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PubMed2000

A population genetics model for multiple quantitative traits exhibiting pleiotropy and epistasis.

We study a population genetics model of an organism with a genome of L(tot)loci that determine the values of T quantitative traits. Each trait is controlled by a subset of L loci assigned randomly from the genome. There is an optimum value for each trait, and stabilizing selection acts on the phenotype as a whole to maintain actual trait values close to their optima. The model contains pleiotropic effects (loci can affect more than one trait) and epistasis in fitness. We use adaptive walk simulations to find high-fitness genotypes and to study the way these genotypes are distributed in sequence space. We then simulate the evolution of haploid and diploid populations on these fitness landscapes and show that the genotypes of populations are able to drift through sequence space despite stabilizing selection on the phenotype. We study the way the rate of drift and the extent of the accessible region of sequence space is affected by mutation rate, selection strength, population size, recombination rate, and the parameters L and T that control the landscape shape. There are three regimes of the model. If LT< >L(tot), there are many small peaks that can be spread over a wide region of sequence space. Compensatory neutral mutations are important in the population dynamics in this case.

Animals↗

PubMed1999

Genetic models for handedness, brain lateralization, schizophrenia, and manic-depression.

There has been a long-standing debate to explain the complex correlation of development of human hand preference with brain lateralization, and occasionally, the correlation of both lateralizations with psychiatric disorders. A major unanswered question in this debate is whether nature (i.e., genetics) or nurture (environment/culture) controls the development of these attributes of human behavior. Simple genetic models have failed to satisfactorily explain the mode of inheritance of psychotic disorders as well as of the handedness trait. This paper advances several hypothetical and testable genetic models to explain the complex inheritance of these traits. In one model, brain lateralization is proposed to result from nonrandom segregation of the 'Watson' and 'Crick' strands of a particular chromosome, causing hemisphere lateralization, and that a gene, designated RGHT (for right), is further proposed to be responsible for the distribution of DNA chains to specific hemispheres. Accordingly, dominant, familially inherited schizophrenia and bipolar disorders are postulated to result from chromosomal rearrangements disrupting strand segregation, while sporadic cases are proposed to occur at increased frequencies in individuals with the recessive handedness genotype. Finally, discordance in monozygotic twins is suggested to occur due to developmental differences in brain lateralization in twins of the recessive genotype. Psychotic disorders are suggested to be due to developmental anomalies of cerebral asymmetry.

Bipolar Disorder↗

PubMed1996

Inclusive fitness arguments in genetic models of behaviour.

My purpose here is to provide a coherent account of inclusive fitness techniques, accessible to a mathematically literate graduate student in evolutionary biology, and to relate these to standard one-locus genetic models. I begin in Sect. 2 with a general formulation of evolutionary stability; in Sect. 3 and Sect. 4 I interpret the basic stability conditions within genetic and inclusive fitness models. In Sect. 5 I extend these concepts to the case of a class-structured population, and in Sect. 6 I illustrate these notions with a sex ratio example. In Sect. 7 I give a proof of the result that under additive gene action and weak selection, an inclusive fitness argument is able to verify an important stability condition (2.5) for one-locus genetic models. Most of these results have been published.

Alleles↗

PubMed1978

Schizophrenia: a study of genetic models and some of their implications.

The likelihoods of observing 25 four-generational families of schizophrenics comprising 1,333 individuals have been calculated on the basis of 12 different genetic models and one control 'sporadic' model. The control model gave a log10 likelihood, L, of -240.92. Five of the genetic models were definitely exlcuded as incompatible with certain pedigrees. The three models with the highest likelihoods were: one locus, the heterozygote having a 10% probability of being classified schizophrenic (L: - 220.05); two interacting loci (L: -219.46), and four polygenes (L: -216.87).

Alleles↗

PubMed2006

Mouse genetic models in alcohol research.

Animal models offer several advantages for the study of complex human disorders such as alcoholism. No animal model replicates all aspects of alcoholism but different components of the disorder can be investigated using various rodent models. In this article, we review a select subset of the most widely used mouse genetic models in alcohol research. Different genetically defined strains and stocks of mice are useful for genetic, physiologic, behavioral and pharmacological studies of this devastating disorder. In the past decade, numerous genomic regions associated with a tendency for various behavioral components of alcoholism have been identified; recent applications of new methods are shedding light on quantitative trait genes. Many of the underlying genes should be identified in the near future.

Alcoholism↗

PubMed2004

A cluster of differentially expressed signal transduction genes identified by microarray analysis in a rat genetic model of alcoholism.

