QUANTITATIVE GENETIC MODELS FOR DEVELOPMENT,EPIGENETIC SELECTION,AND PHENOTYPIC EVOLUTION

Herein we describe a general multivariate quantitative genetic model that incorporates two potentially important developmental phenomena, maternal effects and epigenetic effects. Maternal and epigenetic effects are defined as partial regression coefficients and phenotypic variances are derived in terms of age-specific genetic and environmental variances. As a starting point, the traditional quantitative genetic model of additive gene effects and random environmental effects is cast in a developmental time framework. From this framework, we first extend a maternal effects model to include multiple developmental ages for the occurrence of maternal effects. An example of maternal effects occurring at multiple developmental ages is prenatal and postnatal maternal effects in mammals. Subsequently, a model of intrinsic and epigenetic effects in the absence of maternal effects is described. It is shown that genetic correlations can arise through epigenetic effects, and in the absence of other developmental effects, epigenetic effects are in general confounded with age-specific intrinsic genetic effects. Finally, the two effects are incorporated into the basic quantitative genetic model. For this more biologically realistic model combining maternal and epigenetic effects, it is shown that the phenotypic regressions of offspring on mother and offspring on father can be used in some cases to estimate simultaneously maternal effects and epigenetic effects.     

Nonlinear mixed effects models for repeated measures data

We propose a general, nonlinear mixed effects model for repeated measures data and define estimators for its parameters. The proposed estimators are a natural combination of least squares estimators for nonlinear fixed effects models and maximum likelihood (or restricted maximum likelihood) estimators for linear mixed effects models. We implement Newton-Raphson estimation using previously developed computational methods for nonlinear fixed effects models and for linear mixed effects models. Two examples are presented and the connections between this work and recent work on generalized linear mixed effects models are discussed.     

Organizational and activational effects of sex steroids on brain and behavior: A reanalysis

The actions of sex steroids on brain and behavior traditionally have been divided into organizational and activational effects. Organizational effects are permanent and occur early in development; activational effects are transient and occur throughout life. Over the past decade, experimental results have accumulated which do not fit such a simple two-process theory. Specifically, the characteristics said to distinguish organizational and activational effects on behavior are sometimes mixed, as when permanent effects occur in adulthood. Attempts to determine whether specific cellular processes are uniquely associated with either organizational or activational effects are unsuccessful. These considerations blur the organizational-activational distinction sufficiently to suggest that a rigid dichotomy is no longer tenable.     

Dynamics of a quantitative character subject only to stabilising selection

The implications of stabilising selection on a quantitative trait, in the absence of other evolutionary forces, are theoretically investigated in a randomly mating population. The dynamics of various statistics that describe the alleles contributing to the trait are determined and used to infer the behaviour of the trait. Dynamical solutions of the distribution of allelic effects and the distribution of the trait are found when all initial distributions of allelic effects are Gaussian and linkage disequilibria are neglected. Some results for the behaviour of the mean and the variance of genotypic effects of the population, when subject to a moving optimum, are derived. When the initial distributions of allelic effects are not Gaussian, but possess a small asymmetry, the mean and the variance of the allelic effects differ only slightly from the Gaussian results. By contrast, the third central moments of allelic effects, are, at all loci, strictly zero in the Gaussian case but are generally non-zero for non-symmetric initial distributions. To leading order in a quantitative measure of the asymmetry of the distribution, we determine the third central moment of allelic effects.     

Cohort effects and population dynamics

Cohort effects originate from environmental conditions, and can have long‐term consequences for the cohort's performance. It has been proposed that cohort effects tend to increase population fluctuations. However, differences among individuals, which cohort effects introduce into a population, usually have stabilizing effects. There are thus two different predictions regarding the impact of cohort effects on population fluctuations. We argue that it is important to distinguish between environmental variability and its long‐term effects on individual quality, and approach the question with a population model that can include or exclude such effects. We show that the influence of cohort effects depends on the inherent dynamics: cohort effects can have stabilizing effects if dynamics are inherently unstable. However, the most common outcome is destabilization whenever cohort effects act on top of inherently stable dynamics. Intriguingly, both alternatives are due to individual differences affecting the structure of density dependence in a similar way.     

