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At least 127 records · Page 7Linked to original sources
PubMed2005

Interaction between genetic background and the mating-type locus in Cryptococcus neoformans virulence potential.

The study of quantitative traits provides a window on the interactions between multiple unlinked genetic loci. The interaction between hosts and pathogenic microbes, such as fungi, involves aspects of quantitative genetics for both partners in this dynamic equilibrium. One important pathogenic fungus is Cryptococcus neoformans, a basidiomycete yeast that can infect the human brain and whose mating system has two mating type alleles, a and alpha. The alpha mating-type allele has previously been linked to increased virulence potential. Here congenic C. neoformans strains were generated in the two well-characterized genetic backgrounds B3501alpha and NIH433a to examine the potential influence of genes outside of the mating-type locus on the virulence potential of mating type. The congenic nature of these new strain pairs was established by karyotyping, amplified fragment length polymorphism genotyping, and whole-genome molecular allele mapping (congenicity mapping). Virulence studies revealed that virulence was equivalent between the B3501 a and alpha congenic strains but the alpha strain was more virulent than its a counterpart in the NIH433 genetic background. These results demonstrate that genomic regions outside the mating type locus contribute to differences in virulence between a and alpha cells. The congenic strains described here provide a foundation upon which to elucidate at genetic and molecular levels how mating-type and other unlinked loci interact to enable microbial pathogenesis.

Animals↗
PubMed1999

Decreased ethanol sensitivity and tolerance development in gamma-protein kinase C null mutant mice is dependent on genetic background.

Initial sensitivity and tolerance development to the sedative-hypnotic and hypothermic effects of ethanol were investigated in gamma-protein kinase C (PKC) null mutant mice. Null mutants from a C57BL/6J x 129/SvJ mixed genetic background demonstrated decreased ethanol sensitivity and failed to develop chronic tolerance after 10 days of ethanol liquid diet. However, when the null mutation was introgressed onto a C57BL/6J background for six generations, the "no tolerance" phenotype for sedative-hypnotic and hypothermic effects of ethanol was no longer apparent Outcrossing the gamma-PKC null mutation to a C57BL/6J x 129/SvEvTac mixed background restored the "no tolerance" phenotype to ethanol-induced sedation after chronic ethanol diet; however, as measured by hypothermia, tolerance was still evident in the null mutant mice. These observations and the results of tests of chronic tolerance in the C57BL/6J, 129/SvJ, and 129/SvEvTac background inbred strains indicate that gamma-PKC plays an important role in initial sensitivity and tolerance to ethanol. However, the impact of gamma-PKC is modulated by the background genotype. These results stress the importance of including the effect of genetic background when evaluating the effects of single gene mutations on quantitative behavioral traits.

Animals↗
PubMed2026

Genetic background influences developmental airway smooth muscle program and susceptibility to airway hyperresponsiveness in mice.

Airway structural remodeling and hyperresponsiveness (AHR), hallmarks of asthma, are influenced by genetic variations and adverse exposures. While intrauterine perturbations in lung development have been linked to adult pulmonary disease, the developmental origins of these abnormalities remain poorly understood. Here, we provide evidence of genetic background playing a key role in this process. Using A/J and C57BL/6J mice known for their distinct susceptibility to AHR, we show that A/J embryos selectively develop an aberrant airway smooth muscle (SM) program and AHR in adulthood when exposed transiently to a vitamin A/retinoic acid (RA)-disrupted intrauterine environment in vivo by maternal BMS493 administration. Single-nucleus multiomics identified a mesenchymal cell population overactivating TGF-β targets in response to BMS493 selectively in A/J lungs. These cells, localized to sites of airway SM initiation and p-SMAD2- and -3, exhibited robust BMS493-mediated upregulation of SMAD2/3 targets, including regulators of SM program Pdgfra and Tnc. Functional analyses in vivo and cultured lungs showed aberrant SM formation in areas of overactive TGF-β of BMS493-exposed lungs. These abnormalities were prevented by inhibiting TGF-β signaling in utero in RA-deficient embryos. These findings underscore how distinct genetic backgrounds respond to intrauterine perturbations that program airway structure and function, with potential lasting consequences in postnatal pulmonary function.

Animals↗
PubMed2004

Genetic background of people in the Dominican Republic with or without obese type 2 diabetes revealed by mitochondrial DNA polymorphism.

