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PubMed2000

Patterns of variation in the intergenic spacers of ribosomal DNA in Drosophila melanogaster support a model for genetic exchanges during X-Y pairing.

Detailed analysis of variation in intergenic spacer (IGS) and internal transcribed spacer (ITS) regions of rDNA drawn from natural populations of Drosophila melanogaster has revealed contrasting patterns of homogenization although both spacers are located in the same rDNA unit. On the basis of the role of IGS regions in X-Y chromosome pairing, we proposed a mechanism of single-strand exchanges at the IGS regions, which can explain the different evolutionary trajectories followed by the IGS and the ITS regions. Here, we provide data from the chromosomal distribution of selected IGS length variants, as well as the detailed internal structure of a large number of IGS regions obtained from specific X and Y chromosomes. The variability found in the different internal subrepeat regions of IGS regions isolated from X and Y chromosomes supports the proposed mechanism of genetic exchanges and suggests that only the "240" subrepeats are involved. The presence of a putative site for topoisomerase I at the 5' end of the 18S rRNA gene would allow for the exchange between X and Y chromosomes of some 240 subrepeats, the promoter, and the ETS region, leaving the rest of the rDNA unit to evolve along separate chromosomal lineages. The phenomenon of localized units (modules) of homogenization has implications for multigene family evolution in general.

Animals↗
PubMed1984

A general autosomal/X-linked model.

This paper describes a general genetic model which encompasses both autosomal and X-linked inheritance as submodels. It allows one to test for X-linked inheritance of a trait by comparing the likelihood of X-linked inheritance to the likelihood of the general genetic model. The general model is formulated as two loci, the first representing the trait locus and the second representing the sex chromosomes. The test for X-linked inheritance is a test of linkage between the two loci. Three data sets were analyzed using this approach. Each was also analyzed using a variant of a model introduced by Demenais and Elston [1981], which treats the transmission probabilities as estimable parameters. Similar conclusions were reached using either model.

Alleles↗
PubMed2000

Effect of high NaCl diet on spontaneous hypertension in a genetic rat model with reduced nephron number.

OBJECTIVE: An inherited reduction in nephron number has been implicated in the development of salt-sensitive hypertension and end stage renal disease. The Munich Wistar Frömter (MWF) rat represents a genetic model with a 30-50% reduction of nephrons compared with normal rats. MWF rats develop spontaneous hypertension and increased urinary albumin excretion (UAE). We addressed the question whether the inherited defect in this model leads to salt-sensitive hypertension. METHODS: At the age of 6 weeks, we started male and female MWF/Fub rats and salt-resistant Lewis (Lew) reference rats on either a normal NaCl (0.2%) or a high NaCl (8%) diet (n = 8, each group). Systolic blood pressure (SBP) and UAE were measured at 14 weeks. RESULTS: Under a normal diet, MWF/Fub rats demonstrated significantly elevated SBP compared to Lew rats both in male (165 +/- 2 versus 133 +/- 3 mmHg, P < 0.0001) and female (156 +/- 3 versus 134 +/- 3 mmHg, P < 0.0001) rats. After high NaCl treatment, SBP was significantly higher in both male and female MWF/Fub rats (+55 mmHg and +36 mmHg, P < 0.0001, respectively) compared with MWF/ Fub under a normal diet UAE was also significantly higher in male and female MWF/Fub rats after high NaCl excess (P < 0.0005, respectively). In contrast, both SBP and UAE remained unchanged in response to high NaCl in Lew rats. CONCLUSIONS: Our findings demonstrate that both the hypertension and UAE are sensitive to high NaCl loading in female and male MWF/Fub rats. Thus, an inborn nephron deficit may lead to salt-sensitive hypertension and renal dysfunction.

Albuminuria↗
PubMed2001

Power comparisons between the TDT and two likelihood-based methods.

