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PubMed2004

Consomic rat model systems for physiological genomics.

A consomic rat strain is one in which an entire chromosome is introgressed into the isogenic background of another inbred strain using marker-assisted selection. The development and physiological screening of two inbred consomic rat panels on two genetic backgrounds (44 strains) is well underway. Consomic strains enable one to assign traits and quantitative trait loci (QTL) to chromosomes by surveying the panel of strains with substituted chromosomes. They enable the rapid development of congenic strains over a narrow region and enable one to perform F2 linkage studies to positionally locate QTL on a single chromosome with a fixed genetic background. These rodent model systems overcome many of the problems encountered with segregating crosses where even if linkage is found, each individual in the cross is genetically unique and the combination of genes cannot be reproduced or studied in detail. For physiologists, consomics enable studies to be performed in a replicative or longitudinal manner to elucidate in greater detail the sequential expression of genes responsible for the observed phenotypes of these animals. They often provide the best available inbred control strains for physiological comparisons with the parental strains and they enable one to assess the impact of a causal gene region in a genome by allowing comparisons of the effect of replacement of a specific chromosome on a disease susceptible or a resistant genomic background. Consomic rat strains are proving to be a unique scientific resource that can greatly extend our understanding of genes and their role in the regulation of complex function and disease.

Animals↗
PubMed1997

Genetic profiles of newly inbred Dahl/Iwai salt-sensitive and salt-resistant rats.

Dahl-Iwai salt-sensitive (S) and salt-resistant (R) rat strains were established as inbred strains at Brookhaven National Laboratory, NY, and were introduced into Eisai Co., Ltd., Japan, and designated DIS/Eis and DIR/Eis. To examine whether there are different allele distributions among the substrains of inbred Dahl S and R rats, we determined biochemical and immunological alleles of DIS/Eis and DIR/Eis, and SS/Sea and SR/Sea, which were derived from SS/Jr and SR/Jr, which were developed by Rapp and Dene. Several differences of allele distribution were observed, indicating that the substrains have different genetic backgrounds. The phenotypic differences between the substrains, such as the severity of the hypertension induced, could be ascribed to the different genetic backgrounds.

Alleles↗
PubMedDate not supplied

The use of proline as a nitrogen source causes hypersensitivity to, and allows more economical use of 5FOA in Saccharomyces cerevisiae.

The use of proline as a nitrogen source causes hypersensitivity to 5-fluoro-orotic acid (5FOA) and allows up to 40-fold less of this drug to be used to select for the loss of URA3 function in Saccharomyces cerevisiae. 5FOA hypersensitivity is presumably due to the absence of nitrogen catabolite repression when proline is substituted for (NH4)2SO4 as a nitrogen source. There are two constraints to the use of the proline-5FOA combination: (1) S288c genetic background strains are hypersensitive to 5FOA when grown in proline as a nitrogen source but at least one other genetic background is resistant to low levels of 5FOA under these conditions. (2) The addition of some nutritional supplements confers phenotypic resistance to the 5FOA-proline combination.

Culture Media↗
PubMed1993

The effects of enhanced expression of elongation factor EF-1 alpha on lifespan in Drosophila melanogaster. IV. A summary of three experiments.

This paper summarizes three experiments on the genetic manipulation of fitness components involved in the evolution of lifespan through the introduction of an additional copy of the gene for elongation factor EF-1 alpha into the genome of Drosophila melanogaster. The first experiment checked a prior claim that enhanced expression of elongation factor increased the lifespan of virgin male fruitflies. It used inbred stocks; three treatment and three control lines were available. The second experiment put one treatment and one control insert into different positions on the third chromosome, then measured the influence of six genetic backgrounds on treatment effects in healthier flies. The third experiment put six treatment and six control inserts into the genetic background whose lifespan was most sensitive to the effects of treatment in the second experiment, then measured the influence of insert positions on treatment effects in healthy flies. The treatment never increased the lifespan of virgin males. It increased the lifespan of mated females in inbred flies reared to eclosion at 25 degrees, reduced it in the positions experiment, and made no difference to lifespan in the backgrounds experiment. When it increased lifespan, it reduced fecundity. In inbred flies and in the positions experiment, the treatment reduced dry weight at eclosion of females. Marginal effects of gene substitutions on tradeoffs were measured directly. The results suggest that enhanced expression of elongation factor makes local changes within the bounds of tradeoffs that are given by a pre-existing physiological structure whose basic nature is not changed by the treatment.

