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PubMed2006

Nondisjunction rates of mouse chromosomes involved in heterozygous Rb rearrangements measured by chromosome painting of spermatocytes. II. The effects of trivalent combinations and genetic background.

Chromosome specific nondisjunction rates were quantified by dual-colour FISH in spermatocytes II of Robertsonian heterozygous mice with different trivalent combinations or, alternatively, with different genetic backgrounds. We found that such factors do not influence the proneness to nondisjunction of specific chromosomes.

Animals↗
PubMed2005

Variegation of the phenotype induced by the Gata1low mutation in mice of different genetic backgrounds.

All mice harboring the X-linked Gata1low mutation in a predominantly CD1 background are born anemic and thrombocytopenic. They recover from anemia at 1 month of age but remain thrombocytopenic all their life and develop myelofibrosis, a syndrome similar to human idiopathic myelofibrosis, at 12 months. The effects of the genetic background on the myelofibrosis developed by Gata1low mice was assessed by introducing the mutation, by standard genetic approaches, in the C57BL/6 and DBA/2 backgrounds and by analyzing the phenotype of the different mutants at 12 to 13 (by histology) and 16 to 20 (by cytofluorimetry) months of age. Although all the Gata1low mice developed fibrosis at 12 to 13 months, variegations were observed in the severity of the phenotype expressed by mutants of different backgrounds. In C57BL/6 mice, the mutation was no longer inherited in a Mendelian fashion, and fibrosis was associated with massive osteosclerosis. Instead, DBA/2 mutants, although severely anemic, expressed limited fibrosis and osteosclerosis and did not present tear-drop poikilocytes in blood or extramedullary hemopoiesis in liver up to 20 months of age. We propose that the variegation in myelofibrosis expressed by Gata1low mutants of different strains might represent a model to study the variability of the clinical picture of the human disease.

Aging↗
PubMed1992

The effects of gonadectomy on glucose tolerance of genetically obese (fa/fa) rats: influence of sex and genetic background.

In both humans and rodents the occurrence and severity of obesity-associated non-insulin dependent diabetes mellitus (NIDDM) may be influenced by both gonadal hormones and genetic background. Early gonadectomy (at 3-5 days of age) of female and male Wistar diabetic fatty (WDF) rats and of male Zucker rats allowed us to examine these effects in genetically obese rats carrying the fatty (fa) gene. Impairment of glucose tolerance and insulin sensitivity by obesity, and amelioration or exacerbation (in the case of female rats) of this impairment by gonadectomy were assessed by intragastric glucose tolerance tests when the rats reached adulthood. Both glucose tolerance and insulin sensitivity were significantly deranged in obese WDF rats of both sexes and in obese male Zucker rats compared to lean controls of the same sex and strain. Obese male WDF rats were less glucose tolerant and insulin sensitive than were obese male Zucker rats. Glucose intolerance was not ameliorated by castration in lean or obese male WDF or Zucker rats. Insulin sensitivity was significantly improved by castration in obese male rats of both strains, as fasting plasma insulin levels and total areas under the insulin curves were significantly reduced compared to obese sham-operated controls. This effect was greater in the Zucker than in the WDF male rats. Castration significantly decreased the insulin response areas in obese male Zucker rats, but did not alter those of the obese male WDF rats. Ovariectomy did not alter glucose homeostasis of obese female WDF rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Both genetic background and environmental factors modify the phenotypic expression of H-2 associated genes participating in the polygenic control of antibody responsiveness to Salmonella antigens.

