of cDNAs encoding glycosyltransferases demonstrated to have a role in N-linked glycosylation have already been cloned from these organisms, e.g., GlcNAc transferases and alpha 1,3-fucosyltransferases. However, many more homologues of glycosyltransferases and other glycan modifying enzymes have been predicted by analysis of the genome sequences, but the predictions of full length open reading frames appear to be particularly poor in Caenorhabditis. The use of these organisms as models in glycobiology may be hampered since they all have N-linked glycosylation repertoires unlike those of mammals. Arabidopsis and Drosophila have glycosylation similar to that of other plants or insects, while our new data from MALDI-TOF analysis of PNGase A-released neutral N-glycans of Caenorhabditis indicate that there exists a range of pauci- and oligomannosidic structures, with up to four fucose residues and up to two O-methyl groups. With all these three 'genetic model organisms', however, much more work is required for a full understanding of their glycobiology.

Animals↗

PubMed2002

Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity.

Knockout (KO) mice lacking steroidogenic factor 1 (SF-1) exhibit a phenotype that includes adrenal and gonadal agenesis, impaired gonadotropin expression, and abnormalities of the ventromedial hypothalamic nucleus (VMH). Studies in rodents with lesions of the ventromedial hypothalamus have implicated the VMH in body weight regulation, suggesting that SF-1 KO mice may provide a genetic model of obesity. To prevent death, SF-1 KO mice were rescued with corticosteroid injections, followed by syngeneic adrenal transplants from wild-type (WT) littermates. Corticosterone and ACTH levels in WT and SF-1 KO mice were indistinguishable, documenting restoration of hypothalamic-pituitary-adrenal function. Although weights at earlier ages did not differ significantly from WT littermates, SF-1 KO mice were significantly heavier by 8 wk of age and eventually weighed almost twice as much as WT controls. Obesity in SF-1 KO mice predominantly resulted from decreased activity rather than increased food intake. Leptin was increased markedly, insulin was modestly elevated, and glucose was indistinguishable from WT mice. Although sex steroids in rodents affect weight, ovariectomy did not abolish the weight difference between WT and SF-1 KO mice. These SF-1 KO mice are a genetic model of late-onset obesity that may help elucidate the role of the VMH in weight regulation.

Adrenal Cortex Hormones↗

PubMed2005

Structure and function of two-pore-domain K+ channels: contributions from genetic model organisms.

K+ channels that possess two pore domains in each channel subunit are common in many animal tissues. Such channels are generated from large families of subunits and are implicated in several functions, including temperature sensation, responses to ischaemia, K+ homeostasis and setting the resting potential of the cell. Their activity can be modulated by polyunsaturated fatty acids, pH and oxygen, and some are candidate targets of volatile anaesthetics. However, despite their potential as targets for novel drugs for human health, comparatively little is known about the molecular basis of their diverse physiological and pharmacological properties. Genetic model organisms have considerable potential for improving our understanding of these channels. In this article, we review the contributions of some of these genetic model organisms to recent advances in our knowledge of two-pore-domain K+ channels.

Animals↗

PubMed2005

Combined association and linkage analysis for general pedigrees and genetic models.

A combined score test for association and linkage analysis is introduced, based on a biologically plausible model with association between markers and causal genes and penetrance between phenotypes and the causal gene. The test is based on a retrospective likelihood of marker data given phenotypes, treating the alleles of the causal gene as hidden data. It is defined for arbitrary outbred pedigrees, a wide class of genetic models including polygenic and shared environmental effects and allows for missing marker data. It is multipoint, taking marker genotypes from several loci into account simultaneously. The score vector has one association and one linkage component, which can be used to define separate tests for association and linkage. For complete marker data, we give closed form expressions for the efficiency of the linkage, association and combined tests. These are examplified for binary and quantitative phenotypes with or without polygenic effects. The conclusion is that association tests are comparatively more efficient than linkage tests for strong association, weak penetrance models, small families and non-extreme phenotypes, whereas the linkage test is more efficient for weak association, strong penetrance models, large families and extreme phenotypes. The combined test is a robust alternative, which never performs much worse than the best of the linkage and association tests, and sometimes significantly better than both of them. It should be particularly useful when little is known about the genetic model.