Animals↗
PubMed2000

CC chemokine receptor (CCR)2 is required for langerhans cell migration and localization of T helper cell type 1 (Th1)-inducing dendritic cells. Absence of CCR2 shifts the Leishmania major-resistant phenotype to a susceptible state dominated by Th2 cytokines, b cell outgrowth, and sustained neutrophilic inflammation.

There is growing evidence that chemokines and their receptors regulate the movement and interaction of antigen-presenting cells such as dendritic cells (DCs) and T cells. We tested the hypothesis that the CC chemokine receptor (CCR)2 and CCR5 and the chemokine macrophage inflammatory protein (MIP)-1alpha, a ligand for CCR5, influence DC migration and localization. We found that deficiency of CCR2 but not CCR5 or MIP-1alpha led to distinct defects in DC biology. Langerhans cell (skin DC) density in CCR2-null mice was normal, and their ability to migrate into the dermis was intact; however, their migration to the draining lymph nodes was markedly impaired. CCR2-null mice had lower numbers of DCs in the spleen, and this was primarily due to a reduction in the CD8alpha(1) T helper cell type 1 (Th1)-inducing subset of DCs. Additionally, there was a block in the Leishmania major infection-induced relocalization of splenic DCs from the marginal zone to the T cell areas. We propose that these DC defects, in conjunction with increased expression of B lymphocyte chemoattractant, a B cell-specific chemokine, may collectively contribute to the striking B cell outgrowth and Th2 cytokine-biased nonhealing phenotype that we observed in CCR2-deficient mice infected with L. major. This disease phenotype in mice with an L. major-resistant genetic background but lacking CCR2 is strikingly reminiscent of that observed typically in mice with an L. major-susceptible genetic background. Thus, CCR2 is an important determinant of not only DC migration and localization but also the development of protective cell-mediated immune responses to L. major.

Animals↗
PubMed1997

Generation and analysis of transgenic mice expressing P216L-substituted rds/peripherin in rod photoreceptors.

PURPOSE: In this study, the authors present the biochemical, morphologic, and physiological analyses of a transgenic mouse model for retinal degeneration slow (RDS)-mediated retinitis pigmentosa caused by a proline 216 to leucine (P216L) amino acid substitution in rds/peripherin. METHODS: The authors assembled a mutant rds transgene that encodes rds/peripherin with a P216L substitution. Transgenic mice were generated on wild-type (+/+), heterozygous (rds-/+), and homozygous (rds-/rds-) null genetic backgrounds. These mice were analyzed biochemically, by light and electron microscopy, and by electroretinography. RESULTS: In P216L-transgenic mice on a +/- background, the authors observed expression-level-dependent photoreceptor degeneration and outer-segment shortening. Expression of the P216L transgene on an rds-/+ background resulted in more severe photoreceptor degeneration and outer-segment dysplasia than seen in nontransgenic rds-/+ mutants. Severely dysplastic outer segments were detectable in P216L transgenics on an rds-/rds-null background. The reduction in b-wave amplitudes by electroretinography were well correlated with the degree of photoreceptor degeneration, but not outer-segment dysplasia in these different rds mutants. CONCLUSIONS: The phenotype in P216L-transgenic mice on an rds-/+ genetic background probably is caused by a combination of two genetic mechanisms: a direct dominant effect of the P216L substituted protein, and a reduction in the level of normal rds/peripherin. The expression pattern of the normal and mutant genes in these animals is similar to that predicted for humans with RDS-mediated autosomal-dominant retinitis pigmentosa. These mice may thus be considered an animal model for this disease.

Animals↗
PubMed2000

Viewpoint: are studies in genetically altered mice out of control?

