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PubMed2003

Transgenic rabbits as therapeutic protein bioreactors and human disease models.

Genetically modified laboratory animals provide a powerful approach for studying gene expression and regulation and allow one to directly examine structure-function and cause-and-effect relationships in pathophysiological processes. Today, transgenic mice are available as a research tool in almost every research institution. On the other hand, the development of a relatively large mammalian transgenic model, transgenic rabbits, has provided unprecedented opportunities for investigators to study the mechanisms of human diseases and has also provided an alternative way to produce therapeutic proteins to treat human diseases. Transgenic rabbits expressing human genes have been used as a model for cardiovascular disease, AIDS, and cancer research. The recombinant proteins can be produced from the milk of transgenic rabbits not only at lower cost but also on a relatively large scale. One of the most promising and attractive recombinant proteins derived from transgenic rabbit milk, human alpha-glucosidase, has been successfully used to treat the patients who are genetically deficient in this enzyme. Although the pronuclear microinjection is still the major and most popular method for the creation of transgenic rabbits, recent progress in gene targeting and animal cloning has opened new avenues that should make it possible to produce transgenic rabbits by somatic cell nuclear transfer in the future. Based on a computer-assisted search of the studies of transgenic rabbits published in the English literature here, we introduce to the reader the achievements made thus far with transgenic rabbits, with emphasis on the application of these rabbits as human disease models and live bioreactors for producing human therapeutic proteins and on the recent progress in cloned rabbits.

Animals↗
PubMed2000

Linear modeling of genetic networks from experimental data.

In this paper, the regulatory interactions between genes are modeled by a linear genetic network that is estimated from gene expression data. The inference of such a genetic network is hampered by the dimensionality problem. This problem is inherent in all gene expression data since the number of genes by far exceeds the number of measured time points. Consequently, there are infinitely many solutions that fit the data set perfectly. In this paper, this problem is tackled by combining genes with similar expression profiles in a single prototypical 'gene'. Instead of modeling the genes individually, the relations between prototypical genes are modeled. In this way, genes that cannot be distinguished based on their expression profiles are grouped together and their common control action is modeled instead. This process reduces the number of signals and imposes a structure on the model that is supported by the fact that biological genetic networks are thought to be redundant and sparsely connected. In essence, the ambiguity in model solutions is represented explicitly by providing a generalized model that expresses the basic regulatory interactions between groups of similarly expressed genes. The modeling approach is illustrated on artificial as well as real data.

Animals↗
PubMed2000

[An ADAA model and its analysis method for agronomic traits based on the double-cross mating design].

According to the double-cross mating design and using principles of Cockerham's general genetic model, a genetic model with additive, dominance and epistatic effects (ADAA model) was proposed for the analysis of agronomic traits. Components of genetic effects were derived for different generations. Monte Carlo simulation was conducted for analyzing the ADAA model and its reduced AD model by using different generations. It was indicated that genetic variance components could be estimated without bias by MINQUE(1) method and genetic effects could be predicted effectively by AUP method; at least three generations (including parent, F1 of single cross and F1 of double-cross) were necessary for analyzing the ADAA model and only two generations (including parent and F1 of double-cross) were enough for the reduced AD model. When epistatic effects were taken into account, a new approach for predicting the heterosis of agronomic traits of double-crosses was given on the basis of unbiased prediction of genotypic merits of parents and their crosses. In addition, genotype x environment interaction effects and interaction heterosis due to G x E interaction were discussed briefly.

Crosses, Genetic↗
PubMed2001

[Complex segregation analysis of systemic lupus erythematosus].

OBJECTIVE: To explore the genetic model of systemic lupus erythematosus(SLE). METHODS: Complex segregation analysis was performed by using statistical analysis for genetic epidemiology-REGTL(SAGE-REGTL). The genetic model and gene frequency were estimated. 300 pedigrees with SLE were collected from 300 patients as probands. RESULTS: The complex segregation analysis found the genetic model of SLE to be additive,the gene frequency 0.336. The authors believe the possibility of some different modes coexisting under different circumstances. The genetic effect on young man is stronger than that on old one. CONCLUSION: This study suggests that the genetic mode of SLE could be the major gene trait, and additive mode is the best fitted one.

