SEARCH · PubMed Health

Results for “Phenotype modeling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources

PubMed2000

Niche construction, biological evolution, and cultural change.

We propose a conceptual model that maps the causal pathways relating biological evolution to cultural change. It builds on conventional evolutionary theory by placing emphasis on the capacity of organisms to modify sources of natural selection in their environment (niche construction) and by broadening the evolutionary dynamic to incorporate ontogenetic and cultural processes. In this model, phenotypes have a much more active role in evolution than generally conceived. This sheds light on hominid evolution, on the evolution of culture, and on altruism and cooperation. Culture amplifies the capacity of human beings to modify sources of natural selection in their environments to the point where that capacity raises some new questions about the processes of human adaptation.

Adaptation, Physiological↗

PubMed1999

Interactions among quantitative traits in the course of sympatric speciation.

Sympatric speciation, the origin of two or more species from a single local population, has almost certainly been involved in formation of several species flocks, and may be fairly common in nature. The most straightforward scenario for sympatric speciation requires disruptive selection favouring two substantially different phenotypes, and consists of the evolution of reproductive isolation between them followed by the elimination of all intermediate phenotypes. Here we use the hypergeometric phenotypic model to show that sympatric speciation is possible even when fitness and mate choice depend on different quantitative traits, so that speciation must involve formation of covariance between these traits. The increase in the number of variable loci affecting fitness facilitates sympatric speciation, whereas the increase in the number of variable loci affecting mate choice has the opposite effect. These predictions may enable more cases of sympatric speciation to be identified.

Animals↗

PubMed1999

A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2.

Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on approximately 396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0. 000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod = 2. 67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod = 2.08; P = 0. 00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia.

Bipolar Disorder↗

PubMed2003

Striatal neural grafting improves cortical metabolism in Huntington's disease patients.

Huntington's disease is a hereditary disease in which degeneration of neurons in the striatum leads to motor and cognitive deficits. Foetal striatal allografts reverse these deficits in phenotypic models of Huntington's disease developed in primates. A recent open-label pilot study has shown some clinical improvement or stabilization in three out of five Huntington's disease patients who received bilateral striatal grafts of foetal neurons. We show here that the clinical changes in these three patients were associated with a reduction of the striatal and cortical hypometabolism, demonstrating that grafts were able to restore the function of striato-cortical loops. Conversely, in the two patients not improved by the grafts, striatal and cortical hypometabolism progressed over the 2-year follow-up. Finally, detailed anatomical-functional analysis of the grafted striata, enabled by the 3D fusion of MRI and metabolic images, revealed considerable heterogeneity in the anatomic and metabolic profiles of grafted tissue, both within and between Huntington's disease patients. Our results demonstrate the usefulness of PET measurements of brain glucose metabolism in understanding the effects of foetal grafts in patients with Huntington's disease.

Adult↗

PubMed2003

G x E: a NIAAA workshop on gene-environment interactions.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) sponsored a May 2002 workshop on gene-environment interaction (G x E) research to identify potential roadblocks to further research and to propose solutions to those roadblocks, to optimize investigative opportunities and multidisciplinary or multi-institution collaborations, and to explore ways that NIAAA can facilitate G x E studies. Sessions included panels on animal models; phenotypes; genetic findings in humans; study designs and analytical methods; and assessment of environmental risk. Key among the identified challenges to progress in G x E research were issues of study design and sampling strategies; logistic and methodological costs and constraints; availability and understanding of data analysis techniques; potential stigmatization of study populations; and organizational/bureaucratic structures that are inadequate to address the unique needs of large-scale, multicenter, longitudinal projects. Participants proposed a series of recommendations to address these issues. Session coordinators included: Gayle Boyd, Kendall Bryant, Page Chiapella, Vivian Faden, David Goldman, and Antonio Noronha. Session participants included: Laura Almasy, Henri Begleiter, Raul Caetano, Bruce Dudek, Mary Dufour, Cindy Ehlers, Mary-Anne Enoch, Joel Gelernter, David Goldman, Bridget Grant, Lorraine Gunzerath, Deborah Hasin, Andrew Heath, Victor Hesselbrock, J. Dee Higley, Shirley Hill, Kerry Jang, Raynard S. Kington, Rick Kittles, George Koob, Kenneth Leonard, Ting-Kai Li, Jeffrey Long, William McBride, Matthew McGue, Kathleen Merikangas, Tamara Phillips, Bernice Porjesz, Carol Prescott, Theodore Reich, John Rice, Richard Rose, Charmaine Royal, Arnold Sameroff, Marc Schuckit, Kenneth Sher, Renee Sieving, Robert Taylor, Michael Windle, and Robert Zucker.

