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Results for “Phenotype modeling”

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At least 217 records · Page 12Linked to original sources

PubMed1985

Multivariate path analysis of familial resemblance.

A method is presented for applying path analysis to general multivariate models of familial resemblance. In path models formulated using this approach, variables are defined as column vectors, path coefficients are defined as matrices of path coefficients, and correlations are defined as matrices of correlations. By applying a few simple rules for multivariate path analysis, general multivariate expected correlations can be derived from a path diagram which is essentially as simple as a univariate diagram and which can be used to analyze any number of variables. Multivariate expected correlations for three models of familial resemblance are derived, with particular attention given to the modeling of assortative mating: nuclear families with a phenotypic homogamy model of assortative mating, nuclear families with a social homogamy model of assortative mating, and twins and their parents with phenotypic homogamy. These models are applicable to many of the types of studies commonly undertaken in genetic epidemiology. The simplicity of the technique facilitates analyses of the etiology of variation and covariation among variables measured in such studies.

Female↗

PubMed1999

Multiplex inheritance of component phenotypes in a murine model of lupus.

We analyzed the linkage of GN and a wide spectrum of serological phenotypes associated with systemic lupus erythematosus in a (NZM2410 x C57BL/6)F2 cross. Some phenotypes, such as glomerulonephritis (GN) and anti-chromatin IgG antibody production, were more penetrant in females, but others, such as anti-dsDNA antibody production, did not show a gender bias. These results suggest that gender bias affects only a subset of SLE-component phenotypes, and that NZM2410 can be used to dissect the genetic basis of this phenomenon. Genome scanning linked six chromosomal intervals with the expression of one or more component phenotypes. These loci included two Sle loci previously identified in an (NZM2410 x B6)F1 x NZM2410 backcross, loci identified by others in the NZB/W model. Our analysis also suggested two new intervals on chromosomes (Chrs.) 10 and 11. Detailed analysis of the segregation of different phenotypes within these intervals suggests that they encompass more than one susceptibility locus. This clustering has been a common finding in several murine polygenic traits. Each of NZM2410 susceptibility loci can be aligned with a specific genetic pathways contributing to SLE pathogenesis on the basis of the spectrum of component phenotypes expressed.

Animals↗

PubMed2005

Mixed modelling to characterize genotype-phenotype associations.

We propose using mixed effects models to characterize the association between multiple gene polymorphisms, environmental factors and measures of disease progression. Characterizing high-order gene-gene and gene-environment interactions presents an analytic challenge due to the large number of candidate genes and the complex, undescribed interactions among them. Several approaches have been proposed recently to reduce the number of candidate genes and post hoc approaches to identify gene-gene interactions are described. However, these approaches may be inadequate for identifying high-order interactions in the absence of main effects and generally do not permit us to control for potential confounders. We describe how mixed effects models and related testing procedures overcome these limitations and apply this approach to data from a cohort of subjects at risk for cardiovascular disease. Four (4) genetic polymorphisms in three genes of the same gene family are considered. The proposed modelling approach allows us first to test whether there is a significant genetic contribution to the variability observed in our disease outcome. This contribution may be through main effects of multi-locus genotypes or through an interaction between genotype and environmental factors. This approach also enables us to identify specific multi-locus genotypes that interact with environmental factors in predicting the outcome. Mixed effects models provide a flexible statistical framework for controlling for potential confounders and identifying interactions among multiple genes and environmental factors that explain the variability in measures of disease progression.

Adult↗

PubMed2006

Constructing quantitative models from qualitative mutant phenotypes: preferences in selecting sensory organ precursors.

MOTIVATION: To study biology from the systems level, mathematical models that describe the time-evolution of the system offer useful insights. Quantitative information is required for constructing such models, but such information is rarely provided. RESULTS: We propose a scheme-based on random searches over a parameter space, according to criteria set by qualitative experimental observations-for inferring quantitative parameters from qualitative experimental results. We used five mutant constraints to construct genetic network models for sensory organ precursor formation in Drosophila development. Most of the models were capable of generating expression patterns for the gene Enhancer of split that were compatible with experimental observations for wild type and two Notch mutants. We further examined factors differentiating the neural fate among cells in a proneural cluster, and found two opposite driving forces that bias the choice between middle cells and the peripheral cells. Therefore, it is possible to build numerical models from mutant screening and to study mechanisms behind the complicated network.

