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PubMed2006

Population genetics models of competition between transposable element subfamilies.

Transposable elements are one of the major components of genomes. Some copies are fully efficient; i.e., they are able to produce the proteins needed for their own transposition, and they can move and duplicate into the genome. Other copies are mutated. They may have lost their moving ability, their coding capacity, or both, thus becoming pseudogenes slowly eliminated from the genome through deletions and natural selection. Little is known about the dynamics of such mutant elements, particularly concerning their interactions with autonomous copies. To get a better understanding of the transposable elements' evolution after their initial invasion, we have designed a population genetics model of transposable elements dynamics including mutants or nonfunctional sequences. We have particularly focused on the case where these sequences are nonautonomous elements, known to be able to use the transposition machinery produced by the autonomous ones. The results show that such copies generally prevent the system from achieving a stable transposition-selection equilibrium and that nonautonomous elements can invade the system at the expense of autonomous ones. The resulting dynamics are mainly cyclic, which highlights the similarities existing between genomic selfish DNA sequences and host-parasite systems.

DNA Transposable Elements↗
PubMed2000

Quantitative genetic models for the balance between migration and stabilizing selection.

The evolution of a quantitative trait subject to stabilizing selection and immigration, with the immigrants deviating from the local optimum, is considered under a number of different models of the underlying genetic basis of the trait. By comparing exact predictions under the infinitesimal model obtained using numerical methods with predictions of a simplified approximate model based on ignoring linkage disequilibrium, the increase in the expressed genetic variance as a result of linkage disequilibrium generated by migration is shown to be relatively small and negligible, provided that the genetic variance relative to the squared deviation of immigrants from the local optimum is sufficiently large or selection and migration is sufficiently weak. Deviation from normality is shown to be less important by comparing predictions of the infinitesimal model with a model presupposing normality. For a more realistic symmetric model, involving a finite number of loci only, no linkage and equal effects and frequencies across loci, additional changes in the genetic variance arise as a result of changes in underlying allele frequencies. Again, provided that the genetic variance relative to the squared deviation of the immigrants from the local optimum is small, the difference between the predictions of infinitesimal and the symmetric model are small unless the number of loci is very small. However, if the genetic variance relative to the squared deviation of the immigrants from the local optimum is large, or if selection and migration are strong, both linkage disequilibrium and changes in the genetic variance as a result of changes in underlying allele frequencies become important.

Base Sequence↗
PubMed1981

A genetic model for the inheritance of pituitary tumor susceptibility in F344 rats.

An 8-week period of continuous diethylstilbestrol (DES) treatment results in the development of pituitary tumors in 100% of male or female F344 rats. Similar treatment of Holtzman male or female rats results in a very low incidence of pituitary tumor development (2-6%). A series of crosses was performed between F344 and Holtzman rats to produce the F1 hybrid, the F2 generation, and the backcrosses of the F1 hybrid to either the F344 parent or the Holtzman parent. The incidence of DES-induced pituitary tumors was measured in these animals. The results indicate that pituitary tumor susceptibility does not result from the expression of genes that are simple dominant or recessive genes, since the tumor's incidence in the F1 hybrid is intermediate to that in the parental strains. However, the data are compatible with the involvement of a small number of genetic loci. We present a genetic model involving three independently segregating loci which agrees reasonably well with the experimental results. In the model, the Holtzman strain has normal alleles at these loci which prevent uncontrolled proliferation. The highly inbred F344 strain is homozygous mutant at these three loci and in unable to control DES-induced proliferation.

Animals↗
PubMed1995

Model genetic circuits encoding autoregulatory transcription factors.

Multiple steady-state levels of autoregulatory transcription factors are capable of specifying alternative heritable phenotypes of a cell or an organism. Switching among steady states can result in long-term phenotypic change. In this paper, six model genetic circuits are presented, each encoding a set of autoregulatory transcription factors. The steady-state rate equations for each genetic circuit are formulated and solved to determine conditions under which multiple steady states exist. Each steady state of the genetic circuit constitutes an alternative heritable phenotype resulting from a single genotype.

Animals↗
PubMed2002

Evolution of functionally conserved enhancers can be accelerated in large populations: a population-genetic model.