Alcoholism↗

PubMed2002

The cost of fluctuating inbreeding depression.

We present a phenotypic model for the evolution of self-fertilization in an infinite population of annual hermaphrodites for the case in which fitness and inbreeding depression vary among generations (e.g., due to fluctuations in the environment from year to year). Conditions for the evolution of selfing, mixed mating, and outcrossing are derived and are compared with results from numerical calculations that assume a normal distribution of inbreeding depression. In contrast to the situation in which inbreeding depression does not vary, when inbreeding depression fluctuates in a stochastic manner among generations with a mean less than 0.5, selfing is not necessarily selected. Thus, fluctuating inbreeding depression can be viewed as an additional cost of selfing that may stabilize mixed mating systems. These results emphasize the need to take into account fluctuating inbreeding depression in empirical studies aimed at understanding mating system evolution in annuals.

Biological Evolution↗

PubMed1998

Comorbidity of anxiety and unipolar mood disorders.

Research on relationships between anxiety and depression has proceeded at a rapid pace since the 1980s. The similarities and differences between these two conditions, as well as many of the important features of the comorbidity of these disorders, are well understood. The genotypic structure of anxiety and depression is also fairly well documented. Generalized anxiety and major depression share a common genetic diathesis, but the anxiety disorders themselves are genetically hetergeneous. Sophisticated phenotypic models have also emerged, with data converging on an integrative hierarchical model of mood and anxiety disorders in which each individual syndrome contains both a common and a unique component. Finally, considerable progress has been made in understanding cognitive aspects of these disorders. This work has focused on both the cognitive content of anxiety and depression and on the effects that anxiety and depression have on information processing for mood-congruent material.

Anxiety Disorders↗

PubMed2006

Heritability of serum iron, ferritin and transferrin saturation in a genetically isolated population, the Erasmus Rucphen Family (ERF) Study.

BACKGROUND: Iron has been implicated in the pathogenesis of various disorders. Mutations in the HFE gene are associated with an increase in serum iron parameters. The aim of this study was to estimate the heritability in serum iron parameters explained by HFE. METHODS: Ninety families (980 subjects) were included in the present analysis. Heritability estimation was conducted using the variance component method. The likelihood ratio test was used to compare models. Phenotypic and genetic correlations between serum iron parameters were calculated. RESULTS: The heritability (h(2) +/- SE) estimates were 0.23 +/- 0.07 (p < 0.0001) for iron, 0.29 +/- 0.09 (p < 0.0001) for ferritin and 0.28 +/- 0.07 (p < 0.0001) for transferrin saturation while adjusting for age, age(2) and sex. The HFE genotypes explained between 2 to 6% of the sex and age-adjusted variance in serum iron, ferritin and transferrin saturation. There was a high genetic correlation between serum iron parameters, suggesting pleiotropy between these traits. CONCLUSION: A substantial proportion of the variance of iron, ferritin and transferrin saturation can be explained by additive genetic effects, independent of sex and age. The HFE genotypes explained a considerable proportion of serum iron parameters and may be an important factor in the complex iron network.

Female↗

PubMed2006

A role for CETP TaqIB polymorphism in determining susceptibility to atrial fibrillation: a nested case control study.

