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At least 451 records · Page 25Linked to original sources
PubMed1997

Genetic modeling of susceptibility to nitrogen dioxide-induced lung injury in mice.

We investigated the mode of inheritance of susceptibility to nitrogen dioxide (NO2)-induced lung injury in inbred mice. Susceptible C57BL/6J (B6) and resistant C3H/HeJ (C3) mice, as well as F1, F2, and backcross (BX) populations derived from them, were exposed to 15 parts per million NO2 for 3 h. Six hours after exposure, animals were lavaged, and differential cell counts and cell viability (cytotoxicity) were measured. Statistically significant (P < 0.05) differences in numbers of lavageable macrophages, epithelial cells, and dead cells were found between inbred strains. Distributions of cellular responses in F1 progeny overlapped both progenitors, and mean responses were intermediate. In C3:BX progeny, ranges of responses to NO2 closely resembled C3 mice, and means were not significantly different between populations. Ranges of cellular responses to NO2 in B6:BX and intercross progeny overlapped both progenitors; mean responses of both populations were intermediate to progenitors. Segregation analyses tested goodness of fit of phenotyping data with various inheritance models, and the highest likelihood for each cell response to NO2 was for the hypothesis two-unlinked loci general. We conclude that there are likely two major unlinked genes that account for differential susceptibility to acute NO2 exposure. The chromosomal location of the genes is not known.

Animals↗
PubMed2002

Quantitative genetic modeling of regional brain volumes and cognitive performance in older male twins.

As part of an ongoing longitudinal twin study, data from both MRI brain scanning and from neuropsychological testing were obtained from 139 male-male twin pairs (72 monozygotic [MZ] and 67 dizygotic [DZ]), 69-80 years old at the time of examination. For descriptive purposes, we examined the MZ and DZ intraclass correlations (ICC) of four lobar brain volumes (frontal, temporal, parietal, and occipital), two cerebrospinal fluid (CSF) volumes (lateral ventricle and temporal horn of the lateral ventricles), and two measures of cognitive functioning (verbal memory and executive function). We found that for lobar brain and CSF space volumes, the MZ ICC were significantly greater than zero (r=0.37-0.77) and greater than the corresponding DZ correlations (r=0.02-0.49). Similarly, within-pair correlations for the two neuropsychological factors were statistically significant and significantly larger in MZ twin pairs than in DZ pairs, suggesting the presence of genetic variance. Bivariate genetic analysis revealed that while close to 60% of individual differences in neuropsychological performance were due to genetic influences, less than 50% of genetic effects were in common with those influencing brain volumes. These data may shed light on the genetic liability for brain diseases that affect the elderly.

Aged↗
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↗
PubMed2002

Repeatability of Model Genetic Coefficients Derived from Soybean Performance Trials across Different States.

Crop model testing in diverse environments is essential if modelers wish to make applications or extrapolations to those environments. A recent study demonstrated the effectiveness of optimization techniques for deriving cultivar coefficients for the CROPGRO-Soybean model from typical information provided by soybean performance tests. The objectives of this study were (i) to explore the extent to which cultivar coefficients developed by these approaches from crop performance tests are stable across different regions, (ii) to test the CROPGRO-Soybean model's ability to predict phenology and seed yield using cultivar coefficients that were developed in different regions, and (iii) to investigate whether 3 yr of crop performance data are adequate for developing stable genetic coefficients. A stepwise procedure was applied to derive cultivar coefficients for 10 common cultivars grown in different environments in Georgia and North Carolina. Regarding the transportability of cultivar coefficients across states, we found that the critical daylength coefficients were the most reliable cultivar traits. We found less stability of the cultivar traits that control genetic differences in seed yield potential. The estimated cultivar coefficients developed in Georgia enabled CROPGRO to predict yield and harvest maturity in North Carolina within 3.8% and 3.5 d, respectively, from the observed averages. Using the cultivar coefficients developed from North Carolina environments allowed us to simulate the actual mean yield and harvest maturity in Georgia to within 2.5% and 2.0 d. Furthermore, the model's ability to predict seed yield and maturity with cultivar coefficients developed from 3 yr of data was nearly as good as that derived from much larger data sets.