Analyzing gene expression patterns in genetic models of alcoholism may uncover previously unknown susceptibility genes, and point to novel targets for drug development. Here, we compared expression profiles in alcohol-preferring AA rats with the alcohol-avoiding counterpart ANA line, and unselected Wistar rats. Cingulate cortex, Nc. accumbens, amygdala and hippocampus of each line were analyzed using the Afymetrix RN U34 arrays and dChip 1.1 software. Analysis of line-specific expression revealed 48 differentially expressed genes between AA and ANA rats. Elevated hippocampal neuropeptide Y (NPY) was found in ANA rats in agreement with previous studies. A cluster of MAP-kinases indicating altered signal transduction was upregulated within the Nc. Accumbens of the AA line, and is of particular functional interest. Within the amygdala, a more loosely inter-related cluster of cytoskeleton-associated genes may point to structural abnormalities. The observed dysregulations may contribute to the alcohol-preferring phenotype.

Alcoholism↗

PubMed1985

Quantitative genetic models of female choice based on "arbitrary" male characters.

Multivariate, quantitative genetic models are developed for the evolution of female mating preferences in situations where males contribute only their gametes to their progeny. Although female mating preferences may not be directly subject to selection, they can evolve via genetic correlations with other characters that are undergoing evolutionary change. The first set of models examines the evolutionary origin of mating preferences directed at one or more traits that may or may not be expressed only in males. When several selected characters possess additive genetic variance, an indirect selective force exists for the evolution of multivariate mating preferences. The magnitude of this force is proportional to the covariance between a female's relative preference for a given male's phenotype and the expected viability of his progeny. The contribution of any single character to this covariance determines its potential value as a mate choice criterion. The pattern of genetic and phenotypic covariation may cause selectively unimportant traits to be useful in mate choice. In the extreme, selectively neutral characters may become the objects of mating preferences, if they are relatively immune to random environmental variation and genetically correlated with selectively important characters. The second set of models examines the dynamic evolution of such a selectively neutral ("arbitrary") character that is both the object of a mating preference and genetically correlated with a third trait that affects viability. The outcome of evolution in this three character system is highly indeterminate. As in other sexual selection models, there exists a line of neutral equilibria wherein the mean of the criterion character matches the mean level of mating preference within the population, while the viability trait equilibrates at the phenotypic value conferring maximum viability. This line of equilibria, however, is not likely to be stable unless females choose mates according to absolute mating preferences. Thus, mating preferences that initially may arise as a mean of increasing offspring viability may nevertheless lead to indeterminate and potentially maladaptive evolutionary outcomes.

Animals↗

PubMedDate not supplied

A bivariate quantitative genetic model for a linear Gaussian trait and a survival trait.

With the increasing use of survival models in animal breeding to address the genetic aspects of mainly longevity of livestock but also disease traits, the need for methods to infer genetic correlations and to do multivariate evaluations of survival traits and other types of traits has become increasingly important. In this study we derived and implemented a bivariate quantitative genetic model for a linear Gaussian 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. Model parameters were inferred from their marginal posterior distributions. The required fully conditional posterior distributions were derived and issues on implementation are discussed. The two Weibull baseline parameters were updated jointly using a Metropolis-Hasting step. The remaining model parameters with non-normalized fully conditional distributions were updated univariately using adaptive rejection sampling. Simulation results showed that the estimated marginal posterior distributions covered well and placed high density to the true parameter values used in the simulation of data. In conclusion, the proposed method allows inferring additive genetic and environmental correlations, and doing multivariate genetic evaluation of a linear Gaussian trait and a survival trait.

Animals↗

PubMed1999

Characterization of seizures in the flathead rat: a new genetic model of epilepsy in early postnatal development.

PURPOSE: Disorders in normal central nervous system (CNS) development are often associated with epilepsy. This report characterizes seizures in a novel genetic model of developmental epilepsy, the Flathead (FH) rat. METHODS: Animals (n = 76) ages P0-22 were monitored for clinical and electrographic seizure activity. The effects of various AEDs on seizure frequency and duration also were assessed: phenobarbital (PB; 40 mg/kg), valproate (VPA; 400 mg/kg), or ethosuximide (ESM; 600 mg/kg). RESULTS: FHs display episodes of behavior characterized by whole-body tremor, strub tail, alternating forelimb clonus, and complete tonus. EEG recordings from neocortex reveal that FH seizures are bilateral and begin around P7. Seizures occur at a frequency of approximately six per hour from P7 to P18 and the average duration of seizures increases through development. PB, VPA, and ESM failed to prevent seizures; however, PB significantly increased the interval of seizures but had no effects on the duration of seizures, whereas VPA decreased the duration of seizures and not the interval. CONCLUSIONS: Seizures in FH rats occur at a constant and high frequency through a defined period in early postnatal development, and these seizures are not completely blocked by high doses of PB, VPA, or ESM. Because FH is a single-locus mutant displaying a highly regular pattern of seizure activity, it is an ideal model for examining the process of epileptogenesis in the developing brain, evaluating new AED therapies, and determining the identity of a gene essential to the normal development of cortical excitability.

