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PubMed2000

Genetic epidemiology study of pathological myopia.

OBJECTIVE: To explore the genetic epidemiology of pathological myopia (PM), including hereditary and genetic model. METHODS: The simple segregation analysis was done by SEGRANB. The values of segregation ratio p and the proportion of sporadic cases x were estimated. The complex segregation analysis was performed using SAGE-REGD. The genetic model and gene frequency were estimated. The 62 pedigrees with PM were random samples from hospital patients. RESULTS: By simple segregation analysis, the genetic pattern of N*N is autosomal recessive and the frequency of sporadic cases is approximately 65.72%. The genetic pattern of A*N may be autosomal recessive (but autosomal dominant cannot be excluded), the frequency of sporadic cases is approximately 35.14%. By complex segregation analysis, the genetic model of PM is autosomal recessive and the gene frequency is 0.147385. CONCLUSION: PM is compatible with autosomal recessive inheritance (autosomal dominant not excluded ), the sporadic cases are existent and the gene frequency is 0.147385.

Female↗
PubMedDate not supplied

Induction of a mycoplasma gallisepticum pMGA gene in the chicken tracheal ring organ culture model.

Genetic and molecular methods to investigate the pathogenesis of the poultry respiratory pathogen Mycoplasma gallisepticum are quite limited. Therefore, the objective of this study was to design and evaluate a functional genomics approach to identify M. gallisepticum genes involved in colonization of the poultry respiratory tract. To serve as a transcriptional reporter, a promoterless lacZ gene from Escherichia coli was cloned into the Tn4001 transposon. The transposon was used to randomly mutagenize the chromosome of the M. gallisepticum S6 strain, and a bank of 1386 transposon mutants containing lacZ fusions to mycoplasma chromosomal DNA was assembled. Each mycoplasma clone containing the lacZ reporter was independently screened in the chicken tracheal ring organ culture (TROC) model system for increased production of beta-galactosidase. A twofold or greater increase in beta-galactosidase was consistently observed for eight mutants. In one of the mutants, the transposon was inserted in a pMGA gene encoding a cell surface adhesin involved in hemagglutination. Therefore, these data indicate that screening of a M. gallisepticum transposon reporter bank with a chicken TROC model is useful for the identification of genes induced during poultry colonization and virulence.

Animals↗
PubMed2000

Hippocampal extracellular amino acids and EEG spectral analysis in a genetic rat model of absence epilepsy.

Absence seizures have a clearly defined thalamocortical origin. However, there is evidence from a genetic rat model of absence epilepsy, GAERS, that the underlying cellular and molecular abnormalities may also manifest themselves in other brain regions. As enhanced learning has previously been associated with this rat model, we have studied extracellular amino acid levels and EEG spectra in the hippocampus of these rats, this being a brain region associated with memory and learning. We report significantly higher levels of basal extracellular glutamate within the hippocampus of GAERS, together with transient increases in citrulline and glycine following aggravation of the absence seizures with the GABA(B) agonist, (-)baclofen. Furthermore, there is a reduction in the relative power of the EEG theta frequencies in GAERS, and a slowing of the EEG following administration of (-)baclofen which is not evident in control animals. Administration of a GABA(B) antagonist, CGP 56999, at a dose which blocks absence seizures in GAERS, caused a shift to faster frequencies of the EEG in both GAERS and control rats. It is speculated that the mechanisms underlying absence seizures in GAERS may manifest themselves in other functions modulated by thalamocortical oscillations such as cognitive processing.

Amino Acids↗
PubMed1994

Genetic epidemiology of vitiligo: multilocus recessivity cross-validated.

Vitiligo is a dermatological disorder characterized by hypopigmentary patches that tend to become progressive over time. There are reports of extensive familial aggregation. A genetic model for this disorder was earlier proposed by us. This model postulates that recessive alleles at multiple unlinked autosomal loci interact epistatically in the pathogenesis of vitiligo. The present family study was primarily undertaken to cross-validate the proposed genetic model. Data on 194 families from the United States were collected. Each family was ascertained through an affected proband. Analyses of these data reveal that approximately 20% of probands have at least one first-degree relative afflicted with vitiligo. All types of first-degree relatives of probands show a significant risk of developing vitiligo. Results of segregation and robustness analyses reveal that the genetic model postulated by us previously is the most parsimonious model for the present family data set.

