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PubMed2004

Genetic background affects susceptibility in nonfatal pneumococcal bronchopneumonia.

A nonfatal pneumococcal lung infection model was required to investigate immune responses during recovery, and the interaction of other diseases subsequent to infection. A murine model of nonfatal pneumococcal lung infection was developed and the effect of genetic background on susceptibility was determined in BALB/c and C57BL/6 mice. Bacteria colonised the lungs and mice developed mild clinical illness with pathophysiology similar to human bronchopneumonia. Recovery was associated with immune cell influx, which cleared bacteria but induced tissue damage characteristic of pneumococcal bronchopneumonia. After clearance, immune cell populations returned to normal and tissues appeared less inflamed. Although bacterial exposure and clearance were similar, the extent of immune cell influx and tissue damage differed significantly. Larger numbers of neutrophils and lymphocytes entered lung tissue and the affected area was greater in BALB/c compared with C57BL/6 mice. An inflammatory basis for differences was determined with greater levels of phagocytosis and oxidative burst observed in BALB/c mice. C57BL/6 mice cleared the low inoculum with a reduced immune response; however, C57BL/6 mice are more susceptible to larger inocula, which overwhelms the immune system. These different susceptibilities result from a greater inflammatory response in BALB/c compared with C57BL/6 mice.

Adult↗
PubMed2002

Trypanosoma cruzi: role of host genetic background in the differential tissue distribution of parasite clonal populations.

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, has quite a variable clinical presentation, ranging from asymptomatic to severe chronic cardiac and/or gastrointestinal disease. The reason for that is not completely understood, but both parasite and host genetic traits are certainly involved. Recently, we have demonstrated clinically and experimentally that the genetic variability of T. cruzi is one of the determinants of the pattern of tissue involvement in Chagas' disease. We then decided to turn our attention to the role of host genetic background. To study this, we compared the infection of four lineages of mice [three inbred (BALB/c, DBA-2, and c57Black/6) and one outbred (Swiss)] with two T. cruzi clonal populations, the Col1.7G2 clone and the JG monoclonal strain. The tissue distribution of T. cruzi strains was identical for BALB/c and DBA-2 mice, but very different in C57BL/6 (H-2(b)) and outbred Swiss mice. This result clearly demonstrates the importance of host genetic aspects in the process. Since BALB/c and DBA-2 have the same H-2 haplotype (H-2(d)) and C57BL/6 does not (H-2(b)), it is possible that MHC variability may be involved in influencing the tissue distribution of involvement in experimental Chagas' disease of the mouse.

Animals↗
PubMed1992

Variation in antigenicity and molecular weight of Campylobacter coli VC167 flagellin in different genetic backgrounds.

Campylobacter coli VC167 has been shown to undergo a reversible flagellar antigenic variation between antigenic type 1 (T1) and antigenic type 2 (T2). VC167 contains two flagellin genes, and the products of both genes are incorporated into a complex flagellar filament in both antigenic types. Although there are only minor amino acid changes in the flagellins expressed by T1 and T2 cells, the two antigenic types of flagellins can be distinguished by differences in apparent M(r) on sodium dodecyl sulfate-polyacrylamide gels and by immunoreactivity with T1-specific (LAH1) or T2-specific (LAH2) antiserum. The isolation of stable variants of T1 and T2 has allowed for the transfer via natural transformation of the flagellin structural genes from the T1 background into the T2 background and from the T2 background into the T1 background. In addition, the flagellin genes from VC167 T1 and T2 have been transferred into strains of Campylobacter jejuni. The results indicate that the observed antigenic variations of VC167 flagellins are dependent on the host genetic background and independent of the primary amino acid sequence. These data provide evidence that posttranslational modifications are responsible for the antigenic variation seen in VC167 flagellins.

Antigenic Variation↗
PubMed2000

Development of a set of near isogenic and backcross recombinant inbred lines containing most of the Lycopersicon hirsutum genome in a L. esculentum genetic background: a tool for gene mapping and gene discovery.

A novel population consisted of a set of 99 near isogenic lines (NILs) and backcross recombinant inbred lines (BCRILs) derived from a cross between the cultivated tomato Lycopersicon esculentum cv. E6206 and L. hirsutum accession LA1777 is presented. Most of the lines contain a single defined introgression from L. hirsutum in the L. esculentum genetic background and together, the lines provide a coverage of more than the 85% of the L. hirsutum genome. These lines represent a new tool to uncover the genetic resources hidden in L. hirsutum as well as to study the genes responsible of its unique biology. Furthermore, the study of the allelic frequency and heterozygosity among BCRILs showed that specific genomic regions were likely subjected to unintentional selection pressures during the stock development. Genes involved in the reproductive behavior and (or) pollen viability are hypothesized to be responsible for these alterations.

