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PubMed2003

HLA haplotype is associated with diabetes among atomic bomb survivors.

We examined radiation effects on the relationship between diabetes development and genetic background in atomic-bomb (A-bomb) survivors. Our main aim in this study was to shed light on the role of genetic background in diabetes onset among A-bomb survivors by studying possible relationships between human leukocyte antigen (HLA) genotypes and the diabetes in patients and controls. We examined the effects of different HLA haplotypes on type 2 diabetes development by determining the DQA1 and DRB1 alleles of Hiroshima A-bomb survivors (111 diabetic patients and 774 controls) using the polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method. We noted an increased risk of diabetes in the higher dose group among these patients (trend p = 0.001). The risk of the most heavily exposed group was significantly higher than that of the unexposed group or the low-dose group especially in survivors with the DQA1*03-DRB1*09 or DQA1*0401-DRB1*08 haplotypes (trend p = 0.002 or p = 0.05, respectively). By contrast, in people with other haplotypes, the risk did not increase significantly with increasing dose. These results suggest that individuals with specific HLA haplotypes may have an increased risk of diabetes with increased-dose categories.

Aged↗
PubMed2000

Do Wolbachia influence fecundity in Nasonia vitripennis?

This paper reports the influence of a vertically transmitted symbiont, Wolbachia, on host fitness in the parasitic wasp, Nasonia vitripennis. We measured fecundities of uninfected strains and strains infected with either two Wolbachia variants (wAv,wBv) or one (wAv or wBv). Preliminary tests suggested that double-infected females produce more offspring on average than uninfected females. However, further studies failed to yield consistent fitness effects. To control for host genetic effects, the genotype of the double-infected and uninfected strain was 'replaced' with three different host genetic backgrounds by introgression. Contrary to previous results, we found no convincing evidence for positive fitness effects of Wolbachia in Nasonia vitripennis, once host genetic background was controlled for. It can be concluded that under the experimental design used here, the fecundity effects associated with Wolbachia in N. vitripennis are small or absent.

Animals↗
PubMed1998

Activation of the bgl operon by adaptive mutation.

In growing Escherichia coli K12 cells, the cryptic bgl operon is activated 98% of the time by insertions of IS1 or IS5 into the control region, designated bglR. The activated bgl operon permits utilization of the beta-glucoside sugar arbutin as a sole carbon and energy source. The bgl operon is also activated by late-occurring mutations during prolonged selection on arbutin. The late-occurring mutations that occurred during prolonged carbon starvation in the presence of arbutin were "adaptive mutations" because they were specific to the presence of arbutin, and they did not occur during prolonged starvation in the absence of arbutin. The spectrum of late-arising mutations differed from that of early-arising, growth-dependent mutations in that 20% of the late-arising mutants resulted from mutations at the hns locus. This provides the first direct evidence for adaptive mutagenesis mediated by the insertion of IS elements. Because no special genetic background is required to select Bgl+ mutants, this affords the opportunity to study IS-element-mediated adaptive mutagenesis in a variety of genetic backgrounds, including the backgrounds of natural isolates of E. coli.

Adaptation, Physiological↗
PubMed2003

Role of FAS in HIV infection.

Direct cytopathic effects cannot explain the massive CD4+ T cell depletion in acquired immunodeficiency syndrome (AIDS) patients and several indirect mechanisms may be involved. A role has been proposed for apoptosis of uninfected lymphocytes, since lymphocytes from human immunodeficiency virus-1+ (HIV-1) individuals display increased levels of spontaneous apoptosis. This process may be ascribed in part to cell exhaustion by the chronic uncontrolled infection, but can also be directly induced by viral components, such as gp120, tat or nef. A key role is played by the death receptor Fas, but a role can also be played by other death receptors, such as the TNF and TRAIL receptors. By contrast, death of HIV-infected cells seems to be Fas-independent and driven by other viral components such as vpr and HIV proteases. A further role may be played by depletion of CD4+ T cell itself and hence the withdrawal of survival factors such as cytokines. Different ability of HIV strains to induce death of infected and uninfected cells might play a role in the clinical and biological differences displayed by HIV strains. A further variability may be ascribed to the intrinsic resistance of cells to apoptosis, which may depend on the individual genetic background or the use of drugs inhibiting apoptosis. The observation that when progression of HIV infection is slow due to "apoptosis-resistant" genetic backgrounds of the patients, or defective HIV-1 strains, or successful highly active antiretroviral therapy (HAART), generally also T cell apoptosis is low, suggests that HIV-infected subjects may benefit from therapies aimed to inhibit Fas function and/or spontaneous apoptosis.