Adolescent↗
PubMed2005

In silico phenotypic screening method of mutants based on statistical modeling of genetically mixed samples.

In comprehensive functional genomics projects, systematic analysis of phenotypes is vital. However, conventional phenotypic screening is done mainly by imprecise visual observation of qualitative traits, and, therefore, in silico screening techniques for quantitative traits are required. In this report, we propose in silico phenotypic screening method that utilizes a Gaussian mixture model for the trait distribution in the offspring of a mutagenized line and the likelihood ratio test between the estimated Gaussian mixture model and the wild-type single Gaussian model. In order to evaluate the proposed method, we performed a screening experiment using real trait data of Arabidopsis. In this experiment, the proposed screening method properly distinguished the mutant line from the wild-type line. Furthermore, we conducted power analysis of the proposed method and two conventional methods under various simulated conditions of sample size and distribution of trait frequency. The result of the power analysis confirmed the effectiveness of the proposed method compared to the conventional methods.

Algorithms↗
PubMed1997

Trans gene regulation in adaptive evolution: a genetic algorithm model.

This is a continuation of earlier studies on the evolution of infinite populations of haploid genotypes within a genetic algorithm framework. We had previously explored the evolutionary consequences of the existence of indeterminate-"plastic"-loci, where a plastic locus had a finite probability in each generation of functioning (being switched "on") or not functioning (being switched "off"). The relative probabilities of the two outcomes were assigned on a stochastic basis. The present paper examines what happens when the transition probabilities are biased by the presence of regulatory genes. We find that under certain conditions regulatory genes can improve the adaptation of the population and speed up the rate of evolution (on occasion at the cost of lowering the degree of adaptation). Also, the existence of regulatory loci potentiates selection in favour of plasticity. There is a synergistic effect of regulatory genes on plastic alleles: the frequency of such alleles increases when regulatory loci are present. Thus, phenotypic selection alone can be a potentiating factor in a favour of better adaptation.

Adaptation, Physiological↗
PubMed2005

Extension of a genetic network model by iterative experimentation and mathematical analysis.

Circadian clocks involve feedback loops that generate rhythmic expression of key genes. Molecular genetic studies in the higher plant Arabidopsis thaliana have revealed a complex clock network. The first part of the network to be identified, a transcriptional feedback loop comprising TIMING OF CAB EXPRESSION 1 (TOC1), LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), fails to account for significant experimental data. We develop an extended model that is based upon a wider range of data and accurately predicts additional experimental results. The model comprises interlocking feedback loops comparable to those identified experimentally in other circadian systems. We propose that each loop receives input signals from light, and that each loop includes a hypothetical component that had not been explicitly identified. Analysis of the model predicted the properties of these components, including an acute light induction at dawn that is rapidly repressed by LHY and CCA1. We found this unexpected regulation in RNA levels of the evening-expressed gene GIGANTEA (GI), supporting our proposed network and making GI a strong candidate for this component.

Arabidopsis↗
PubMed2005

Brain MRI abnormalities in schizophrenia: same genes or same environment?

BACKGROUND: Structural brain volume abnormalities are among the most extensively studied endophenotypes in schizophrenia. Bivariate genetic model fitting (adjusted to account for selection) was used to quantify the genetic relationship between schizophrenia and brain volumes and to estimate the heritability of these volumes. METHOD: We demonstrated by simulation that the adjusted genetic model produced unbiased estimates for endophenotype heritability and the genetic and environmental correlations. The model was applied to brain volumes (whole brain, hippocampus, third and lateral ventricles) in a sample of 14 monozygotic (MZ) twin pairs concordant for schizophrenia, 10 MZ discordant pairs, 17 MZ control pairs, 22 discordant sibling pairs, three concordant sibling pairs, and 114 healthy control subjects. RESULTS: Whole brain showed a substantial heritability (88%) and lateral ventricles substantial common environmental effects (67%). Whole brain showed a significant genetic correlation with schizophrenia, whereas lateral ventricles showed a significant individual specific correlation with schizophrenia. There were significant familial effects for hippocampus and third ventricle, but the analyses could not resolve whether these were genetic or environmental in origin (around 30%each). CONCLUSIONS: Using genetic model fitting on twin and sibling data we have demonstrated differential sources of covariation between schizophrenia and brain volumes, genetic in the case of whole brain volume and individual specific environment in the case of lateral ventricles.