Animals↗

PubMed1994

Genetic models for the inheritance of the silver colour mutation of foxes.

We consider genetic models for the inheritance of the particular colour patterns of silver foxes. The models are evaluated by computation of statistical likelihoods based on observations of related foxes in extended pedigrees. Problems caused by incomplete paternity information are addressed by inferences based on phenotypic observations. The unreliability of subjective evaluations of fur colour also provides difficulty, in particular crossfoxes emerge as being difficult to differentiate. No evidence of linkage between Agouti locus and Extension locus is found in this dataset.

Alleles↗

PubMed2004

Annual fish as a genetic model for aging.

Advancement in the genetics of aging and identification of longevity genes has been largely due to the model organisms such as Caenorhabditis elegans and Drosophila melanogaster. However, knowledge gained from these invertebrates will not be able to identify vertebrate-specific longevity genes. The mouse has a relatively long life span of about 3 years, which limits its utility for screening of longevity genes. Fish have been used in aging studies. However, systematic comparison of survivorship curves for fish is lacking. In this study, we compared the survivorship curves of zebrafish and 2 different annual fish, namely, Cynolebias nigripinnis and Nothobranchius rachovii. These studies established that Nothobranchius rachovii has the shortest life span (8.5 months, at which time 10% of population remains). We also established that it is possible to breed Nothobranchius rachovii under laboratory conditions, and showed that their embryos can be stored for several months and hatched at any time by adding water. In addition, we have isolated 31 cDNA markers out of 71 attempted amplifications based on corresponding homologous genomic sequences in zebrafish and Fugu available from public databases, suggesting that approximately 40% of the genes from Nothobranchius rachovii could be easily isolated. Thus, the ability to be bred under laboratory conditions and the availability of cDNA markers for mapping, along with the major advantage of a relatively short life span, make Nothobranchius rachovii an attractive vertebrate genetic model for aging over other available vertebrate models.

Aging↗

PubMed2006

Population genetic models of male and mutual mate choice.

Examples of male mate choice are becoming increasingly common, even in polygynous species. We create a series of population genetic models to examine the evolutionary equilibria and dynamics resulting from male mate choice during polygyny, alone and in the context of mutual mate choice by both sexes. We find that unless males with a preference are able to increase their overall courtship output, male preference will be lost. This loss can be counteracted if males choose females not based on arbitrary traits, but based on a trait that indicates high fertility or viability. We also conclude that if male and female preferences and traits are all controlled by different loci, the male and female mate choice systems are decoupled; the presence of a male preference then has no influence on the equilibria or dynamics of female mate choice. If male and female traits are coupled by pleiotropy, it becomes possible for a male preference to be maintained, regardless of whether preferences between the sexes are pleiotropic or controlled by separate loci.

Animals↗

PubMed1999

Genetic models for the study of insulin-like growth factors (IGF) and muscle development in birds compared to mammals.

IGFs are important positive modulators of overall body and muscle growth in different species. Genetic variation in IGF-I gene expression exists as shown by the possibility of genetic selection for high or low circulating IGF-I concentrations in mice and the associated variations in growth potential. Targeted over-expression of IGF-I in transgenic mice results in muscle hypertrophy, but it is yet unknown whether genetic variability in muscle IGF-I gene expression exists. Much less data are available in birds. This review is focussed on the potential role of IGFs on chicken muscle development. Apart from the absence of a type 2 IGF receptor (IGF-II receptor), the general characteristics of the chicken IGF system seem to be similar to mammalian species. In different genetic models with altered growth rates or body composition, differences in the IGF system are observed suggesting its importance in regulating body growth in those species. The components for a paracrine action of IGF are also present in chicken muscle but it has not yet been demonstrated if they contribute to differences in muscle development.

Animals↗

PubMed2006

Teratogen-induced, dietary and genetic models of congenital diaphragmatic hernia share a common mechanism of pathogenesis.

