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PubMed1999

Stochastic properties of one-parameter discrete model of genetic diversity in the unique random parameter case.

Stochastic properties of previously introduced one parameter discrete model of genetic diversity (M. Yu. Shchelkanov et al, J. Biomol. Struct. Dyn. 15, 887-894 (1998)) are investigated. Two approaches are compared: (A) when the on-step substitution number and/or the number of substitution steps are random variables; (B) referred parameters are replaced by mathematical expectations of the respective variables. It has been demonstrated, that estimations of sequence measure based on the number of replication steps are more under the assumption of case (A) as compared with (B). Thus, real biological situation relating to the case (A) could additionally promote the increasing of distinctions between different taxons (e.g. HIV, etc.). Peculiarities of one-parameter discrete model of genetic diversity during calculation of the distinctions between symbol (e.g. nucleotide) sequence sets are also discussed.

Genetic Variation↗
PubMed2001

A study of occlusal variation in the primary dentition of Australian twins and singletons.

In this study, we quantified the extent of variation in different occlusal features of Australian children of European descent with complete primary dentitions, but no permanent teeth present in the mouth. The study group consisted of 412 individuals, aged between 3 and 7 years, including 70 monozygous (MZ) twin pairs, 68 same-sexed dizygous (DZ) twin pairs, 11 opposite-sexed DZ twin pairs, and 114 singletons. Occlusal traits, including inter-dental spacing, incisal overbite and overjet, arch breadth and arch depth, were obtained directly from dental casts or indirectly from photocopies or impressions of the casts. Descriptive statistics summarised the data and indicated that distributions were similar to those published for other populations. Univariate genetic analysis, using the structural equation modelling package Mx, was carried out on the quantitative data using the normal assumptions of the twin model. Genetic modelling indicated that a model incorporating additive genetic (A) and unique environmental variation (E) was the most parsimonious for interdental spacing, overbite, overjet and arch dimensions. Estimates of heritability for interdental spacing ranged from 0.62 to 0.81. Estimates for overbite and overjet were 0.53 and 0.28, respectively, and estimates for arch dimensions ranged from 0.69 to 0.89. These results indicated a moderate to relatively high genetic contribution to observed variation.

Australia↗
PubMed2006

Elevated circulating levels of markers of oxidative-nitrative stress and inflammation in a genetic rat model of metabolic syndrome.

Metabolic syndrome is a cluster of metabolic diseases that in essence greatly promotes progression of atherosclerosis. We used a genetic model of the metabolic syndrome, the SHR/NDmcr-cp (SHR/cp) rat, from 6 to 40 weeks of age to investigate whether systemic oxidative stress, a major cause of atherosclerosis, increases in this syndrome. Nine-week-old male rats already showed manifestations of metabolic syndrome, including heavier body weight, higher blood pressure and higher levels of serum glucose, insulin and various lipids compared to the age-matched Wistar Kyoto (WKY) rats used as a genetic control. These metabolic parameters gradually progressed with age. Likewise, the serum levels of oxidative stress markers, including lipid peroxides, which oxidatively modify low-density lipoprotein (LDL) and 8-hydroxydeoxyguanosine (8-OHdG), gradually increased in SHR/cp rats. The serum levels of 3-nitrotyrosine and 3-chlorotyrosine also persistently increased, indicating the involvement of peroxynitrite or myeloperoxidase-catalyzed oxidation. In addition, high-sensitivity C-reactive protein (hsCRP), an early marker of inflammation, temporarily increased in SHR/cp rats compared to WKY rats. These findings suggest that oxidative stress, as well as nitrative stress and inflammation, increases in the metabolic syndrome, which may contribute to the development of atherosclerosis.

Animals↗
PubMed1986

Genetics of schizophrenia: I. Familial patterns and mode of inheritance.

The purpose of this article is to review and condense the available literature on genetic modeling in schizophrenia research. The principles underlying genetic models and the various applications of these models to family data are reviewed. It is concluded that despite the advances in statistical genetics, the mode of inheritance of schizophrenia remains elusive. The conflicting results are attributed to variation in methods for data collection and analysis and to the heterogeneous nature of the disorder. The possibility is also raised that most previous genetic analyses of schizophrenia may have been compromised by methodological drawbacks. Although the use of advanced genetic models in conjunction with adequate data may shed more light on the genetic contribution to schizophrenia, the limitations of this approach in genetically heterogeneous disorders must be recognized. Alternative methods, such as studies with biological susceptibility traits and genetic markers, may be more useful in unraveling the specific genetic components that underlie the transmission of schizophrenia.