Because the use of transgenic and gene-targeted models has increased in popularity, the number of reports describing unpredictable phenotypic effects caused by variation in the genetic background used to generate or propagate these models has steadily increased. There are now many examples in which animals containing the same exact genetic manipulation exhibit profoundly different phenotypes when present on diverse genetic backgrounds, demonstrating that genes unrelated, per se, to the ones being targeted can play a significant role in the observed phenotype. Herein, I will discuss (1) the source of genetic variability in mutant mouse models, (2) the appropriateness of using inbred mice as controls, and (3) strategies to help minimize genetic variation between experimental and control mice.

Animals↗
PubMed2001

Sexual diploids of Aspergillus nidulans do not form by random fusion of nuclei in the heterokaryon.

The sexual stage of Aspergillus (Emericella) nidulans consists of cleistothecia containing asci, each with eight ascospores. The fungus completes the sexual cycle in a homokaryotic or a heterokaryotic mycelium, respectively. The common assumption for the last 50 years was that different nuclear types are not distinguishable when sexual development is initiated. When cultured on a medium limited for glucose supplemented with 2% sorbitol, sexual development of A. nidulans is slowed and intact tetrads can be isolated. Through tetrad analysis we found that unlike haploid nuclei fuse preferentially to the prezygotic diploid nucleus. When heterokaryons are formed between nuclei of different genetic backgrounds, then recombinant asci derived from opposite nuclei are formed exclusively. Strains in the same heterokaryon compatibility group with moderate differences in their genetic backgrounds can discriminate between the nuclei of a heterokaryon and preferentially form a hybrid diploid nucleus, resulting in 85% recombinant tetrads. A. nidulans strains that differ at only a single genetic marker fuse the haploid nuclei at random for formation of diploid nuclei during meiosis. These results argue for a genetically determined "relative heterothallism" of nuclear recognition within a heterokaryon and a specific recruitment of different nuclei for karyogamy when available.

Aspergillus nidulans↗
PubMed2006

Ethnic differences in occurrence of TDS-- genetics and/or environment?

It has been hypothesized that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the so-called testicular dysgenesis syndrome (TDS). TDS was suggested to be a result of disruption of embryonal programming and gonadal development during foetal life and as aetiological factor, an impact of adverse environmental factors such as hormone disrupters, probably acting upon a susceptible genetic background, was suggested. Extensive studies considering the risk of TDS-related diseases in Denmark compared with Finland, showed higher sperm counts and lower risk of cryptorchidism and testicular cancer among Finns. However, when comparing these two populations, the question arises, to which degree this difference might be due to discrepancy in genetic background. A more obvious example of the impact of genetic factors on the risk of TDS concerns Afro-Americans having significantly lower incidence of testicular cancer when compared with Caucasians living in the USA. A yet unexplored scenario is a possible interaction between genetic and environmental/lifestyle-related factors, certain genotypes making individuals more susceptible to adverse exogenous exposures. Studying such interactions has biological, epidemiological and public health-related implications. It will help us to understand the background for the defects in male reproductive organs, facilitate proper design of epidemiological studies and add to identifying individuals susceptible to certain environmental and lifestyle-related hazards. Such 'susceptibility genes' need to be identified, those involved in the synthesis, action and metabolism of sex steroids being strong candidates.

Cryptorchidism↗
PubMed1999

Genetic line and major histocompatibility complex effects on primary and secondary antibody responses to T-dependent and T-independent antigens.

