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PubMed2003

Modeling and dissection of longitudinal blood pressure and hypertension phenotypes in genetic epidemiological studies.

We discuss analyses of the Genetic Analysis Workshop 13 data from the Framingham Heart Study and simulations based on this study. We summarize analyses that investigated measures of systolic blood pressure or hypertension as the main phenotype, with the main focus being the modeling of this complex longitudinal phenotype. The approaches include familial aggregation methods and one-stage and two-stage linkage methods. For one-stage linkage methods, phenotype modeling is carried out jointly with the linkage analysis or incorporated in the analysis design. For two-stage linkage methods, phenotypes are first modeled in order to develop summary measures that are then analyzed in a subsequent linkage analysis. Results depend on phenotype selection and on how analyses account for longitudinality, treatment effects, and heterodasticity.

Blood Pressure↗
PubMed2000

Multivariate models of mixed assortment: phenotypic assortment and social homogamy for education and fluid ability.

Phenotypic assortment is assumed to be the principal mechanism of spouse similarity in most biometrical studies. Other assortment mechanisms, such as social homogamy, may be plausible. Two models are presented that consider phenotypic assortment and social homogamy simultaneously (i.e., mixed assortment), where selective associations between social background factors (Model I) versus selective associations between total environments (Model II) distinguish the models. A series of illustrative analyses was undertaken for education and fluid ability available on a sample of 116 Swedish twin pairs and their spouses. On the basis of several fit criteria Model I was preferred over Model II. Both social homogamy and phenotypic assortment may contribute to spouse similarity for educational attainment and fluid ability. Furthermore, spouse similarity for fluid ability may arise indirectly from social homogamy and phenotypic assortment for educational attainment. Power analyses indicated greater observed power for Model I than Model II. Additional power analyses indicated that considerably more twin-spouse sets would be needed for Model II than Model I, to resolve social homogamy and phenotypic assortment. Effects of misspecification of mechanisms of spouse similarity are also briefly discussed.

Adult↗
PubMed2006

Behavioral phenotypes and pharmacology in genetic mouse models of Parkinsonism.

Prior to the discovery of genes associated with familial forms of Parkinson's disease, animal models of Parkinson's disease mainly consisted of toxin models based exclusively on the degeneration of nigrostriatal dopamine neurons. These traditional models have provided valuable insight into symptomatic treatments for Parkinson's disease; however, they lack the broad extra-nigral pathology and the progression that is observed in the disease. The novel genetic mouse models recently generated are advantageous because they have mutations that are known to cause familial Parkinson's disease and thus they have good construct validity. To maximize the utility of these models, a thoughtful phenotypical characterization is important. Our laboratory has assembled a battery of behavioral tests to assess sensorimotor function in genetic mouse models of Parkinsonism. This review discusses the sensitivity of these tests in different genetic mice in addition to their behavioral response to dopamine agonists.

Animals↗
PubMed2006

Antisocial and seizure susceptibility phenotypes in an animal model of epilepsy are normalized by impairment of brain corticotropin-releasing factor.

Social interaction phenotyping is an unexplored niche in animal modeling of epilepsy despite the sensitivity of affiliative behaviors to emotionality and stress, which are known seizure triggers. Thus, the present studies examined the social phenotype of seizure-susceptible El and nonsusceptible ddY strains both in untreated animals and following preexposure to a handling stressor. The second aim of the present studies was to evaluate the dependence of sociability in El mice on the proconvulsive, stress neuropeptide corticotropin-releasing factor (CRF) using CRF-SAP, a conjugate of CRF and the toxin saporin, which selectively reduced CRF peptide levels in the basolateral amygdala of El mice. El mice exhibited lower social investigation times than ddY counterparts, whereas central administration of CRF-SAP normalized social investigation times relative to ddY controls. Moreover, handling-induced seizures in El mice were reduced by 50% following treatment with CRF-SAP relative to saporin alone-injected El controls. The results of this study suggest that tonically activated CRF systems in the El mouse brain suppress affiliative behavior and facilitate evoked seizures.

Analysis of Variance↗
PubMed2003

Gene dosage and selective expression modify phenotype in a Drosophila model of human mitochondrial disease.