Animals↗

PubMed2003

Selection of more aggressive variants of the gI101A human breast cancer cell line: a model for analyzing the metastatic phenotype of breast cancer.

In vivo models utilizing orthotopic injection of tumor cells into nude mice have proven valuable for the study of metastasis. However, breast cancers are among the more difficult of human tumors to grow in immunodeficient mice, with a relatively low tumor take. Fewer still develop spontaneous metastases. The injection of GI101A breast cancer cells into the mammary fatpad (mfp) produced lung metastases in 25% of tumor-bearing mice. Selecting cells from the lung metastases and recycling in vivo resulted in the isolation of a series of variant cell lines. These cell lines were tested for tumorigenicity and metastasis in nude mice following mfp injection compared with the original cell line, and in vitro expression of factors associated with the metastatic phenotype measured. The in vivo selected cell lines were more aggressive, with higher tumor take, faster local growth rate and increased incidence (> or = 85%) and extent of lung metastasis. However, the metastasis-selected variants showed no increases in expression of the growth factor receptors EGFR or HER-2, and the pro-angiogenic factors VEGF-A and IL-8. Immunohistochemistry of mfp tumors revealed no differences in microvessel density (counting CD-31 positive structures) and cell proliferation (PCNA-positive cells) comparing the GI101A line with selected variants. No TUNEL-positive cells were detected in the tumors of the metastasis-derived variant, with a small number of cells undergoing apoptosis detected in sections of GI101A tumors. In vitro, the metastasis-derived variants were found to have a more robust expression of phosphorylated PKB/Akt, with or without EGF or serum stimulation, suggesting an association between Akt activation and metastatic ability. This new series of isogenic cell lines may be valuable for identifying molecular mechanisms involved in the metastatic progression of breast cancer.

Angiogenesis Inducing Agents↗

PubMed2004

Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes.

Two mouse models are widely used for Down syndrome (DS) research. The Ts65Dn mouse carries a small chromosome derived primarily from mouse chromosome 16, causing dosage imbalance for approximately half of human chromosome 21 orthologs. These mice have cerebellar pathology with direct parallels to DS. The Ts1Cje mouse, containing a translocated chromosome 16, is at dosage imbalance for 67% of the genes triplicated in Ts65Dn. We quantified cerebellar volume and granule cell and Purkinje cell density in Ts1Cje. Cerebellar volume was significantly affected to the same degree in Ts1Cje and Ts65Dn, despite that Ts1Cje has fewer triplicated genes. However, dosage imbalance in Ts1Cje had little effect on granule cell and Purkinje cell density. Several mice with dosage imbalance for the segment of the Ts65Dn chromosome not triplicated in Ts1Cje had phenotypes that contrasted with those in Ts1Cje. These observations do not readily differentiate between two prevalent hypotheses for gene action in DS.

Animals↗

PubMed2003

Lifetime selection on heritable life-history traits in a natural population of red squirrels.

Despite their importance in evolutionary biology, heritability and the strength of natural selection have rarely been estimated in wild populations of iteroparous species or have usually been limited to one particular event during an organism's lifetime. Using an animal-model restricted maximum likelihood and phenotypic selection models, we estimated quantitative genetic parameters and the strength of lifetime selection on parturition date and litter size at birth in a natural population of North American red squirrels, Tamiasciurus hudsonicus. Litter size at birth and parturition date had low heritabilities (h2 = 0.15 and 0.16, respectively). We considered potential effects of temporal environmental covariances between phenotypes and fitness and of spatial environmental heterogeneity in estimates of selection. Selection favored early breeders and females that produced litter sizes close to the population average. Stabilizing selection on litter size at birth may occur because of a trade-off between number of offspring produced per litter and offspring survival or a trade-off between a female's fecundity and her future reproductive success and survival.