Congenital diaphragmatic hernia (CDH) is a frequently occurring, major congenital abnormality that has high mortality and significant morbidity in survivors. Currently, the pathogenesis of CDH is poorly understood. In this study, we have compared the anatomical characteristics of diaphragm defects in the well-described nitrofen model with the pathogenesis of CDH in vitamin A-deficient rats and wt1 null-mutant mice, representing teratogen-induced, dietary and genetic models of CDH, respectively. Our histological investigations, aided by three-dimensional reconstruction of the developing diaphragm, revealed a common pathogenic mechanism with regards to the location of the diaphragm defect in the foramen of Bochdalek (posterolateral diaphragm) and specific abnormalities within the primordial diaphragm. Furthermore, our analysis of postmortem specimens highlighted similarities in human cases of CDH and these animal models, supporting our hypothesis that CDH in humans arises from a defect in the primordial diaphragm. Immunohistochemical data were consistent with the defect in the primordial diaphragm being in the nonmuscular component. Importantly, these data show that very distinct models of CDH all share a common pathogenic mechanism and, together with supporting evidence from pathological specimens, highlight our proposed pathogenic model for CDH.

Animals↗

PubMed1999

Use of genetic models in respiratory neurobiology and sleep.

In this review, two issues are highlighted: 1) the difficulties that can form major hurdles in trying to understand a disease or a fundamental biologic process at the genetic and molecular level and 2) the potential opportunities that genetic models such as the Drosophila or c-elegans can provide in answering clinically or biologically relevant questions. This review also lists in some detail the areas in which these models have been helpful and successes have been scored. For such models to be used, however, requires the "dissection" of a biologic or a disease process into a tractable phenotype that can be assayed in a genetic model and have relevant and interpretable conclusions. The hope is that questions pertaining to sleep, arousal, respiratory neurobiology, and their disorders can be formulated in such a way to be addressed in models that can lend themselves to very exciting discoveries.

Animals↗

PubMed1984

A quantitative genetic model of two-policy games between relatives.

Equations are derived for the change per generation of the population mean of the probability that an individual adopts a policy 1 as opposed to a policy 2 in a behavioral interaction between two diploid individuals of the same generation in which two policies are possible. The probability is assumed to be a quantitative genetic trait determined by many additively acting genes of small effects and an independent environmental component. Equations are derived for the case that interactions occur at random between all members of the population and also for the case that interactions occur between relatives of the same average degree of relatedness. It is assumed that each group of relatives and the number of such groups is sufficiently large. For a quantitative genetic trait with the additional assumption of unlinked loci the latter equation can be heuristically derived from the first by substituting the corresponding inclusive fitness effects. When per locus selection coefficients are small and linkage equilibrium holds, the average degree of relatedness can be equated approximately with Wright's coefficient of relationship. Thus, the quantitative genetic model provides a genetic basis for the inclusive fitness approach toward games between relatives. By contrast, in a monogenic system with major gene effects we obtain substantially different results which contradict those obtained by the inclusive fitness approach in game theory. Applications are made to the hawk-dove game, and the simple and iterated forms of the prisoner's dilemma.

Altruism↗

PubMed2006

A model genetic system for testing the in vivo function of peptide toxins.

We have developed a model genetic system for analyzing the function of peptide toxins from animal venoms. We engineered and propagated strains of Drosophila melanogaster expressing heat-inducible transgenes encoding either kappa-ACTX-Hv1c or omega-ACTX-Hv1a, two insect-specific neurotoxic peptides found in the venom of the Australian funnel-web spider Hadronyche versuta. Heat induction of transgene expression for 20 min was sufficient to kill all transgenic flies, indicating that the ion channels targeted by these toxins are viable insecticide targets. The unusual phenotype of flies induced to express omega-ACTX-Hv1a recapitulates that of a hypomorphic allele of the high-voltage-activated calcium channel Dmca1D, suggesting that this is likely to be the target of omega-ACTX-Hv1a.

Amino Acid Sequence↗

PubMed1984

Line-of-descent and genealogical processes, and their applications in population genetics models.

A variety of results for genealogical and line-of-descent processes that arise in connection with the theory of some classical selectively neutral population genetics models are reviewed. While some new results and derivations are included, the principle aim is to demonstrate the central importance and simplicity of genealogical Markov chains in this theory. Considerable attention is given to "diffusion time scale" approximations of such genealogical processes. A wide variety of results pertinent to (diffusion approximations of) the classical multiallele single-locus Wright-Fisher model and its relatives are simplified and unified by this approach. Other examples where such genealogical processes play an explicit role, such as the infinite sites and infinite alleles models, are discussed.

Alleles↗