People in the Dominican Republic are considered to be genetically heterogeneous owing to the post-Colombian admixture of Native American, African, and European populations. To characterize their genetic background, nucleotide sequences of the D-loop region of human mitochondrial DNA (mtDNA) were examined in 33 healthy women and 50 gender-matched patients with obese type 2 diabetes (OD) from the Dominican Republic. Phylogenetic analysis of 198 mtDNA lineages including Native Americans, Africans, and Europeans enabled us to assess relative genetic contributions of the three ancestral fractions to the two groups in the Dominican Republic. In the OD group, the majority (64.0%) of the mtDNA lineages were from African ancestry, whereas the Native American fraction was predominant (51.5%) in the healthy group, with both showing smallest amounts (14.0% and 9.1%, respectively) of European contribution. This difference in maternal genetic background between the two groups was similarly demonstrated by phylogenetic analysis at the population level based on net nucleotide diversities between populations. These findings may imply ethnic-specific predisposition to OD, a possible association of an unidentified factor from African ancestry with OD in the Dominican Republic population.

Adult↗
PubMed1999

Physicochemical properties of maize starches expressing dull and sugary-2 mutants in different genetic backgrounds.

Isogenic lines carrying the du or su(2) genes in five different maize inbred lines were developed, and the effect of the starch-modifying genes on general, thermal, pasting, and gel textural properties of starch was studied. Swelling power of du and su(2) starches was significantly lower than that of normal starch. The peak viscosity of du starches was reduced, peaks were sharper, and the setback was lower than in normal starches. The hardness of du starch gels increased and the adhesiveness decreased severalfold during 7 days of storage, indicating unstable gel texture. The su(2)/su(2) starches had flatter viscosity peaks than normal starches, with extremely low viscosity and almost zero breakdown and setback. In the su(2) starch gels hardness and adhesiveness did not change significantly during 7 days of storage. For most measured properties, there was considerable variation among different inbred backgrounds carrying the same mutant genotypes. Genetic background and starch-modifying genes can both be manipulated to select specific desired starch properties.

Calorimetry, Differential Scanning↗
PubMed2006

Genetic background of primary iron overload syndromes in Japan.

The different prevalences of iron overload syndromes between Caucasians and Asians may be accounted for by the differences in genetic background. The major mutation of hemochromatosis in Celtic ancestry, C282Y of HFE, was reported in a Japanese patient. Five patients of 3 families with the hepatic transferrin receptor gene (TFR2)-linked hemochromatosis were found in different areas of Japan, suggesting that TFR2 is a major gene in Japanese people. Three patients with mutations in the hemojuvelin gene, HJV, showed also middle-age-onset hemochromatosis. A heterozygous mutation in the H ferritin gene, FTH1, was found in a family of 3 affected patients. Another autosomal dominant SLC40A1-linked hyperferritinemia (ferroportin disease) was found in 3 patients of 2 families. Two patients with hemochromatosis were free from any mutations in the genes investigated. In conclusion, the genetic backgrounds of Japanese patients with primary iron overload syndromes were partially clarified, showing some phenotype-genotype correlations.

Adult↗
PubMed1997

Influence of the route of allergen administration and genetic background on the murine allergic pulmonary response.

We used various ovalbumin sensitization and challenge protocols to determine the importance of the route of allergen administration and the genetic background in modulating the physiologic, inflammatory, and immunologic features characteristic of allergen-induced asthma. In BALB/c mice, induction of maximal airway hyperresponsiveness and airspace eosinophilia required administration of ovalbumin by both the intraperitoneal and the intranasal routes (combination protocol), whereas intraperitoneal immunization alone resulted in maximal ovalbumin-specific IgE plasma levels. Thus, a systemic immune response to allergen, in addition to, or independent of IgE production, as well as local allergen challenge were necessary for maximal induction of pulmonary disease. BALB/c mice treated with ovalbumin by the combination protocol had increased Th2-type cytokine mRNA levels in bronchial lymph node tissue compared with control mice. In contrast, C57BL/6 mice treated with ovalbumin by the combination protocol had significantly decreased responses compared with BALB/c mice for all parameters of allergic pulmonary disease examined, with the exception of airspace eosinophilia. Genetic background has a striking and selective effect on the phenotype of murine allergic pulmonary disease. Further analysis of this murine model should be useful in helping define the critical pathogenetic events in allergen-induced asthma.

Administration, Intranasal↗
PubMedDate not supplied

The genetic background of inflammatory bowel disease.