The effects of MHC and nonMHC (background) genetics on the kinetics of primary and secondary antibody responses to T-cell-dependent (SRBC) and T-cell-independent [Brucella abortus (BA)] antigens were investigated. Eight genetic groups were represented, with four homozygous MHC haplotypes [B1-IrGATlow (IrGAT = immune response to GAT locus); B1-IrGAThigh; B19-Ir-GATlow; B19-IrGAThigh] on two genetic backgrounds, the S1 and G lines. Birds were injected simultaneously with BA and SRBC at 4 and 7 wk of age, and blood samples were taken weekly from 4 to 10 wk of age for measurement of total agglutinating serum antibody levels. A quadratic equation and its first derivative were computed for each bird to approximate individual curve parameters: y max, the maximum titer; t max, the time required to achieve y max; and c coefficient, the rate of decline in the titer. Curve parameters of birds from different lines were analyzed separately by using the General Linear Model procedure. A second analysis that included line effect evaluated the nonMHC gene effects and their interactions with erythrocyte antigen B locus (Ea-B) or IrGAT. In the S1 line, there was an interaction (P < 0.05) between MHC haplotypes and sex for primary response to BA. In contrast, there were no significant main effects nor interactions in the G line background for primary and secondary responses to BA and SRBC. There was an effect (P < 0.05) of line background on y max for primary BA and for secondary SRBC responses. A positive correlation (P < 0.05) was found between the c coefficients of BA and SRBC secondary responses, suggesting that the rate of decline in the secondary response is similar between these T-dependent and T-independent responses. The overall results of this study indicate complex interactions between specific MHC alleles and the nonMHC background of the lines in which they are studied.

Animals↗
PubMed2000

Requirement of Bmp8b for the generation of primordial germ cells in the mouse.

In the mouse embryo, the generation of primordial germ cells (PGCs) from the epiblast requires a bone morphogenetic protein-4 (BMP4) signal from the adjacent extraembryonic ectoderm. In this study, we report that Bmp8b, a member of the Gbb-60A class of the BMP superfamily, is expressed in the extraembryonic ectoderm in pregastrula and gastrula stage mouse embryos and is required for PGC generation. A mutation in Bmp8b on a mixed genetic background results in the absence of PGCs in 43% null mutant embryos and severe reduction in PGC number in the remainder. The heterozygotes are unaffected. On a largely C57BL/6 background, Bmp8b null mutants completely lack PGCs, and Bmp8b heterozygotes have a reduced number of PGCs. In addition, Bmp8b homozygous null embryos on both genetic backgrounds have a short allantois, and this organ is missing in some more severe mutants. Since Bmp4 heterozygote embryos have reduced numbers of PGCs, we used a genetic approach to generate double-mutant embryos to study interactions of Bmp8b and Bmp4. Embryos that are double heterozygotes for the Bmp8b and Bmp4 mutations have similar defects in PGC number as Bmp4 heterozygotes, indicating that the effects of the two BMPs are not additive. These findings suggest that BMP4 and BMP8B function as heterodimers and homodimers in PGC specification in the mouse.

Animals↗
PubMed1991

Activity of the simian virus 40 early promoter-enhancer in herpes simplex virus type 1 vectors is dependent on its position, the infected cell type, and the presence of Vmw175.

We have studied some of the parameters governing the expression of a foreign promoter-reporter gene construct incorporated into herpes simplex virus (HSV) type 1. These include the genetic background of the parental virus, the site of transgene insertion within the HSV genome, and the infected cell type. The genetic background of the vector constructs denoted delta 3 was an HSV type 1 mutant deleted for nearly the entire coding portion of Vmw175 (ICP4), the product of the essential immediate-early gene IE3. For vectors denoted +, the IE3 deletion had been repaired by marker rescue. We used as a reporter gene the bacterial chloramphenicol acetyltransferase (CAT) gene, driven by the simian virus 40 (SV40) early promoter and enhancer region. The SV40-cat hybrid gene was inserted either into the HSV thymidine kinase (TK) locus to create the vectors TKScat delta 3 and TKScat+ or into an intergenic site within the BamHI z fragment of the short unique portion of the viral genome to create the vectors GScat delta 3 and GScat+. In Vero and BHK cells infected with TKScat delta 3, CAT activity was first detected at 10 h postinfection and continued to accumulate until 36 h postinfection. In cells of primate origin infected with the replication-competent vector TKScat+, or in primate cells which complement the IE3 deficiency and which were infected with TKScat delta 3, CAT activity was significantly lower than in cells of rodent origin. However, levels of CAT were increased in the presence of cycloheximide, suggesting that the low production of CAT in primate cells was due to repression of SV40-cat hybrid gene expression. In contrast with results with TKScat delta 3 and TKScat+, CAT activity was not detectable in any of the tested cell types infected with GScat delta 3 or GScat+ except under conditions of cycloheximide reversal. These results show that while HSV gene products expressed in the presence of Vmw175 inhibited SV40-cat expression in the tk locus in a cell-type-specific manner, HSV gene products expressed in the presence or absence of Vmw175 inhibited SV40-cat expression in the BamHI z locus independently of cell type.