BACKGROUND: Studies investigating the genetic and environmental characteristics of atrial fibrillation (AF) may provide new insights in the complex development of AF. We aimed to investigate the association between several environmental factors and loci of candidate genes, which might be related to the presence of AF. METHODS: A nested case-control study within the PREVEND cohort was conducted. Standard 12 lead electrocardiograms were recorded and AF was defined according to Minnesota codes. For every case, an age and gender matched control was selected from the same population (n = 194). In addition to logistic regression analyses, the multifactor-dimensionality reduction (MDR) method and interaction entropy graphs were used for the evaluation of gene-gene and gene-environment interactions. Polymorphisms in genes from the Renin-angiotensin, Bradykinin and CETP systems were included. RESULTS: Subjects with AF had a higher prevalence of electrocardiographic left ventricular hypertrophy, ischemic heart disease, hypertension, renal dysfunction, elevated levels of C-reactive protein (CRP) and increased urinary albumin excretion as compared to controls. The polymorphisms of the Renin-angiotensin system and Bradykinin gene did not show a significant association with AF (p > 0.05). The TaqIB polymorphism of the CETP gene was significantly associated with the presence of AF (p < 0.05). Using the MDR method, the best genotype-phenotype models included the combination of micro- or macroalbuminuria and CETP TaqIB polymorphism, CRP >3 mg/L and CETP TaqIB polymorphism, renal dysfunction and the CETP TaqIB polymorphism, and ischemic heart disease and CETP TaqIB polymorphism (1000 fold permutation testing, P < 0.05). Interaction entropy graph showed that the combination of albuminuria and CETP TaqIB polymorphism removed the most entropy. CONCLUSION: CETP TaqIB polymorphism is significantly associated with the presence of AF in the context of micro- or macroalbuminuria, elevated C-reactive protein, renal dysfunction, and ischemic heart disease.

Atrial Fibrillation↗

PubMed2006

Quantifying cardiovascular flow dynamics during early development.

The relationship between developing biologic tissues and their dynamic fluid environments is intimate and complex. Increasing evidence supports the notion that these embryonic flow-structure interactions influence whether development will proceed normally or become pathogenic. Genetic, pharmacological, or surgical manipulations that alter the flow environment can thus profoundly influence morphologic and functional cardiovascular phenotypes. Functionally deficient phenotypes are particularly poorly described as there are few imaging tools with sufficient spatial and temporal resolution to quantify most intra-vital flows. The ability to visualize biofluids flow in vivo would be of great utility in functionally phenotyping model animal systems and for the elucidation of the mechanisms that underlie flow-related mechano-sensation and transduction in living organisms. This review summarizes the major methodological advances that have evolved for the quantitative characterization of intra-vital fluid dynamics with an emphasis on assessing cardiovascular flows in vertebrate model organisms.

Animals↗

PubMed2007

Significant change in insulin production, glucose tolerance and ER stress signaling in transgenic mice coexpressing insulin-siRNA and human IDE.

The dual expression system for the suppression and clearance of insulin has not been previously used to produce transgenic mice for diabetes-related disease. The aim of this study was to produce new transgenic mice coexpressing specific insulin small interfering RNA (siRNA) sequences and the human insulin degrading enzyme (hIDE) gene in order to examine the diabetes-like phenotype. To achieve this, a new lineage of transgenic mice was produced by the microinjection of the dual expression constructs (pH1/siRNAinsulin-CMV/hIDE) into mouse fertilized eggs. The results showed that overexpressing the insulin siRNA and hIDE genes resulted in the induction of the human enzyme, impaired glucose tolerance and lower serum insulin levels compared to the Non-Tg mice. Moreover, the Tg mice aged 20 weeks had a significantly activated ER stress signaling compared to their Non-Tg counterparts, which may be associated with the suppression of insulin production in the pancreas and the degradation of insulin in the liver, respectively. Therefore, insulin-suppressed transgenic mice can be used to examine diabetes as a new diabetes-like phenotype model, which results in a lower level of circulating insulin without the destruction of pancreatic islets.

Animals↗

PubMed1975

Molecular genetics of GM1 beta-galactosidase.

