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PubMed1999

Genetic model-free linkage analysis using the maximum-likelihood-binomial method for categorical traits.

Within the simulated data of the 11th Genetic Analysis Workshop, we searched for the genes controlling the disease. We analyzed 200 families from Studies 2 and 3 presenting both mild and severe forms of disease. Linkage analysis was performed using the recently developed genetic model-free maximum-likelihood-binomial (MLB) method which overcomes the problem of multiple sibs by considering the sibship as a whole. The MLB allowed us to consider the disease as either a binary (affected/unaffected) or an ordered categorical (differentiating the two forms of disease and including effects of environmental factors) phenotype. In both studies, two regions provided evidence for linkage at a significance level below 10(-4). One is located on chromosome 3 (from D3G041 to D3G047), and the other on chromosome 5 (from D5G034 to D5G041). In Study 2, the most significant results were obtained by combining both forms of disease, suggesting that they are under the same genetic control, while in Study 3, the stronger results were obtained when considering severe subjects alone, suggesting that only the severe form is under the control of both locus B and C. The subsequent knowledge of the true model allowed a posterior interpretation of our results, in particular the difference in optimal coding schemes observed between Studies 2 and 3, and the failure to locate locus A.

Alleles↗

PubMed1986

Genetic rat models for hypertension: guidelines for breeding, care and use.

Hypertension is a complex, multifactorial, polygenic disturbance of blood pressure homeostasis. The development of genetic rat models has contributed significantly to the acquisition of new knowledge on the pathophysiology of hypertension. Since there are multiple genetic rat models currently available and actively in use, and since there is need for guidelines for the breeding, care and use of such animal models, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) convened an international committee of experts to prepare such guidelines, a synopsis of which is herein presented.

Animal Welfare↗

PubMed1998

Induction of convulsive seizures by acoustic priming in a new genetically defined model of epilepsy (Noda epileptic rat: NER).

Noda epileptic rat (NER) is a mutant rat, found in a Crj: Wistar colony, which exhibits a tonic clonic convulsion spontaneously about once per 30 h from 14 weeks of age. We performed modified acoustic priming, that is, repeated weekly sound stimulations from 3 weeks of age. In addition, characteristics of audiogenic seizure (AGS), and ictal/interictal electroencephalograms (EEGs) were examined. We also studied the effect of repeated weekly stimulations from 14 weeks of age on AGS susceptibility in another NER. From 9 weeks of age, the NER primed from 3 weeks of age had a high incidence (100%) of AGS: a typical seizure was composed of sudden wild running and/or jumping (WRJ) followed by clonic or tonic-clonic convulsion. The severity and the duration of the AGS were intensified and prolonged with an increase in age, respectively. By contrast, the NER repeatedly stimulated from the age of 14 weeks, rarely showed AGS (20-40(%). The majority of the seizures in this NER were WRJ. The cortical and hippocampal EEG during the tonic convulsion showed a low-voltage spike-wave (5-7 Hz). This evolved into a high-amplitude spike- or polyspike-waves associated with the clonic convulsion. Immediately after cessation of the seizures, the EEG showed a flattening or diffuse slowing. In interictal EEG analysis, sporadic spikes predominantly in the hippocampus and spike-wave bursts in both the cortex and hippocampus occurred from 11 and 20 weeks of age, respectively. These results indicate that AGS susceptibility in NER can be induced consistently by modified acoustic priming and this rat strain is a new genetic model useful for experimental studies of human epilepsy.

Acoustic Stimulation↗

PubMed1983

Models of epidemics and endemicity in genetically variable host populations.

A discrete time genetics model is developed for populations that are undergoing selection due to infectious disease. It is assumed that the generation time of the host and infectious agent are not-synchronous and that only the host population is evolving. Two classes of epidemic processes are considered. The first class is for infectious agents that confer immunity following infection, while the second class is for those that do not confer immunity. The necessary and sufficient conditions are found in order for the disease to persist in a stable polymorphic host population. These conditions are shown to depend on the density of susceptibles, the selection coefficients, and the severity and class of the disease process.