Age Factors↗

PubMed1998

Characterization of the differentiated phenotype of an organotypic model of skin derived from human keratinocytes and dried porcine dermis.

A number of skin models have been developed, but a simple method for rapidly producing large quantities of differentiated epidermis has been missing. We show the differentiated phenotype of human keratinocytes in organotypic culture arising in vitro by air-exposure of keratinocytes cultured with feeders on dried pig dermis. Keratinocytes were seeded at low density on the dermis covered with irradiated NIH-3T3 feeder cells and after reaching confluence lifted to the air-medium interface. A well differentiated epidermis with distinct basal, spinous, granular and stratum corneum layers was formed within 1 week. In this way, 100 cm2 of the differentiated recombined human/pig skin (D-RHPS) can be obtained from 106 secondary keratinocytes in 14 days. The entire keratinocyte life cycle takes place on the dermal substrate - from single cells to stratified epidermis. The differentiation was characterized using a panel of monoclonal antibodies. Similarly as in the normal skin, keratin 14 was expressed in all cell layers, keratin 10 in suprabasal layers, beta1-integrin and epitopes to antibody LH8 in the basal layer, involucrin and transglutaminase in the granular and horny layer of the epidermis. Keratins 16 and 7/17, which are absent in the normal epidermis, but present suprabasally in the psoriatic one, were expressed strongly in all suprabasal layers and in a subpopulation of basal cells. The keratinocytes can be combined with two other cell types cultured either on the dermal side of the dermis and/or on the bottom of the dish. It appears that this simple skin model can be used in studies of epithelial/mesenchymal interactions and interactions between epidermal cells and infectious agents. It may be particularly useful for the study of human papilloma viruses.

3T3 Cells↗

PubMed1995

A human melanoma cell line transduced with an interleukin-4 gene by a retroviral vector releases biologically active IL-4 and maintains the original tumor antigenic phenotype.

Experimental models of vaccination with tumor cells engineered to produce interleukin-4 (IL-4) have shown that the local release of this cytokine is associated with the development of antitumor immunity that may induce regression of established cancer. The aim of this study was to transduce a human melanoma cell line with the gene coding for human IL-4, and to analyze cytokine production, phenotypic characteristics, and antigen expression after transduction. A retroviral vector, constructed by inserting IL-4 cDNA into the LXSN vector, was used to infect the human melanoma cell line Me14932, known to express the MHC class I HLA-A2 and the melanoma-associated antigen Melan-A/MART-1, recognized by HLA-A2-restricted T-cells. The confluence of all G418-resistant cells (Me14932/IL-4) was then analyzed for proviral integration and IL-4 mRNA expression. Substantially stable IL-4 release was detected by ELISA in the supernatant of transduced cells, ranging from 1.6 to 4.6 ng/ml per 10(5) cells per 24 hr; such a cytokine displayed a specific biologic activity, as revealed by the stimulation of blast cell proliferation and the inhibition of lymphokine activated killer cell (LAK) induction by IL-2. After 200 Gy irradiation, IL-4 release remained detectable for 5 weeks, whereas cell proliferation ceased within 7 days. Morphology and immunophenotypic characteristics of the parental cell line (expression of MHC classes I and II, ICAM-1, LFA 3, melanoma-associated antigens, etc.) were retained by the IL-4 gene-transduced melanoma as assayed by microscopy and immunofluorescence; likewise, susceptibility to lysis by LAK cells as well as a T-cell clone recognizing the Melan-A/MART-1 antigen did not change. These results, together with the lack of replication-competent retrovirus, suggest that the Me14932/IL-4 cell line displays suitable characteristics for its use in the treatment of HLA-matched melanoma patients.

Antigens, Neoplasm↗

PubMed2000

Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model.