The molecular genetics of GM1 beta-galactosidase is reviewed. This enzyme exists in two forms, A and B. Form A is monomeric with a molecular weight of 72,000 and appears to be coded by a single autosomal locus. Form B is polymeric and cross-reacts with anti-A antibodies; it is coded wholly or in part by the same locus that codes for A. The simultaneous loss of A and B in GM1 gangliosidosis is explained. None of the other beta-galactosidases, including neutral beta-galactosidase, ceramide lactoside beta-galactosidase or cerebroside beta-galactosidase cross-react with anti-A antibodies, demonstrating that they are coded by loci separate from A. GM1 beta-galactosidase A is heterocatalytic, cleaving beta-D-galactose from ganglioside GM1, lactose, N-acetyllactosamine, and galactose-containing glycoproteins such as asialofetuin, red cell stromal glycoproteins and keratan sulfate. The pleotropic effects of a single mutation affecting the locus for beta-galactosidase A can be explained by a one gene:one polypeptide:many substrates model. Phenotypic variability among beta-galactosidase A mutants may result from better residual activity of the mutant enzyme for one substrate than for another. Patients with normal intelligence and severe bony deformities, who are homozygous for a mutation affecting the enzyme, illustrate this point. Thus far all human mutants for GM1 beta-galactosidase studied are structural mutants, synthesizing nearly normal quantities of mutant enzyme; one is a proven Km mutant, the others are very likely so.

Chromosome Aberrations↗

PubMed1999

Regression diagnostics for the class A regressive model with quantitative phenotypes.

Regression diagnostic methods are developed and investigated under the Class A regressive model proposed by Bonney [(1984) Am J Med Genet 18:731-749]. We call a family whose phenotypic distribution does not conform to the same genetic model as the majority of the families an etiotic family. The exact case-deletion approach for identifying etiotic families, based on examining the changes in each model parameter estimate by excluding one family at a time, is very time-consuming. We proposed three alternative diagnostic methods: the empirical influence function (EIF), the one-step approximation, and the approximated one-step approach. These methods can be computed efficiently and were incorporated into the existing software package S.A.G.E. A thorough Monte-Carlo investigation of the performance of the diagnostic methods was conducted and generally supports the EIF approach as the recommended alternative. The phenotypic variance is the parameter whose associated regression diagnostic most frequently and correctly identified etiotic families in the models that were examined. An analysis of body mass index data from 402 individuals in 122 Muscatine, Iowa families is used to illustrate the methods. A Class A regressive model with a recessive major locus and equal mother-offspring and father-offspring correlations provided the best-fitting model. The proposed regression diagnostics identified up to 7.4% of the 122 families as etiotic. As a result of this investigation, case-deletion diagnostic assessment is now a practical component in the analysis of quantitative family data.

Adolescent↗

PubMed2006

Echocardiographic characterization of the cardiovascular phenotype in rodent models.

Echocardiographic techniques are commonly utilized to describe the rodent cardiovascular phenotype. These approaches are contrasted with other in vivo methods and are positioned in the assay selection process by a review of studies from our laboratory and others. Although not conventionally considered a biomarker, the technique has the potential to be exploited as a marker of intentional or unanticipated toxic biological effects in the preclinical development of drugs and chemicals.

Animals↗

PubMed2006

Mixture models and subpopulation classification: a pharmacokinetic simulation study and application to metoprolol CYP2D6 phenotype.

Mixture models are applied in population pharmacometrics to characterize underlying population distributions that are not adequately approximated by a single normal or lognormal distribution. In addition to obtaining individualized maximum a posteriori Bayesian post hoc parameter estimates, the subpopulation to which an individual was classified can be determined. However, the accuracy of the classification of subjects to subpopulations is not well studied. We investigated the impact of several factors on the accuracy of classification in mixture models applied to pharmacokinetics using a simulation strategy. The availability of actual subject data allowed us to evaluate mixture model classification in a potentially common application, namely, the classification of clearance into poor metabolizer (PM) or extensive metabolizer (EM) subgroups with the known phenotype status in subjects receiving metoprolol. The factors explored in the simulation study were the magnitude of difference between the clearances in two subpopulations, the between subject variability in clearance, the mixing-fraction, and the population sample size. Populations were simulated at various levels of the above factors and analyzed with a mixture model using NONMEM. The population pharmacokinetics of metoprolol were modeled with the EM/PM phenotype as a known covariate, and without the phenotype covariate using a mixture model. Within the range of scenarios studied, the proportion of subjects classified into the correct subpopulation was high. The simulation-estimation study suggests that a greater separation between two subpopulations, a smaller variability in the parameter distribution, a larger sample size, and a smaller size subpopulation tend to be associated with a greater accuracy of subpopulation classification when a mixture model is applied to pharmacokinetic data. In a population pharmacokinetic analysis of metoprolol, a drug that undergoes polymorphic metabolism, it was possible to correctly identify phenotype status using a mixture model.