Breeding↗
PubMed2006

Genetic background of HSH in three Polish families and a patient with an X;9 translocation.

Hypomagnesemia with secondary hypocalcemia (HSH) is a rare inherited disease, characterised by neurological symptoms, such as tetany, muscle spasms and seizures, due to hypocalcemia. It has been suggested that HSH is genetically heterogeneous, but only one causative gene, TRPM6, on chromosome 9 has so far been isolated. We have now studied the genetic background of HSH in four Polish patients belonging to three families, and a HSH patient carrying an apparently balanced X;9 translocation. The translocation patient has long been considered as an example of the X-linked form of HSH. We identified six TRPM6 gene mutations, of which five were novel, in the Polish patients. All the alterations were either nonsense/splicing or missense mutations. The clinical picture of the patients was similar to the HSH patients reported earlier. No genotype-phenotype correlation could be detected. Sequencing did not reveal any TRPM6 or TRPM7 gene mutations in the female HSH patient with an X;9 translocation. Isolation of the translocation breakpoint showed that the chromosome 9 specific breakpoint mapped within satellite III repeat sequence. The X-chromosomal breakpoint was localised to the first intron of the vascular endothelial growth factor gene, VEGFD. No other sequence alterations were observed within the VEGFD gene. Even though the VEGFD gene was interrupted by the X;9 translocation, it seems unlikely that VEGFD is causing the translocation patient's HSH-like phenotype. Furthermore, re-evaluation of patient's clinical symptoms suggests that she did not have a typical HSH.

Amino Acid Sequence↗
PubMed2001

Increased entry into the IFN-gamma effector pathway by CD4+ T cells selected by I-Ag7 on a nonobese diabetic versus C57BL/6 genetic background.

IFN-gamma-mediated Th1 effects play a major role in the pathogenesis of autoimmune diabetes in nonobese diabetic (NOD) mice. We analyzed functional responses of CD4(+) T cells from NOD and B6.G7 MHC congenic mice, which share the H2(g7) MHC region but differ in their non-MHC genetic background. T cells from each strain proliferated equally to panstimulation with T cell lectins as well as to stimulation with glutamic acid decarboxylase 524-543 (self) and hen egg lysozyme 11-23 (foreign) I-A(g7)-binding peptide epitopes. Despite comparable proliferative responses, NOD CD4(+) T cells had significantly increased IFN-gamma intracellular/extracellular protein and mRNA responses compared with B6.G7 T cells as measured by intracellular cytokine analysis, time resolved fluorometry, and RNase protection assays. The increased IFN-gamma production was not due to an increase in the amount of IFN-gamma produced per cell but to an increase in the number of NOD CD4(+) T cells entering the IFN-gamma-producing pathway. The increased IFN-gamma response in NOD mice was not due to increased numbers of activated precursors as measured by activation/memory markers. B6.G7 lymphoid cells demonstrated an absolute decrease in IFN-gamma mRNA, an increase in IL-4 mRNA production, and a significantly decreased IFN-gamma:IL-4 mRNA transcript ratio compared with NOD cells. CD4(+) T cells from C57BL6 mice also showed significantly decreased IFN-gamma production compared with CD4(+) T cells from NOD.H2(b) MHC-congenic mice (which have an H2(b) MHC region introgressed onto an NOD non-MHC background). Therefore, the NOD non-MHC background predisposes to a quantitatively increased IFN-gamma response, independent of MHC class II-mediated T cell repertoire selection, even when compared with a prototypical Th1 strain.

Animals↗
PubMed1998

Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations.

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.

Adaptation, Physiological↗
PubMed1991

Host genetic background effect on the frequency of mouse mammary tumor virus-induced rearrangements of the int-1 and int-2 loci in mouse mammary tumors.

The frequency with which int-1 and int-2 are rearranged in mouse mammary tumors by mouse mammary tumor virus (MMTV)-induced insertional mutagenesis is a consequence of the host genetic background. In 75% of C3H mammary tumors, int-1 is rearranged by MMTV insertion, whereas only 30% of BALB/cfC3H tumors contain a virus-induced rearrangement of int-1. This difference is significant (P less than 0.005) and could not be accounted for by the potentially additive effect of the genetically transmitted Mtv-1-encoded virus in C3H mice. Similarly, MMTV-induced rearrangement of the int-2 gene in mammary tumors of the R111 mouse strain (59%) occurred at a significantly (P less than 0.025) higher frequency than in BALB/cfR111 (25%) mammary tumors. Moreover, in BALB/cfR111 mammary tumors, there is evidence that rearrangement of int-1 and int-2 does not occur independently (P less than 0.025). These results suggest that the long history of inbreeding for high tumor incidence of C3H and R111 mouse strains has selected for the fixation of host mutations which either complement the action of the particular int gene or affect the sensitivity of specific subpopulations of mammary epithelium to infection by particular strains of MMTV.

