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At least 235 records · Page 13Linked to original sources
PubMed2001

Phenotype-driven genetic approaches in mice: high-throughput phenotyping for discovering new models of cardiovascular disease.

Cardiovascular diseases such as hypertension, atherosclerosis, cardiac hypertrophy homocysteinemia and arrhythmias impose great health, social and financial costs. Some of these diseases are single gene traits that segregate in a simple Mendelian manner. Most are genetically complex, however, and result from combinations of large numbers of genes (polygenic and epistatic traits) or from interactions between genetic and environmental factors (multifactorial traits). Insights into the genetic control of these diseases could lead to improved diagnosis and treatment as well as a deeper understanding of basic physiological processes.

Animals↗
PubMedDate not supplied

Gene dosage effects on MDH isozyme expression in diploid, triploid, and tetraploid treefrogs of the genus Hyla.

Electrophoretic staining intensities at a polymorphic malate dehydrogenase locus (MDH-1) in the tetraploid treefrog Hyla versicolor and diploid Hyla chrysoscelis were compared using intraspecific and interspecific crosses. Gene dosage levels within the three ploidies were additive for the expression of isozymes encoded by this locus. Using densitometry, phenotypes from intraspecific tetraploid progeny conformed to a tetraploid gene dosage model, while phenotypes from interspecific hybrids conformed to a triploid gene dosage model. Intra- and interspecific progeny phenotypes and ratios agree with theoretical models predicting differences in such phenotypes and ratios, depending on the ploidy of the parents involved. Heterozygous phenotypes revealed that diploid crosses produced only symmetrically heterozygous progeny while tetraploid crosses produced two classes of asymmetrically heterozygous progeny in addition to symmetrically heterozygous progeny. Interspecific crosses produced only asymmetrically heterozygous progeny. Interspecific crosses involving a homozygous diploid genotype and symmetrically heterozygous tetraploid genotype produced three progeny phenotypes, while the reciprocal cross produced only two progeny phenotypes. the value of interspecific crosses between diploids and tetraploids in determining gene silencing at duplicated loci is considered.

Animals↗
PubMed2002

Social variables affect phenotype in the neuroma model of neuropathic pain.

When the degree of genetic determination of a trait (i.e. its heritability) is high, one tends to presume that environmental factors will not modify its expression by much. Contrary to this expectation, we show here in rats that a psychosocial-behavioral variable, the identity of cagemates, can largely over-ride genetic predisposition to pain behavior. We used selection-line rats that consistently show high (HA) or low (LA) pain phenotype (autotomy) in the neuroma model of neuropathic pain. Normally, HA animals show autotomy after nerve injury while LA animals do not. However, when caged together with HA rats, LA rats showed high levels of autotomy. This occurred even when the individual HA cagemates were familiar preoperatively, and it did not depend on the actual performance of autotomy by the HA rats. Indeed, cage bedding soiled by HA rats was sufficient to induce a modest level of autotomy in LA animals. Chemical cues associated with HA rats, perhaps in combination with behavioral characteristics, are apparently able to induce pain phenotype despite the powerful protection otherwise rendered by the LA genotype. Social factors must be considered in behavior-related research on rodents that have undergone genetic modification. More generally, the overwhelming influence that psychosocial-behavioral variables have on pain perception, and on pain behavior, in humans may have evolutionary roots deeper than has previously been appreciated.

Animals↗
PubMed2005

A likelihood approach for quantitative-trait-locus mapping with selected pedigrees.

Selective sampling is a cost-effective design for mapping quantitative trait loci (QTLs). A unified framework, which naturally combines two complementary sources of linkage information in the data, is proposed for the mapping of QTLs using selected pedigrees. Score statistics for detecting linkage are introduced for single-locus models (univariate or bivariate phenotypes) and two-locus epistasis models. A computer implementation of the methods for single-locus univariate-phenotype models is provided for nuclear families with arbitrary number of sibs and is freely available.

Algorithms↗
PubMed1995

So what do you propose we use instead? A reply to Block.

