Auxin: its role in genetic tumor induction

Seedlings of the tumor-prone amphiploid Nicotiana suaveolens X N. langsdorffii were grown on nutrient medium supplemented with indoleacetic acid (IAA) and scored at regular intervals for the incidence of tumor formation. IAA at 2 x 10(-5)m caused a significant reduction in the rate of tumor formation. Plants were also grown on nutrient medium under two different intensities of illumination, and the endogenous level of IAA was determined in 23-day-old seedlings. Those grown under 2000 ft-c of illumination had a higher incidence of tumors and a significantly lower level of endogenous IAA than those grown under 500 ft-c of illumination. A correlation in time between decline in the endogenous level of IAA and onset of tumor formation was demonstrated in greenhouse-grown plants.     

Polyomavirus tumor induction in mice: influences of viral coding and noncoding sequences on tumor profiles.

We determined the DNA sequences of the noncoding regions of two polyomavirus strains that differ profoundly in their abilities to induce tumors in mice. Differences between strains were found, both on the late side of the replication origin in the region containing known enhancer elements and on the early side of the origin, affecting the number and location of large-T-antigen-binding sites. By constructing and analyzing recombinant viruses between these high- and low-tumor strains, we attempted to localize determinants which affect the frequency and histotype of tumors. Seven recombinants were constructed and propagated in vitro, and the tumor profile of each was established by inoculation into newborn C3H mice. Recombinants containing noncoding sequences from the high-tumor strain and coding sequences from the low-tumor strain behaved like the latter, inducing tumors at a low frequency and strictly of mesenchymal origin. Reciprocal recombinants with noncoding sequences of the low-tumor strain linked to structural determinants from the high-tumor strain induced several types of epithelial tumors typical of the high-tumor strain but at reduced frequency, in addition to mesenchymal tumors. A high frequency and full diversity of epithelial tumors required, in addition to structural regions from the high-tumor strain, noncoding sequences on the early side of the origin also present in this strain. A high-tumor profile thus resulted from the combined effects of structural and regulatory determinants in the high-tumor strain, with the former affecting primarily the tissue tropism and the latter affecting the frequency of tumors. No differential effects of the enhancer regions from the late side of the origin in the two virus strains were seen in this study.     

Leishmania major infection of inbred mice: unmasking genetic determinants of infectious diseases

Leishmania major infection of inbred mice leads to a major dichotomous response—death or survival—that depends on the strain of mice. This finding has motivated efforts to locate genetic determinants of disease susceptibility. Genotyping studies have confirmed a complex multilocus trait, but studies directed at the biology of the response suggest identifiable components of susceptibility that may direct the genetic investigations. A confluence of parasite variables—residence in macrophages, class II-dependent immunity, and avoidance of early IL-12 induction—with host factors—a prominent helper T-cell precursor frequency to a dominant parasite epitope and a bias in IL-4 gene activation—conspires to drive an aberrant immune response in animals that suffer fatal disease. These insights may lead to an understanding of factors that focus responses on dominant antigens and that mold the naive T-cell repertoire. Collectively, such factors might contribute to the pathogenesis of other infectious and autoimmune diseases. BioEssays 21:510–518, 1999. © 1999 John Wiley & Sons, Inc.     

Effect of DNA synthesis on induction of preneoplastic and neoplastic lesions in rat liver by a single dose of methylazoxymethanol acetate

A single intravenous injection of methylazoxymethanol (MAM) acetate in doses of either 20 or 35 mg/kg body weight to male Sprague-Dawley rats induced altered liver cell foci and later, liver neoplasms in a dose related manner. Sequential observations in the rats given 35 mg/kg and thereafter fed an iron-loading diet revealed that the number of iron-excluding foci/cm2 increased with time. Partial hepatectomy (PH) before the high dose of MAM acetate resulted in 100% lethality while hepatectomy before the low dose carcinogen exposure lead to a higher incidence of neoplasms than in rats that received carcinogen alone. PH after either high or low dose carcinogen exposure did not result in a greater occurrence of liver neoplasms.     

Allergic asthma: influence of genetic and environmental factors

Allergic asthma is a chronic airway inflammatory disease in which exposure to allergens causes intermittent attacks of breathlessness, airway hyper-reactivity, wheezing, and coughing. Allergic asthma has been called a "syndrome" resulting from a complex interplay between genetic and environmental factors. Worldwide, >300 million individuals are affected by this disease, and in the United States alone, it is estimated that >35 million people, mostly children, suffer from asthma. Although animal models, linkage analyses, and genome-wide association studies have identified numerous candidate genes, a solid definition of allergic asthma has not yet emerged; however, such studies have contributed to our understanding of the multiple pathways to this syndrome. In contrast with animal models, in which T-helper 2 (T(H)2) cell response is the dominant feature, in human asthma, an initial exposure to allergen results in T(H)2 cell-dependent stimulation of the immune response that mediates the production of IgE and cytokines. Re-exposure to allergen then activates mast cells, which release mediators such as histamines and leukotrienes that recruit other cells, including T(H)2 cells, which mediate the inflammatory response in the lungs. In this minireview, we discuss the current understanding of how associated genetic and environmental factors increase the complexity of allergic asthma and the challenges allergic asthma poses for the development of novel approaches to effective treatment and prevention.     

Importance of biochemical marker genes in inbred strains of mice. Some problems on checking genetic purity of inbred strains (author's transl)

In order to check genetic purity of inbred strains of mice, we surveyed five biochemical variants in certain 69 strains, some of which had established from Japanese fancy mice. The loci examined were Hemoglobin beta-chain, Malic enzyme (supernatant form), Isocitrate dehydrogenase (supernatant form), Serum esterase-1, and Serum esterase-2. These loci were all in homozygous states as far as examined, however some subline divergences were found in a few strains, that is to say, sublines were found to be fixed with different alleles as some loci, Important of biochemical marker genes to check genetic purity of strains and several derived problems are mentioned.     