Adolescent↗
PubMed1987

A hypothetical model of genetic control of tooth-crown growth in man.

Twins and families were investigated to obtain information about inheritance of tooth-crown size. Sixty twin pairs and 100 families were examined using four methods of estimation. The results suggest genetically controlled interactions between tooth germs during their formation. A hypothetical model of odontogenesis is presented.

Humans↗
PubMed2001

Cross-fostering and cross-breeding of HAB and LAB rats: a genetic rat model of anxiety.

Recently, two Wistar rat lines, bred and selected for either high (HAB) or low (LAB) anxiety-related behavior on the elevated plus-maze, were described as a novel psychopathologic animal model. The behavioral and neuroendocrine responses to exposure to an emotional stressor were markedly enhanced in HAB rats compared with LAB rats, thus resembling patients suffering from psychiatric diseases. The present study focused on the developmental and genetic basis of the line-specific differences by using cross-fostering and cross-breeding approaches. For the cross-fostering paradigm, neonate HAB offspring were nursed by a LAB foster mother, and vice versa, until weaning. In the cross-breeding approach, HAB females were mated with LAB males, and vice versa, to create an intermediate F1 generation. Thereafter, the F1 animals were strictly sibling-mated to produce a segregating F2 generation. At 10 weeks of age, anxiety-related behavior of all animals was tested on the elevated plus-maze. The robustness of emotionality was assessed in rats of both lines throughout their entire lifetime. Serving this purpose, the frequency of ultrasound isolation calls, indicative of the emotionality of newborn rats, was monitored in regularly-fostered HAB and LAB pups on postnatal day 11. In addition, the timecourse of anxiety-related behavior was studied by repeated testing on the elevated plus-maze at the ages of 10 weeks, 6 months, 16 months, and 19 months. The cross-fostering approach failed to reveal behavioral differences between regularly and cross-fostered HAB and LAB rats, indicating no line-specific differences in maternal care or maternally-influenced development, at least after postnatal day 1. In contrast, cross-breeding resulted in F1 and F2 offspring displaying intermediate behavioral patterns on the elevated plus-maze which were exactly in between those shown in HAB and LAB control rats, thus confirming a genetic basis of the differences in anxiety. Cross-breeding revealed no differences related to the gender of the offspring or to the line-derivation of sire or dam, indicating an autosomal, rather than heterosomal, heredity of the divergent emotionality in HABs and LABs. Further, we were able to show stable and robust emotional differences in rats of both lines during their entire lifetime. HAB rats showed an enhanced frequency of ultrasound isolation calls on postnatal day 11 (p < 0.05) and a lower open arm exploration of the elevated plus-maze throughout adulthood (p < 0.01) compared with the same-aged LABs. In conclusion, the extremely divergent anxiety levels of HAB and LAB rats are maintained during their whole lives and are determined genetically, rather than being learned. These findings may be important for further studies on the genetic basis of emotionality.

Aging↗
PubMed1996

Life events and personality in late adolescence: genetic and environmental relations.

The relationship between life events and personality was investigated in the Minnesota Twin/Family Study, using 216 monozygotic and 114 dizygotic 17-year-old male twin pairs. Participants completed a life events interview designed for adolescents and the Multidimensional Personality Questionnaire. Life events were categorized into three types: life events to which all members of a family would be subject and those affecting an individual, which can be broadly construed as either nonindependent or independent. Univariate genetic model fitting indicated the presence of significant genetic effects (h2 = 49%) for nonindependent nonfamily life events but not for the other two types of life events. Bivariate genetic model fitting further confirmed that the significant phenotypic correlation between nonindependent life events and personality is in part genetically mediated. Specifically, the findings suggest that genetically influenced individual differences in constraint play a substantial role in life events whose occurrence is not independent of the individual's behavior.

Adolescent↗
PubMed2001

Intra-uterine and genetic influences on the relationship between size at birth and height in later life: analysis in twins.