Alleles↗

PubMed1984

Models of genetic control by repression with time delays and spatial effects.

Two models for cellular control by repression are developed in this paper. The models use standard theory from compartmental analysis and biochemical kinetics. The models include time delays to account for the processes of transcription and translation and diffusion to account for spatial effects in the cell. This consideration leads to a coupled system of reaction-diffusion equations with time delays. An analysis of the steady-state problem is given. Some results on the existence and uniqueness of a global solution and stability of the steady-state problem are summarized, and numerical simulations showing stability and periodicity are presented. A Hopf bifurcation result and a theorem on asymptotic stability are given for the limiting case of the models without diffusion.

Diffusion↗

PubMed2005

Studies on multiple trait and random regression models for genetic evaluation of beef cattle for growth.

A simulation study examined issues important for genetic evaluation of growth in beef cattle by random regression models with cubic Legendre polynomials (RRML) and linear splines with three knots (RRMS) compared with multiple-trait models (MTM). Parameters for RRML were obtained by conversion from covariance functions. Parameters for MTM and RRMS were extracted from RRML at 1, 205, and 365 d; parameters for RRMS were the same as MTM for all effects except the permanent environment and the residual. Four data sets were generated assuming RRML included records at 1, 205, and 365 d; at 1, 160 to 250, and 320 to 410 d; at 1, 100, 205, 300, and 365 d; and at 1, 55 to 145, 160 to 250, 275 to 325, and 320 to 410 d. Accuracies were computed as correlations between the true (simulated) and predicted breeding values. With the first data set, excellent agreement in accuracy was obtained for all models. With the second data set, the accuracy of MTM dropped by up to 1.5% compared with the first data set, but accuracy was unchanged for both RRML and RRMS. With the third (fourth) data set, accuracies of RRML were up to 2.4% (2.5%) higher than with the first (second) data set. Small differences in accuracy between RRML and RRMS were found with the third and fourth data sets, which were traced to inflated correlations especially between 1 and 205 d in RRMS; inflation could be decreased by adding one extra knot at 100 d to RRMS. Diagonalization of random coefficients was crucial for RRML but not for RRMS, resulting in approximately six (two) times faster convergence with RRML (RRMS). Reduction of dimensionality in RRML associated with small eigenvalues caused a less accurate evaluation for birth weight. Genetic evaluation of growth by RRM requires careful implementation. The RRMS is simpler to implement than the RRML.

Age Factors↗

PubMedDate not supplied

Aggravation of absence seizures by carbamazepine in a genetic rat model does not induce neuronal c-Fos activation.

The mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity within the thalamocortical circuitry. We used c-Fos immunohistochemistry (cFos-ir) to examine patterns of neuronal activation and the relationship to seizure expression following administration of carbamazepine in a rat model of absence epilepsy (Genetic Absence Epilepsy Rats of Strasbourg, GAERS). Female ovariectomized GAERS implanted with extradural EEG electrodes received either 20 mg/kg carbamazepine or vehicle IP. Seizure expression was quantified by measuring the total number and duration of spike-wave discharges (SWD) and with the individual burst discharge lengths over a 90-minute EEG. This was correlated with cFos-ir in thalamocortical slices from rats killed 180 minutes after carbamazepine administration. Carbamazepine-treated rats (n = 5) had a significantly greater total duration of SWD than vehicle-treated rats (17.9% versus 8.8%, P = 0.04). Despite this aggravation of seizures, the level of cFos-ir did not differ between the treatment groups. A positive correlation was found between cFos-ir in the reticularis thalami (Rt) and the total seizure duration (R = 0.66, P = 0.04) and mean burst length (R = 0.68, P = 0.03) but not total number of seizures. The lack of difference in cFos activation patterns between carbamazepine and vehicle-treated animals suggests that the mechanism for carbamazepine aggravation of absence seizures may not involve neuronal activation but rather enhanced neuronal synchronization. The association between increased neuronal activation in the Rt and seizure burden in GAERS provides further support for the critical role of this structure in the maintenance, but not initiation, of absence seizure activity.