Apoptosis↗
PubMed2005

Role of Toll-like receptor-4 in genetic susceptibility to lung injury induced by residual oil fly ash.

The mechanisms of susceptibility to particle-induced lung injury are not clearly understood. To evaluate the contribution of genetic background to pulmonary pathogenesis, we compared the lung injury responses to residual oil fly ash (ROFA) in inbred mouse strains and calculated heritability estimates. Significant interstrain (genetic) variation was observed in ROFA-induced lung inflammation and hyperpermeability phenotypes; broad-sense heritability ranged from approximately 0.43 to 0.62, and the coefficient of genetic determination ranged from 0.28 to 0.45. C3H/HeJ (HeJ) mice were most resistant to the ROFA-induced injury responses. This was particularly important, as HeJ mice contain a dominant negative mutation in Toll-like receptor-4 (Tlr4). We then characterized ROFA-induced injury and TLR4 signaling in HeJ mice and its coisogenic strain C3H/HeOuJ (OuJ; Tlr4 normal) to understand the potential role of Tlr4 in this model. ROFA-induced lung injury was significantly greater in OuJ mice compared with HeJ mice. ROFA also significantly enhanced transcript and protein levels of lung TLR4 in OuJ but not in HeJ mice. Greater activation of downstream signal molecules (i.e., MYD88, TRAF6, IRAK-1, NF-kappaB, MAPK, AP-1) was observed in OuJ mice than in HeJ mice before the development of ROFA-induced pulmonary injury. Putative TLR4-dependent inflammatory genes that were differentially induced by ROFA in the two strains include interleukin-1beta and tumor necrosis factor-alpha. Results support an important contribution of genetic background to particle-mediated lung injury, and Tlr4 is a candidate susceptibility gene.

Animals↗
PubMed1976

Vaginal septa in mice: incidence, inheritance, and effect on reproductive, performance.

Dorso-ventral vaginal septa were observed in 38% of the recently weaned BALB/cJ female mice in the production colony at The Jackson Laboratory. The frequency of septa in two other BALB/c substrains and eight different inbred strains ranged from 0 to 8%. The vaginal anomaly was similar regardless of genetic background although individual variations were observed. The remainder of the reproductive tract was normal. Microscopically, the septum consisted of a fibrous partition covered by normal epithelium. Genetic analysis was undertaken by outcrossing septate BALB/cJ females to C57BL/6J, DBA/2J, or BALB/cBy males. Examination of female F1 and F2 progeny indicated more than one recessive gene was involved and genetic background influenced expression of these genes. Reproductive performance of septate and nonseptate BALB/cJ females was compared using several criteria. Fewer septate females were fertile, but the fecundity of fertile septate females was not affected.

Animals↗
PubMed2002

Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2.

Ventricular septal defects are common in human infants, but the genetic programs that control ventricular septation are poorly understood. Here we report that mice with a targeted disruption of the cardiovascular basic helix-loop-helix factor (CHF)1Hey2 gene show isolated ventricular septal defects. These defects result primarily in failure to thrive. Mice often succumbed within the first 3 wk after birth and showed pulmonary and liver congestion. The penetrance of this phenotype varied, depending on genetic background, suggesting the presence of modifier genes. Expression patterns of other cardiac-specific genes were not affected. Of the few animals on a mixed genetic background that survived to adulthood, most developed a cardiomyopathy but did not have ventricular septal defects. Our results indicate that CHF1 plays an important role in regulation of ventricular septation in mammalian heart development and is important for normal myocardial contractility. These mice provide a useful model for the study of the ontogeny and natural history of ventricular septal defects and cardiomyopathy.

Animals↗
PubMed1992

The basis of decreased recombination in certain outcrosses of Neurospora crassa.