Among the earliest and most important stages during tumorigenesis is the activation of the angiogenic process, an event that is termed the "switch to the angiogenic phenotype." We have developed an in vivo system that can reliably recapitulate the stages in tumor development that represent this transition. Using this model, we have harvested and studied tumor nodules that can be distinguished from each other on the basis of their degree of vascularization. Angiogenic tumor nodules were characterized by the presence of capillary vessels as determined by factor VIII immunohistochemistry, and both angiogenic and proteolytic activities in vitro. In contrast, preangiogenic nodules were devoid of microvessels and showed little angiogenic or proteolytic activity in vitro. Addition of a specific metalloproteinase inhibitor resulted in the abrogation of both angiogenic and proteolytic activities of the angiogenic nodules in vitro. Comparative substrate gel electrophoresis detected the presence of a prominent matrix metalloproteinase (MMP-2) in the angiogenic nodules when compared with the preangiogenic ones. Suppression of MMP-2 activity by antisense oligonucleotides in the vascular nodules resulted in the loss of angiogenic potential both in vitro and in vivo in the chick chorioallantoic membrane assay. Moreover, this suppression of MMP-2 activity in angiogenic nodules inhibited tumor growth in vivo by approximately 70%. These results strongly implicate the activity of MMP-2 as a requirement for the switch to the angiogenic phenotype and validate this model as a reliable and reproducible tool by which to study other cellular and biochemical factors involved in the acquisition of the angiogenic phenotype.

Animals↗

PubMed1992

Two cloned cerebral endothelial cell phenotypes: an in vitro model for angiogenesis?

Expression of smooth muscle alpha-actin and migratory behaviour of cloned cerebral endothelial cells (cEC) which exhibited two distinct phenotypes (type I, type II) were studied. Removal of mitogenic factors (alpha ECGF, ECGS) and heparin from the culture medium resulted in a smooth muscle-like appearance (type II) of the cells, expression of smooth muscle alpha-actin protein and smooth muscle actin mRNA and in an increased migratory activity. In contrast, addition of growth factors and heparin led to a cobblestone-like phenotype (type I) which lacked the expression of smooth muscle alpha-actin but expressed other proteins as determined by 2-D-gel electrophoresis.

Actins↗

PubMed1998

A model for hepatocarcinogenesis treating phenotypical changes in focal hepatocellular lesions as epigenetic events.

The major paradigm for mathematically describing the carcinogenic process has been through the use of multistage models. Multistage models are made up of numerous compartments representing cells in various stages on the way to malignancy and where movement from one cell class to another is assumed to have exponential waiting time. Once a cell is in a particular class, clonal expansion through a linear birth-death process increases the size of the compartment. These models are characterized by movement of single cells from one compartment to another rather than clonal colonies of cells. However, there is some evidence to suggest that, in certain organs for certain types of agents, preneoplastic lesions with different phenotypes arise directly from an entire clonal colony rather than from a single cell within that colony. This manuscript describes a simple mathematical model of carcinogenesis using both persistent changes of single or several cells (to start the process) and shifting of colonies to describe the stages of the model. Likelihoods for the use of the model with data on colonies of preneoplastic lesions are described and applied to real data.

Animals↗

PubMed1987

Epigenetic canalization and phenotypic change: a minimax model.

A selectionist model of phylogenic behaviour is presented in which epigenetic canalization fulfills the pivotal rôle. It is shown that directional selection will result in stress induce creodal destabilization and in genetic unmasking. Both processes will in turn result in a rapid increase in phenotypic variance for natural selection to act on, and hence a sudden increase in the rate of phylogenic change. Acting on the epigenome via internal selection and on phenotypic peripherals via stabilizing selection, natural selection will also assure phenotypic stasis by means of increased genetic concealment, deepened canalization and developmental constraints. The latter two factors allow for the application of a minimax rule of phenotypic change: that part of an organism with the minimum potential for phenotypic change (hence the maximum canalization) will govern the direction of the maximum phenotypic change of the other parts. The hierarchialization of phenotypic change predicted by the minimax rule explains the coexistence of gradualistic and punctuational changes within lineages of the same species.

Animals↗

PubMed2023

Retinal Phenotyping of a Murine Model of Lafora Disease.

Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a-/- mice by examining knockout (KO; Epm2a-/-) and control (WT) littermates at two time points (10 and 14 months, respectively). In vivo exams included electroretinogram (ERG) testing, optical coherence tomography (OCT) and retinal photography. Ex vivo retinal testing included Periodic acid Schiff Diastase (PASD) staining, followed by imaging to assess and quantify LB deposition. There was no significant difference in any dark-adapted or light-adapted ERG parameters between KO and WT mice. The total retinal thickness was comparable between the groups and the retinal appearance was normal in both groups. On PASD staining, LBs were observed in KO mice within the inner and outer plexiform layers and in the inner nuclear layer. The average number of LBs within the inner plexiform layer in KO mice were 1743 ± 533 and 2615 ± 915 per mm2, at 10 and 14 months, respectively. This is the first study to characterize the retinal phenotype in an Epm2a-/- mouse model, demonstrating significant LB deposition in the bipolar cell nuclear layer and its synapses. This finding may be used to monitor the efficacy of experimental treatments in mouse models.

Mice↗

PubMed2006

Deletion of vitamin E enhances phenotype of Alzheimer disease model mouse.

Increased oxidative damage is a prominent and early feature in Alzheimer disease (AD). However, whether it is a primary cause or merely a downstream consequence in AD pathology is still unknown. We previously generated alpha-tocopherol transfer protein knockout (Ttpa-/-) mice, in which lipid peroxidation in the brain was significantly increased by complete depletion of alpha-tocopherol (alpha-Toc). Here we crossed AD transgenic (APPsw) model mice (Tg2576) with Ttpa-/- mice. The resulting double-mutant (Ttpa-/- APPsw) mice showed earlier and more severe cognitive dysfunction in the Morris water maze, novel-object recognition, and contextual fear conditioning tests. They also showed increased amyloid beta-peptide (Abeta) deposits in the brain by immunohistochemical analysis, which was ameliorated with alpha-Toc supplementation. In this report we provide clear evidence indicating that chronic lipid peroxidation due to alpha-Toc depletion enhances AD phenotype in a mouse model.

Alzheimer Disease↗

PubMed2006

Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL.

The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.

ATP Binding Cassette Transporter 1↗

PubMed1986

The use of measured genotype information in the analysis of quantitative phenotypes in man. I. Models and analytical methods.

Improved laboratory methods allow one to investigate the contribution of measured allelic variability at a locus physiologically involved in determining the expression of a quantitative trait. We present statistical methods that incorporate measured genotype information into the analysis of a quantitative phenotype that allows one simultaneously to detect and estimate the effects of a measured single locus and residual polygenic effects. Likelihoods are presented for the joint distribution of the quantitative phenotype and a measured genotype that are appropriate when the data are collected as a sample of unrelated individuals or as a sample of nuclear families. Application of this method to the analysis of serum cholesterol levels and the concentration of the group specific component (Gc) are presented. The analysis of the contribution of the common Gc polymorphism to the determination of quantitative variability in Gc using samples of related and unrelated individuals presents, for the first time, the simultaneous estimation of the frequencies and the effects of the genotypes at a measured locus, and the contribution of residual unmeasured polygenes to phenotypic variability.

Genotype↗

PubMed1985

Methoxyphenamine metabolism in rat models of human debrisoquine phenotypes.

The metabolism of the beta 2-adrenoceptor agent methoxyphenamine was investigated in rats of the Lewis and Dark Agouti strains, which are proposed models for human extensive and poor metabolizers of debrisoquine, respectively. Following oral ingestion of 20 mg kg-1 of methoxyphenamine, Dark Agouti excreted, on the average, significantly more methoxyphenamine and less O-demethylmethoxyphenamine and 5-hydroxymethoxyphenamine in 0- to 24-h urine than Lewis. In contrast, the N-demethylation of methoxyphenamine showed no interphenotype differences between the two strains. It is possible that in rats, the form of cytochrome P-450, which controls the 4-hydroxylation of debrisoquine, may also control the O-demethylation and aromatic 5-hydroxylation of methoxyphenamine.

Animals↗