Animals↗

PubMed1988

Familial risk of dementia associated with a biologic subtype of Alzheimer's disease.

Increased platelet membrane fluidity is a stable familial trait that identifies a prominent subgroup of patients with Alzheimer's disease. Patients in this subgroup have distinct clinical features, including an early age at symptomatic onset and a rapidly progressive course. The morbid risk of Alzheimer's-type dementia was studied in 421 first-degree relatives of 43 patients who met current consensus criteria for probable Alzheimer's disease and 47 healthy controls. Relatives of patients showed an approximate 50% (90- to 95-year) lifetime risk of dementia, regardless of the platelet membrane phenotype of the respective proband, which was over four times the control value. However, relatives of patients with increased platelet membrane fluidity who developed dementia exhibited symptoms significantly earlier than relatives of patients with normal platelet membrane fluidity. Alternative genetic models that describe the relationship of platelet membrane fluidity and Alzheimer's disease are discussed.

Actuarial Analysis↗

PubMed1997

Hypothalamic neurohistochemistry of the murine anorexia (anx/anx) mutation: altered processing of neuropeptide Y in the arcuate nucleus.

Neuropeptide Y is one of the most powerful neurochemical stimulants of food intake known. The neuronal substrate for this action is believed to be the neuropeptide Y-expressing cell population in the hypothalamic arcuate nucleus. In this study, mice homozygous for the anorexia mutation (anx) were investigated histochemically; anx is a recessive mutation that causes decreased food intake and starvation, leading to death 22 days after birth. We were interested to see whether any hypothalamic neurochemical abnormalities could be detected in this genetic model of starvation. By using immunohistochemistry and in situ hybridization, the hypothalamic distributions of neuropeptide Y, cholecystokinin, galanin, and serotonin, all messenger molecules postulated to be involved in the regulation of food intake and energy metabolism, were investigated. Immunoreactivities for somatostatin, the excitatory amino acid aspartate, and acetylcholinesterase were also studied. Neuropeptide Y-like immunoreactivity was increased markedly in arcuate cell bodies and decreased in terminals in the arcuate nucleus and other hypothalamic regions of anx/anx mice compared with normal litter mates. In situ hybridization for neuropeptide Y mRNA, however, showed no significant difference in gene expression in the arcuate nucleus. In addition, immunoreactivities for aspartate, acetylcholinesterase, and somatostatin in the arcuate nucleus were decreased in anx/anx mice. For cholecystokinin, galanin, and serotonin, no certain differences in hypothalamic immunoreactivity could be seen. These data suggest that a defect in neuropeptide Y-ergic signalling in the arcuate neurons may contribute to the failure to thrive in anx/anx mice.

Animals↗

PubMed1994

Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction.

BACKGROUND: Improvements in screening techniques have made significant contributions to the early detection of breast cancer. Physicians thus face the task of providing appropriate screening schedules for their patients. One group for whom this is particularly important are those women with a family history of breast cancer. METHODS: In this report, data from the Cancer and Steroid Hormone Study, a population-based, case-control study conducted by the Centers for Disease Control, are used to provide age-specific risk estimates of breast cancer for women with a family history of breast cancer. The data set includes 4730 patients with histologically confirmed breast cancer age 20-54 years and 4688 control subjects who were frequency matched to patients by geographic region and 5-year age intervals. The data set also includes family histories of breast cancer in mothers and sisters of both patients and control subjects. RESULTS: Genetic models fit previously to these data by the authors have provided evidence for a rare autosomal dominant allele that results in increased susceptibility to breast cancer. In addition, these models predict that women who carry the allele are at greater risk of developing breast cancer at any age than are women who do not carry the allele. The increase in risk in carriers versus noncarriers does, however, decrease with increasing age. Based on the parameters of this model, age-specific risks for a woman with one or more relatives affected with breast cancer at various ages at onset are given. CONCLUSIONS: These tables can be used for the purpose of counseling women at high risk of breast cancer development, that is, women with a family history of breast cancer.