Crossing over in a multiply marked segment of linkage group I was conspicuously reduced in outcrosses between a marked laboratory strain and each of six unrelated wild-collected strains, compared with crosses between inbred laboratory strains. The marked chromosome segment was transferred intact from the inbred strain to one of the wild-collected strains by seven recurrent backcrosses, and conversely, the corresponding segment of the wild strain was transferred to the inbred background by backcrossing to the multiply marked laboratory strain. Recombination was then monitored in crosses from parents having the marked and unmarked chromosome segments from the same or from unrelated sources. Meiotic crossing-over in the marked segment remained low in crosses between parents that were dissimilar with respect to genetic background, but crossing over was restored to a high level when the genetic background of both parents was that of the inbred laboratory strain, regardless of the source of the marked segments. Reduced recombination in outcrosses was therefore not due to heterologies in the marked segment but must be attributed to modifiers that are unlinked or distant from the monitored region.

Chromosomes, Fungal↗
PubMed2005

Triple knockouts reveal gene interactions affecting fertility of male mice.

Triple knockout mice were used to investigate the interactions of five genes that were expressed in meiotic and haploid spermatogenic cells in mice, transition protein 2 (Tnp2), proacrosin (Acr), histone H1.1 (H1.1), histone H1t (H1t), and sperm mitochondria-associated cysteine-rich protein (Smcp). TNP2 functions in the replacement of histones and the initial condensation of the spermatid nucleus. The linker histone subtypes H1.1 and H1t are expressed at high levels in meiotic and early haploid cells. ACR, a protease that is stored as a proenzyme in the acrosome, is activated during the acrosome reaction and functions in binding of sperm to the zona pellucida. SMCP is a structural protein in the outer membranes of sperm mitochondria that functions in motility. Previous work demonstrates that homozygous knockout mice lacking each of these proteins individually exhibit no defect in fertility on mixed genetic backgrounds. In contrast, the present study demonstrates that five triple knockout lines, Acr/H1.1/Smcp, Acr/Tnp2/Smcp, Tnp2/H1.1/Smcp, Acr/H1t/Smcp, Tnp2/H1t/Smcp, exhibit drastic reductions in fertility on mixed genetic backgrounds. Analysis of fertility parameters reveal that the decreased fertility is due to line-dependent defects in sperm motility in vitro correlated with reduced migration in the female reproductive tract, and decreased fertilization due to defects in adhesion of sperm to the zona pellucida, the membrane surrounding the egg. It was also found that triple knockout males, that are hemizygous for one locus and homozygous for two other loci, are as subfertile as homozygous triple knockout males, a phenomenon known as haploinsufficiency. These findings demonstrate that male fertility involves synergistic interactions of genes that function in sperm motility and sperm-egg adhesion during fertilization.

Acrosome Reaction↗
PubMed2003

Modulation of medullary thyroid carcinoma penetrance suggests the presence of modifier genes in a RET transgenic mouse model.

We described previously a thyroid phenotype for transgenic mice expressing an activated Ret oncogene driven from a human calcitonin promoter. Medullary thyroid carcinomas (MTC), a tumor of the thyroid parafollicular C cells, occur in this transgenic line with a pathology analogous to that seen in patients with multiple endocrine neoplasia type 2 (MEN2). When the transgene was introgressed onto four different genetic backgrounds, between 0 and 98% of transgenic progeny developed thyroid tumors by 10 months of age, indicating that tumor penetrance could be modulated by genetic background. Furthermore, tumors on the CBA/ca and C57BL/6J backgrounds were significantly larger than those arising in BALB/c transgenic mice. These results are relevant to human MEN2 disease, because this model system may be used to study genes modifying thyroid tumor penetrance in the dominantly inherited human cancer syndrome.

Animals↗
PubMed1995

Genetic mapping of the determinants of plaque morphology of coxsackievirus B4.