The genetic control of responsiveness to flagellar (f) and somatic (s) antigens of Salmonellae was studied in high (H) and low (L) lines of mice selected for the character 'antibody response to sheep erythrocytes'. The minimal immunogenic dose was, for the two antigens, lower in H than in L mice and the dominance of the responder phenotype was then greater in F1 hybrid females than in males. Genes associated with H-2 locus intervene in the responses to each antigen. Their expression was found to vary according to the conditions of immunization and to the sex. The quantifiable H-2 effect was measured in interline hybrids, i.e. on an heterogeneous genetic background equivalent to that of F2. In the case of the flagellar (f) antigen, the H-2 locus was responsible in secondary response for about 50% of the interline difference in the two sexes. In the primary response, the H-2 effect was only observed in females. It was smaller (25% of the interline difference) and independent of the antigen dose. In contrast, with somatic (s) antigen the H-2 locus did not intervene in the control of secondary response. The H-2 effect in the primary response was again only found in females. Unexpectedly, the allele linked to the H-2 phenotype of L mice had a more favourable effect on hybrid responsiveness than that linked to the phenotype of H mice.

Animals↗
PubMedDate not supplied

A mouse model for Niemann-Pick disease. Influence of genetic background on disease expression in spm/spm mice.

Sphingomyelinosis (spm), an autosomal recessive mutation in mice originally occurred in the C57BL/KsJ inbred strain. Spm/spm mice of this genetic background show striking hepatosplenomegaly with a marked accumulation of sphingomyelin and cholesterol due to a deficiency of sphingomyelinase. However, in spm/spm mice of C57BL/6J and DBA/2J backgrounds, hepatosplenomegaly was not pronounced in spite of marked elevation of hepatic lipid concentrations. The lifespan of C57BL/6J-spm/spm and DBA/2J-spm/spm mice was shorter than that of C57BL/KsJ-spm/spm mice. This appeared to be associated with the comparatively rapid rise in hepatic lipid concentrations, which in turn might be related to the absence of hepatomegaly. Histological study revealed the formation of massive foam cell clusters in the livers and spleens of C57BL/KsJ-spm/spm mice, whereas in the case of C57BL/6J-spm/spm and DBA/2J-spm/spm mice, diffusely scattered foam cells were found. These findings suggest that the functions of reticuloendothelial system (RES) play a crucial role in the development of hepatosplenomegaly in response to lipid accumulation.

Animals↗
PubMed1995

Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype.

Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the inner cell mass. On a 129/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background, the mutants lived for up to 3 weeks and showed abnormalities in skin, kidney, brain, liver, and gastrointestinal tract. The multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular activities.

Abnormalities, Multiple↗
PubMed1986

Genetic background affects integration frequency of ecotropic proviral sequences into the mouse germ line.

Germ line acquisition of ecotropic proviruses occurs at a high frequency in the progeny of SWR/J-RF/J hybrid mice carrying two genetically linked RF/J ecotropic proviral loci, Emv-16 and Emv-17 (N. A. Jenkins and N. G. Copeland, Cell 43:811-819, 1985). To determine if genetic background affects proviral integration frequency, I analyzed a series of crosses in which the two RF/J proviral loci were transferred onto different provirus-negative background strains. Unlike SWR/J-RF/J hybrid progeny, few CBA/CaJ-RF/J hybrid mice were identified that carried new germ line proviral loci. These results indicate that genetic factors other than the linked RF/J proviral loci contribute to the increased frequency of germ line provirus integration seen in the SWR/J-RF/J hybrids. The frequency of proviral acquisition appeared to increase when females carrying Emv-16, Emv-17, and at least one new proviral locus were further backcrossed, suggesting that integration frequency can be increased by genetic manipulation. The breeding data are consistent with the hypothesis that virus from the mother infects the egg or the early embryo. Analysis of the transmission frequency and cosegregation patterns of new proviral loci indicated that viral integration occurs after the first round of DNA replication and before the germ line is set aside during embryogenesis, with a majority of viral integrations occurring at the two-cell stage of development, and independent viral integrations can occur in the same or in different cells of the embryo.

Animals↗
PubMed2005

Impact of genetic background on spontaneous or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced intestinal tumorigenesis in Min/+ mice.

We have studied the impact of genetic background on susceptibility to spontaneous or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced intestinal tumorigenesis. The increase in small intestinal tumor number after PhIP exposure was 3.8- and 3.7-fold above the spontaneous levels in multiple intestinal neoplasia (Min)/+ F1 mice with AKR/J and A/J backgrounds, respectively, compared with only 3-fold in C57BL/6J mice. In the colon, PhIP increased the number of tumors slightly more in C57BL/6J mice (3.3-fold) than in A/J mice (3.0-fold). AKR/J mice had no colonic tumors. Most of the tumors were located in the distal two-thirds of the small intestine in all three strains.