Animals↗
PubMed2005

Genetic background of type I protein C deficiency in Finland.

In contrast to other populations the usually rare type II form of protein C deficiency is as common in Finland as type I deficiency. We recently reported that a single mutation explained virtually all cases of type II protein C deficiency in Finland, indicating strong founder effect. We now investigated in the same population the genetic background of type I protein C deficiency. Thirty-eight apparently unrelated families were studied. They represent the vast majority of all families with type I deficiency in Finland. A genetic defect was identified in 23 (61%) families who carried 13 different mutations. Only three of the 13 mutations have been reported in other populations. Unlike in type II deficiency, considerable heterogeneity in mutations was found in type I deficiency. Our results indicate interesting differences in mutational histories of these two different forms of protein C deficiency in Finland.

DNA Mutational Analysis↗
PubMed2006

Gastric and intestinal phenotypic marker expression in early differentiated-type tumors of the stomach: clinicopathologic significance and genetic background.

PURPOSE: Gastric and intestinal phenotypic cell markers are expressed in gastric carcinomas, irrespective of their histologic type. In the present study, we determined the clinicopathologic significance of phenotypic marker expression in early-stage gastric differentiated-type tumors and the association between marker expression and genetic alterations. EXPERIMENTAL DESIGN: Phenotypic marker expression was determined by examining the expressions of human gastric mucin (HGM), MUC6, MUC2, and CD10 in 63 gastric adenomas, 133 early differentiated-type carcinomas, and 24 follow-up cases with gastric adenoma. Tumors were classified into gastric, gastric and intestinal mixed, or intestinal phenotypes according to the immunopositivity of the above markers. The presence of mutations in APC, K-ras, and p53 and the microsatellite instability status were also determined in all tumors. RESULTS: The expressions of HGM and MUC6, representing gastric or gastric and intestinal mixed phenotypes, were significantly associated with high-grade atypia in the 63 gastric adenomas. Among the 133 early differentiated-type carcinomas, HGM expression was significantly associated with mixed-type (with an undifferentiated-type component) tumors and lymph node metastasis. MUC2 expression was inversely associated with submucosal invasion. A multivariate analysis revealed that gastric adenomas were significantly associated with the intestinal phenotype and were inversely associated with p53 mutation compared with early differentiated-type carcinomas. Among all 196 tumors, APC mutation was significantly associated with CD10 expression and the intestinal phenotype and was inversely associated with the expressions of HGM and MUC6. The microsatellite instability status was significantly associated with MUC6 expression. Malignant transformation from gastric adenoma to carcinoma was shown in 5 of the 24 follow-up cases of gastric adenoma. The malignant transformation was significantly associated with the gastric and intestinal mixed phenotype and was inversely associated with APC mutation. No malignant transformation was found in intestinal phenotype gastric adenomas with APC mutation. CONCLUSIONS: Our present findings show that phenotypic marker expression is associated with tumor aggressiveness during the early stage of gastric differentiated-type tumors. Differences in the biological behavior of tumors with different phenotypes may result from differences in the genetic backgrounds during the incipient phase of gastric tumorigenesis.

Adenoma↗
PubMed2000

The adjuvant effect of particles-importance of genetic background and pre-sensitisation.

BACKGROUND: We have previously reported that simple and well-characterised particles, such as polystyrene particles (PSP), have an IgE adjuvant effect in mice. The purpose of this study was to explore the importance of genetic background concerning the adjuvant effect of PSP in different strains of mice. METHODS: Inbred NIH/Ola, BALB/c and C3H/HeJ mice were given two intraperitoneal injections with either PSP plus OVA or OVA alone, and then an intraperitoneal challenge with OVA alone. NIH/Ola mice were also pre-sensitised to develop a weak or strong IgE response to OVA, and then given an intraperitoneal challenge with PSP plus OVA or OVA alone. Serum levels of total and allergen-specific IgE and IgG2a were measured. RESULTS: PSP had a specific IgE and IgG2a adjuvant effect in NIH/Ola mice but not in C3H/HeJ and BALB/c mice. Weakly pre-sensitised NIH/Ola mice showed the same response pattern as the naive NIH/Ola mice. In contrast, strongly pre-sensitised mice showed an antibody response pattern similar to that of high-responder BALB/c mice. CONCLUSIONS: Our results indicate that the allergen responder status, either genetic or induced, is of importance for the adjuvant effect from particles. The IgE and IgG2a adjuvant effect may depend on the genetically determined susceptibility of an individual to be influenced by exposure to the adjuvant. Therefore, the allergy-enhancing effect from particle pollution may differ between individuals.