Genetic Counseling↗
PubMed2005

Lack of evidence of association between MTHFR C677T polymorphism and congenital heart disease in a TDT study design.

INTRODUCTION: Hyperhomocysteinemia is frequently associated with congenital defects of the heart and neural tube. A common missense mutation in the MTHFR gene (C to T substitution at position 677 changing valine to alanine) produces a variant with reduced enzymatic action, resulting in higher plasma levels of homocysteine. The aim of this study is to investigate whether MTHFR C677T functional genetic variant is associated with an increased risk of congenital heart disease (CHD) development using a family-based case-control design and the Transmission Disequilibrium Test (TDT) approach. METHODS: We selected 91 consecutive patients with congenital heart disease for the study. From these patients we were able to obtain samples on 147 parents. The C677T polymorphism at the MTHFR gene was determined from each participant. RESULTS: A statistically significant association was disclosed in univariate analysis using a family-based case-control design (p<0.0001 assuming an additive genetic model, p<0.0001 assuming a dominant genetic model, and p=0.01 assuming a recessive genetic model). This association was explained by an increased frequency of the T allele in patients as compared to their fathers. However, by using a TDT approach a highly non-significant result was obtained and no association could be defined between this locus and congenital heart disease. CONCLUSIONS: We did not find sufficient evidence for an association between MTHFR C677T genotype and congenital heart disease in our study group. Previous reports on such association may be due to population genetic structure.

Algorithms↗
PubMed2000

Basic properties of populations generated in the frame of one-parameter discrete model of genetic diversity.

Previously, when discussing the properties of one parameter discrete model of genetic diversity (M.Yu. Shchelkanov et al, J. Biomol. Struct. Dyn. 15, 887-894 (1998)), we took into account Hamming distance distribution only between precursor and arbitrary descendant sequences. However, really there are sets of sequence populations produced during amplification process. In the presented work we have investigated Hamming distance distributions between sequences from different descendant sets produced in the frame of one parameter discrete model. Two basic descendant generation operators (so called amplifiers) are introduced: 1) the last generation amplifier, L, which produces descendants with precursor elimination; 2) all generations amplifier, G, which produces descendants without precursor elimination. Generalization of one-parameter discrete model for the case when precursor sequences do not coincide are carried out. Using this generalization we investigate the distribution of Hamming distances between L- and G-generated sequences. Basic properties of L and G operators, L/G-choice alternative problem have been discussed. Obtained results have common theoretical significance, but they are more suitable for high level genetic diversity process (for example, HIV diversity).

Genetic Variation↗
PubMed2006

Models and partition of variance for quantitative trait loci with epistasis and linkage disequilibrium.

BACKGROUND: A genetic model about quantitative trait loci (QTL) provides a basis to interpret the genetic basis of quantitative traits in a study population, such as additive, dominance and epistatic effects of QTL and the partition of genetic variance. The standard quantitative genetics model is based on the least squares partition of genetic effects and also genetic variance in an equilibrium population. However, over years many specialized QTL models have also been proposed for applications in some specific populations. How are these models related? How to analyze and partition a QTL model and genetic variance when both epistasis and linkage disequilibrium are considered? RESULTS: Starting from the classical description of Cockerham genetic model, we first represent the model in a multiple regression setting by using indicator variables to describe the segregation of QTL alleles. In this setting, the definition of additive, dominance and epistatic effects of QTL and the basis for the partition of genetic variance are elaborated. We then build the connection between this general genetic model and a few specialized models (a haploid model, a diploid F2 model and a general two-allele model), and derive the genetic effects and partition of genetic variance for multiple QTL with epistasis and linkage disequilibrium for these specialized models. CONCLUSION: In this paper, we study extensively the composition and property of the genetic model parameters, such as genetic effects and partition of genetic variance, when both epistasis and linkage disequilibrium are considered. This is the first time that both epistasis and linkage disequilibrium are considered in modeling multiple QTL. This analysis would help us to understand the structure of genetic parameters and relationship of various genetic quantities, such as allelic frequencies and linkage disequilibrium, on the definition of genetic effects, and will also help us to understand and properly interpret estimates of the genetic effects and variance components in a QTL mapping experiment.