We compare the statistical power of the transmission disequilibrium test (TDT) with that of two likelihood-based linkage tests, the classical LOD score and a modified LOD score in which a linkage disequilibrium (LD) parameter is incorporated into the likelihood (LD-LOD). We hypothesize that, when LD is present, the LD-LOD will have the greatest power of the three tests because the TDT breaks a multiplex pedigree into triads, and the LOD score has previously been shown to have lower power when LD is present but not accounted for. We test this hypothesis using a simulation study in which we generate affected sib-pair (ASP) pedigrees under a range of genetic models, varying the genotypic relative risk (GRR) from 6 to 16. Because the likelihood-based tests require that a genetic model be specified, we compare the tests under two scenarios. First, we assume the true genetic model in the analysis, and second, we compare the tests when the LD-LOD (LOD) is maximized over two wrong genetic models. For the generating models we considered, we find that the LD-LOD has greater power than the TDT even when the genetic models is mis-specified and the results corrected for multiple tests. Extreme differences occur under the multiplicative and dominant models, for which the difference in power is as high as 40% at complete LD. The LOD score provides the lowest power in the presence of LD for the range of GRR considered here.

Adult↗
PubMed2003

Dynamic modeling of genetic networks using genetic algorithm and S-system.

MOTIVATION: The modeling of system dynamics of genetic networks, metabolic networks or signal transduction cascades from time-course data is formulated as a reverse-problem. Previous studies focused on the estimation of only network structures, and they were ineffective in inferring a network structure with feedback loops. We previously proposed a method to predict not only the network structure but also its dynamics using a Genetic Algorithm (GA) and an S-system formalism. However, it could predict only a small number of parameters and could rarely obtain essential structures. In this work, we propose a unified extension of the basic method. Notable improvements are as follows: (1) an additional term in its evaluation function that aims at eliminating futile parameters; (2) a crossover method called Simplex Crossover (SPX) to improve its optimization ability; and (3) a gradual optimization strategy to increase the number of predictable parameters. RESULTS: The proposed method is implemented as a C program called PEACE1 (Predictor by Evolutionary Algorithms and Canonical Equations 1). Its performance was compared with the basic method. The comparison showed that: (1) the convergence rate increased about 5-fold; (2) the optimization speed was raised about 1.5-fold; and (3) the number of predictable parameters was increased about 5-fold. Moreover, we successfully inferred the dynamics of a small genetic network constructed with 60 parameters for 5 network variables and feedback loops using only time-course data of gene expression.

Algorithms↗
PubMed2002

Robust TDT-type candidate-gene association tests.

In studies of association between genetic markers and a disease, the transmission disequilibrium test (TDT) has become a standard procedure. It was introduced originally as a test for linkage in the presence of association and can be used as a test for association under appropriate assumptions. The power of the TDT test for association between a candidate gene and disease depends on the underlying genetic model and the TDT is the optimal test if the additive model holds. Related methods have been obtained for a given mode of inheritance (e.g. dominant or recessive). Quite often, however, the true model is unknown and selection of a single method of analysis is problematic, since use of a test optimal for one genetic model usually leads to a substantial loss of power if another genetic model is the true one. The general approach of efficiency robustness has suggested two types of robust procedures, which we apply to TDT-type association tests. When the plausible range of alternative models is wide (e.g. dominant through recessive) our results indicate that the maximum (MAX) of several test statistics, each of which is optimal for quite different models, has good power under all genetic models. In situations where the set of possible models can be narrowed (e.g. dominant through additive) a simple linear combination also performs well. In general, the MAX has better power properties than the TDT for the study of candidate genes when the mode of inheritance is unknown.

Alleles↗
PubMed1998

Epileptiform activity and changes in field potential responses induced by low [Mg2+]0 in a genetic rat model of absence epilepsy.

The genetic absence epilepsy rats of Strasbourg (GAERS) display alterations in cortical synaptic transmission possibly facilitating the generation of ictaform activity and the late development into convulsive epilepsy. We studied low Mg2+-induced epileptiform activities and their long term effects on field potentials (fp) evoked by paired pulse stimulation in hippocampal area CA1 (CA1), medial entorhinal cortex (EC) and frontal cortex (FC) in in-vitro-slice preparations from GAERS and control (NE) adult rats (6 months). Omitting Mg2+-ions from artificial cerebrospinal fluid (ACSF) caused recurrent short discharges (in CA1) and seizure-like events (in EC) in both GAERS and NE rats. Latency to onset of activity as well as discharge pattern, frequency and amplitude of such events did not differ between the two strains, neither in CA1 nor in EC. In the FC, however, epileptiform events occurred in NE rats, but not in GAERS. Field potentials in normal ACSF were similar in both strains in CA1 and FC, while they were smaller in the EC of GAERS. Low [Mg2+]0 caused long-term changes of fp only in area CA1 where the population spikes were depressed in GAERS and increased in NE rats. We concluded that susceptibility to low [Mg2+]0-induced epileptic activity in EC and hippocampal area CA1 is not higher in GAERS than in NE adult rats. However, some properties like synaptic coupling in EC and long-term changes in synaptic efficacy induced by epileptiform activity in CA1 differ from that in NE rats. Whether the particularities in GAERS may be related to kindling by absence epileptic activities will be studied in further experiments.