Adjuvants, Immunologic↗
PubMedDate not supplied

Familial ureteroceles: an evidence for genetic background?

In the pediatric population, ureteroceles may present with different clinical pictures, and the severity of the renal damage is greater than in adults. Ureterocele, an anomaly of ureteric budding, is likely a component of a spectrum of anomalies including vesicoureteral reflux and ureteral duplications. Both have been confirmed to have a genetic and familial basis. We document the largest series of familial cases of ureteroceles, giving evidence for genetic background. We retrospectively reviewed the charts of patients with familial ureteroceles seen between 1992 and 2002. Coexisting ureteral anomalies and features of the cases were documented and compared to sporadic cases and all familial cases within the literature. This is the largest series of familial ureterocele patients in the literature. The review of the literature revealed seven publications with seven ureterocele families (15 affected patients) between 1936 and 2002. Comparing sex, ureterocele location, and single versus duplex systems, familial series are similar to other sporadic cases. Three of the families have twin siblings with ureteroceles. Familial cases, despite their rarity, raise the issue of the genetic origin of uretereoceles. Family members of ureterocele cases should be informed and followed carefully, especially twins. Increased reporting and genetic analysis of familial ureteroceles may prove to link the genetic mouse models of abnormal ureteric budding to the human conditions.

Adult↗
PubMed2002

Clinical features, treatment and genetic background of Treacher Collins syndrome.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development. The major features of the disease include midface hypoplasia, micrognathia, microtia, conductive hearing loss and cleft palate. Current procedures of surgical treatment of TCS are discussed and novel findings concerning the genetic background of TCS are described. The TCS locus has been mapped to chromosome 5q31.3-32. The TCOF1 gene contains 26 exons and encodes a 1411 amino acid protein named treacle. In the TCOF1 gene 51 mutations have been identified. Most of these mutations are insertions or deletions, which result in an introduction of a premature termination codon into the reading frame. Mutational spectra support the hypothesis that TCS results from haploinsufficiency of treacle.

Chromosomes, Human, Pair 5↗
PubMed1995

Conditional hitchhiking of mitochondrial DNA: frequency shifts of Drosophila melanogaster mtDNA variants depend on nuclear genetic background.

Tests were performed of the selective neutrality of mitochondrial DNA (mtDNA) variants from geographic populations of Drosophila melanogaster in Argentina (ARG) and Central Africa (CAF). The two populations were completely reproductively compatible. The two distinct mtDNA haplotypes from the two populations were competed in replicate experimental populations on three nuclear genetic backgrounds: homozygous ARG, homozygous CAF, or hybrid ARG/CAF. Mitochondrial haplotype frequencies did not change significantly on either of the two homozygous nuclear backgrounds, and there was no change after experimental perturbation of haplotype frequencies. On the hybrid background, the ARG haplotype frequency increased significantly for the first two generations in all replicate populations but then did not change in subsequent generations. After perturbation, the ARG haplotype frequency increased in only one of four replicates. There is no evidence for selective differences among mtDNA variants in homozygous nuclear contexts or for nuclear-mitochondrial coadaptation. While some "fitness" difference among mtDNA variants is required to account for the observed frequency shifts, it appears that in these hybrid populations, mtDNA is hitchhiking on fitness variation among hybrid segregating nuclear genes. These results have implications for the use of mtDNA in the study of hybrid zones and gene flow.

Africa, Central↗
PubMed1997

Different developmental arrest points in RAG-2 -/- and SCID thymocytes on two genetic backgrounds: developmental choices and cell death mechanisms before TCR gene rearrangement.