Adult↗

PubMed2002

From fins to limbs to fins: limb evolution in fossil marine reptiles.

Limb osteology and ontogenetic patterns of limb ossification are reviewed for extinct lineages of aquatically adapted diapsid reptiles. Phylogenies including these fossil taxa show that paddle-like limbs were independently derived, and that the varied limb morphologies were produced by evolutionary modifications to different aspects of the limb skeleton. Ancient marine reptiles modify the limb by reducing the relative size of the epipodials, modifying the perichondral and periosteal surface of elements distal to the propodials, and evolving extremes of hyperphalangy and hyperdactyly. Developmental genetic models illuminate gene systems that may have controlled limb evolution in these animals.

Alligators and Crocodiles↗

PubMed1996

Familial temporal lobe epilepsy: a common disorder identified in twins.

We describe a new syndrome of familial temporal lobe epilepsy in 38 individuals from 13 unrelated white families. The disorder was first identified in 5 concordant monozygotic twin pairs as part of a large-scale twin study of epilepsy. When idiopathic partial epilepsy syndromes were excluded, the 5 pairs accounted for 23% of monozygotic pairs with partial epilepsies, and 38% of monozygotic pairs with partial epilepsy and no known etiology. Seizure onset for twin and nontwin subjects usually occurred during adolescence or early adult life. Seizure types were simple partial seizures with psychic or autonomic symptoms, infrequent complex partial seizures, and rare secondarily generalized seizures. Electroencephalograms revealed sparse focal temporal interictal epileptiform discharges in 22% of subjects. Magnetic resonance images appeared normal. Nine affected family members (24%) had not been diagnosed prior to the study. Pedigree analysis suggested autosomal dominant inheritance with age-dependent penetrance. The estimated segregation ratio was 0.3, indicating an overall penetrance of 60% assuming autosomal dominant inheritance. The mild and often subtle nature of the symptoms in some family members may account for lack of prior recognition of this common familial partial epilepsy. This disorder has similarities to the El mouse, a genetic model of temporal lobe epilepsy with a major gene on mouse chromosome 9, which is homologous with a region on human chromosome 3.

Adolescent↗

PubMed2004

Recombination in HIV and the evolution of drug resistance: for better or for worse?

The rapid evolution of drug resistance remains a major obstacle for HIV therapy. The capacity of the virus for recombination is widely believed to facilitate the evolution of drug resistance. Here, we challenge this intuitive view. We develop a population genetic model of HIV replication that incorporates the processes of mutation, cellular superinfection, and recombination. We show that cellular superinfection increases the abundance of low fitness viruses at the expense of the fittest strains due to the mixing of viral proteins during virion assembly. Moreover, we argue that whether recombination facilitates the evolution of drug resistance depends critically on how resistance mutations interact to determine viral fitness. Contrary to the commonly held belief, we find that, under the most plausible biological assumptions, recombination is expected to slow down the rate of evolution of multi-drug-resistant virus during therapy.

Drug Resistance, Viral↗

PubMed2006

Tol2 transposon-mediated transgenesis in Xenopus tropicalis.

The diploid frog Xenopus tropicalis is becoming a powerful developmental genetic model system. Sequencing of the X. tropicalis genome is nearing completion and several labs are embarking on mutagenesis screens. We are interested in developing insertional mutagenesis strategies in X. tropicalis. Transposon-mediated insertional mutagenesis, once used exclusively in plants and invertebrate systems, is now more widely applicable to vertebrates. The first step in developing transposons as tools for mutagenesis is to demonstrate that these mobile elements function efficiently in the target organism. Here, we show that the Medaka fish transposon, Tol2, is able to stably integrate into the X. tropicalis genome and will serve as a powerful tool for insertional mutagenesis strategies in the frog.