Unfortunately, Block's brilliant critique is terribly biased, much like a legal brief that presents only one side of the issues at suit. It does not distinguish between the Big Five model of phenotypic personality attributes from alternative models of the causal underpinnings of personality differences. Ironically, it attempts to explain away the extensive evidence for the Big Five model as largely the result of data prestructuring, with no acknowledgement of the unique contribution of the lexical approach to minimizing such problems. Even more seriously, it omits a good deal of crucial evidence favorable to the Big Five model, including studies of Block's own Q-set and independent investigations of personality-related terms in other languages. Sadly, Block's closing suggestions provide little in the way of specific proposals for alternatives that he would have us use instead.

Factor Analysis, Statistical↗
PubMed1993

Is a low serum concentration of alpha 1-antitrypsin associated with an increased susceptibility for byssinosis in cotton mill workers? Considerations regarding analytical quality requirements and economical consequences.

We have previously demonstrated an association between development of the cotton lung disease byssinosis and endotoxin concentrations in the work environment. Endotoxin has been shown to exert its effects through granulocyte activation and hence release of elastase and other proteases at the bronchoalveolar surface. alpha 1-Antitrypsin is a protease inhibitor, and hence, alpha 1-Antitrypsin concentrations in the blood and then on the alveolar surface might be important for the protection against endotoxin effects. Airborne endotoxin concentrations in the work place and S-alpha 1-Antitrypsin (a1A) was measured in 226 workers in cotton mills in Vejle and of these 206 were further phenotyped. The following models were considered: Model 1. The S-a1A concentration is determining the risk for development of byssinosis. The lower the concentration, the higher the risk. Model 2. The degree of exposure to endotoxin is determining. The higher the airborne concentration and the longer time working in that, the higher is the risk. Model 3. The phenotype of a1-A is determining. Only MS and/or MZ phenotypes represent a risk disposition. The goals for analytical quality for a1-A measurements were estimated in the two relevant models. The specifications are: Regarding model 1: analytical coefficient of variation CVA < 3% and analytical bias--1 mumol/L < BA < +1 mumol/L. Model 2: a1-A is not of significant importance and specifications cannot be evaluated. Regarding model 3: There is a direct relationship between cut-off point and analytical performance, e.g. an imprecision of SA 3 mumol/L and cut-off of 38 mumol/L will allow for a BA of -1 mumol/L.

Byssinosis↗
PubMed2000

Bivariate animal model estimates of genetic, phenotypic, and environmental correlations for production, reproduction, and somatic cells in Jerseys.

Correlations were obtained between 18 response variables of a Jersey herd (Florida Agricultural Experiment Station, Gainesville) for 374 first lactations. Estimates were from the use of multivariate, derivative-free, restricted maximum likelihood procedures with the simplex method of partial maximization. Estimates agreed closely with those obtained previously by other methods in this and other dairy populations. All correlations between yields were high and positive; those between yields and days from parturition to first service were negative and near zero. Correlations between yields and somatic cell scores were moderate and negative; those between yields and constituent percentages in general were negative, except for the yield and percentage of the same constituent. Genetic correlations between chloride content and somatic cells and between measures of somatic cells were 1.0. Results suggest that single-trait selection for milk yield should result in correlated increases in constituent yields with slight decreases in percentage composition of constituents and somatic cell counts.

Animals↗
PubMed1994

Vascular smooth muscle cells grown on Matrigel. A model of the contractile phenotype with decreased activation of mitogen-activated protein kinase.

Vascular smooth muscle cells have been shown to exist in two phenotypic states which have been designated proliferative and contractile. The properties of rat aortic vascular smooth muscle cells grown on Matrigel were compared with cells grown on untreated plastic culture dishes. Cells grown on Matrigel manifested at least four important properties characteristic of the contractile phenotype as compared with cells grown on plastic. The cells grown on Matrigel had altered morphology similar to in vivo studies of contractile vascular smooth muscle. The cells had a low proliferative index, showed enhanced levels of the smooth muscle isoform of alpha-actin, and had an enhanced contractile response to the vasoconstrictor arginine vasopressin. All of these changes were maintained through at least five passages and could be reversed by replating cells grown on Matrigel back to uncoated plastic dishes. Changes in post-receptor signaling pathways which could account for the altered physiologic responses of the cells were investigated. Cells grown on Matrigel showed no alterations in agonist-induced mobilization of intracellular Ca2+ or agonist-stimulated cAMP levels. However, stimulation of mitogen-activated protein kinase (MAP kinase) by both vasoconstrictors and growth factors was inhibited by 50% in cells grown on Matrigel as compared with plastic. This decrease in agonist-induced MAP kinase was associated with a decrease in the levels of both p42 and p44 MAP kinase protein and a decrease in tyrosine phosphorylation of both isoforms in cells grown on Matrigel. Alterations in MAP kinase activation can account at least in part for the observed physiologic responses of contractile vascular smooth muscle. Growth of vascular smooth muscle cells on Matrigel represents a useful model to examine phenotypic-dependent alterations in post-receptor signaling.