To analyze the early development of T cell precursors in the absence of TCR gene rearrangement, recombinase-activating gene-deficient (RAG-2 -/-) thymocytes were compared with thymocytes from SCID mice on the C.B-17 (BALB) and B6 genetic backgrounds. RAG-2 -/- thymocytes accumulate as quiescent cells with a heat-stable Ag (HSA)-positive CD25+ CD44- c-kit(low) phenotype, resembling normal cells just before selection for functional TCR beta-chain expression. CD44 and c-kit progressively down-regulate in the HSA+ subset, providing a background-independent and TCR-independent developmental clock. On this basis, compared with RAG-2 -/- thymocytes, SCID thymocytes 1) arrest at more heterogeneous, and generally earlier, stages; 2) accumulate to lower overall cell numbers; and 3) maintain higher populations of cycling and activated G1 cells, showing both increased responsiveness and increased cell death. B6-SCID thymocytes appear to die particularly early. Low levels of Fas were observed on "advanced" HSA+ SCID thymocytes but not on any RAG-2 -/- thymocytes, suggesting a potential difference in activation state or mechanism of death. In both RAG-2 -/- and SCID thymocytes, there are also two discrete subsets of HSA(low) CD25- CD44+ c-kit+ cells: a Sca-1+ CD44++ CD122- NK1.1- putative progenitor subset and an NK-like Sca-1- CD44+(+) CD122+ NK1.1+ subset. The absolute cell numbers in these HSA(low) subsets and the extent of NK cell differentiation, measured by perforin expression, are nearly constant in all the mutant strains analyzed, in contrast to the HSA+ CD25+ population, which was expanded in the RAG-2 -/-. Thus, the SCID thymocytes appear to undergo a normal generation but a premature death as compared with the RAG-2 -/- thymocytes.

Animals↗
PubMed2000

[QTLs and epistasis underlying rice (Oryza sativa L.) panicle length in different genetic background and environments].

A double haploid (DH) population and a recombinant inbred (RI) population derived from a cross between a japonica male parent Azucena and indica female parents, IR64 and IR1552 respectively, were used in both field and pot experiments for detecting QTLs and epistasis for rice panicle length in different genetic background and different environments. Panicle length (PL) was measured at maturity. QTLs for PL were detected using single marker analysis and interval mapping. Epistasis effects on the trait were also analyzed. Nine QTLs were detected in DH population, including 5 QTLs detected from field experiment and 4 from pot experiment, among them 3 QTLs mapped on chromosomes 1 and 4 were identified in both field and pot experiments. No significant epistasis effect was detected for PL. Four QTLs were detected in RI population, among them 2 from field condition and 2 from pot experiment. 6 pairs of epistasis loci were detected in RI population. One QTL mapped on chromosome 4 and two pairs of epistatic loci were detected in both field and pot experiments. One QTL on chromosome four was identified in both populations, and one marker locus RG323 on chromosome one was involved in additive effect in DH population, but epistasis effects in RI population.

Chromosome Mapping↗
PubMed2004

In vivo evidence that genetic background controls impulse-dependent dopamine release induced by amphetamine in the nucleus accumbens.

Amphetamine is known to increase dopamine (DA) release by acting directly on dopamine transporters (DAT), primarily through a mechanism that is independent of impulse flow. We present evidence to show that impulse-dependent increase in DA outflow in the nucleus accumbens (NAc) is produced by amphetamine depending on genetic background. Systemic amphetamine produced higher accumbal DA release in the widely exploited C57BL/6J background than in the DBA/2J. By contrast, intra-accumbens perfusion using increasing doses of amphetamine dramatically increased DA outflow in the DBA/2J background, whereas very low DA outflow was evident in C57BL/6J mice. The fast sodium channel blocker tetrodotoxin infused through the microdialysis probe abolished accumbal DA release induced by systemic amphetamine only in the C57BL/6J background. Finally, medial prefrontal excitotoxic lesion abolished amphetamine-induced mesoaccumbens DA release in C57BL/6J mice, without significantly affecting it in the DBA/2J background. These results represent the first functional evidence in an in vivo study that amphetamine can increase DA release in the NAc mainly through an impulse-dependent mechanism regulated by prefronto-cortical glutamatergic transmission. Moreover, they point to a genetic control of impulse-dependent DA release in the accumbens, providing an exploitable tool to investigate aetiological factors involved in psychopathology and drug addiction.

Amphetamine↗
PubMed1984

Bipolar mood disorders: an affected sibling study. I. Genetic background and course of illness.

The study uses the 'affected (and hospitalized) siblings method' to investigate aspects of correlation in the psychopathology of bipolar mood disorders. In part one, age of onset, duration of phases, and course of illness are the points of interest. The sample includes 307 sibling groups (701 hospitalized individuals). The incidence of pure or schizoaffective type mania in at least 1 sibling has been the criterion for selection. The genetic background is also presented and the question is raised whether double tainting is the rule rather than the exception. The hypothesis that schizophrenic syndromes and mood disorders develop from separate genetic pools is supported. Strong evidence against the unipolar/bipolar dichotomy is presented. The investigation brings the breadth of the cyclothymic spectrum and inhomogeneity with respect to the course of bipolar disorders into perspective.

Adolescent↗