Animals↗
PubMed2003

The pattern of ocular dominance columns in cat primary visual cortex: intra- and interindividual variability of column spacing and its dependence on genetic background.

We present a comprehensive analysis of the intrinsic variability of the periodicity of ocular dominance columns in cat primary visual cortex (area 17) and its relationship to genetic background and visual experience. We characterized the intra-areal and interindividual variability of column spacing in a large set (n = 49) of ocular dominance patterns adapting a recently developed technique for the two-dimensional analysis of orientation column patterns. Patterns were obtained from three different cat colonies (termed F, M and D), the cats having either normal visual experience or experimentally induced strabismus. Two-dimensional maps of local column spacing were calculated for every pattern. In individual cortices, local column spacings varied by > 50% with the majority of column spacings ranging between 0.6 and 1.5 mm in different animals. In animals from colonies F and M (n = 29), the mean column spacing ranged between 1.03 and 1.27 mm and exhibited no significant differences, either between the two breeds or between strabismic and normal animals. The mean spacing was moderately clustered in the left and right brain hemisphere of individual animals but not in littermates. In animals from colony D (n = 2), average column spacing ranged between 0.73 and 0.95 mm, and was thus significantly different from the distribution of spacings in animals from breeds F and M, suggesting an influence of genetic factors on the layout of ocular dominance columns. Local column spacing exhibited a considerable systematic intra-areal variation, with largest spacings along the representation of the horizontal meridian and smallest spacings along the peripheral representation of the vertical meridian. The total variability of ocular dominance column spacing comprised 24% systematic intra-areal variation, 18% interindividual differences of mean column spacing and 58% nonsystematic intra-areal variability.

Animals↗
PubMedDate not supplied

[Genetic background of ADHD: population studies, genes of the catecholamine system].

Attention-deficit hyperactivity disorder (ADHD) begins in early childhood. In this article we review the studies supporting a genetic background of this disorder. ADHD occurs in 3-10% of the general population. Family studies reveal a 5 times more likely frequency of ADHD among first-degree relatives than in the general population. Monozygotic twin concordance rate for ADHD is 81%, whereas for dizygotic twins it is 29%. One of the ADHD predisposing factors is dopaminergic neurotransmission abnormality. According to other studies there is a relationship between polymorphism of dopamine transporter gene (DAT), dopamine receptors genes: DRD2, DRD3, DRD4, DRD5, dopamine-beta-hydroxylase gene (DBH) and catechol-O-methyltransferase gene (COMT) and ADHD. In other articles authors describe abnormalities of the serotonergic system, such as the polymorphism of the serotonin transporter gene (5HTT/SERT), serotonin receptors genes 5HT2A and 5HT1B in the development ofADHD. Another possible factor in ADHD background is the dysregulation of the adrenergic system. The most frequently studied is the connection between polymorphism of norepinephrine transporter gene (NET), adrenergic receptors genes: alpha 2A (ADRA2A), alpha 1C (ADRA1C), alpha 2C and monoamine oxidase A gene (MAO-A).

Attention Deficit Disorder with Hyperactivity↗
PubMed2003

Genetic background influences therapeutic effectiveness of VEGF.

Therapeutic angiogenesis has emerged as a promising therapy, but some patients are refractory to exogenous growth factors. In order to identify the genetic determinants of post-natal angiogenesis and physiological vessel formation, we investigated the genetic factors that affected ischemia-induced development of collaterals in mice. An ischemic hindlimb model was generated in C57BL/6, C3H/He, and BALB/c mice. Angiogenesis was markedly different among the mice as determined by the restoration of blood perfusion and capillary density of the ischemic muscle. Impaired collateral vessel formation in BALB/c mice was associated with reduced expression of vascular endothelial cell growth factor (VEGF). Intramuscular gene transfer of VEGF promoted collateral formation in C57BL/6J mice, but not in BALB/c mice. Ineffectiveness of VEGF in BALB/c mice was associated with impaired expression of VEGF receptor. Our findings suggest that genetic background may influence spontaneous collateral formation and therapeutic effectiveness of exogenous VEGF. Alternative strategies other than administration of VEGF alone might be needed to attain optimal angiogenesis in some patients.