Epidemiological studies have consistently shown a positive association between size at birth (i.e. birth weight or birth length) and height in children, adolescents and adults. To examine whether this association is explained by genetic or nongenetic (intra-uterine) factors, we investigated birth weight, birth length and height in 60 dizygotic and 68 monozygotic adolescent twin pairs still living with their parents. Birth weight of the twins was obtained from their mothers. Height was measured in a standardised way. The mean age was 17+/-1.7 years for the dizygotic twins and 16+/-1.8 years for the monozygotic twins. Both dizygotic and monozygotic twins with the lowest birth weight from each pair had a height that was lower compared to their co-twins with the highest birth weight (dizygotic twins: 172.2+/-7.9 vs. 173.8+/-9.4 cm [p = 0.05]; monozygotic twins: 171.1+/-9.4 vs. 171.8+/-9.5 cm [p = 0.01]). Similarly, both dizygotic and monozygotic twins with the shortest birth length from each pair had a height that was lower compared to their co-twins with the longest birth length (dizygotic twins: 172.3+/-7.9 vs. 174.9plus minus9.7 cm [p < 0.05]; monozygotic twins: 168.9+/-10.6 vs. 169.9+/-10.2 cm [p < 0.01]). In addition, intra-pair differences in birth weight and birth length were significantly associated with differences in height in both dizygotic twins (regression coefficient: 4.3 cm/kg [95% confidence interval: 1.0 to 7.5] and 0.96 cm/cm [0.17 to 1.74], respectively) and monozygotic twins (2.8 cm/kg [1.4 to 4.1] and 0.73 cm/cm [0.40 to 1.06], respectively). These associations were stronger in dizygotic than in monozygotic twins, but this difference was not statistically significant (for birth weight p = 0.4; and for birth length p = 0.6). However, genetic model fitting indicated that models incorporating a genetic source of the covariance gave a better description of the observed association of birth weight and length with height in later life than models not incorporating this genetic source. The results were similar for data on adult height after 12 years of follow-up in a subgroup of these twin pairs. These data suggest that the association between size at birth and height in later life is influenced by non-genetic intra-uterine and by genetic factors.

Adolescent↗
PubMed2003

Structured antedependence models for genetic analysis of repeated measures on multiple quantitative traits.

Simultaneous analysis of correlated traits that change with time is an important issue in genetic analyses. Several methodologies have already been proposed for the genetic analysis of longitudinal data on single traits, in particular random regression and character process models. Although the latter proved, in most cases, to compare favourably to alternative approaches for analysis of single function-valued traits, they do not allow a straightforward extension to the multivariate case. In this paper, another methodology (structured antedependence models) is proposed, and methods are derived for the genetic analysis of two or more correlated function-valued traits. Multivariate analyses are presented of fertility and mortality in Drosophila and of milk, fat and protein yields in dairy cattle. These models offer a substantial flexibility for the correlation structure, even in the case of complex non-stationary patterns, and perform better than multivariate random regression models, with fewer parameters.

Animals↗
PubMedDate not supplied

ABO genotyping in Italian blood donors.

BACKGROUND: Traditional ABO blood group serology is based on the immunoreactivity of antisera with the carbohydrate A, B and H antigens. Progress in the molecular biology of the ABO system has recognized the molecular basis of the red cell (RBC) antigens and has provided a genetic model for ABO polymorphism at the molecular level. Recently, this genetic model was tested in a large number of individuals. MATERIALS AND METHODS: In this study we applied DNA analysis to determine the frequency of ABO genotypes in a group of blood donors for whom the ABO type was known. Two hundred and fifty healthy Italian blood donors were analyzed using polymerase chain reaction (PCR) to amplify two different regions of genomic DNA, each of which contained a different nucleotide polymorphism. The amplified product was digested with 4 restriction enzymes that revealed differences among A, B and O individuals. To analyze the genes at polymorphic sites 261 and 703 we used the restriction enzymes BstE II and Kpn I, and Hpa II and Alu I and compared the PCR determined genotypes to serologically determined phenotypes. RESULTS AND CONCLUSIONS: The results were consistent for all unrelated individuals; however, 2 of 100 individuals with the 0 phenotype carried one allele that differed from the proposed genetic model. This novel O allele, termed 0(2) by Yamamoto et al., was found in our series with a frequency of 1%. The blood group AB0 genotype of 250 healthy Italian blood donors was: 13 AA/AO(2), 37 AO(1), 11 BB, 39 B0(1), 50 AB, 98 0(1)0(1) and 2 0(1)0(2). This method should be applicable not only in forensic medicine but also in immunohematology when serology fails.