Actins↗
PubMed1999

Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy.

Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertrophic cardiomyopathy (FHC). Patients with cTnT mutations generally exhibit mild or no ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. To understand the functional basis of these phenotypes, we created transgenic mouse lines expressing 30%, 67%, and 92% of their total cTnT as a missense (R92Q) allele analogous to one found in FHC. Similar to a mouse FHC model expressing a truncated cTnT protein, the left ventricles of all R92Q lines are smaller than those of wild-type. In striking contrast to truncation mice, however, the R92Q hearts demonstrate significant induction of atrial natriuretic factor and beta-myosin heavy chain transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocytes from R92Q mice have increased basal sarcomeric activation, impaired relaxation, and shorter sarcomere lengths. Isolated working heart data are consistent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with FHC. These mice represent the first disease model to exhibit hypercontractility, as well as a unique model system for exploring the cellular pathogenesis of FHC. The distinct phenotypes of mice with different TnT alleles suggest that the clinical heterogeneity of FHC is at least partially due to allele-specific mechanisms.

Alleles↗
PubMed2005

Use of the l1 norm for selection of sparse parameter sets that accurately predict drug response phenotype from viral genetic sequences.

We describe the use of the l1 norm for selection of a sparse set of model parameters that are used in the prediction of viral drug response, based on genetic sequence data of the Human Immunodeficiency Virus (HIV) reverse-transcriptase enzyme. We discuss the use of the l1 norm in the Least Absolute Selection and Shrinkage Operator (LASSO) regression model and the Support Vector Machine model. When tested by cross-validation with laboratory measurements, these models predict viral phenotype, or resistance, in response to Reverse-Transcriptase Inhibitors (RTIs) more accurately than other known models. The l1 norm is the most selective convex function, which sets a large proportion of the parameters to zero and also assures that a single optimal solution will be found, given a particular model formulation and training data set. A statistical model that reliably predicts viral drug response is an important tool in the selection of Anti-Retroviral Therapy. These techniques have general application to modeling phenotype from complex genetic data.

Algorithms↗
PubMed2007

HIV-1 viral fitness estimation using exchangeable on subsets priors and prior model selection.

The phenotype-genotype problem is a fundamental problem of biology where an organism's genotype (genetic information) predicts its phenotype (observable characteristic). Viral fitness, defined as the reproductive capacity of a virus compared to a standard, is a continuous phenotype. We construct models to predict viral fitness as a function of mutation away from the standard wildtype virus. Data of this nature are difficult to analyse because there are potentially many more parameters than observations. We treat this issue as a regression problem using a prior with both a shrinkage component and a variable selection component. The key to practical implementation of the model is the prior specification for the regression coefficients. We use results from the scientific literature to construct several informative exchangeable within subsets priors (ESP). We use prior model selection (PMS) to select among our priors. Two novel graphics present results from five models each with 71 predictors.

Codon↗
PubMed2006

The lysyl oxidase LOX is absent in basal and squamous cell carcinomas and its knockdown induces an invading phenotype in a skin equivalent model.

Lysyl oxidase initiates the enzymatic stage of collagen and elastin cross-linking. Among five isoforms comprising the lysyl oxidase family, LOX is the better studied. LOX is associated to an antitumor activity in ras-transformed fibroblasts, and its expression is down-regulated in many carcinomas. The aim of this work was to shed light on LOX functions within the epidermis by studying its expression in human basal and squamous cell carcinomas and analyzing the effect of its enzymatic activity inhibition and protein absence on human keratinocytes behavior in a skin equivalent. In both carcinomas, LOX expression by epidermal tumor cells was lacking, while it was up-regulated around invading tumor cells in association with the stromal reaction. Lysyl oxidase activity inhibition using beta-aminoproprionitrile in a skin equivalent model prepared with both primary human keratinocytes and HaCaT cell line affected keratin 10 and filaggrin expression and disorganized the collagen network and the basement membrane. In spite of all these changes, no invasion phenotype was observed. Modelization of the invasive phenotype was only noticed in the skin equivalent developed with LOX antisense HaCaT cell line, where the protein LOX is specifically absent. Our results clearly indicate that lysyl oxidase enzymatic activity is essential not only for the integrity maintenance of the dermis but also for the homeostasis of the epidermis. Moreover, LOX protein plays a role in the skin carcinomas and invasion but not through its enzymatic activity.