Animals↗
PubMed2003

Recent developments from genetic mouse models of seizures.

The use of genetically altered mice has revolutionised biomedical research into the genetics and neurobiological mechanisms contributing to complex human disorders such as epilepsy. Recent studies using mutant mice have expanded our knowledge of the key roles that abnormalities in synaptic function and formation play in epileptogenesis, and further illustrate just how closely some mouse models resemble human epilepsy. Broader utilisation of epileptic mouse mutants should provide new molecular targets for developing novel anti-epileptic drugs, and also improved means for predicting their efficacy in currently refractory forms of epilepsy.

Animals↗
PubMed1993

[A genetic-epidemiological model of predisposition to ischemic heart disease (1)].

A genetic and epidemiological sample of 20-59-year-old males, Moscow residents (n = 3141), was surveyed. The authors obtained data on the prevalence of coronary heart disease from epidemiological criteria and genealogical data on cardiovascular diseases by the "Familial History" questionnaire in the first-degree relatives who were interviewed by using a genetic and mathematical monolocus diallelic model. It was found that out of the 10 possible variants under study a genetic and environmental variant with independent penetrance of 3 genotypes adequately describes the prevalence of coronary heart disease in the families and in the population. This suggest that both genetic and environmental factors have an influence on the prevalence of coronary heart disease and that there is a possible genetic polymorphism of the disease.

Adult↗
PubMed2004

Genetic simplex modeling of Eysenck's dimensions of personality in a sample of young Australian twins.

The relative stability and magnitude of genetic and environmental effects underlying major dimensions of adolescent personality across time were investigated. The Junior Eysenck Personality Questionnaire was administered to over 540 twin pairs at ages 12, 14 and 16 years. Their personality scores were analyzed using genetic simplex modeling which explicitly took into account the longitudinal nature of the data. With the exception of the dimension lie, multivariate model fitting results revealed that familial aggregation was entirely explained by additive genetic effects. Results from simplex model fitting suggest that large proportions of the additive genetic variance observed at ages 14 and 16 years could be explained by genetic effects present at the age of 12 years. There was also evidence for smaller but significant genetic innovations at 14 and 16 years of age for male and female neuroticism, at 14 years for male extraversion, at 14 and 16 years for female psychoticism, and at 14 years for male psychoticism.

Adolescent↗
PubMed1998

Structured epidemic models and the spread of influenza in the central Canadian subarctic.

Patterns of transmission of infectious diseases within and among populations are strongly affected by population structure, which can either facilitate or limit interactions among people from different groups. Results from several theoretical studies show that nonrandom mixing among subgroups can affect the time when an infectious disease is introduced to the population, the speed of propagation of the disease, and the severity of an epidemic. Because many of these models focus on the effects of population structure, they are functionally similar to models used to describe the genetic structure of a population. One major difference between genetic models and epidemic models is that genetic models, with a time scale of the order of generations, incorporate migrations (or permanent movement) among subgroups, whereas epidemic models, with a time scale of the order of days or weeks, must incorporate short-term mobility among subgroups. Such mobility can be included in models for epidemic spread by explicitly incorporating the process by which residents from different locations interact with one another. We present a derivation of a mobility model for epidemic processes and apply it to the spread of the 1918-1919 influenza epidemic among the Cree and Métis people associated with three Hudson's Bay Company posts in the central Canadian Subarctic. The model distinguishes mobility from population effects. Results indicate that social organization (population effects) and social responses to the epidemic were more important than movement patterns (mobility) in explaining the differential impact of this virgin soil epidemic on the three study communities.