Childbearing in crisis: war, migration and fertility in Angola

This study examines the short- and long-term effects of war-induced and war-unrelated migration on fertility outcomes using data from two peri-urban municipalities of Greater Luanda in Angola. In the short term, results from multi-level discrete-time logistic regression models indicate that net of other factors, war-unrelated migration is associated with a lower probability of birth than war-induced migration in a given year. Similar results are obtained when the effects of migration are lagged by a year. At the same time, the effects of war-triggered migration do not differ significantly from those of not migrating in a given year but are statistically significant when the effects of migration are lagged by a year. In the long term, the effects of migration experience on cumulative fertility are negligible and not statistically significant net of demographic and socioeconomic variables. Interpretations of the results are offered in the context of Angola and their broader implications are reflected on.     

Models to estimate maternally controlled genetic variation in quantitative seed characters

Summary Estimating quantitative contributions to specific traits can be accomplished from a variety of genetic models (Mather 1949; Mather and Jinks 1971; Falconer 1981). Residual genetic effects, those beyond main and interaction effects of the embryo genotype, are often pooled under a single classification, termed maternal effects. Maternal contributions to seed-related traits can originate from various maternal sources (e.g., endosperm, testa and cytoplasm). Quantitative contributions of a maternal nature are not predictable from parental performance and effects are largely non-persistent over generations (Jinks et al. 1972). The methods used to determine maternal effects in quantitative traits often do not measure quantitative genetic parameters, while those that do are either complex or partially resolve potential contributions of individual sources of maternal effects. We present simple genetic models for estimating quantitative genetic parameters which take into account maternal effects expressed in the major seed tissues of higher plants.     

Fitness consequences of maternal and grandmaternal effects

Transgenerational effects are broader than only parental relationships. Despite mounting evidence that multigenerational effects alter phenotypic and life‐history traits, our understanding of how they combine to determine fitness is not well developed because of the added complexity necessary to study them. Here, we derive a quantitative genetic model of adaptation to an extraordinary new environment by an additive genetic component, phenotypic plasticity, maternal and grandmaternal effects. We show how, at equilibrium, negative maternal and negative grandmaternal effects maximize expected population mean fitness. We define negative transgenerational effects as those that have a negative effect on trait expression in the subsequent generation, that is, they slow, or potentially reverse, the expected evolutionary dynamic. When maternal effects are positive, negative grandmaternal effects are preferred. As expected under Mendelian inheritance, the grandmaternal effects have a lower impact on fitness than the maternal effects, but this dual inheritance model predicts a more complex relationship between maternal and grandmaternal effects to constrain phenotypic variance and so maximize expected population mean fitness in the offspring.     

The mapping of epistatic effects onto a genealogical tree in haploid populations

In this paper we present a model that maps epistatic effects onto a genealogical tree for a haploid population. Prior work has demonstrated that genealogical structure causes the genotypic values of individuals to covary. Our results indicate that epistasis can reduce genotypic covariance that is caused by genealogical structure. Genotypic effects (both additive and epistatic) occur along the branches of a genealogical tree, from the base of the tree to its tips. Epistasis reduces genotypic covariance because there is a reweighting of the contribution of branches to the states of genotypes compared to the additive case. Branches near the tips of a genealogical tree contribute proportionally more genetic effects with epistasis than without epistasis. Epistatic effects are most numerous at basal positions in a genealogical tree when a population is constant in size and experiencing no selection, optimizing selection, diversifying selection or directional selection, indicating that epistatic effects are typically old. For a population that is growing in size, epistatic effects are most numerous at midpoints in a genealogical tree, indicating epistatic effects are of moderate age. Our results are important in that they suggest epistatic effects may typically explain deep (old) divergences and broad patterns of divergence that exist in populations, except in growing populations. In a growing population, epistatic effects may cause more within group divergence higher up in a tree and less between group divergence that is deep in a tree. The distribution of the number of epistatic effects and the expected variance and covariance in the number of epistatic effects is also provided assuming neutrality.     

Effects of corticotropin releasing hormone on appetitive behaviors.

Corticotropin releasing hormone (CRH) is a 41-residue hypothalamic neuropeptide that has been shown to have potent behavioral effects in animals and has been implicated in clinical disorders in man. This review focuses on those aspects of the behavioral effects of CRH related to food-associated behaviors. The effects of CRH on food intake are compared with its effects on performances maintained by food presentation, and contrasted with the effects of CRH on performances maintained by other events. The effects of CRH antagonists and drugs that interact with the behavioral effects of CRH are also reviewed, particularly with respect to their direct effects on food intake. Lastly, data assessing the effects of CRH administration on central neurotransmitter levels are presented and compared with levels seen in clinical populations. The effect of CRH on food intake seen in animals is consistent with a putative role for CRH in clinical syndromes where appetite suppression is apparent. Since some of the effects of CRH on food intake are subject to pharmacological intervention, strategies directed at peptidergic mechanisms of psychiatric disorders should be explored.     