Administration, Oral↗

PubMed2004

Serial induction of mutations by ethylnitrosourea in PC12 cells: a new model for a phenotypical characterization of the neurotoxic response to 6-hydroxydopamine.

Here we show that the serial generation of allelic mutations by treatment with the mutagen ethylnitrosourea (ENU) in PC12 cells provides a new model for the phenotypical dissection of biological properties. We tested this approach in the neurotoxic 6-OHDA model of Parkinson's disease in PC12 cells which has been widely used as an in vitro model for the investigation of the molecular pathogenesis of neuronal cell death and for novel treatment approaches. ENU treatment at doses of 0.2 and 0.3 mg/ml for 1 h resulted in 35 and 25% surviving PC12 cells, respectively, which showed mutation frequencies of approximately 10 mutations per genome. Clones derived from single ENU treated PC12 cells showed marked differences in their resistance against 6-OHDA. The phenotypical analysis of resistant and sensitive clones showed a differential transcriptional regulation of multiple genes. The applicability of this approach could be demonstrated by the identification of the rat TM9SF1 gene coding for a transmembrane protein of the nonaspanin superfamily as a regulated gene in PC12 clones resistant against 6-OHDA. Our data demonstrate the suitability of this model for the investigation of the molecular pathogenesis of neurodegeneration and for high-throughput analysis, e.g. for drug discovery.

Animals↗

PubMed1998

Antisense modulation of the ICAM-1 phenotype of a model human bone marrow stromal cell line.

Efficient stable gene transfer was achieved in a model human bone marrow stromal cell line, KM-102, using both Epstein-Barr virus and BK virus episomal expression vectors. Using this episomal expression system, effective overexpression and inhibition of ICAM-1 expression was achieved in stably transfected KM-102 cells by sense and antisense RNA gene transfer, respectively. Loss of surface ICAM-1 on antisense KM-102 transfectants did not significantly affect adhesion to LFA-1-bearing JY hematopoietic cells. However, KM-102 ICAM-1 overexpressors demonstrated enhanced binding (2.5-fold) to phorbol ester-treated, but not untreated, LFA-1-bearing JY cells. The increased binding could be blocked with anti-ICAM-1 antibodies. These findings suggest that while ICAM-1 is not required for basal adhesion between stromal and hematopoietic cells, stromal ICAM-1 may contribute to stromal:leukemic cellular interaction when bound to the phorbol ester-dependent high-avidity state of hematopoietic LFA-1.

BK Virus↗

PubMed1997

Homology modeling of Neurospora crassa geranylgeranyl pyrophosphate synthase: structural interpretation of mutant phenotypes.

A model of the tertiary structure of the Neurospora crassa carotenogenic prenyltransferase, geranylgeranyl pyrophosphate synthase (GGPPS), is presented, based on structural homology with other prenyltransferases and on the crystal structure of recombinant avian farnesyl pyrophosphate synthase (FPPS). The conserved aspartate-rich motifs DDxx(xx)D and associated basic residues, considered to be the active sites for binding and catalysis in all prenyltransferases, are highly conserved in the N. crassa GGPPS protein, while other regions display a lower degree of sequence homology; thus the GGPPS model structure is predicted to be highly reliable in the active site region. A number of carotene-deficient mutants have been generated utilizing the repeat-induced point mutation (RIP) mechanism: mutant al-3RIP1 carries a Ser-to-Asn mutation in position 336 which falls within the predicted active site of the enzyme. Analysis of the model structure of this mutant indicates that Ser336 may be involved in substrate uptake. Two other mutants, al-3RIP3 and al-3RIP6, carry mutations in positions in the GGPPS protein, homologous to regions of the avian FPPS enzyme proposed to be involved in enzyme dimerization and substrate uptake, respectively, suggesting an explanation for the reduced carotene content of these mutants.

Alkyl and Aryl Transferases↗