Journal Article↗
PubMed2001

Xiphophorus interspecies hybrids as genetic models of induced neoplasia.

Fishes of the genus Xiphophorus (platyfishes and swordtails) are small, internally fertilizing, livebearing, and derived from freshwater habitats in Mexico, Guatemala, Belize, and Honduras. Scientists have used these fishes in cancer research studies for more than 70 yr. The genus is presently composed of 22 species that are quite divergent in their external morphology. Most cancer studies using Xiphophorus use hybrids, which can be easily produced by artificial insemination. Phenotypic traits, such as macromelanophore pigment patterns, are often drastically altered as a result of lack of gene regulation within hybrid fishes. These fish can develop large exophytic melanomas as a result of upregulated expression of these pigment patterns. Because backcross hybrid fish are susceptible to the development of melanoma and other neoplasms, they can be subjected to potentially deleterious chemical and physical agents. It is thus possible to use gene mapping and cloning methodologies to identify and characterize oncogenes and tumor suppressors implicated in spontaneous or induced neoplasia. This article reviews the history of cancer research using Xiphophorus and recent developments regarding DNA repair capabilities, mapping, and cloning of candidate genes involved in neoplastic phenotypes. The particular genetic complexity of melanoma in these fishes is analyzed and reviewed.

Animals↗
PubMed1993

Genetic models of human obesity--family studies.

Childhood obesity is predictive of obesity as an adult, and individual differences in body weight relative to height (body mass index) in adults are important predictors of morbidity as well as mortality from atherosclerotic cardiovascular disease. The observation of strong familial correlations does not ensure that genes are involved in the determination of body mass index, because individuals in families share environments as well as genes. However, several recent studies have found evidence for both additive (polygene) and nonadditive (major gene) components. A question that results from these analyses is--what gene(s) has been inherited that carries an associated risk, most likely mediated by environmental exposures, for obesity? Studies to identify genetic loci linked to familial obesity should add to our understanding of the genetic factors involved in the determination of obesity and may lead to early identification of individuals and families at high risk for the chronic disorders that are associated with obesity.

Body Mass Index↗
PubMed1997

A molecular genetic model of astrocytoma histopathology.

As the molecular events responsible for astrocytoma formation and progression are being clarified, it is becoming possible to correlate these alterations with the specific histopathological and biological features of astrocytoma, anaplastic astrocytoma and glioblastoma multiforme. In WHO grade II astrocytomas, autocrine stimulation by the plateletderived growth factor system coupled with inactivation of the p53 gene may lead to a growth stimulus in the face of decreased cell death with slow net growth ensuing. Such cells would also have defective responses to DNA damage and impaired DNA repair, setting the stage for future malignant change. Such biological scenarios recapitulate many of the clinicopathological features of WHO grade II astrocytomas. Anaplastic astrocytomas further display release of a critical cell cycle brake that involves the CDKN2/p16, RB and CDK4 genes. This results in mitoses seen histologically; clinically, there is more conspicuous, rapid growth. Finally, glioblastomas may emerge from the microenvironmental outgrowth of more malignant clones in a complex vicious cycle that involves necrosis, hypoxia, growth factor release, angiogenesis and clonal selection; growth signals mediated by activation of epidermal growth factor receptors may precipitate glioblastomas. It is clear as well that glioblastoma multiforme can arise via a number of independent genetic pathways, although the clinical significance of these distinctions remains unclear.

Apoptosis↗
PubMed2006

A genetic model for muscle-eye-brain disease in mice lacking protein O-mannose 1,2-N-acetylglucosaminyltransferase (POMGnT1).