Aminopropionitrile↗
PubMed2006

Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2).

Genomic disorders are conditions that result from DNA rearrangements, such as deletions or duplications. The identification of the dosage-sensitive gene(s) within the rearranged genomic interval is important for the elucidation of genes responsible for complex neurobehavioral phenotypes. Smith-Magenis syndrome is associated with a 3.7-Mb deletion in 17p11.2, and its clinical presentation is caused by retinoic acid inducible 1 (RAI1) haploinsufficiency. The reciprocal microduplication syndrome, dup(17)(p11.2p11.2), manifests several neurobehavioral abnormalities, but the responsible dosage-sensitive gene(s) remain undefined. We previously generated a mouse model for dup(17)(p11.2p11.2), Dp(11)17/+, that recapitulated most of the phenotypes observed in human patients. We have now analyzed compound heterozygous mice carrying a duplication [Dp(11)17] in one chromosome 11 along with a null allele of Rai1 in the other chromosome 11 homologue [Dp(11)17/Rai1(-) mice] in order to study the relationship between Rai1 gene copy number and the Dp(11)17/+ phenotypes. Normal disomic Rai1 gene dosage was sufficient to rescue the complex physical and behavioral phenotypes observed in Dp(11)17/+ mice, despite altered trisomic copy number of the other 18 genes present in the rearranged genomic interval. These data provide a model for variation in copy number of single genes that could influence common traits such as obesity and behavior.

Animals↗
PubMed2006

Chlorpyrifos affects phenotypic outcomes in a model of mammalian neurodevelopment: critical stages targeting differentiation in PC12 cells.

The organophosphate insecticide chlorpyrifos (CPF) adversely affects mammalian brain development through multiple mechanisms. To determine if CPF directly affects neuronal cell replication and phenotypic fate, and to identify the vulnerable stages of differentiation, we exposed PC12 cells, a model for mammalian neurodevelopment, to CPF concentrations spanning the threshold for cholinesterase inhibition (5-50 microM) and conducted evaluations during mitosis and in early and mid-differentiation. In undifferentiated cells, exposure to 5 microM CPF for 1-3 days reduced DNA synthesis significantly without eliciting cytotoxicity. At the same time, CPF increased the expression of tyrosine hydroxylase (TH), the enzymatic marker for the catecholamine phenotype, without affecting choline acetyltransferase (ChAT), the corresponding marker for the cholinergic phenotype. Upon exposure to nerve growth factor (NGF), PC12 cells developed neuritic projections in association with vastly increased TH and ChAT expression accompanying differentiation into the two phenotypes. CPF exposure begun at the start of differentiation significantly reduced ChAT but not TH activity. In contrast, when CPF was added in mid-differentiation (4 days of NGF pretreatment), ChAT was unaffected and TH was increased slightly. Thus, CPF exerts stage-specific effects, reducing DNA synthesis in the undifferentiated state, impairing development of the cholinergic phenotype at the start of differentiation, and promoting expression of the catecholaminergic phenotype both in undifferentiated and differentiated cells. CPF administration in vivo produces deficits in the number of neurons and cholinergic function, and because we were able to reproduce these effects in vitro, our results suggest that CPF directly influences the phenotypic fate of neuronal precursors.

Animals↗
PubMed2005

Use of tissue recombination to predict phenotypes of transgenic mouse models of prostate carcinoma.