ABO Blood-Group System↗
PubMed2001

Genetic and nongenetic bases for the L-shaped distribution of quantitative trait loci effects.

The L-shaped distribution of estimated QTL effects (R(2)) has long been reported. We recently showed that a metabolic mechanism could account for this phenomenon. But other nonexclusive genetic or nongenetic causes may contribute to generate such a distribution. Using analysis and simulations of an additive genetic model, we show that linkage disequilibrium between QTL, low heritability, and small population size may also be involved, regardless of the gene effect distribution. In addition, a comparison of the additive and metabolic genetic models revealed that estimates of the QTL effects for traits proportional to metabolic flux are far less robust than for additive traits. However, in both models the highest R(2)'s repeatedly correspond to the same set of QTL.

Linkage Disequilibrium↗
PubMed2002

The Fawn-Hooded (FH/Wjd) rat: a genetic animal model of comorbid depression and alcoholism.

The Fawn-Hooded (FH/Wjd) rat is an inbred strain of rat that has been reported to exhibit both high immobility in the forced swim test and high voluntary ethanol intake, measures that have been periodically linked with depression and alcoholism in humans. The present paper will first present a survey of the literature and previously unpublished findings that bear on the question of whether FH/Wjd rats should be considered genetic animal models of depression and alcoholism. Subsequently, behavioral studies of the FH/Wjd rats, the non-drinking ACI/N strain, and their F1 and F2 intercrosses will be described. Under free choice conditions, the FH/Wjd rat drinks up to 6 g/kg 10% ethanol per day. This intake was sufficient to render the rats tolerant to the hypothermic effects of injected ethanol (2.5 g/kg). Rats that had been voluntarily drinking for at least 6 weeks also exhibited withdrawal-induced anxiety in the social interaction, elevated plus maze, and ultrasonic vocalization tasks. The FH/Wjd rat exhibits a 25-30% increase in alcohol intake when the alcohol is returned after a 24-h period of deprivation. It responds to drugs that are effective in humans with a reduction in alcohol intake. Therefore, the FH/Wjd rat meets most of the criteria for an animal model of alcoholism. Chronic antidepressant treatments correct several of the abnormalities exhibited by the FH/Wjd rats, including the exaggerated immobility in the forced swim test. Therefore, the FH/Wjd rats also fulfill some of the criteria for an animal model of depression. On the contrary, inbred ACI/N rats do not drink much alcohol voluntarily and are quite active in the forced swim test. The FH/Wjd and ACI/N rats were intercrossed to obtain the F1 and F2 progenies, which were then tested for alcohol intake and immobility. Alcohol intake and immobility were distributed in different patterns in the F1 and F2 progenies. Alcohol intake was intermediate in the F1 progeny, while immobility was closer to the FH/Wjd parents. In the F2 progeny, chi-square analyses indicated that the distributions were significantly different. In addition, there were no significant litter effects, indicating that maternal effects did not appear to occur. There were also no significant differences among rats with different coat colors, suggesting that the Fawn-Hooded phenotype can be separated from the measures of alcohol intake and immobility. We conclude that the FH/Wjd rat is a genetic animal model of depression and alcoholism, but that the two measures reflective of these states are under separate genetic controls.

Alcoholism↗
PubMed2004

Autoradiographic imaging of altered synaptic alphabetagamma2 and extrasynaptic alphabeta GABAA receptors in a genetic mouse model of anxiety.