Adolescent↗
PubMed2005

A comparison of interval mapping procedures including the QTL-cluster mapping.

Using the deterministic sampling, patterns of the log-likelihood surfaces expected in some interval mapping procedures for estimating the position of, and the effect for, QTL(s) were investigated for the situations where a single QTL or closely linked QTLs are contained in a chromosome segment bracketed with two markers. The mapping procedures compared were the conventional, likelihood-based interval mapping (IM), the regression interval mapping (RIM), and the QTL-cluster mapping (CM) in which the conditional probabilities of transmission of the whole segment marked by the flanking markers were taken into consideration. The half-sib design was used here, and several cases of the true genetic model were considered, differing in the number of QTLs contained in the marker interval, the linkage phase for the sire, and the magnitude of the QTL(s) effect. For the true genetic models where a single QTL or closely linked QTLs being in coupling phase are contained in the interval, with (R)IM, clear global maxima of the log-likelihood were observed within the range of the marker interval. It was shown that the estimates of the QTL(s) effect at the marked segment level are expected to be unbiased. On the other hand, in a setting where the linkage phase for the linked QTLs located in the interval was different from coupling and repulsion, there was found a ridge along the interval for the log-likelihood surface with (R)IM, indicating the dependency between the estimates of the position of, and the effect for, the putative QTL. For this case, it was found that the position of the putative QTL could be estimated as that of one of the flanking markers, and the estimate of the QTL effect be biased. In contrast, it was revealed that CM is expected to provide the unbiased estimate of the QTL(s)-effect at the segment level for any case of the true genetic models considered here. If the aim is for marker-assisted selection rather than mapping closely linked QTLs individually, then the CM approach is considered to be useful.

Chromosome Mapping↗
PubMedDate not supplied

Genetic evidence for bidirectional effects of early lexical and grammatical development.

This article addresses the autonomy hypothesis of vocabulary and grammar and bootstrapping mechanisms in early language development. Two birth cohorts of 1,505 and 1,049 same-sex twin pairs from the UK were assessed at 2 and 3 years on grammar and vocabulary, using adapted versions of the MacArthur Communicative Development Inventory. Vocabulary and grammar correlate strongly at both 2 and 3 years in both cohorts. Multivariate genetic modeling reveals a consistently high genetic correlation between vocabulary and grammar at 2 and 3 years. This finding suggests the same genetic influences operate for both vocabulary and grammar, a finding incompatible with traditional autonomy hypothesis, at least in early acquisition. Crosslagged longitudinal genetic models indicate both lexical and syntactical bootstrapping operate from 2 to 3 years.

Child Language↗
PubMed2002

Generating samples under a Wright-Fisher neutral model of genetic variation.

A Monte Carlo computer program is available to generate samples drawn from a population evolving according to a Wright-Fisher neutral model. The program assumes an infinite-sites model of mutation, and allows recombination, gene conversion, symmetric migration among subpopulations, and a variety of demographic histories. The samples produced can be used to investigate the sampling properties of any sample statistic under these neutral models.

Computational Biology↗
PubMed2004

Song learning accelerates allopatric speciation.

The songs of many birds are unusual in that they serve a role in identifying conspecific mates, yet they are also culturally transmitted. Noting the apparently high rate of diversity in one avian taxon, the songbirds, in which song learning appears ubiquitous, it has often been speculated that cultural transmission may increase the rate of speciation. Here we examine the possibility that song learning affects the rate of allopatric speciation. We construct a population-genetic model of allopatric divergence that explores the evolution of genes that underlie learning preferences (predispositions to learn some songs over others). We compare this with a model in which mating signals are inherited only genetically. Models are constructed for the cases where songs and preferences are affected by the same or different loci, and we analyze them using analytical local stability analysis combined with simulations of drift and directional sexual selection. Under nearly all conditions examined, song divergence occurs more readily in the learning model than in the nonlearning model. This is a result of reduced frequency-dependent selection in the learning models. Cultural evolution causes males with unusual genotypes to tend to learn from the majority of males around them, and thus develop songs compatible with the majority of the females in the population. Unusual genotypes can therefore be masked by learning. Over a wide range of conditions, learning therefore reduces the waiting time for speciation to occur and can be predicted to accelerate the rate of speciation.