Protein O-mannose beta1,2-N-acetyglucosaminyltransferase 1 (POMGnT1) is an enzyme involved in the synthesis of O-mannosyl glycans. Mutations of POMGnT1 in humans result in the muscle-eye-brain (MEB) disease. In this study, we have characterized a null mutation generated by gene trapping with a retroviral vector inserted into the second exon of the mouse POMGnT1 locus. Expression of POMGnT1 mRNA was abolished in mutant mice. Glycosylation of alpha-dystroglycan was also reduced. POMGnT1 mutant mice were viable with multiple developmental defects in muscle, eye, and brain, similar to the phenotypes observed in human MEB disease. The present study provides the first genetic animal model to further dissect the roles of POMGnT1 in MEB disease.

Animals↗
PubMed2006

Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency.

This study investigated the role of cellular antioxidant defense mechanisms in modulating the neurotoxicity of domoic acid (DomA), by using cerebellar granule neurons (CGNs) from mice lacking the modifier subunit of glutamate-cysteine ligase (Gclm). Glutamate-cysteine ligase (Glc) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis. CGNs from Gclm (-/-) mice have very low levels of GSH and are 10-fold more sensitive to DomA-induced toxicity than CGNs from Gclm (+/+) mice. GSH ethyl ester decreased, whereas the Gcl inhibitor buthionine sulfoximine increased DomA toxicity. Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors and of N-methyl-D-aspartate (NMDA) receptors blocked DomA toxicity, and NMDA receptors were activated by DomA-induced l-glutamate release. The differential susceptibility of CGNs to DomA toxicity was not due to a differential expression of ionotropic glutamate receptors, as evidenced by similar calcium responses and L-glutamate release in the two genotypes. A calcium chelator and several antioxidants antagonized DomA-induced toxicity. DomA caused a rapid decrease in cellular GSH, which preceded toxicity, and the decrease was primarily due to DomA-induced GSH efflux. DomA also caused an increase in oxidative stress as indicated by increases in reactive oxygen species and lipid peroxidation, which was subsequent to GSH efflux. Astrocytes from both genotypes were resistant to DomA toxicity and presented a diminished calcium response to DomA and a lack of DomA-induced L-glutamate release. Because polymorphisms in the GCLM gene in humans are associated with low GSH levels, such individuals, as well as others with genetic conditions or environmental exposures that lead to GSH deficiency, may be more susceptible to DomA-induced neurotoxicity.

Animals↗
PubMed1991

Regeneration of autologous and allogenic nerve grafts in a rat genetic model: preliminary report.

The authors report observations concerning rejection and regeneration processes of allogenic peripheral neural tissue, depending on different genetic mismatches in a rat model. Five groups representing different rat strains (n = 100) were subjected to orthotopic grafting of 2.5-cm segments of sciatic nerve. Combinations represented different genetic barriers, including the Major Histocompatibility Complex (MHC), a non-MHC, a subgroup (A) of the MHC, a group representing MHC plus non-MHC, and an autologous control group. Animals were examined after one, two, and 12 weeks; additional evaluations in some of the experimental groups were done at six and eight weeks. Regeneration in varying degrees was evident in all groups at 12 weeks.

Animals↗
PubMed1999

Mouse genetic model for left-right hand usage: context, direction, norms of reaction, and memory.