Journal Article↗

PubMed1991

Genetics of post-hatching survival potential of Australorp chicks infected as embryos by subgroup A Rous sarcoma virus: further support to 4-allele genetic model.

Embryos (II day-old) of Australorp breed were inoculated via chorioallantoic membrane (CAM) with subgroup A Rous sarcoma virus, and hatched subsequently. The post-hatch survival period in chicks was recorded upto the last chick that died by virus-induced liver tumour, which had a range from 3 to 50 days with an average of 13 +/- 8.7 days. The survival potential of progency tested Australorp parents selected on the basis of negative CAM-infection and those selected on uninoculated embryos, differed significantly (P less than 0.01) while maintaining an inverse relationship between liver tumour mortality and degrees of infection of CAMs. The homozygous susceptibles lacking either ar1 or ar2 or both alleles of the tva (tumour virus a) locus died within 7 days of post-hatching, supporting thereby 4-allele genetic model of tva locus recently proposed for the control of LT- and CAM-infection phenotypes.

Alleles↗

PubMed1980

Schizophrenia: the testing of genetic models by pedigree analysis.

Simulated pedigrees of schizophrenia generally show a clear peak in their likelihood surface corresponding to analysis by the genetic models, which served as the basis for the simulation. The likelihood surface obtained with real data permits determination of the allelic frequency and the selection of an optimal one-locus, two-locus, and four-locus model. These three models have certain features in common, notably, a relatively high frequency of the allele predisposing to schizophrenia (about 20%) and a relatively low index of genetic determination (23%--34%). However, direct likelihood comparisons do not permit distinctions between the one-locus, two-locus, and four-locus models. The most likely interpretation of this finding is that the etiology of schizophrenia is heterogeneous or even nongenetic. However, a simple model with a single completely recessive locus and incomplete penetrance in the homozygote also produces a flat likelihood surface closely resembling that obtained with the real data. With reservation, this single-locus model may be put forward as a potentially useful working hypothesis.

Alleles↗

PubMed2001

A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy.

Guanylyl cyclase-A (NPR-A; GC-A) is the major and possibly the only receptor for atrial natriuretic peptide (ANP) or B-type natriuretic peptide. Although mice deficient in GC-A display an elevated blood pressure, the resultant cardiac hypertrophy is much greater than in other mouse models of hypertension. Here we overproduce GC-A in the cardiac myocytes of wild-type or GC-A null animals. Introduction of the GC-A transgene did not alter blood pressure or heart rate as a function of genotype. Cardiac myocyte size was larger (approximately 20%) in GC-A null than in wild-type animals. However, introduction of the GC-A transgene reduced cardiac myocyte size in both wild-type and null mice. Coincident with the reduction in myocyte size, both ANP mRNA and ANP content were significantly reduced by overexpression of GC-A, and this reduction was independent of genotype. This genetic model, therefore, separates a regulation of cardiac myocyte size by blood pressure from local regulation by a GC-mediated pathway.

Animals↗

PubMed1999

[Dorsal closure in Drosophila. A genetic model for wound healing?].

Dorsal closure (DC) is a morphogenetic movement that establishes the dorsal ectoderm of the drosophila embryo. During this process, the two lateral epithelia stretch toward the dorsal midline, the suture line of the two leading edges. Cell migration during DC relies both on cell shape change controlled by the activity of the JNK pathway in the leading edge cells and modification of cell adhesiveness, probably dependent upon activation of the Dpp (TGF-beta) pathway. Coupling of the JNK and TGF-beta pathways is essential. The sequence of the cellular and molecular events of DC highlights interesting common features with wound healing in vertebrates. Like DC, wound healing relies on the migration of epithelia bordered by leading edges controlling the direction and speed of the movement. This review summarizes recent data concerning the control of epithelial morphogenesis during DC and the bases of wound healing. The molecular and cellular events that underlie these two analogous migratory processes are detailed, discussed and compared. We suggest that DC is a good genetic model for wound healing studying.

Animals↗

PubMed1988

Human stomach alcohol and aldehyde dehydrogenases (ALDH): a genetic model proposed for ALDH III isozymes.