The genetic determinants of plaque size of two variants of coxsackie-virus B4, CB4-P and CB4-V, were identified using a panel of recombinant, chimeric viruses. When grown in monkey kidney cells, CB4-V yielded large plaques with an average size of 1.0 cm while CB4-P yielded small plaques with an average size of 0.4 cm. Two genetic domains, the 5' untranslated region and the VP4 gene sequence, independently influenced plaque size. Recombinant viruses containing the CB4-P genetic background with point mutations in either the VP1 or VP2 coding sequences had small plaque phenotypes. However, two additional chimerics containing the CB4-P genetic background with either a point mutation in the VP4 sequence or four substitutions in the 5' untranslated region, had large plaque phenotypes. Plaque size correlated with growth kinetics under single-step conditions. Large-plaque variants replicated to higher titers than small-plaque variants. Comparison of the growth kinetics of the recombinant viruses revealed some differences in viral replication. These data suggest that both the 5' untranslated region and arg-16 of VP4 influence viral replication but at different stages of the replication cycle.

Animals↗
PubMed1994

Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice.

We report that keratin 8 (mK8) gene disruption causes colorectal hyperplasia in FVB/N mice. The intestinal lesions affect uniformly the cecum, colon, and rectum but not the small intestine. The elongation of the crypts is accompanied by an inflammation of the lamina propria and submucosa. Hepatic, renal, and pancreatic functions tested in clinical assays are within nonpathological range, suggesting that the major defect lies in colonic epithelial cells. Still, small but consistent elevation in the hepatic enzymes alanine (AST) and asparate (ALT) aminotransferase are observed, along with a 70% increase in spleen weight. No homozygous mouse line has been established, because of a markedly reduced fertility of the mK8-/- females. Previously, we reported that the mK8- targeted mutation causes embryonic lethality in (C57B1/6x129Sv) mice. This strong effect of the genetic background on the mK8- mutant phenotype emphasizes the importance of using several inbred mouse strains to reveal the polygenic contribution to mutant phenotypes. Our results demonstrate that genetic modifiers of K8/K18 filament functions, with profound effects on embryogenesis and gut functional integrity, are differentially active in the FVB/N and C57B1/6 genetic backgrounds. More importantly, the increase in mK8-/- gut epithelial cell number, rather than cell disruption, contrasts with the known function of epidermal keratins in providing mechanical strength.

Aging↗
PubMed1972

The effects of heterozygosity changes on viability in Drosophila melanogaster.

The viability effects of chromosomes from an old and from a new laboratory strain of D. melanogaster were studied in eight factorial combinations and at two heterozygosity levels. The combinations were so constructed that heterozygosity level could be varied in the third chromosomes of the carriers of a homozygous lethal marker, in the third chromosomes of their wild-type segregants, and in the genetic backgrounds of both. Excluding the effect of the marker and the exceptional outcomes of two of the combinations, and taking into account both large and small deviations from theoretical expectation, the following summary is given as the simplest consistent explanation of the results: 1) If total heterozygosities of two segregant types tend toward equality their viabilities tend toward equality also, whether background heterozygosity is high or low; if background heterozygosities is higher the tendency toward equality is slightly greater. 2) If total heterozygosity of two segregant types are unequal the less heterozygous type has the lower viability; the difference is more pronounced when background heterozygosity is low, less when it is high. 3) Differences between segregant viabilities are correlated with differences between the total heterozygosities of the two segregants; genetic background is effective to the extent, and only to the extent, that it contributes to the magnitude of this difference. This in turn appears to underlie, at least partly, the expression of a pronounced interchromosomal epistasis. Thus in this study viability is seen to depend upon both the quantity and distribution of heterozygosity, not only among the chromosomes of an individual but among the individuals of a given combination as well.

Analysis of Variance↗
PubMed2001

Germline transmission of a transferred human chromosome 21 fragment in transchromosomal mice.

We generated transchromosomal (Tc) mice containing a human chromosome 21 fragment (hCF21) using mouse embryonic stem (ES) cells with the transferred hCF21. Here we report breeding analyses that test the maintenance rate of the hCF21 in Tc mice of two different genetic backgrounds, MCH (ICR) and C57BL/6. Fluorescence in situ hybridization and polymerase chain reaction-based DNA analyses revealed that the structure of the hCF21 fragment including the CBR1, SIM2, HLCS, and D21S268 markers, was approximately 5 Mb in size, and was transmitted at least to the F3 generation. Though the retention rate of the hCF21 was variable among individual mice, for example, 21%-92% in brain and 10%-92% in tail fibroblasts, the C57BL/6 background yielded a higher retention rate than did the MCH (ICR). These results suggest that the hCF21 could be maintained stably in Tc mice, depending on the genetic background. The panel of Tc mice will be a useful model to investigate the function of genes on the hCF21 fragment in various tissues through germinal transmission.