Human mitochondrial disease manifests with a wide range of clinical phenotypes of varying severity. To create a model for these disorders, we have manipulated the Drosophila gene technical knockout, encoding mitoribosomal protein S12. Various permutations of endogenous and transgenic alleles create a range of phenotypes, varying from larval developmental arrest through to mild neurological defects in the adult, and also mimic threshold effects associated with human mtDNA disease. Nuclear genetic background influences mutant phenotype by a compensatory mechanism affecting mitochondrial RNA levels. Selective expression of the wild-type allele indicates critical times and cell-types in development, in which mitochondrial protein synthesis deficiency leads to specific phenotypic outcomes.

Journal Article↗
PubMed1987

Monotonic change of the mean phenotype in two-locus models.

It is shown that the mean phenotype monotonically approaches the optimum in a class of symmetric, two-locus, two-allele models with stabilizing selection. In this model, mean fitness does not change monotonically. Thus, Fisher's fundamental theorem does not hold, even though another quantity of evolutionary interest, the mean phenotype, can be shown to change monotonically. Using this quantity, it is proven that global stability results for this model.

Genetics, Population↗
PubMed2006

Mice congenic for a locus that determines phenotype in the neuroma model of neuropathic pain.

A common strategy for identifying physiological processes responsible for pain is to compare animal strains that show high versus low pain phenotype. However, this approach yields only weak inference because most strains differ from one another at a large number of genetic loci. We undertook a congenic breeding program aimed at transposing the gene(s) that confers dominant (low) pain phenotype in the neuroma model of neuropathic pain from mice of the C58/J strain onto a genetic background that normally expresses high pain phenotype (C3H/HeN). Successful transposition, and the observation of equal numbers of phenotypically high and low offspring in each of 11 generations of selective breeding, provides evidence that the trait is largely controlled by a single gene (or linked cluster) of major effect.

Animals↗
PubMed2006

Power of mixed-model QTL mapping from phenotypic, pedigree and marker data in self-pollinated crops.

The power of QTL mapping by a mixed-model approach has been studied for hybrid crops but remains unknown in self-pollinated crops. Our objective was to evaluate the usefulness of mixed-model QTL mapping in the context of a breeding program for a self-pollinated crop. Specifically, we simulated a soybean (Glycine max L. Merr.) breeding program and applied a mixed-model approach that comprised three steps: variance component estimation, single-marker analyses, and multiple-marker analysis. Average power to detect QTL ranged from <1 to 47% depending on the significance level (0.01 or 0.0001), number of QTL (20 or 80), heritability of the trait (0.40 or 0.70), population size (600 or 1,200 inbreds), and number of markers (300 or 600). The corresponding false discovery rate ranged from 2 to 43%. Larger populations, higher heritability, and fewer QTL controlling the trait led to a substantial increase in power and to a reduction in the false discovery rate and bias. A stringent significance level reduced both the power and false discovery rate. There was greater power to detect major QTL than minor QTL. Power was higher and the false discovery rate was lower in hybrid crops than in self-pollinated crops. We conclude that mixed-model QTL mapping is useful for gene discovery in plant breeding programs of self-pollinated crops.

Chromosome Mapping↗
PubMed2025

Simple scaling laws control the genetic architectures of human complex traits.

Genome-wide association studies have revealed that the genetic architectures of complex traits vary widely, including in terms of the numbers, effect sizes, and allele frequencies of significant hits. However, at present we lack a principled way of understanding the similarities and differences among traits. Here, we describe a probabilistic model that combines the effects of mutation, drift, and stabilizing selection at individual sites with a genome-scale model of phenotypic variation. In this model, the architecture of a trait arises from the distribution of selection coefficients of mutations and from two scaling parameters. We fit this model for 95 highly polygenic quantitative traits of different kinds from the UK Biobank. Notably, we infer that all these traits have fairly similar, though not identical, distributions of selection coefficients. This similarity suggests that differences in architectures of highly polygenic traits arise mainly from the two scaling parameters: the mutational target size and heritability per site, which vary by orders of magnitude among traits. When these two scale factors are accounted for, we find that the architectures of all 95 traits are very similar.

Humans↗
PubMed2005

Murine succinate semialdehyde dehydrogenase (SSADH) deficiency, a heritable disorder of GABA metabolism with epileptic phenotype.