Available evidence indicates that genetic factors are essential in providing the susceptibility to the majority of the various forms of inflammatory bowel disease occurring in man. It is also clear that the genetic susceptibility to these diseases is complex, and that more than one gene may predispose (the concept of multilocus/oligogenic inheritance), and likely in different etiologic combinations (the concept of genetic heterogeneity). Paradigms are now available that should lead to the identification of a number of these predisposing genes. These paradigms include the candidate gene approach, systematic genome wide scans, and mouse human synteny. While genome wide scans are currently limited to multiplex family linkage studies, both candidate genes and mouse human synteny can be approached in either linkage or association paradigms. Eventually whole genome association studies will be available as well. Identification of inflammatory bowel disease predisposing genes should lead to their incorporation in studies of natural history, investigation of environmental risk factors, and especially utilization of genetic markers in clinical trials. This will allow us to identify the best therapy available for the individual patient based on their unique genetic constitution. With advances in molecular technology, the search for genes influencing traits and diseases with a complex genetic background, such as the inflammatory bowel diseases, has become a realistic task. Although exogenous or infectious agents may contribute to the pathogenesis or may trigger the onset of disease, and the immune system almost certainly mediates the tissue damage, it is clear from available data that genetic factors determine the susceptibility of a given individual to inflammatory bowel disease (reviewed below). Thus, genetic studies are essential for the delineation of the basic etiologies of the various forms of inflammatory bowel disease and thus can aid in the development of radically new and specific therapies. In this review, we will discuss the importance and complexity of genetic factors in inflammatory bowel disease, methods and problems in the genetic dissection of complex traits, and future directions of genetic studies in inflammatory bowel disease.

Animals↗
PubMed2001

Leptin-deficient mice backcrossed to the BALB/cJ genetic background have reduced adiposity, enhanced fertility, normal body temperature, and severe diabetes.

A deficiency of leptin synthesis in mice results in a complex phenotype characterized by morbid obesity, diabetes, sterility, and defective thermogenesis. To determine whether the genetic background could alter the pleiotropic effects of leptin deficiency, we backcrossed the ob mutation for 10 generations from the C57BL/6J to the BALB/cJ genetic background. Compared with C57BL/6J ob/ob mice, BALB/cJ ob/ob mice showed at 27 wk of age a 35-40% reduction in body weight attributed to a 60% decrease in white adipose tissue mass. Food intake was not significantly different between the two obese strains, suggesting distinct utilization of energy intake. In the fed state, BALB/cJ ob/ob mice had elevated insulin and triglycerides levels, demonstrating a worsening effect on diabetes. At the reproductive level and in contrast to sterile C57BL/6J ob/ob mice, male and female BALB/cJ ob/ob mice were capable of reproducing after a mating period of 16 and 32 wk, respectively. At thermoneutrality, the body temperature of BALB/cJ ob/ob mice was 2.9 C higher than that of C57BL/6J ob/ob mice, whereas exposure of both groups to 4 C demonstrated a prolonged cold tolerance of BALB/cJ ob/ob mice. These studies show that the abnormalities caused by leptin deficiency can be genetically dissected and separated from each other, suggesting discrete pathways controlled by leptin modifier genes.

Adipose Tissue↗
PubMed1981

Dwarfism in diverse genetic backgrounds. 4. Effects of dietary energy.

The interactions in the response of dwarf and normal genotypes to dietary energy were studied in lines of chickens divergently selected for high or low juvenile body weight. The genetic background of the dwarf genotype significantly affected body weights, egg production, and egg quality. The dietary energy levels used did not significantly affect these traits or the differences due to genetic background. Dwarf chickens were able to adapt to wide ranges of dietary energy when the diets contained sufficient crude protein.

Animal Feed↗
PubMed2005

Genetic background regulates semaphorin gene expression and epileptogenesis in mouse brain after kainic acid status epilepticus.

The host response to neural injury, which can include axonal sprouting and synaptic reorganization is likely to be under tight genetic regulatory control at the level of the genome and may be implicated in epileptogenesis. Despite its importance, however, the molecular basis of synaptic reorganization is unclear. We have studied the development of synaptic reorganization, semaphorin gene expression, and epileptogenesis in hippocampus of epileptogenic sensitive (FVB/NJ) and epileptogenic resistant (C57BL/6J) mice (i.e. distinct genetic backgrounds) after kainic acid-induced status epilepticus. Our results support the hypothesis that disruption of transcriptional regulation of axon guidance genes leads to a differential loss of tonic neuropilin-2 dependent activation of semaphorin 3F receptors on hippocampal neurons on distinct genetic backgrounds. This results in rearranged synaptic circuitry and thus promotes epileptogenesis. These findings may define biologic principles underlying the role of semaphorin signaling which may broadly apply to other systems undergoing neural regeneration.