Canada↗
PubMed2005

New probabilistic graphical models for genetic regulatory networks studies.

This paper introduces two new probabilistic graphical models for reconstruction of genetic regulatory networks using DNA microarray data. One is an independence graph (IG) model with either a forward or a backward search algorithm and the other one is a Gaussian network (GN) model with a novel greedy search method. The performances of both models were evaluated on four MAPK pathways in yeast and three simulated data sets. Generally, an IG model provides a sparse graph but a GN model produces a dense graph where more information about gene-gene interactions may be preserved. The results of our proposed models were compared with several other commonly used models, and our models have shown to give superior performance. Additionally, we found the same common limitations in the prediction of genetic regulatory networks when using only DNA microarray data.

Algorithms↗
PubMed2003

Effects of remacemide in two models of genetically determined generalized epilepsy, the GAERS and the audiogenic Wistar AS.

The antiepileptic effects of remacemide were assessed in two models of genetically determined generalized epilepsy. The model of non-convulsive epilepsy used was a model of absence seizures, the GAERS (genetic absence epilepsy rats from Strasbourg), and the model of convulsive seizures was an audiogenic rat model, the Wistar AS. In the eight GAERS studied, the three doses of remacemide (20, 40, and 80 mg/kg) dose-dependently reduced the expression of spike-and-wave discharges (SWDs) that had almost totally disappeared at the highest dose used, 80 mg/kg. However, at the latter dose, the effect of remacemide may be partly due to a change in the vigilance level of the animals. In the Wistar AS, the dose of 20 mg/kg prolonged by twofold the latencies to wild running and tonic seizures, and prevented their expression in one rat out of the eight studied. At 40 mg/kg, the expression of wild running and tonic seizures was inhibited in seven and maintained in one of the eight rats studied. The present results support the effects of remacemide in tonic/clonic seizure, which was the first target of the drug, and confirm the effect of the anticonvulsant on absence seizures.

Acetamides↗
PubMed2004

Evolutionary model with genetics, aging, and knowledge.

We represent a process of learning by using bit strings, where 1 bits represent the knowledge acquired by individuals. Two ways of learning are considered: individual learning by trial and error, and social learning by copying knowledge from other individuals or from parents in the case of species with parental care. The age-structured bit string allows us to study how knowledge is accumulated during life and its influence over the genetic pool of a population after many generations. We use the Penna model to represent the genetic inheritance of each individual. In order to study how the accumulated knowledge influences the survival process, we include it to help individuals to avoid the various death situations. Modifications in the Verhulst factor do not show any special feature due to its random nature. However, by adding years to life as a function of the accumulated knowledge, we observe an improvement of the survival rates while the genetic fitness of the population becomes worse. In this latter case, knowledge becomes more important in the last years of life where individuals are threatened by diseases. Effects of offspring overprotection and differences between individual and social learning can also be observed. Sexual selection as a function of knowledge shows some effects when fidelity is imposed.

Aging↗
PubMed1992

sar: a genetic mouse model for human sarcosinemia generated by ethylnitrosourea mutagenesis.

A mouse mutant with sarcosinemia was found by screening the progeny of ethylnitrosourea-mutagenized mice for aminoacidurias. Paper chromatography, column chromatography, and gas chromatography-mass spectrometry identified high levels of sarcosine in the urine of the mutant mice. While sarcosine cannot be detected in the urine of plasma of normal mice, the urinary sarcosine level of 102 +/- 58 mmol per g of creatinine in the mutant mice was at the upper range of the urinary levels (1.5-4.5 mmol of sarcosine per g of creatinine) observed in humans with sarcosinemia. Similarly, the plasma sarcosine level of 785 +/- 153 mumol/liter in the sarcosinemic mice was at the upper range of the plasma sarcosine levels (53-760 mumol/liter) observed in affected humans. Sarcosine dehydrogenase [sarcosine:(acceptor) oxidoreductase (demethylating), EC 1.5.99.1] activity was deficient in sarcosinemic mice. The sarcosinuria phenotype in these mice was inherited as an autosomal recessive trait. This mouse mutant provides a useful genetic model for human sarcosinemia and for development of therapeutic approaches for genetic disease.

Amino Acid Metabolism, Inborn Errors↗