The evolution of cis-regulatory elements (or enhancers) appears to proceed at dramatically different rates in different taxa. Vertebrate enhancers are often very highly conserved in their sequences, and relative positions, across distantly related taxa. In contrast, functionally equivalent enhancers in closely related Drosophila species can differ greatly in their sequences and spatial organization. We present a population-genetic model to explain this difference. The model examines the dynamics of fixation of pairs of individually deleterious, but compensating, mutations. As expected, small populations are predicted to have a high rate of evolution, and the rate decreases with increasing population size. In contrast to previous models, however, this model predicts that the rate of evolution by pairs of compensatory mutations increases dramatically for population sizes above several thousand individuals, to the point of greatly exceeding the neutral rate. Application of this model predicts that species with moderate population sizes will have relatively conserved enhancers, whereas species with larger populations will be expected to evolve their enhancers at much higher rates. We propose that the different degree of conservation seen in vertebrate and Drosophila enhancers may be explained solely by differences in their population sizes and generation times.

Animals↗
PubMed2006

Effect of systemic and intracortical administration of phenytoin in two genetic models of absence epilepsy.

1. Spontaneous 7-10 Hz spike-wave discharges (SWDs) are the electroencephalographic hallmark of absence seizures, as can be observed in WAG/Rij as well as in GAERS, two commonly used well-validated genetic rat models of absence epilepsy. A local upregulation of sodium channels within the perioral region of the primary somatosensory cortex indicated an initiation site for SWDs in WAG/Rij rats, in line with a new theory that assumes that SWDs have a cortical focal origin in the perioral region of the somatosensory cortex. We tested whether bilateral microinfusion at this focal site of the sodium channel blocker phenytoin, which is known to aggravate SWDs after systemic administration, reduces SWDs in both models. 2. WAG/Rij rats and GAERS, chronically provided with cortical EEG electrodes and bilateral cortical cannula's, were used. The EEGs were recorded before and after or systemic or bilateral infusion of phenytoin. 3. Microinfusion of phenytoin at the perioral region of the somatosensory cortex produced an immediate cessation of seizure activity in WAG/Rij rats, while systemic injection produced an increase in both genetic models. Microinfusion of the same and higher concentrations of phenytoin in GAERS at the same stereotactic coordinates showed no effect. Phenytoin was effective in GAERS 2 mm more posteriorly.4. The data suggest that both genetic models have a cortical area at which diametrically opposite effects of phenytoin can be found compared to systemic injections: a decrease after local microinfusion and aggravation after systemic administration, although the exact cortical location may be different. Moreover, a deficit in sodium channels might be an ethiological factor underlying an increased probability for the initiation of SWDs in the somatosensory cortex.

Action Potentials↗
PubMed2006

A bivariate quantitative genetic model for a threshold trait and a survival trait.

Many of the functional traits considered in animal breeding can be analyzed as threshold traits or survival traits with examples including disease traits, conformation scores, calving difficulty and longevity. In this paper we derive and implement a bivariate quantitative genetic model for a threshold character and a survival trait that are genetically and environmentally correlated. For the survival trait, we considered the Weibull log-normal animal frailty model. A Bayesian approach using Gibbs sampling was adopted in which model parameters were augmented with unobserved liabilities associated with the threshold trait. The fully conditional posterior distributions associated with parameters of the threshold trait reduced to well known distributions. For the survival trait the two baseline Weibull parameters were updated jointly by a Metropolis-Hastings step. The remaining model parameters with non-normalized fully conditional distributions were updated univariately using adaptive rejection sampling. The Gibbs sampler was tested in a simulation study and illustrated in a joint analysis of calving difficulty and longevity of dairy cattle. The simulation study showed that the estimated marginal posterior distributions covered well and placed high density to the true values used in the simulation of data. The data analysis of calving difficulty and longevity showed that genetic variation exists for both traits. The additive genetic correlation was moderately favorable with marginal posterior mean equal to 0.37 and 95% central posterior credibility interval ranging between 0.11 and 0.61. Therefore, this study suggests that selection for improving one of the two traits will be beneficial for the other trait as well.