To image the possible alterations in brain regional GABAA receptor subtype properties in a genetic animal model of human anxiety, mice heterozygous for the deletion of GABAA receptor gamma2 subunit (gamma2+/-) were studied using ligand autoradiographic assays on brain cryostat sections. The [35S]TBPS binding assay was designed to reveal impaired GABA and channel site coupling shown to be more prominent in recombinant alpha1/6beta3 than in alpha1/2beta3gamma2 or beta2 subunit-containing GABAA receptors expressed in HEK 293 cells. Increased GABA-insensitive [35 S]TBPS binding in the gamma2+/- mouse brains was evident in the cerebral cortex and in subcortical regions, the alterations being regionally similar to the loss of gamma2 subnunit-dependent benzodiazepine (BZ) sites as revealed by [3H]Ro 15-4513 autoradiography. As the gamma2 subunit protein is needed for synaptic clustering of GABAA receptors, these results indicate that the extrasynaptic alphabeta3 receptors can be visualized in vitro as atypical GABA-insensitive [35S]TBPS binding sites. The results suggest that GABAAergic synaptic inhibition is widely decreased in the brains of anxiety-prone gamma2+/- mice, while extrasynaptic GABAA receptors are increased. These autoradiographic imaging findings further demonstrate the need to develop GABAA receptor subtype-selective in vivo ligands to aid in assessing the contributions of various subcellular receptor populations in anxious and other patient groups.

Animals↗
PubMed2002

A first formal link between the price equation and an optimization program.

The Darwin unification project is pursued. A meta-model encompassing an important class of population genetic models is formed by adding an abstract model of the number of successful gametes to the Price equation under uncertainty. A class of optimization programs are defined to represent the "individual-as-maximizing-agent analogy" in a general way. It is then shown that for each population genetic model there is a corresponding optimization program with which formal links can be established. These links provide a secure logical foundation for the commonplace biological principle that natural selection leads organisms to act as if maximizing their "fitness", provides a definition of "fitness", and clarifies the limitations of that principle. The situations covered do not include frequency dependence or social behaviour, but the approach is capable of extension.

Adaptation, Biological↗
PubMed1996

[Laterality in twins].

The literature on twins and laterality is reviewed: Both monozygotic (MZ) and dizygotic twins (DZ) show a low concordance in all functional and morphological asymmetries. The proportions of R-R, R-L and L-L pairs in MZ twins and in DZ twins are in binomial distribution. The incidence of left-handedness is the same in MZ twins and DZ twins, but higher than in singletons. Other laterality signs do not show this tendency. The whole issue of twinning is as yet unresolved, yet it is clear already that no simple genetic model for the inheritance can be applied. The present review discusses three genetic models and associated problems with each. The overall tendency to a higher rate of left-handedness in twins could be due to such pathological factors (associated with twinning) as intrauterine crowding and perinatal stress, but is not due to so-called "mirror imaging"-phenomena in twins.

Functional Laterality↗
PubMed1987

Tissue somatostatin levels in three models of genetic obesity in rats.

A potential role for somatostatin (SRIF) in the pathogenesis of the hyperinsulinemia of obese rats was considered. SRIF like immunoreactivity (ng/mg protein) was therefore measured in hot 2 N acetic acid extracts of pancreas, stomach, pituitary, and hypothalamus in tissues obtained from three models of genetic obesity in rats. These models included the obese and lean controls of LA/N-cp, SHR/N-cp, and Zucker rats. To assess the effects of diet on SRIF levels, mixed diets were provided ad lib which contained a carbohydrate as either sucrose or starch. Some groups were fed chow diets. No significant dietary effects on tissue levels of SRIF were obtained. However, two of the three models (Zucker and SHR/N-cp) showed phenotypic effects on SRIF levels in pancreas; namely, obese rats showed a significantly greater concentration of SRIF (P less than 0.0005 and less than 0.0002, respectively) than did the lean littermates. These findings were confirmed by measurement of total pancreas SRIF content. Gastric levels were significantly altered only in the obese Zucker rats (P less than 0.005) where obese tissues had lower concentrations than those of lean animals. However similar directional changes in pancreas and stomach were observed in all models. It is concluded that the hyperinsulinemia of the obese animals studied is not due to absolute deficiency in pancreatic SRIF content. It is postulated however that decreased pancreatic SRIF secretion (paracrine or otherwise) relative to pancreatic insulin content could still play a role.

Animals↗