Animals↗
PubMed1994

Genomic imprinting: lessons from mouse transgenes.

Genomic imprinting is a non-Mendelian form of inheritance that results in an expression difference between the two parental alleles of an autosomal locus. The study of mouse transgenes has provided us with descriptions of a variety of imprinting or parent-of-origin effects, thereby anticipating similar inheritance phenomena in non-transgenic mice. Many mouse transgenes exhibit parent-of-origin behavior only on mixed strain backgrounds, whereas others are imprinted on inbred strain backgrounds. In the former cases, the parent-of-origin effects are due to strain-specific modifiers of DNA methylation and expression. These are inherited in a parent-specific fashion and exert their effects after fertilization. In the latter cases, true germline transgene imprinting, the creation of an imprinted locus occurs in a series of sequential steps. First, there is an erasure of the imprint from the previous generation in both male and female fetal germ cells. Second, upon completion of gametogenesis, distinctive methylation patterns have been placed on the transgene sequences of the two mature gametes. Third, only one of these inherited patterns is maintained in the early, pre-implantation embryo. The pattern of the other parental allele is erased. Finally, the methylation pattern of the alleles evolve in the later stages of development, but nonetheless the methylation difference (imprint) of the locus persists. Transgene imprinting behaviors, either on mixed strain backgrounds and on inbred genetic backgrounds, have counterparts in endogenous genetic phenomena.

Alleles↗
PubMed1994

The coexistence of systemic lupus erythematosus with other autoimmune diseases: the kaleidoscope of autoimmunity.

Patients with systemic lupus erythematosis (SLE) often manifest features of other autoimmune diseases. In this review, we provide a detailed compendium of features of SLE that overlap with other conditions. This compendium is important because a critical feature in our understanding of autoimmunity has been the clustering of coexisting/different autoimmune diseases both within an affected patient and within a pedigree. Indeed, autoimmune disorders share a variety of similar clinical and serological defects. For example, all autoimmune disorders are associated with the elaboration of autoantibodies and/or the production of self-reactive mononuclear cell populations; many have high levels of immune complexes and defects in cell-mediated immunity. Several diseases share similar genetic backgrounds, as reflected by study of loci within the major histocompatibility complex. In part the coassociation is due to common genetic tendencies with different environmental precipitating agents (trigger mechanisms). It is likely that many factors can modulate the immune system to autoimmunity in the presence of an appropriate genetic background, eg, drugs, viral infections, UV irradiation, and toxins, ie, toxic oil syndrome and L-tryptophan-induced eosinophilic myalgia. The coexistence of SLE with other autoimmune diseases is an excellent venue to understand these events, and we believe that the presence of other autoimmune diseases in patients with SLE can be called the kaleidoscope of autoimmunity.

Autoimmune Diseases↗
PubMed2006

[Significance of the identification of hereditary cancer for routine oncological diagnosis].

Genetic factors are likely to be the primary determinants of the cancer seen in around 5 - 10 % of all cancer patients. More than 20 inherited cancer syndromes are now known. For many of these cases molecular genetic diagnostic may be accomplished. Within the scope of genetic counselling and testing, which can validate the genetic background of cancer, the interdisciplinary cooperation of Primary Care Physicians (PCP) and human geneticists is necessary. The results of our empirical study on risk identification in familial cancer suggest that PCP in the acute care inform cancer patients only to a little extent about the possible genetic background of their disease. PCP also very rarely initiate genetic counselling and testing, which would be desirable for preventive reasons.

Genetic Predisposition to Disease↗
PubMed1990

Genetic instability of clathrin-deficient strains of Saccharomyces cerevisiae.