Murine models of inborn errors of metabolism represent an established approach for investigating pathophysiological mechanisms associated with the corresponding human disorder. Our laboratory studies human inherited defects of GABA synthesis and degradation. One of these, succinate semialdehyde dehydrogenase (SSADH) deficiency (or gamma-hydroxybutyric aciduria; OMIM 271980; E.C. 1.2.1.24), has recently been modeled via gene targeting in the mouse. SSADH-/- mice succumb to early lethality in status epilepticus at postnatal (PN) days 20 - 26. Numerous metabolic, neurochemical and neurophysiological abnormalities have been documented using in vitro and in vivo approaches, substantially altering our thoughts about the complexity of the corresponding human condition. Moreover, novel preclinical treatment paradigms have been developed through drug trials in gene-ablated animals. The greatest utility of this animal, however, may reside in its transition from early absence seizures to generalized convulsions and eventual status epilepticus. Accurate neurochemical assessment during this transition may provide clues to the same transition process in patients, for which the underlying mechanisms remain undefined.

Animals↗
PubMed2004

Resolving within- and between-population variation in feeding ecology with a biomechanical model.

Studies of phenotypic plasticity have emphasized the effect of the environment on the phenotype, but plasticity can also be used as a tool to study the functional significance of key traits. By inducing variation in phenotypes and testing quantitative models that predict performance based on biological mechanisms, we can develop functionally general models of performance. Pumpkinseed sunfish from lakes with high snail availability have large levator posterior muscles (which are used to crush snail shells), whereas fish from lakes with few snails have relatively small muscles. Here we: (1) quantify differences in the feeding ability of an ontogenetic series of pumpkinseed from two populations; and (2) evaluate whether a biomechanical model can resolve the observed ontogenetic and between-population variation in feeding ecology. Mass, but not length, of the levator posterior muscle in fish from Three Lakes (a lake rich in snails) was greater than for comparably sized fish from Wintergreen Lake (a lake with few snails). Handling times were shorter, crushing strengths were 71% greater, and foraging rate (snail tissue mass consumed per time) and the fraction of thick-shelled snails in the diet were approximately 100% greater for fish from Three Lakes compared to comparably sized fish from Wintergreen. These between-lake differences were not significant after adjusting for variation in pharyngeal morphology, suggesting that the biomechanical model of snail crushing resolved observed ontogenetic and population-level variation in the feeding ecology of pumpkinseed.

Analysis of Variance↗
PubMed2000

Identification of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes, genotypes and molecular modelling.

In order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.

Amino Acid Substitution↗
PubMed2004

Rett syndrome: of girls and mice--lessons for regression in autism.

Rett syndrome (RTT) is a neurodevelopmental disorder occurring almost exclusively in females. Regression is a defining feature of RTT. During the regression stage, RTT girls display many autistic features, such as loss of communication and social skills, poor eye contact, and lack of interest, and initially may be given the diagnosis of autism. The discovery of the genetic cause of RTT, mutations in the MECP2 gene, a transcriptional repressor, has promoted the early diagnosis of RTT and development of mouse models. The phenotype of one mouse model includes features such as regression and abnormal behavioral and social interactions. The timing of the period of regression in RTT--during ages 1 to 2 years--parallels the period of intense synaptic development. The effects of the MECP2 mutation also increases concomitantly with peak synaptogenesis. Neuropathological findings in Rett include the selective reduction of dendritric spines in the pyramidal cells of RTT brains; this feature has also been reported in autism. Studies have observed that MECP influences the expression of brain-derived neurotrophic factor and thus may influence synaptic plasticity. Abnormalities in synapse maintenance and modulation may contribute to regression in RTT and autism. Studies of the clinical aspects of the regression period and of the mouse model may be useful in understanding the pathophysiology of RTT and other neurodevelopmental disorders such as autism. A recent study observed abnormal expression of MeCP2 in RTT and other neurodevelopmental disorders such as autism. Although the genetic background and certain clinical features differ in RTT and autism, a similar mechanism involving MeCP2 regulation and expression may contribute to regression.