Algorithms↗
PubMed2000

Deficit of striatal parvalbumin-reactive GABAergic interneurons and decreased basal ganglia output in a genetic rodent model of idiopathic paroxysmal dystonia.

The underlying mechanisms of various types of hereditary dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model of a type of paroxysmal dystonia, the dt(sz) mutant hamster, pointed to striatal dysfunctions. In the present study, immunhistochemical experiments demonstrated a marked decrease in the number and density of parvalbumin-immunoreactive GABAergic interneurons in all striatal subregions of mutant hamsters. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABA(A) receptor agonist muscimol on severity of dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome after striatal injections to a similar extent as after systemic treatment, supporting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striatal GABAergic projection neurons, as suggested by recent extracellular single-unit recordings in dt(sz) hamsters, should lead to an abnormal neuronal activity in the basal ganglia output nuclei. Indeed, a significantly decreased basal discharge rate of entopeduncular neurons was found in dt(sz) hamsters. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activity in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiology of hyperkinesias. The results indicate that striatal interneurons deserve attention in basic and clinical research of those movement disorders.

Action Potentials↗
PubMed1986

Primate population structure: evaluation of models.

Genetic markers among macaques on Cayo Santiago island were analyzed in an attempt to infer aspects of mating structure. Several models that included high levels of gene flow among groups could not be distinguished, but the data are clearly incompatible with group endogamy and with high variance in male fitness. Drift effective size is approximately one half census size in this population.

Animals↗
PubMed2007

Evaluation of the cancer chemopreventive efficacy of rice bran in genetic mouse models of breast, prostate and intestinal carcinogenesis.

Brown rice is a staple dietary constituent in Asia, whereas rice consumed in the Western world is generally white, obtained from brown rice by removal of the bran. We tested the hypothesis that rice bran interferes with development of tumours in TAg, TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) or Apc(Min) mice, genetic models of mammary, prostate and intestinal carcinogenesis, respectively. Mice received rice bran (30%) in AIN-93G diet throughout their post-weaning lifespan. In TAg and TRAMP mice, rice bran did not affect carcinoma development. In TRAMP or wild-type C57Bl6/J mice, dietary rice bran increased kidney weight by 18 and 20%, respectively. Consumption of rice bran reduced numbers of intestinal adenomas in Apc(Min) mice by 51% (P<0.01), compared to mice on control diet. In parallel, dietary rice bran decreased intestinal haemorrhage in these mice, as reflected by increased haematocrit. At 10% in the diet, rice bran did not significantly retard Apc(Min) adenoma development. Likewise, low-fibre rice bran (30% in the diet) did not affect intestinal carcinogenesis, suggesting that the fibrous constituents of the bran mediate chemopreventive efficacy. The results suggest that rice bran might be beneficially evaluated as a putative chemopreventive intervention in humans with intestinal polyps.

Animals↗
PubMed2003

Bayesian estimation of parameters of a structural model for genetic covariances between milk yield in five regions of the United States.

Inference about genetic covariance matrices using multiple-trait models is often hindered by lack of information. This leads to imprecise estimates of genetic parameters and of breeding values. Patterns in a genetic covariance matrix can be exploited to reduce the number of parameters and to increase quality of inferences. A structural model for genetic covariances was developed and fitted to milk yield data in five regions of the United States. This was compared with a standard multiple-trait analysis using a deviance information criterion, a measure of quality of fit. Data consisted of 3,465,334 Holstein first-lactation records from daughters of 43,755 sires in five regions of the United States (Midwest, Northeast, Northwest, Southeast, Southwest). Parameters of the structural model included an intercept and effects of measures of genetic and of management similarity on genetic covariances. Genetic similarity depended on the number of records contributed by sires that were common to a pair of regions. Management similarity was a function of the quantity of concentrate used to produce 1000 kg of milk in each pair of regions. The structural and the multiple-trait models gave similar estimates of genetic covariances, but the number of parameters was 8 in the former vs. 15 in the latter. Hence, estimates of genetic covariances were more precise with the structural model. A deviance information criterion suggested a slight superiority of the multiple-trait model, although probably within sampling error. For both models, genetic correlations between milk yield in five regions of the United States were larger than 0.93.