The Production of Quality in Child-Care Centers: Another Look

Data from the Cost, Quality, and Outcomes Study (Helburn, 1995) are used to examine the effects of group size, staff-child ratio, and teacher qualifications on the quality of child care provided in day care centers. The Cost, Quality, and Outcomes data are from a representative 4-state sample of day care centers with a design that makes it possible to control for unobserved differences across centers that could cause biased estimates of the effects of interest. The empirical results indicate that group size has small and statistically insignificant effects on child-care quality. A higher staff-child ratio appears to have beneficial effects on child-care quality when unobserved differences across centers are not accounted for. These effects become much smaller when unobserved differences are accounted for. The effects of teacher education and training are also generally not robust, but some measures of education and training have quantitatively and statistically significant effects even accounting for unobserved differences across centers. The implications of the results for future research on the determinants of child-care quality and for public policy are discussed.     

Pièges et artéfacts en imagerie TEP/TDM : intérêts des post-traitements

In PET imaging, quantification of the acquired data can be achieved by using a series of correction techniques to minimize the effects inherent in the imaging process of emission tomography. Quantitative images can be reconstructed after correcting the detected emission data for the presence of random and scattered coincidences, attenuation effects, effects associated with the variable detectors sensitivity, effects related to the geometry of the device and the effects of dead-time. All these effects are well accounted for in the PET imaging market. However, other effects can degrade the quality of the PET images, such as the finite spatial resolution generating partial volume effects, or the patient movements including respiratory and cardiac physiological movements. In the thoracic field, the effects of respiratory motion on PET images are characterized by a loss of detection sensitivity due to the associated blur. Several methods have been developed to correct for these effects, but still without a wide acceptance in clinical routine. These research areas are therefore still very active.     

The actions and side effects of Anabolic Steroids in sport and social abuse

Anabolic steroids (AS) derived from testosterone have both anabolic (muscle and strength enhancing) and androgenic (primary and secondary sexual) effects. Efforts to limit the androgenic while enhancing the anabolic effects have not been successful. Alterations to the structure of testosterone, so as to improve the pharmacokinetics of AS, have resulted in drugs, which are orally active, have a longer plasma half life and may be administered as depot injections. Therapeutic doses of AS produce statistically significant effects on strength and athletic performance in well-controlled scientific and clinical trials. At low, therapeutic doses, diet and an intensive training regime are equally important in producing a statistically significant increase in strength. Higher doses 6–7000mg per week are regularly administered in sport and produce the greatest increases in muscle strength erythropoiesis and lean body mass. Patterns of steroid abuse can be complex, reflecting a desire to minimise side effects, and avoid detection. AS side effects are of many types. AS increase salt and water retention leading to an expansion of the blood volume, but effects of steroids on blood pressure are equivocal and most cardiovascular side effects appear to be reversible. Abuse of AS causes an increase in blood triglyceride and cholesterol levels and this is associated with a decline in High Density Lipoproteins (HDLs) and an increase in the Low Density (LDL) type. Though these effects are reversible they are associated with an increased risk of both acute and chronic cardiovascular pathology. The most serious irreversible anabolic steroid side effects are associated with carcinomas-mainly of the liver, prostate and kidney. Hepatic carcinomas are strongly associated with abuse of the orally active 17alpha methyl substituted steroids, which also produce a reversible jaundice. In males, anabolic steroid abuse causes suppression of LH and FSH release leading to inhibition of testosterone production often accompanied by testicular atrophy, and azoospermia. High, chronic doses of the drugs may also cause moderate to severe feminising effects in the form of gynaecomastia. Male secondary sexual characteristics are a side effect of AS abuse in women. Increased insulin resistance and elevated fasting blood glucose levels are the commonest non-gonadal endocrine side effects of AS.     

Family Effects on Antipredator Behavior in the Field Cricket, Gryllus Integer

Most animals have antipredator mechanisms. These may include a variety of behaviors. One such behavior is “freezing”, i.e. becoming immobile in response to a predator. This paper is focused on freezing behavior in a species of field cricket, Gryllus integer. We studied this behavior in both nymphs and adults, and looked for family effects, as well as the effects of sex. Our research shows that there are no family effects in nymphs, but there are family effects in adults. No sex differences occur between the sexes at either stage of development. Because all of the crickets were reared under identical conditions in the laboratory, such family effects are likely due to genetic effects, maternal effects, or both.     