Animals↗
PubMed2000

Genetic background of osteoporosis.

Osteoporosis is a systemic disorder of decreased skeletal mass as measured by bone mineral density (BMD), and disturbed skeletal architecture and function which results in an increased risk for bone fractures with consecutively increased morbidity and mortality. Twin and family studies have shown an important genetic component of BMD of about 40-60%. This exceeds other well known factors influencing BMD such as environmental factors like dietary calcium, physical activity or several drugs and diseases. Therefore, interest increased in the genetic background of bone mineral density. Polymorphisms of the Vitamin D receptor gene were the first to be published in this area. Studies on other loci or candidate genes such as the estrogen receptor gene or the collagen type I alpha1 gene also showed associations with bone mineral density that could explain at least a part of the genetic background of osteoporosis. Recently published data suggest that these genetic markers of bone metabolism are important in interaction with each other or in certain bone-affecting diseases. In the future, genetic studies on osteoporosis will have to screen further relevant genes and markers for bone metabolism as well as to evaluate the complex interactions of genetic influences, so that it would be possible to calculate a patient's individual risk for osteoporosis in the context of environmental influences.

Family↗
PubMed1999

Outcome of Staphylococcus aureus-triggered sepsis and arthritis in IL-4-deficient mice depends on the genetic background of the host.

Disruption of the IL-4 gene in two inbred mouse strains revealed a dual role of IL-4 in Staphylococcus aureus sepsis and arthritis depending on the host's genetic background. IL-4 was protective in 129SV mice, since 5 days after S. aureus inoculation IL-4(-/-) mice displayed 70% mortality as compared to survival of all 129SV wild-type counterparts. On the other hand, IL-4 was detrimental in C57BL/6 mice, since survival of IL-4(-/-) C57BL/6 mice was increased, as compared to wild-type controls, due to decreased staphylococcal growth. Altogether, our results show the dual role of IL-4 in S. aureus sepsis and arthritis, depending on the genetic background of the host.

Animals↗
PubMed1995

Yeast vectors for the controlled expression of heterologous proteins in different genetic backgrounds.

An expression system for Saccharomyces cerevisiae (Sc) has been developed which, depending on the chosen vector, allows the constitutive expression of proteins at different levels over a range of three orders of magnitude and in different genetic backgrounds. The expression system is comprised of cassettes composed of a weak CYC1 promoter, the ADH promoter or the stronger TEF and GPD promoters, flanked by a cloning array and the CYC1 terminator. The multiple cloning array based on pBIISK (Stratagene) provides six to nine unique restriction sites, which facilitates the cloning of genes and allows for the directed cloning of cDNAs by the widely used ZAP system (Stratagene). Expression cassettes were placed into both the centromeric and 2 mu plasmids of the pRS series [Sikorski and Hieter, Genetics 122 (1989) 19-27; Christianson et al., Gene 110 (1992) 119-122] containing HIS3, TRP1, LEU2 or URA3 markers. The 32 expression vectors created by this strategy provide a powerful tool for the convenient cloning and the controlled expression of genes or cDNAs in nearly every genetic background of the currently used Sc strains.

Cloning, Molecular↗
PubMed2002

Effects of genetic background on prostate and taste bud carcinogenesis due to SV40 T antigen expression under probasin gene promoter control.

The incidence of prostate carcinomas in African-American men is greater than in white men, indicating genetic factors are involved in risk of this neoplasia. Recently, we have developed a transgenic rat model of prostate cancer, featuring development of malignancies within 15 weeks of age at very high incidence. Male transgenic rats with a Sprague-Dawley genetic background were mated with wild-type females of F344, Wistar and ACI strains. F1 male transgenic hybrids with female Wistar and ACI rats had significantly lowered incidences of prostate carcinomas. However, the serum level of testosterone, and expression of the transgene, probasin, and the androgen receptor did not correlate with the strain variation in tumor development. Furthermore, immunohistochemical analysis of the SV40 Tag and the androgen receptor also did not reveal any differences between the strains. The transgenic rats additionally developed taste bud neuroblastomas at 100% incidence and this was suppressed in F1 male transgenic offspring with the ACI, but not the other strains. These results clearly show that genetic background influences prostate carcinogenesis and taste bud tumorigenesis in rats and that the present transgenic rats could provide a good model to identify specific factors.