Isozyme phenotypes of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) from human gastroendoscopic as well as surgical gastric biopsies were determined by starch gel electrophoresis and agarose isoelectric focusing. gamma gamma ADH isozymes were expressed predominantly in the mucosal layer of the stomach, whereas beta beta isozymes were in the muscular layer. In the 56 gastroendoscopic mucosal biopsies examined, the homozygous ADH3 1-1 phenotype was found in 75% of the samples, and the heterozygous ADH3 2-1 phenotype in 25%. Accordingly, the gene frequencies of the alleles ADH1/3 and ADH2/3 were calculated to be 0.88 and 0.12, respectively. Using a modified agarose isoelectric focusing procedure, gastric ALDH I, ALDH II, and up to five ALDH III forms could be clearly resolved. The ALDH III isozymes accounted for more than 80% of the total ALDH activities in gastric mucosa and exhibited Km values in the millimolar range for propionaldehyde at pH 9.0. Forty-five percent of the 55 gastroendoscopic biopsies studied lacked ALDH I isozyme. The complex gastric ALDH III isozyme phenotypes seen in these biopsies fall into three patterns. They can be interpreted by a genetic hypothesis, based on a dimeric molecule, in which there are two separate genes, ALDH3a and ALDH3b, with the ALDH3b locus exhibiting polymorphism. The homozygous phenotypes ALDH3b 1-1 and ALDH3b 2-2 were found to be 4 and 76%, respectively, and the heterozygous ALDH3b 2-1 phenotype 20%, of the total. Therefore, the allele frequencies for ALDH1/3b and ALDH2/3b were calculated to be 0.14 and 0.86, respectively. Several lines of biochemical evidence consistent with this genetic model are discussed.

Alcohol Dehydrogenase↗

PubMed2003

Linking dynamical and population genetic models of persistent viral infection.

This article develops a theoretical framework to link dynamical and population genetic models of persistent viral infection. This linkage is useful because, while the dynamical and population genetic theories have developed independently, the biological processes they describe are completely interrelated. Parameters of the dynamical models are important determinants of evolutionary processes such as natural selection and genetic drift. We develop analytical methods, based on coupled differential equations and Markov chain theory, to predict the accumulation of genetic diversity within the viral population as a function of dynamical parameters. These methods are first applied to the standard model of viral dynamics and then generalized to consider the infection of multiple host cell types by the viral population. Each cell type is characterized by specific parameter values. Inclusion of multiple cell types increases the likelihood of persistent infection and can increase the amount of genetic diversity within the viral population. However, the overall rate of gene sequence evolution may actually be reduced.

Biological Evolution↗

PubMed2000

[Study of genetic models of maize kernel traits].

Two sets of NCII mating design including 21 different maize inbreds were used to study the genetic models of five maize kernel traits--kernel length, width, ratio of kernel length and width, kernel thickness and weight per 100 kernels. Ten generations including P1, P2, F1, F2, B1, B2 and their reciprocal crosses RF1, RF2, RB1, RB2 were obtained. Three years' data were obtained and analyzed using mainly two methods: (1) precision identification for single cross and (2) mixed liner model MINQUE approach for diallel design. Method 1 showed that kernel traits were primarily controlled by maternal dominance, endosperm additive and dominance effect (maternal dominance > endosperm additive > endosperm dominance). Cytoplasmic effect was detected in one of the two crosses studied. Method 2 revealed that in the total variance of kernel traits, maternal genotypic effect contributed more than 60%, endosperm genotypic effect contributed less than 40%. Cytoplasmic effect only existed in kernel length and 100 kernel weight, with the range of 10% to 30%. The results indicated that kernel genetic performance was quite largely controlled by maternal genotypic effect.

Models, Genetic↗

PubMed2006

Nucleus-specific abnormalities of GABAergic synaptic transmission in a genetic model of absence seizures.