Asymmetry of paw usage in the laboratory mouse is an experimental model for left-right asymmetry of hand usage. Given a set number of reaches into a centrally placed food tube (an unbiased or U-world test), individual mice exhibit a number of left and right paw reaches that is reliably expressed on retesting. Whereas different inbred strains appear to have equal numbers of individual mice with a left- or a right-preferred paw after a U-world test, there are significant differences among strains in the degree or strength of lateralization of the preferred paw. We report here a systematic series of tests of paw usage with naive mice and retests of the individuals in test chambers with the food tube biased to the left or to the right, contrasting the highly lateralized C57BL/6J and the very weakly lateralized (or ambilateral) CDS/Lay inbred strains and their (B6 x CDS) F1 generation. The results caused a shift in the paradigm of paw usage. There is an unexpected qualitative difference in paw usage between C57BL/6J and CDS/Lay. C57BL/6J is random in its left-right paw usage, but it is conditioned by the left or right direction of the initial biased-world test and by usage. CDS/Lay is constitutively equal-pawed, responds very little to direction of the test chamber, and is not conditioned by it. The probability of left-paw versus right-paw usage depends on both the genotype and the context of the test. The (B6 x CDS) F1 generation suggests that constitutive equal-paw usage of CDS/Lay is dominant to experience-conditioned paw usage of C57BL/6J. There is also an apparent quantitative difference between the very weakly lateralized (ambilateral) preferred paw usage in CDS/Lay and the highly lateralized preferred paw usage in C57BL/6J. The difference in degree of lateralization of preferred paw usage between the constitutively equal-pawed CDS/Lay strain and (B6 x CDS) F1 generation must originate from allelic differences at other gene loci between the CDS/Lay and C57BL/6J parental strains. The SWV and NOD/Lt strains were also assessed in asymmetrical tests because they were known to be weakly lateralized and similar to each other in a U-world test and to be significantly different from both C57BL/6J and CDS/Lay. SWV is experience-conditioned and weakly lateralized; NOD/Lt is constitutively equal-pawed and weakly lateralized. Further analysis will determine the genetic cause of the qualitative difference between constitutive equal-paw and experience-conditioned paw usage and the genetic cause of the quantitative differences in degree of lateralization of the preferred paw within each type of paw usage.

Animals↗
PubMed2003

Genetic Models in Applied Physiology. HXB/BXH rat recombinant inbred strain platform: a newly enhanced tool for cardiovascular, behavioral, and developmental genetics and genomics.

This review deals with the largest set of rat recombinant inbred (RI) strains and summarizes past and recent accomplishments with this platform for genetic mapping and analyses of divergent and complex traits. This strain, derived by crossing the spontaneously hypertensive rat, SHR/Ola, with a Brown Norway congenic, BN-Lx, carrying polydactyly-luxate syndrome, is referred to as HXB/BXH. The RI strain set has been used for linkage and association studies to identify quantitative trait loci for numerous cardiovascular phenotypes, including arterial pressure, stress-elicited heart rate, and pressor response, and metabolic traits, including insulin resistance, dyslipidemia and glucose handling, and left ventricular hypertrophy. The strain's utility has been enhanced with development of a new framework marker-based map and strain distribution patterns of polymorphic markers. Quantitative trait loci for behavioral traits mapped include loci for startle motor response and habituation, anxiety and locomotion traits associated with elevated plus maze, and conditioned taste aversion. The polydactyly-luxate syndrome Lx mutation has allowed the study of alleles important to limb development and malformation phenotypes as well as teratogens. The RI strains have guided development of numerous congenic strains to test locus assignments and to study the effect of genetic background. Although these strains were originally developed to aid in studies of rat genetic hypertension and morphogenetic abnormalities, this rodent platform has been shown to be equally powerful for a wide spectrum of traits and endophenotypes. These strains provide a ready and available vehicle for many physiological and pharmacological studies.

Animals↗
PubMedDate not supplied

Phenotypic and dynamical transitions in model genetic networks. I. Emergence of patterns and genotype-phenotype relationships.

Genotype-phenotype interactions during the evolution of form in multicellular organisms is a complex problem but one that can be aided by computational approaches. We present here a framework within which developmental patterns and their underlying genetic networks can be simulated. Gene networks were chosen to reflect realistic regulatory circuits, including positive and negative feedback control, and the exchange of a subset of gene products between cells, or within a syncytium. Some of these networks generate stable spatial patterns of a subset of their molecular constituents, and can be assigned to categories (e.g., "emergent" or "hierarchic") based on the topology of molecular circuitry. These categories roughly correspond to what has been discussed in the literature as "self-organizing" and "programmed" processes of development. The capability of such networks to form patterns of repeating stripes was studied in network ensembles in which parameters of gene-gene interaction were caused to vary in a manner analogous to genetic mutation. The evolution under mutational change of individual representative networks of each category was also simulated. We have found that patterns with few stripes (< or =3) are most likely to originate in the form of a hierarchic network, whereas those with greater numbers of stripes (> or =4) originate most readily as emergent networks. However, regardless of how many stripes it contains, once a pattern is established, there appears to be an evolutionary tendency for emergent mechanisms to be replaced by hierarchic mechanisms. These results have potential significance for the understanding of genotype-phenotype relationships in the evolution of metazoan form.