Saccharomyces cerevisiae strains carrying a mutation in the clathrin heavy chain gene (CHC1) are genetically unstable and give rise to heterogeneous populations of cells. Manifestations of the instability include increases in genome copy number as well as compensatory genetic changes that allow better growing clathrin-deficient cells to take over the population. Increases in genome copy number appear to result from changes in ploidy as well as alterations in normal nuclear number. Genetic background influences the frequency at which cells with increased genome content are observed in different Chc- strains. We cannot distinguish whether genetic background affects the rate at which aberrant nuclear division events occur or a growth advantage of cells with increased nuclear and/or genome content. However, survival of chc1-delta cells does not require an increase in genome copy number. The clathrin heavy chain gene was mapped 1-2 cM distal to KEX1 on the left arm of chromosome VII by making use of integrated 2 mu plasmid sequences to destabilize distal chromosome segments and allow ordering of the genes.

Canavanine↗
PubMedDate not supplied

Etrurians vs Greeks: May ACE I/D polymorphism still be considered as a marker of susceptibility to SSc?

OBJECTIVE: SSc is characterized by immune dysfunction and microvascular involvement. A different genetic background may determine a different polymorphic allele frequency between different populations, and data from literature reported conflicting results about the role of genetic components in predisposing to the disease. We carried out this study in order to compare the ACE I/D polymorphism genotype distribution and alleles frequency in two different populations from the Mediterranean area. METHODS: Forty-eight Italian and 41 Greek SSc patients compared with 112 Italian and 93 Greek controls, have been studied. The ACE I/D polymorphism has been analysed. RESULTS: The genotype distribution and allele frequency were in Hardy-Weinberg equilibrium for Italian and Greek SSc patients and controls. Among the Italian patients a significantly higher ACE D allele frequency than in the controls was found, whereas among the Greeks a higher prevalence was observed in the healthy subjects. A significant difference in ACE D allele frequency between Italian and Greek controls was observed (p = 0.04). ACE D allele was associated to the predisposition to SSc in Italians, but not in Greeks. CONCLUSION: We confirm that Italian SSc patients have a higher ACE D allele frequency that is not present in the Greek patients. Thus, the two populations living in different Mediterranean areas and resulting from the Mediterranean civilization, do not show the same ACE-gene related allele frequencies. Other populations of the Mediterranean area must be investigated by using unlinked genetic markers to verify the homogeneity of the genetic background, and to test for a "true" difference in their ethnic origin.

Amino Acid Substitution↗
PubMed1992

Immunological and beta-cell-specific characteristics of diabetes-prone BB/OK rats and their congenic derivatives--a comparative study.

In a comparative study congenic rat strains bearing either the genetic background of diabetic BB/OK rats and the MHC (RTla) of diabetes-resistant LEW.1A rats (BB.1A/OK) or vice versa carrying the genetic background of LEW.1A rats in combination with the MHC (RTlu) of diabetic BB/OK rats (LEW.1BB/OK) and their parental rat strains BB/OK and LEW.1A were checked for insulin secretion of pancreatic islets, for the number of splenic and peripheral blood mononuclear cells (MNC) as well as for the mitogenic response of splenic MNC. Glucose stimulated insulin secretion of isolated islets of Langerhans was not different in 50, 70 and 100 day-old congenic rats and the progenitor rat strains excluding an impact of the genotype on this beta-cell-specific function. The number of splenic and peripheral blood MNC was reduced in BB/OK and BB.1A/OK rats compared to LEW.1A and LEW.1BB/OK rats. Splenic MNC from BB/OK and BB.1A/OK rats displayed a strongly decreased total [3H]thymidine incorporation under basal conditions as well as upon mitogenic stimulation by ConA in comparison with MNC from LEW.1A and LEW.1BB/OK rats. Thus, the occurrence of lymphopenia and the impairment of mononuclear cell proliferation in BB/OK rats is not related to the RTlu haplotype of the MHC but is linked to non-MHC genes as indicated by the phenotypic expression of these traits in congenic BB.1A/OK rats.

Animals↗