Animals↗

PubMed1994

Multilocus DNA fingerprinting: the independence problem in quantitative paternity testing.

A simulation study was performed in order to determine whether or not the assumption of independence, made in the quantitative analysis of multilocus DNA fingerprints, represents an inadmissible over-simplification. A total of 10,000 cases of true and false paternity, respectively, were simulated in twenty replicas of various genetic models. Log-likelihood ratios (paternity vs. non-paternity; LR) were calculated using published likelihood formulae and assuming position-wise independence. The resulting LR distributions were compared to (i) the results of a classical analysis of the underlying genotype data, and (ii) the distributions expected from the likelihood model employed in the LR calculations. Although considerable discrepancies were observed between these distributions, decision making about paternity appeared to be only marginally affected, especially when only a fraction of each multilocus DNA fingerprint was analyzed.

Chromosome Mapping↗

PubMed1984

Genetic epidemiology of breast cancer: segregation analysis of 200 Danish pedigrees.

An investigation of the genetic epidemiology of breast cancer involving complex segregation analysis of 200 breast cancer pedigrees of Danish extraction is presented. The observed distribution of breast cancer is compatible with transmission of an autosomal-dominant gene with no evidence for residual family resemblance. The gene frequency of the abnormal allele is 0.00756, and the displacement between the homozygous genotype means is 1.695. The gene frequency accounts for a significant proportion of breast cancer in young women, whereas by an advanced age a majority (87%) of affected women are phenocopies. Genetic modeling of other breast cancer families and results of linkage studies are reviewed.

Adult↗

PubMed1984

Segregation analyses of stuttering.

Although stuttering is known to be a familial disorder, no clear evidence regarding precise mode of transmission has arisen from previous research. In this report segregation analysis is applied to data on 386 stuttering probands and their first-degree relatives in an effort to discriminate among possible genetic models for the transmission of stuttering. Two different segregation analysis programs, PAP and POINTER, gave comparable results with respect to both hypothesis testing and parameter estimation. Specifically, the transmission of stuttering observed in these families cannot be adequately explained by a Mendelian major locus. The hypothesis of no polygenic component in the transmission of stuttering can, however, be rejected. Existence in these data of potential heterogeneity and possible violations of assumptions concerning ascertainment are considered in interpreting the results.

Adolescent↗

PubMed2001

Stratified case sampling and the use of family controls.

We compare the asymptotic relative efficiency (ARE) of different study designs for estimating gene and gene-environment interaction effects using matched case-control data. In the sampling schemes considered, cases are selected differentially based on their family history of disease. Controls are selected either from unrelated subjects or from among the case's unaffected siblings and cousins. Parameters are estimated using weighted conditional logistic regression, where the likelihood contributions for each subject are weighted by the fraction of cases sampled sharing the same family history. Results showed that compared to random sampling, over-sampling cases with a positive family history increased the efficiency for estimating the main effect of a gene for sib-control designs (103-254% ARE) and decreased efficiency for cousin-control and population-control designs (68-94% ARE and 67-84% ARE, respectively). Population controls and random sampling of cases were most efficient for a recessive gene or a dominant gene with an relative risk less than 9. For estimating gene-environment interactions, over-sampling positive-family-history cases again led to increased efficiency using sib controls (111-180% ARE) and decreased efficiency using population controls (68-87% ARE). Using case-cousin pairs, the results differed based on the genetic model and the size of the interaction effect; biased sampling was only slightly more efficient than random sampling for large interaction effects under a dominant gene model (relative risk ratio = 8, 106% ARE). Overall, the most efficient study design for studying gene-environment interaction was the case-sib-control design with over-sampling of positive-family-history-cases.

Bias↗