Androgen-Binding Protein↗
PubMed1996

Selection of rotavirus VP7 gene in the genetic background of simian rotavirus SA11: implications for rotavirus reassortant vaccine development.

We previously reported that the VP7 gene from simian rotavirus SA11 with G-serotype 3(G3-VP7 gene) was preferentially selected in the genetic background of SA11 compared with the G1- or G2-VP7 gene. In the present study, selection of the G4-VP7 gene in competition with G1-, G2- or G3-VP7 gene in the SA11 background was analyzed through mixed infection experiments using SA11 and SA11-human rotavirus single-VP7 gene-substitution reassortants with G-serotypes 1, 2, and 4 (G1-, G2- and G4-reassortant). In virus clones from coinfection of SA11 and G4-reassortant, the frequency of G4 virus decreased to 7% at the 3rd passage and the G4 virus disappeared at the 10th passage, whereas the majority of the clones possessed G3 specificity. However, the predominance of either of the viruses coinfected was not observed in the mixed infection with G4-reassortant and G1- or G2-reassortant. Although growth kinetics of SA11 and G4-reassortant was similar, G4-reassortant showed significantly smaller plaque size than SA11, G1- and G2-reassortant did. These results indicated that the G3-VP7 gene from SA11 might be preferentially selected in the SA11 genetic background compared with the G4-VP7 gene, and suggested that the introduction of a single G4-VP7 gene may affect growth characteristics of recipient virus SA11. These results together with our previous findings suggested the significance of genetic compatibility between recipient viral genes and foreign VP7 gene in the development of multivalent reassortant rotavirus vaccines.

Animals↗
PubMed2005

Comparison of genetic backgrounds of methicillin-resistant and -susceptible Staphylococcus aureus isolates from Portuguese hospitals and the community.

In order to understand the origins of the dominant methicillin-resistant Staphylococcus aureus (MRSA) clones in Portuguese hospitals, we compared the genetic backgrounds of nosocomial MRSA with methicillin-susceptible S. aureus (MSSA) isolates from the same hospitals (n=155) and from the community (n=157) where they were located. Pulsed-field gel electrophoresis, spa typing, multilocus sequence typing, and agr type analysis revealed that the genetic backgrounds correspondent to the dominant MRSA clones in Portuguese hospitals during the last 15 years (Iberian ST 247, Brazilian ST 239, and EMRSA-15 ST 22) were scarcely or not found among the present MSSA collection. The four major MSSA clones encountered (A-ST 30, B-ST 34, C-ST 5, and H-ST 45) correspond, or are very similar, to the background of other international MRSA pandemic clones, i.e., EMRSA-16, New York/Japan, Pediatric, and Berlin clones. However, with the exception of the Pediatric clone, none of these MRSA clones has been detected in Portugal. Our findings suggest the three major MRSA clones identified in Portuguese hospitals have not originated from the introduction of SCCmec into dominant MSSA backgrounds present in the Portuguese nosocomial or community environment but were probably imported from abroad. In contrast, the MRSA Pediatric clone might have originated in our country by the acquisition of SCCmec type IV into MSSA clone C. Furthermore, we provide evidence that the introduction of SCCmec into sensitive clones is most likely a relatively infrequent event that seems to depend not exclusively on the presence of a successful MSSA lineage.

Anti-Bacterial Agents↗
PubMed2002

A novel methicillin-resistance cassette in community-acquired methicillin-resistant Staphylococcus aureus isolates of diverse genetic backgrounds.

Until recently, it has been unclear whether community-acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) isolates represent the spread of hospital MRSA isolates into the community. In 2 CA-MRSA isolates, a novel genetic element, designated staphylococcal cassette chromosome mec (SCCmec) type IV, was found; it differs from SCCmec types I-III in its small size and absence of non-beta-lactam genetic-resistance determinants. To study the prevalence of type IV SCCmec, polymerase chain reaction characterization of SCCmec was performed on DNA from 12 CA-MRSA isolates. The 12 CA-MRSA isolates were from diverse genetic backgrounds, as evidenced by their stratification into 5 pulsed-field gel electrophoresis types, 4 coagulase types, and 2 ribotypes. Eleven of the 12 isolates contained the novel SCCmec type IV element. Ten were resistant only to beta-lactam antibiotics. SCCmec type IV is present on the genome of CA-MRSA isolates. Its relatively small size and presence in isolates of diverse genetic backgrounds suggest that it may spread among S. aureus isolates.

Community-Acquired Infections↗