Biological Evolution↗
PubMed2004

Modeling genetic networks from clonal analysis.

In this report a systematic approach is used to determine the approximate genetic network and robust dependencies underlying differentiation. The data considered is in the form of a binary matrix and represent the expression of the nine genes across the 99 colonies. The report is divided into two parts: the first part identifies significant pair-wise dependencies from the given binary matrix using linear correlation and mutual information. A new method is proposed to determine statistically significant dependencies estimated using the mutual information measure. In the second, a Bayesian approach is used to obtain an approximate description (equivalence class) of network structures. The robustness of linear correlation, mutual information and the equivalence class of networks is investigated with perturbation and decreasing colony number. Perturbation of the data was achieved by generating bootstrap realizations. The results are refined with biological knowledge. It was found that certain dependencies in the network are immune to perturbation and decreasing colony number and may represent robust features, inherent in the differentiation program of osteoblast progenitor cells. The methods to be discussed are generic in nature and not restricted to the experimental paradigm addressed in this study.

Animals↗
PubMedDate not supplied

Group-structured genetic models in analyses of the population and behavioral ecology of poikilothermic vertebrates.

Estimates of gene correlations among individuals within and among populations are frequently derived from statistical analyses of genetic data (e.g., F statistics). These measures can be important tools in molecular ecology and conservation, and offer important insights into population breeding structure. Using recently derived theory developed for group-structured populations, we show that fixation indices, when combined with basic population ecological and demographic data can be used to investigate population mating systems and to predict dispersal rates, trajectories and asymptotic levels of fixation indices, and effective population size. Four case studies of poikilothermic vertebrates are used to demonstrate the broad utility of evolutionary and ecological inferences afforded by group-structured models.

Animals↗
PubMed2005

Alteration of kappa-opioid receptor system expression in distinct brain regions of a genetic model of enhanced ethanol withdrawal severity.

Abrupt withdrawal from chronic alcohol exposure can produce convulsions that are likely due to ethanol (EtOH) neuroadaptations. While significant efforts have focused on elucidating dependence mechanisms, the alterations contributing to EtOH withdrawal severity are less well characterized. The present studies examined the kappa-opioid receptor (KOP-R) system in Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice, selected lines that display severe and mild convulsions upon removal from chronic EtOH exposure. Previous data demonstrated significant increases in whole brain prodynorphin (Pdyn) mRNA in WSP mice only during EtOH withdrawal. No significant effects of EtOH exposure or withdrawal were observed in WSR mice. The present study characterized Pdyn mRNA and the KOP-R in WSP and WSR mice during EtOH withdrawal using in situ hybridization (ISH) and KOP-R autoradiography. Analyses were performed in brain regions that express Pdyn mRNA and/or KOP-R and that might participate in seizure circuitry: the piriform cortex, olfactory tubercle, nucleus accumbens, caudate-putamen, claustrum, dorsal endopiriform nucleus, and cingulate cortex. ISH analyses confirmed previous findings; EtOH withdrawal increased Pdyn mRNA in multiple brain regions of WSP mice, but not WSR. Basal KOP-R binding was higher in WSR mice than in WSP mice, suggesting an anti-convulsant role for receptor activation. Finally, increased KOP-R density was present during EtOH withdrawal in WSP mice. These data suggest that differences in the KOP-R system among the lines might contribute to their selected difference in EtOH withdrawal severity.

Alcohol Withdrawal Seizures↗