Bayes Theorem↗
PubMed2002

Adenoviral gene transfer of aspartoacylase into the tremor rat, a genetic model of epilepsy, as a trial of gene therapy for inherited epileptic disorder.

The tremor rat (tm/tm) is a genetic model of epilepsy that exhibits absence-like seizures characterized by 5-7 Hz spike-wave-like complexes in cortical and hippocampal electroencephalograms (EEGs). A deletion of the aspartoacylase (ASPA) gene and resultant high levels of N-acetyl-aspartate (NAA) in the brain have been found in tremor rats. We attempted to determine whether gene transfer of ASPA inhibited absence-like seizures in tremor rats using recombinant adenovirus. Recombinant adenovirus (5x10(7) pfu) carrying the rat ASPA gene (AxASPA) or beta-galactosidase gene (AxLacZ), as a control virus, was intracerebroventricularly administered to premature tremor rats aged 7 weeks. Cortical and hippocampal EEG were recorded with chronically implanted electrodes before and after viral administration. The absence-like seizures were increased in AxLacZ-administered control rats with age. However, the increase was significantly inhibited in AxASPA-administered rats at 1 week after treatment. These results suggest that gene transfer of ASPA is effective in inhibiting the generation of absence-like seizures, probably by reducing the NAA level.

Adenoviridae↗
PubMed1983

Testing genetic models in populations which contain pedigree errors.

In a genetic analysis of a polymorphic system, differences between the observed type of an individual and that expected from the parental types can arise either from an incorrect model or from pedigree errors. Such pedigree errors can cause severe difficulties in studies of the mode of inheritance of a novel polymorphic system. A method is proposed which overcomes the problem by including sire and dam error rates explicitly in the genetic model. The error rates are estimated by maximum likelihood, and likelihood ratio tests used to compare different models or estimates from different data sets. The proposals are applied to a study of the inheritance of the bovine serum AmI amylases.

Animals↗
PubMed2026

Interfering with DNA repair pathways to enhance CRISPR-Cas9-mediated homology-directed repair in a chelicerate genetic model.

The two-spotted spider mite, Tetranychus urticae, is a major pest and an emerging genetic model. Recent CRISPR-Cas9 advances, especially the SYNCAS method for maternal delivery of Cas9 ribonucleoproteins, have enabled precise genome editing in this and other difficult-to-transform arthropods. Yet SYNCAS-mediated knockins vary in efficiency, possibly due to competition between DNA repair pathways, whose mechanisms in T. urticae and other chelicerates remain unknown. Here, we provide the first functional analysis of double-strand break repair in a chelicerate. Loss of DNA polymerase theta (Polθ) redirects repair almost entirely toward homology-directed repair, whereas absence of Ligase IV has no detectable impact. Using a reporter assay targeting phytoene desaturase, we demonstrate that Polθ-deficient strains enhance incorporation of repair templates, even when mutations are distant from the cut site. Also, insertion of larger fragments is improved. Finally, disrupting Polθ imposes only a modest fitness cost, highlighting its value for future genome engineering in this species.

Acari↗
PubMed1992

Twin studies of Alzheimer disease: II. Some predictions under a genetic model.

The twin method for investigating genetic and environmental causes of disease has been applied mostly in early-onset illnesses. Analysis of late-onset disorders requires reexamination of common assumptions about the relation between genetic causes and the degree of concordance expected. This paper considers Alzheimer disease (AD) as an example of a late-onset disorder with putative genetic factors. For argument it employs the strong hypothesis that AD is an autosomal dominant trait with age-dependent expression, as described by a previously published parametric model. That model encompasses 2 principal variants of disease: a rare form with onset in middle life, and a more common late-onset type which is nonetheless eventually fully penetrant. The present work then specifies the probability that, when a given member of a twin pair (the proband) is affected, an identical or fraternal co-twin also shows the disease. Such probability is expressed as a function of the age at onset of the proband and the current age of the pair. Even under strong working assumptions regarding genetic influence, the expected proportion of identical co-twins actually affected with AD will not exceed 40% until the subjects are about 80 years old. Therefore, except in very old subjects, modest twin concordance is a feeble argument against genetic causes, or in favor of exclusively environmental ones. In this sense the interpretation of results of twin studies in AD and other late-onset disorders differs substantially from studies of diseases with early onset.