克隆和有性亲体效应及其调控机制

植物表型受自身基因型、所处环境及其亲体所经历环境的共同影响;其中,亲体环境对子代表型的影响被称为亲体效应。亲体效应不仅可通过有性繁殖产生的种子传递给后代(即有性亲体效应),也可以通过克隆生长等无性繁殖产生的分株传递给后代(即克隆亲体效应)。亲体效应对植物种群,特别是对有性繁殖受限、缺乏遗传变异的克隆植物种群的长期进化可能发挥着极其重要的作用,因此,对亲体效应研究进展的梳理非常必要。对克隆亲体效应和有性亲体效应的内涵进行了阐释,并论述了克隆和有性亲体效应对子代表型、适合度、种内/种间竞争能力以及种群/群落结构和功能的潜在影响;阐述了亲体效应的潜在调控机制,包括供给机制、代谢物质调控机制、表观遗传机制等;论述了克隆亲体效应在克隆植物适应进化中的作用。未来可以就克隆亲体效应的遗传稳定性及其对克隆生活史性状变异的贡献程度,以及克隆和有性亲体效应引起的表型多样性对种内/种间关系、种群/群落多样性及生态系统结构、功能和稳定性的影响开展深入研究。     

Principal stratification in causal inference

Many scientific problems require that treatment comparisons be adjusted for posttreatment variables, but the estimands underlying standard methods are not causal effects. To address this deficiency, we propose a general framework for comparing treatments adjusting for posttreatment variables that yields principal effects based on principal stratification. Principal stratification with respect to a posttreatment variable is a cross-classification of subjects defined by the joint potential values of that posttreatment variable tinder each of the treatments being compared. Principal effects are causal effects within a principal stratum. The key property of principal strata is that they are not affected by treatment assignment and therefore can be used just as any pretreatment covariate. such as age category. As a result, the central property of our principal effects is that they are always causal effects and do not suffer from the complications of standard posttreatment-adjusted estimands. We discuss briefly that such principal causal effects are the link between three recent applications with adjustment for posttreatment variables: (i) treatment noncompliance, (ii) missing outcomes (dropout) following treatment noncompliance. and (iii) censoring by death. We then attack the problem of surrogate or biomarker endpoints, where we show, using principal causal effects, that all current definitions of surrogacy, even when perfectly true, do not generally have the desired interpretation as causal effects of treatment on outcome. We go on to forrmulate estimands based on principal stratification and principal causal effects and show their superiority.     

Innovative combination strategy to enhance effect and diminish adverse effects of glucocorticoids: another promise?

In a paper by Zimmermann and colleagues in this issue of Arthritis Research & Therapy, results of extended laboratory research with the drug combination of prednisolone and dipyridamole are reported. There seems to be a boost and extension of the glucocorticoid effect by the combination, without a clear increase of adverse effects, potentially allowing the application of lower dosages. However, laboratory models are not patients and the glucocorticoid mechanisms leading to effects and adverse effects are manifold. The next required step will be to demonstrate the improved therapeutic window in patients in adequate comparative clinical trials, assessing predefined beneficial effects and adverse effects in a standardized way.     

REVERSING MOTHER'S CURSE: SELECTION ON MALE MITOCHONDRIAL FITNESS EFFECTS

Many essential organelles and endosymbionts exhibit a strict matrilineal pattern of inheritance. The absence of paternal transmission of such extranuclear components is thought to preclude a response to selection on their effects on male viability and fertility. We overturn this dogma by showing that two mechanisms, inbreeding and kin selection, allow mitochondria to respond to selection on both male viability and fertility. Even modest levels of inbreeding allow such a response to selection when there are direct fitness effects of mitochondria on male fertility because inbreeding associates male fertility traits with mitochondrial matrilines. Male viability effects of mitochondria are also selectable whenever there are indirect fitness effects of males on the fitness of their sisters. When either of these effects is sufficiently strong, we show that there are conditions that allow the spread of mitochondria with direct effects that are harmful to females, contrary to standard expectation. We discuss the implications of our findings for the evolution of organelles and endosymbionts and genomic conflict.     

Effect of DOPA and dopamine on the motility of isolated rat duodenum in vitro]

The motor effects of DOPA and Dopamine on the isolated rat duodenum in vitro have been studied by establishing successive dose- response curves. These effects are either excitatory or inhibitory according to the concentrations used. In every case they are of small amplitude. The inhibitory effects do not exist in the presence of alpha, and beta blocking agents. The excitatory effects are suppressed by using a serotoninergic blocking agent.