Animals↗
PubMed2006

Development of a wide population of chromosome single-segment substitution lines in the genetic background of an elite cultivar of rice (Oryza sativa L.).

Naturally occurring allelic variations underlying complex traits are useful resources for the functional analysis of plant genes. To facilitate the genetic analysis of complex traits and the use of marker-assisted breeding in rice, we developed a wide population consisting of 217 chromosome single-segment substitution lines (SSSLs) using Oryza sativa L. 'Hua-Jing-Xian74' (HJX74), an elite Indica cultivar, as recipient, and 6 other accessions, including 2 Indica and 4 Japonica, as donors. Each SSSL contains a single substituted chromosome segment derived from 1 of the 6 donors in the genetic background of HJX74. The total size of the substituted segments in the SSSL population was 4695.0 cM, which was 3.1 times that of rice genome. To evaluate the potential application of these SSSLs for quantitative trait loci detection, phenotypic variations of the quantitative traits of days to heading and grain length in the population consisting of 210 SSSLs were observed under natural environmental conditions. The results demonstrated that there was a wide range of phenotypic variation in the traits in the SSSL population. These genetic materials will be powerful tools to dissect complex traits into a set of monogenic loci and to assign phenotypic values to different alleles at the locus of interest.

Chromosome Mapping↗
PubMed2002

Endogenous enzyme activities and polyamine levels in diverse rice cultivars depend on the genetic background and are not affected by the presence of the hygromycin phosphotransferase selectable marker.

We used the polyamine biosynthetic pathway and rice as a relevant model to understand the genetic basis of variation in endogenous levels of metabolites and key enzymes involved in the pathway. Wild-type tissues and also tissues containing a commonly used selectable marker gene were employed. We detected a wide variation in levels of arginine decarboxylase activity and in the three polyamines, putrescine, spermidine and spermine, in different tissues and varieties, but this was not dependent on the presence of the selectable marker. A more-extensive profile of enzyme activities (ADC, ODC, SAMDC, DAO and PAO) and polyamine levels in different tissues was generated in two different varieties. Our results indicate that genetic background is important in terms of the basal levels of metabolites and enzyme activity, particularly in situations in which we aim to engineer metabolic pathways that are also encoded by homologous endogenous genes. We did not find any evidence that the presence of a selectable marker in any way influences enzyme activity or metabolite levels.

Journal Article↗
PubMed2000

Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy.

Corticobasal degeneration is a sporadic form of tauopathy, involving the cerebral cortex and extrapyramidal motor system. A series of affected subjects was genotyped for a set of genetic markers along the tau protein gene. A specific haplotype is significantly overrepresented in patients versus controls. This haplotype is the same already reported in association with progressive supranuclear palsy. These data show that corticobasal degeneration and progressive supranuclear palsy, in addition to several clinical, pathological, and molecular features, may have the same genetic background.

Aged↗
PubMed2000

Segmental manifestation of Darier disease. What is the genetic background in type 1 and type 2 mosaic phenotypes?

Darier disease is an autosomal dominant disorder which may occasionally become manifest in a segmental form. Two clinical phenotypes with a different genetic background have been elaborated in recent years. More than 50 patients with isolated linear disease expression have been documented. In this phenotype the skin outside the segmental affection is absolutely normal. Such a phenotype is explained by a postzygotic mutation with somatic mosaicism which was labeled as type 1 manifestation of segmental forms in autosomal skin disorders. A patient with classical type 1 segmental Darier disease is presented. On the other hand, only 3 patients with Darier disease showing a segmental manifestation in combination with a diffuse distribution have so far been observed. These cases correspond to the recently described type 2 manifestation of segmental forms of autosomal dominant disorders. We describe a fourth patient with type 2 segmental Darier disease. The genetic explanation of such a phenotype is possible with the assumption that a germline mutation for the disease exists but, in addition, a postzygotic mutation is needed resulting in loss of heterozygosity. Hence, in a circumscribed region a homozygous or hemizygous state of the mutation is apparent which can explain the enhanced severity of the segmental manifestation.