Animals↗
PubMedDate not supplied

Phenotypic and dynamical transitions in model genetic networks. II. Application to the evolution of segmentation mechanisms.

Knowledge of the genetic control of segmentation in Drosophila has made insect segmentation a paradigmatic case in the study of the evolution of developmental mechanisms. In Drosophila, the patterns of expression of segmentation genes are established simultaneously in all segments by a complex set of interactions between transcriptional factors that diffuse in a syncytium occupying the whole embryo. Such mechanisms cannot act in short germ-band insects where segments appear sequentially from a cellularized posterior proliferative zone. Here, we compare mechanisms of segmentation in different organisms and discuss how the transition between the different types of segmentation can be explained by small and progressive changes in the underlying gene networks. The recent discovery of a temporal oscillation in expression during somitogenesis of vertebrate homologs of the pair-rule gene hairy enhances the plausibility of an earlier proposal that the evolutionary origin of both the short- and long germ-band modes of segmentation was an oscillatory genetic network (Newman 1993). An implication of this scenario is that the self-organizing, pattern-forming system embodied in an oscillatory network operating in the context of a syncytium (i.e., a reaction-diffusion system)-which is hypothesized to have originated the simultaneous mode of segmentation-must have been replaced by the genetic hierarchy seen in modern-day Drosophila over the course of evolution. As demonstrated by the simulations in the accompanying article, the tendency for "emergent" genetic networks, associated with self-organizing processes, to be replaced through natural selection with hierarchical networks is discussed in relation to the evolution of segmentation.

Animals↗
PubMed1986

Sequential estimation of genetic and phenotypic parameters in multitrait mixed model analysis.

Single-trait and multitrait (2-, 3-, 4-, and 5-trait) restricted maximum likelihood methods were applied to the same set of data with complete information on all traits. Results suggest that parameter estimates from a data set vary depending upon the type of analysis (single- or multitrait model) and upon the other traits included in multitrait analysis. The choice of parameter estimation method for a breeding design should be based on the breeding goal. In parameter estimation or sire evaluation, traits included in a multitrait analysis should correspond to the traits of interest in the breeding goal. Multitrait analysis explores all intercorrelations simultaneously in parameter estimation and thus provides a complete picture of all interrelationships among traits. In contrast, single-trait analysis produces pairwise (simple) correlations and ignores the possible contribution of other related traits under study to the pairwise correlation. The 5-trait model analysis through canonical transformation was about 300% more efficient in terms of computer time than single-trait model analysis of the same 5 traits. In this study, parameter estimates converged faster under multitrait analysis through canonical transformation than under single-trait analysis.

Animals↗
PubMed1997

Editing disease-associated autoantibodies.

We have generated site-directed transgenic mice whose transgenes code for anti-DNA antibodies. These antibodies are representative of the lupus-associated anti-DNAs seen in mouse models of autoimmunity and human SLE, and have the usual characteristics of pathogenic autoantibodies. As conventional transgenics in nonautoimmune mice, anti-DNA B cells have been shown to be deleted or inactivated. Autoreactive B cells can also escape negative regulation by a process called receptor editing. Here we describe two combined immunoglobulin H and L chain site-directed transgenic mouse models and characterize their editing phenotypes. One model, 3H9R/Vkappa4R, has a deletion-prone phenotype and undergoes editing, primarily by inactivation of the light chain by leap-frogging events. In the other model, 3H9R/Vkappa8R, B cells are susceptible to anergy and maintain most of their HR and LR chains. These studies clarify the relationship between editing and other mechanisms of tolerance.

Alleles↗
PubMed2003

Modeling language acquisition in atypical phenotypes.

An increasing number of connectionist models have been proposed to explain behavioral deficits in developmental disorders. These simulations motivate serious consideration of the theoretical implications of the claim that a developmental disorder fits within the parameter space of a particular computational model of normal development. The authors examine these issues in depth with respect to a series of new simulations investigating past-tense formation in Williams syndrome. This syndrome and the past-tense domain are highly relevant because both have been used to make strong theoretical claims about the processes underlying normal language acquisition. The authors conclude that computational models have great potential to advance psychologists' understanding of developmental deficits because they focus on the developmental process itself as a pivotal causal factor in producing atypical phenotypic outcomes.

Humans↗