Analysis of Variance↗
PubMedDate not supplied

The future of path analysis, segregation analysis, and combined models for genetic dissection of complex traits.

Appropriate combined models are discussed for the analysis of complex traits. It is argued that combined models may be necessary for optimally extracting the information from family studies. It is further argued that, especially as we face genes with much smaller effects, our ability to find these genes will depend on how precisely and accurately we are able to model the interrelationships. We need these newer models and methods for optimally extracting the information from family data, and we also need to reorient ourselves as to how we interpret the very information extracted. It is projected that path and segregation analysis, as seen in terms of combined models, will be useful in the new millennium.

Chromosome Segregation↗
PubMed2005

Differential association of family subsystem negativity on siblings' maladjustment: using behavior genetic methods to test process theory.

This study investigated the family context of adolescent sibling similarity and differentiation in maladjustment (antisocial behavior and depression) by examining negativity in different subsystems. Two hypotheses were proposed: (1) Parental and sibling negativity tends to diffuse through the family system, especially because of the high level of reciprocity in sibling relationships, leading to sibling similarity; and (2) interparental (coparenting) conflict disrupts cohesive functioning and thereby motivates and facilitates sibling differentiation and niche picking. To control for the effects of similar genes between siblings, the authors used behavioral genetic models with a genetically informed sample of 720 two-parent families, each with at least 2 adolescent siblings. Results for the differences in shared environmental influences across groups high and low in each of the domains of family negativity provided partial support for the hypotheses. The results further understanding of influences on individual differences and support a theory of how parent-child and interparental relationships intersect with sibling relationship dynamics.

Adaptation, Psychological↗
PubMed1985

Interaction of spatial diffusion and delays in models of genetic control by repression.

A class of models based on the Jacob and Monod theory of genetic repression for control of biosynthetic pathways in cells is considered. Both spatial diffusion and time delays are taken into account. A method is developed for representing the effects of spatial diffusion as distributed delay terms. This method is applied to two specific models and the interaction between the diffusion and the delays is treated in detail. The destabilization of the steady-state and the bifurcation of oscillatory solutions are studied as functions of the diffusivities and the delays. The limits of very small and very large diffusivities are analyzed and comparisons with well-mixed compartment models are made.

Biometry↗
PubMed2004

Stem and progenitor cell therapies: insights from non-human primate models.

Genetic marking strategies in the non-human primate model have elucidated a number of principles relevant to implementation of clinical stem cell therapies, including the lineage potential, number and lifespan of hematopoietic stem and progenitor cells, and differences in the functional properties of marrow cells mobilized into the peripheral blood utilizing different regimens.

Animals↗
PubMedDate not supplied

Reduced primary antibody responses in a genetic animal model of depression.

OBJECTIVE: Clinical depression is associated with multiple abnormalities of immune function, including reduced virus-specific responses. This study tested the hypothesis that the Flinders Sensitive Line (FSL) rat, a promising genetic animal model of depression, would exhibit reductions in antigen-specific primary antibody responses to immunization. METHODS: FSL (N = 13) and control Flinders Resistant Line (FRL; N = 14) rats were immunized with the protein antigen keyhole limpet hemocyanin (KLH; 300 microg/kg), and KLH-specific immunoglobulin (Ig)M, IgG, IgG1, and IgG2a responses were measured before and 3, 5, 7, 11, and 14 days after immunization. In separate experiments, production of interferon-gamma (IFN-gamma) by cells from naive and KLH-immunized animals was measured in vitro to determine whether strain differences in antibody production might be associated with differential production of this regulatory cytokine. RESULTS: KLH-specific production of IgM (p <.01) and IgG2a (p <.05) was significantly reduced in the FSL rats compared with the FRL controls. There were no strain differences in IgG or IgG1 production. Although IFN-gamma production between the two strains was similar in naive animals, cells from KLH-immunized FSL rats produced significantly less IFN-gamma when stimulated with KLH in vitro than cells from KLH-immunized FRL controls (p =.01). CONCLUSIONS: This study extends previous reports of altered immune function in the FSL rats to include reduced in vivo antigen-specific antibody responses. Moreover, diminished production of IFN-gamma by KLH-primed lymphocytes may contribute to lower antibody production in these animals. Collectively, these data suggest deficiencies in type 1 T-helper cell-mediated immunity in the FSL rats.

Animals↗