Adult↗
PubMed2003

Role of repeated lung injury and genetic background in bleomycin-induced fibrosis.

Current hypotheses of the pathogenesis of many forms of pulmonary fibrosis suggest that (i) a stimulus results in repeated or prolonged episodes of lung injury, and (ii) genetic factors modulate the outcome of the injury. The commonly employed single-exposure bleomycin model results in only temporary fibrosis. Therefore, we evaluated whether repeated bleomycin exposures, in the setting of a genetic background more likely to develop a T helper 2 (Th2) response, would induce prolonged fibrosis. Lung fibrosis was induced by intratracheal bleomycin injection, either as a single exposure or as three consecutive exposures. We found that bleomycin induced a Th2-like environment in both Th1-biased C57BL/6J and Th2-biased DBA/2 mice. We also found histologic changes and collagen increases consistent with lung injury/fibrosis at early time points, but prolonged fibrosis only after multiple exposures in the Th2-biased DBA/2 mice. We also determined if impaired healing of bleomycin-induced injury would prolong fibrosis in the C57BL/6J mice. Endothelial nitric oxide (which protects endothelial cells from oxidant-induced injury) synthase knockout animals on a C57BL/6J background also had prolonged fibrosis, similar to DBA/2 mice, after multiple bleomycin exposures. This was specific to eNOS, as inducible nitric oxide synthase knockout animals cleared the fibrosis as effectively as wild-type C57BL/6J mice. This data indicate that healing of injury/fibrosis after bleomycin is complex and can be determined by a number of genetic and environmental factors.

Animals↗
PubMed2003

Genetic background conditions the effect of sex steroids on the inflammatory response during endotoxic shock.

OBJECTIVE: The contribution of gender to the mortality and morbidity of trauma patients is controversial. In addition, a genetic contribution has been recently indicated. The influence of these two variables was studied in a murine model of endotoxemia. DESIGN: Prospective, controlled, and randomized animal study. SETTING: A university research laboratory. SUBJECTS: Female and male mice (6-8 wks old) were injected with lipopolysaccharide (15 mg/kg). Additionally, mice were gonadectomized and supplemented with 5-alpha-dihydrotestosterone (357 mg/day), 17-beta-estradiol (23.8 microg/day), or placebo for 21 days and injected with lipopolysaccharide. Tumor necrosis factor-alpha was measured in plasma samples obtained after 1.5 hrs of lipopolysaccharide injection. MEASUREMENTS AND MAIN RESULTS: Higher tumor necrosis factor-alpha plasma levels were observed in C57BL/6J (B6) female mice as compared with males. Because this phenotype is not sex linked, we evaluated the role of sex steroids. Castrated male B6 mice showed higher lipopolysaccharide-induced tumor necrosis factor-alpha plasma levels than nonoperated controls. These lipopolysaccharide-induced tumor necrosis factor-alpha levels were further increased after the administration of 17-beta-estradiol to castrated B6 male mice as compared with nonoperated male or female mice. In addition, 17-beta-estradiol-supplemented castrated mice showed a higher frequency of mortality than castrated males without hormone replacement or nonoperated mice. Analysis of castrated male mice from other strains (A/J, DBA/2J, AKR/J, BALB/cJ) supplemented with 17-beta-estradiol presented the opposite effect, a reduction in lipopolysaccharide-induced tumor necrosis factor-alpha plasma levels. CONCLUSIONS: These results suggest that sex steroids can modulate the inflammatory response and the outcome after injury in mice. The effect of sex steroids depends on the genetic background.

Analysis of Variance↗