Age Factors↗
PubMed1989

Testing genetic models for IDDM by the MASC method.

The MASC method has been applied to the GAW5 data. The method uses the simultaneous information on association and segregation of the HLA marker with the disease and the segregation of the HLA marker in affected families. It also takes into account the differential risk for parents of a patient, as well as the different HLA haplotype sharing, according to the HLA genotype of the patient. The goodness of fit of several genetic models has been tested. The observed data are not compatible with a two-allele, one-locus model, but they fit a three-allele, one-locus model and a complementation two-locus model if additional familial correlation is allowed.

Diabetes Mellitus, Type 1↗
PubMed1986

Opioid receptor alterations in a genetic model of generalized epilepsy.

Autoradiography was used to examine opioid receptor binding in the Mongolian gerbil, a genetic model of the epilepsies. Coronal brain sections of seizure-resistant (SR) and seizure-sensitive (SS) (both pre- and post-seizure conditions) gerbils were labeled with [3H]dihydromorphine. SS (pre-seizure) gerbils demonstrated overall greater brain opioid binding when compared to SR animals. The periaqueductal gray, substantia nigra and medial geniculate body were specific areas in SS (pre-seizure) gerbils which demonstrated highly significant increases in opioid binding compared to SR animals (% increase vs SR were 98%, 91.3% and 42.9%, respectively). Scatchard analysis demonstrated that the increase in opioid binding was due to an increase in the total number of receptors without a significant change in receptor affinity (i.e. periaqueductal gray area: total number of binding sites was 12.7 (SR) and 18.0 fmol/mg tissue (SS pre-seizure), while Kd values were 4.0 (SR) and 4.0 mM (SS pre-seizure). Opioid binding was also increased in the SS (post-seizure) animals when compared to SR animals, especially in the substantia nigra. However, when compared to SS (pre-seizure) gerbils, there was a general but not significant, decrease in opioid binding in SS post-seizure gerbils. The increased opioid binding in the SS (pre-seizure) gerbil compared to SR gerbils could reflect an up-regulation due to a deficit in endogenous ligand (e.g. a deficit in synthesis or decreased release) which could underlie the seizure diathesis in the gerbil.

Animals↗
PubMed1995

A genetic model for absent chylomicron formation: mice producing apolipoprotein B in the liver, but not in the intestine.

The formation of chylomicrons by the intestine is important for the absorption of dietary fats and fat-soluble vitamins (e.g., retinol, alpha-tocopherol). Apo B plays an essential structural role in the formation of chylomicrons in the intestine as well as the VLDL in the liver. We have developed genetically modified mice that express apo B in the liver but not in the intestine. By electron microscopy, the enterocytes of these mice lacked nascent chylomicrons in the endoplasmic reticulum and Golgi apparatus. Because these mice could not form chylomicrons, the intestinal villus enterocytes were massively engorged with fat, which was contained in cytosolic lipid droplets. These mice absorbed D-xylose normally, but there was virtually no absorption of retinol palmitate or cholesterol. The levels of alpha-tocopherol in the plasma were extremely low. Of note, the absence of chylomicron synthesis in the intestine did not appear to have a significant effect on the plasma levels of the apo B-containing lipoproteins produced by the liver. The mice lacking intestinal apo B expression represent the first genetic model of defective absorption of fats and fat-soluble vitamins and provide a useful animal model for studying nutrition and lipoprotein metabolism.

Animals↗
PubMed1981

A new genetic model proposing that the Se gene is a structural gene closely linked to the H gene.

The Se gene is classically considered as a regulatory gene controlling the expression of the structural gene H in external secretions. Under this hypothesis, Bombay (h/h) individuals should not be able to express the Se gene. Statistical analysis of the 44 published Bombay pedigrees suggests on the contrary that there is no suppression of Se in Bombay individuals, and that both Se and H loci can be fully expressed at the phenotypic level. Based on a lod score of 12.9 at 1% recombination units and the existence of two different acceptors for the biosynthesis of the H antigen, a new genetic model is proposed in which H and Se would be two closely linked structural genes coding for two different 2-alpha-L-fucosyltransferases.

ABO Blood-Group System↗