Animals↗
PubMed2000

Varied expression of a Y-linked P[w+] insert due to imprinting in Drosophila melanogaster.

During gametogenesis, a gene can become imprinted affecting its expression in progeny. We have used the expression of a Y-linked P[w+]YAL transposable DNA element as a reporter system to investigate the effect of parental origination on the expression of the w+ insert. Expression of w+ was greater in male progeny when the Y chromosome, harboring the insert, was inherited from the parental male rather than from the parental female. Imprinting was not due to a genetic background influence in the males, since the only difference among the males was the parental origin of the Y chromosome. It was also observed that the genetic background can affect imprinting, since w+ expression was also higher in males when the Y was derived from C(1)DX attached-X parental females rather than from C(1)RM attached-X parental females. Though the heterochromatic imprinting mechanism is unknown, a mutated Heterochromatin Protein 1 (HP1) gene, which is associated with suppression of position-effect variegation, increases expression of the w+ locus in the P[w+]YAL insert, indicating that HP1 may play a role in Y chromosome packaging.

Animals↗
PubMed1999

An early-onset congenic strain of the motor neuron degeneration (mnd) mouse.

The mouse mutant motor neuron degeneration (mnd/mnd) has been proposed as a model of neuronal ceroid lipofuscinosis (NCL) on the basis of widespread abnormal accumulating lipopigment and neuronal and retinal degeneration. Clinically, the mutant on a C57Bl/6 genetic background shows a progressive motor abnormality starting by 6 months of age, with death prior to 12 months. When mnd is outcrossed to the AKR/J genetic background, ca. 40% of the mnd/mnd F2 progeny show early onset (onset by 4.5-5 months and death by 7 months). A congenic strain of mnd has now been produced by eight generations of backcross onto the AKR background. Mice on this background show average onset at 4 months, and most are moribund prior to 5.5 months. The early onset appears to correlate with levels of abnormal accumulating material, and should prove useful in elucidating NCL neurodegenerative mechanisms.

Age Factors↗
PubMed2004

Differences in the immune response to long term Abeta vaccination in C57BL/6 and B6D2F1 mice.

The cerebral accumulation of beta-amyloid (Abeta) is a pathological hallmark of Alzheimer's disease (AD). Abeta vaccination or anti-Abeta specific antibodies may be a possible therapeutic option for AD. Previously, we demonstrated variation in the humoral response between B6D2F1 and C57BL/6 during short term (14 weeks) Abeta immunization. In the present study, we determined the humoral and cellular immune responses in these same mouse strains to a longer period of Abeta vaccination and further refined the major B cell epitope to Ass1-7. B6D2F1 mice generated a greater humoral and Th1 immune response versus C57BL/6 mice. Immunization with 25 microg Abeta produced a greater T cell response in B6D2F1 mice compared to 50 or 100 microg Abeta but resulted in comparable humoral immunity. Thus, Abeta vaccination is affected by the genetic background and amount of Abeta peptide used as immunogen. These data may help explain some differences observed in Abeta immunization studies in mice of various genetic backgrounds and aid in the design of Abeta vaccines.

Alzheimer Vaccines↗
PubMed2000

Genetic difference in susceptibility and fatality of three strains of mice experimentally infected with Neodiplostomum seoulense.

The genetic influence on host susceptibility to Neodiplostomum seoulense infection and fatality of the host was studied in 3 inbred strains of mice (BALB/c [H-2d], C3H/He [H-2k], and C57BL/6 [H-2b]). The survival of the mice, worm expulsion kinetics, worm size, number of eggs produced per day (EPD), and number of uterine eggs were observed from day 1 to day 40 postinfection (PI) with 100 or 200 metacercariae per mouse. Infection with N. seoulense was highly lethal to all 3 strains of mice, but the lethality was dose-dependent and varied according to the genetic backgrounds of the mice. The C3H/He mice exhibited the highest mortality, the lowest worm burdens and EPD, and the quickest expulsion of worms. It is suggested that different genetic backgrounds of mice appear to affect the host's capacity to expel N. seoulense and the fatality of the hosts themselves.

Animals↗