Human and experimental studies indicate that molecular genetic changes in GABA(A) receptors may underlie the expression of spike-and-waves discharges (SWDs) occurring during absence seizures. However, the full spectrum of the genetic defects underlying these seizures has only been partially elucidated, the expression and functional profiles of putative abnormal protein(s) within the thalamocortical network are undefined, and the pathophysiological mechanism(s) by which these proteins would lead to absence paroxysms are poorly understood. Here we investigated GABA(A) inhibitory postsynaptic currents (IPSCs) in key thalamocortical areas, i.e., the somatosensory cortex, ventrobasal thalamus (VB) and nucleus reticularis thalami (NRT), in preseizure genetic absence epilepsy rats from Strasbourg (GAERS), a well-established genetic model of typical absence seizures that shows no additional neurological abnormalities, and compared their properties to age-matched non-epileptic controls (NECs). Miniature GABA(A) IPSCs of VB and cortical layers II/III neurons were similar in GAERS and NEC, whereas in GAERS NRT neurons they had 25% larger amplitude, 40% faster decay. In addition, baclofen was significantly less effective in decreasing the frequency of NRT mIPSCs in GAERS than in NEC, whereas no difference was observed for cortical and VB mIPSCS between the two strains. Paired-pulse depression was 45% smaller in GAERS NRT, but not in VB, and was insensitive to GABA(B) antagonists. These results point to subtle, nucleus-specific, GABA(A) receptor abnormalities underlying SWDs of typical absence seizures rather than a full block of these receptors across the whole thalamocortical network, and their occurrence prior to seizure onset suggests that they might be of epileptogenic significance.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1993

Glucose sensitivity of ATP-sensitive K+ channels is impaired in beta-cells of the GK rat. A new genetic model of NIDDM.

In the Goto-Kakizaki rat, a new genetic model of NIDDM, insulin response to glucose is selectively impaired. To elucidate the mechanism of this abnormality, we studied the properties of ATP-sensitive K+ channels, the inhibition of which is a key step of insulin secretion induced by fuel substrates, using the patch-clamp technique. The glucose-sensitivity of KATP channels was considerably reduced in GK rats. However, the inhibitory effects of ATP on channel activity and unitary conductance were not significantly different between control and GK rats. Thus, it appears that the impaired insulinotropic action of glucose in beta-cells of GK rats is attributable to insufficient closure of the KATP channels, probably because of deficient ATP production by impaired glucose metabolism. KATP-channel activities in both control and diabetic beta-cells were found to be equally suppressed by glyceraldehyde and 2-ketoisocaproate. These results strongly suggest that the step responsible for the metabolic dysfunction of diabetic beta-cells is located within the glycolytic pathway before glyceraldehyde-3-phosphate or in the glycerol phosphate shuttle.

Adenosine Triphosphate↗

PubMed2003

The teleost fish medaka (Oryzias latipes) as genetic model to study gravity dependent bone homeostasis in vivo.

Long-term space flight and microgravity result in bone loss that can be explained by reduced activity of bone-forming cells (osteoblasts) and/or an increase in activity of bone resorbing cells (osteoclasts). Osteoprotegerin (OPG) has been shown to regulate the balance between osteoblast and osteoclast cell numbers and is involved in maintaining constant bone mass under normal gravitational conditions. The small bony fish medaka (Oryzias latipes) has attracted increasing attention as a genetic model system to study normal embryonic developmental and pathological processes. To analyze the molecular mechanisms of bone formation in this small vertebrate, we have isolated two opg genes, opgl and opg2, from medaka. Our phylogenetic analysis reveals that both genes originated from a common ancestor by fish-specific gene duplication and represent the orthologs of the mammalian opg gene. Both opg genes are differentially expressed during embryonic and larval development, in adult tissues and in cultured primary osteoblast-like cells. Furthermore, we have characterized the opg2 promoter region and identified consensus binding sites for the transcription factor core-binding-factor-1A (CBFA1). In mammals, CBFA1 has been shown to be a regulator of opg expression and to be essential for several steps during osteoblast differentiation. Here we show that sequence and expression domains of opg, cbfal and a member of the dlx gene family are highly conserved between medaka and higher vertebrates. This suggests that not only single genes but entire genetic networks for bone formation are conserved between teleosts and mammals. These findings will open medaka fish as a genetic model to monitor bone formation under different gravity conditions in a living whole animal allowing the identification of novel factors involved in bone homeostasis.

Animals↗

PubMed2006

Testing genetic models of mate choice evolution in the wild.

Understanding the mechanisms driving the evolution of mate choice, particularly the importance of indirect genetic benefits, remains a challenge, especially in wild populations. Three recent studies have attempted to quantify the importance of indirect benefits in wild bird populations using approaches derived from quantitative genetic models of mate choice. In all three cases, no support was found for a role of indirect benefits in the evolution of mate choice. These studies suggest that a quantitative genetic approach can illuminate this long-standing problem and that alternative models for the evolution of mate preferences should be tested in wild populations.

Animals↗