Transgenic mouse models of cancer represent a powerful approach for exploring disease processes and testing potential therapeutic interventions. Currently, it is difficult to predict if a specific genetic manipulation will result in a desirable phenotype. The present study tests the idea that tissue recombinants recapitulate the pathologic features of the neoplastic prostate seen in transgenic mice, and would thus be suitable predictive models for new mouse design. The large probasin-large T-antigen (LPB-Tag) transgenic lines 12T-7f and 12T-10 were used as a basis for this study. Tissue recombinants of bladder epithelium (BlE) and urogenital sinus mesenchyme (UGM) were implanted under the renal capsule of athymic mice. Recombinants composed of BlE from 12T-10 LPB-Tag and wild-type (wt) UGM faithfully recapitulated the histopathologic and temporal features of intact transgenic mice of this line. Tissue recombinants using BlE from 12T-7f mice and wt UGM developed epithelial proliferation with atypia that lacked the associated hypercellular stroma seen in the intact 12T-7f line. Recombinants using 12T-7f UGM demonstrated that the hypercellular stroma results from stromal cell expression of the SV40 large T antigen. Corresponding to the recombinant phenotypes, stromal Tag immunostaining was observed in prostate tissues from intact 12T-7f but not 12T-10 mice. Similar stromal expression of Tag was also noted in the hypercellular TRAMP prostatic stroma. Further analysis revealed a previously unreported pattern of SV40T expression in the LADY and TRAMP models including ductus deferens and seminal vesicle stroma as well as region and cell type-specific patterns in the epididymis. The present study demonstrates the utility of using tissue recombination to explore organ-specific phenotypes. Recombination strategies should enable quick and cost-effective screening for likely phenotypes in transgenic animals. This comparison of tissue recombination to existing models shows that this approach can elicit new information on well-characterized models.

Animals↗
PubMedDate not supplied

Are MG-63 and HOS TE85 human osteosarcoma cell lines representative models of the osteoblastic phenotype?

The aim of this study was to perform a systematic comparison of two widely used osteosarcoma cell lines and ascertain their relevance as experimental models for investigating osteoblast function. We have therefore compared growth, differentiated cell function, integrin expression and adhesive profiles of MG-63, HOS TE85, and human bone derived cells. Both osteosarcoma cell lines proliferated more rapidly than osteoblast-like cells with HOS cells exhibiting the shortest doubling time. HOS cells expressed higher levels of alkaline phosphatase than MG-63 cells under basal conditions but only MG-63 cells showed the increased enzyme activity following 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) administration, which is characteristic of bone derived cells. Osteocalcin was not detected in supernatants from any cells under basal conditions but levels produced by MG-63 cells on addition of 1,25(OH)2D3 were comparable with those of osteoblast-like cells. alpha 1, alpha 2, alpha 3, alpha 5, alpha V, and beta 1 integrin subunits were detected on all cells and there was no staining for alpha L, alpha M, beta 2, and beta 3. alpha 3 and beta 1 were the major subunits detected on MG-63, HOS, and bone derived cells but relative concentrations of other alpha subunits were dependent on cell type; alpha 4 and alpha 6 subunits could only be detected on osteosarcoma cell lines. Short term, serum-free cell adhesion assays showed that the three cell types adhered in a saturable manner to collagen I, fibronectin, and laminin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2005

Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine.

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive weakness and spasticity of the lower limbs. Dominant mutations in the human SPG4 gene, encoding spastin, are responsible for the most frequent form of HSP. Spastin is an ATPase that binds microtubules and localizes to the spindle pole and distal axon in mammalian cell lines. Furthermore, its Drosophila homolog, Drosophila spastin (Dspastin), has been recently shown to regulate microtubule stability and synaptic function at the Drosophila larval neuromuscular junction. Here we report the generation of a spastin-linked HSP animal model and show that in Drosophila, neural knockdown of Dspastin and, conversely, neural overexpression of Dspastin containing a conserved pathogenic mutation both recapitulate some phenotypic aspects of the human disease, including adult onset, locomotor impairment, and neurodegeneration. At the subcellular level, neuronal expression of both Dspastin RNA interference and mutant Dspastin cause an excessive stabilization of microtubules in the neuromuscular junction synapse. In addition, we provide evidence that administration of the microtubule targeting drug vinblastine significantly attenuates these phenotypes in vivo. Our findings demonstrate that loss of spastin function elicits HSP-like phenotypes in Drosophila, provide novel insights into the molecular mechanism of spastin mutations, and raise the possibility that therapy with Vinca alkaloids may be efficacious in spastin-associated HSP and other disorders related to microtubule dysfunction.

Adenosine Triphosphatases↗