Animals↗
PubMed2003

Genetic animal models of anxiety.

The focus of this review is on progress achieved in identifying specific genes conferring risk for anxiety disorders through the use of genetic animal models. We discuss gene-finding studies as well as those manipulating a candidate gene. Both human and animal studies thus far support the genetic complexity of anxiety. Clinical manifestations of these diseases are likely related to multiple genes. While different anxiety disorders and anxiety-related traits all appear to be genetically influenced, it has been difficult to ascertain genetic influences in common. Mouse studies have provisionally mapped several loci harboring genes that affect anxiety-related behavior. The growing array of mutant mice is providing valuable information about how genes and environment interact to affect anxious behavior via multiple neuropharmacological pathways. Classical genetic methods such as artificial selection of rodents for high or low anxiety are being employed. Expression array technologies have as yet not been employed, but can be expected to implicate novel candidates and neurobiological pathways.

Animals↗
PubMed2005

Viral vectors as tools to model and treat neurodegenerative disorders.

The identification of disease-causing genes in familial forms of neurodegenerative disorders and the development of genetic models closely replicating human central nervous system (CNS) pathologies have drastically changed our understanding of the molecular events leading to neuronal cell death. If these achievements open new opportunities of therapeutic interventions, including gene-based therapies, the presence of the blood-brain barrier and the post-mitotic and poor regenerative nature of the target cells constitute important challenges. Efficient delivery systems taking into account the specificity of the CNS are required to administer potential therapeutic candidates. In addition, genetic models in large animals that replicate the late stages of the diseases are in most cases not available for pre-clinical studies. The present review summarizes the potential of viral vectors as tools to create new genetic models of CNS disorders in various species including primates and the recent progress toward viral gene therapy clinical trials for the administration of therapeutic candidates into the brain.

Blood-Brain Barrier↗
PubMed2005

The nk model and population genetics.

The nk model of fitness interactions is examined. This model has been used by previous authors to investigate the effects of fitness epistasis on substitution dynamics in molecular evolution, and to make broader claims about the importance of epistasis. To examine these claims, an infinite-allele approximation is introduced. In this limit, it is shown that the nk model is, at an appropriate level of description, formally identical to the non-epistatic House-of-Cards model--a well-studied model in theoretical population genetics. It is further shown that in many parameter regimes, the analytical results obtained from this infinite-allele approximation are very close to results from the full nk model (with a finite number of alleles per locus). The findings presented shed light on a number of previous results.

Alleles↗
PubMed1995

Immunopathogenesis of lupus nephritis: new insights from experimental models.

Genetic analysis of systemic lupus erythematosus (SLE) in several lupus-prone mice has revealed that multiple, unlinked genes are required for the expression of various autoimmune manifestations, and that several, quite distinct genetic backgrounds are compatible with this disease. Although the nature of these genetic components has not been fully defined, it is becoming clear that certain genes such as the major histocompatibility complex class II genes and the genes regulating apoptosis apparently play a major role in the development of autoimmune responses characteristic in SLE. Analysis of the nephritogenic potential of monoclonal autoantibodies underlines the importance of qualitative features of autoantibodies in the pathogenesis of lupus nephritis. Strikingly, "wire-loop" glomerular lesions characteristic in human lupus nephritis can be induced by the direct localization of murine IgG3 antibodies with cryoglobulin activity without the involvement of immune complex formation. The remarkable correlation of IgG3 production with the development and acceleration of murine lupus nephritis, in association with enhanced activation of the TH1 subset which can lead to an increase in IgG3 production, is highly significant. The production process of more pathogenic autoantibodies appears to be genetically regulated. Further identification of the genetic defects present in lupus-prone mice, but lacking in mice with non-autoimmune backgrounds, is of paramount importance for the understanding of the immunopathogenetic mechanism of lupus nephritis and for the development of new therapeutic approaches for SLE.

Animals↗