Hormonal regulation of genetic tumor induction: Cytokinin and abscisic acid

Young seedlings of the tumor-prone amphiploid Nicotiana suaveolens? N. langsdorjfii were grown aseptically on nutrient mediumin a controlled environment chamber. At regular intervals theincidence of tumor formation was scored and plants were harvested.Total cytokinin activity was determined by means of the cucumbercotyledon bioassay, while ABA activity was measured by radioimmunoassay.A close correlation between onset of tumor formation and elevationin endogenous cytokinin activity was demonstrated, but no correlationwas observed between onset of tumorigenesis and change in thelevel of ABA. In addition, exposure of plants to exogenous ABAdid not alter therate of tumor formation. These results arediscussed in relation to the trigger mechanism for tumor inductionin the Nicotiana system. ¹A preliminary report of some of this work was presented atthe American Society of Plant Physiologists meeting in June1978. ³Present address: Department of Biology, West Virginia University,Morgantown, West Virginia 26506, U.S.A. (Received March 10, 1979; )     

Comparison of mouse mammary tumor virus-specific DNA in inbred, wild and Asian mice, and in tumors and normal organs from inbred mice.

The crystal and molecular structure of the dimer of variable domains of the Bence-Jones protein ROY has been determined by Patterson function search procedures, using the known structure of the protein REI. The structure has been partially refined at 3.0 Å resolution to a crystallographic R-factor value of 0.33. One of the 18 residues differentiating ROY from REI is the substitution of Tyr96 for Leu96, a substitution which makes the combining site of the ROY dimer larger. Substantial movement of Tyr49 suggests that point substitutions in the hypervariable segments may affect the conformation of neighbouring residues in the antigen-combining site, possibly producing differences in specificity larger than might otherwise be expected.     

Comparison of three inbred lines of mice by overall and genetic radiosensitivity

The radiosensitivities of three mouse strains (BALB/cLacY, C3H/SnY, and 101/HY) have been compared using the following parameters: survival after irradiation at a dose of 6-7 Gy, chromosome aberration frequency in bone marrow cells after irradiation at a dose of 1.5 Gy, and the change in testis weight and frequency of abnormal sperm heads (ASHs) after irradiation at doses from 0.5 to 4 Gy. Strain BALB/c is the most radiosensitive with respect to the survival and chromosome aberration frequency in the bone marrow but the most resistant with respect to the change in testis weight and the frequency of abnormal sperm heads. Strain 101/HY was the most resistant with respect to survival and chromosome aberration frequency in bone marrow after irradiation but the most radiosensitive with respect to testis damage.     

The genetic structure of recombinant inbred mice: high-resolution consensus maps for complex trait analysis

Background  

Recombinant inbred (RI) strains of mice are an important resource used to map and analyze complex traits. They have proved particularly effective in multidisciplinary genetic studies. Widespread use of RI strains has been hampered by their modest numbers and by the difficulty of combining results derived from different RI sets.     

Trichinella spiralis: genetic basis for differential expression of phase-specific intestinal immunity in inbred mice

Responsiveness of mouse strains after phase-specific immunization with Trichinella spiralis is compared. Two strains ($\text{NFR}\text{N, NFS/N}$) showed strong overall responsiveness. The response type could be characterized in phase-specific terms as: strongly anti-adult, weakly to moderately anti-preadult, and strongly antifecundity. By comparison, congenic mice of the C₅₇B1 $\text{10}\text{Sn}$ background (B10·A, B10·D₂, B10·S, B10·Q) displayed poor total responses that could be characterized as: weakly anti-adult, very weakly anti-preadult, weakly anti-fecundity after preadult immunization, and mixed (weak and strong) after adult immunization. The $\text{C}{}_3\text{H}\text{HeJ}$ mouse appeared to be intermediate between the B10·BR and the $\text{NFR}\text{N}$ strains in overall responsiveness. Genetic determinants of anti-preadult or anti-adult responses of $\text{NFR}\text{N}$ strain mice were dominant over their B10 congenic counterparts as shown in F₁, crosses of $\text{NFR}\text{N}$ × B1O·BR mice. Since the $\text{NFR}\text{N}$ (predominantly H-2^q) and the $\text{NFS}\text{N}$ (H-2^S) are both strong responders, while the B10·Q(H-2^q) and B10·S (H-2^S) are weak, it is suggested that the major genes controlling anti-preadult and anti-adult responses are not linked to the major histocompatibility complex. However, variations in anti-adult immunity and anti-fecundity in the B10 congenic mice (B10·Q and B10·S are the strongest responders) suggest that minor genes linked to the MHC exert some control over these responses. Some evidence was obtained for gene complementation as the F₁ cross of $\text{NFR}\text{N}$ and $\text{NFS}\text{N}$ mice responded more vigorously than the parental lines. We conclude that multiple genes determine anti-T. spiralis intestinal responses in mice. The major genes are unlinked to the major histocompatibility complex whereas several minor genes are linked.     

The genetic structure of recombinant inbred mice: High-resolution consensus maps for complex trait analysis

Background

Recombinant inbred (RI) strains of mice are an important resource used to map and analyze complex traits. They have proved particularly effective in multidisciplinary genetic studies. Widespread use of RI strains has been hampered by their modest numbers and by the difficulty of combining results derived from different RI sets.

Results

We have increased the density of typed microsatellite markers 2- to 5-fold in each of several major RI sets that share C57BL/6 as a parental strain (AXB, BXA, BXD, BXH, and CXB). A common set of 490 markers was genotyped in just over 100 RI strains. Genotypes of another ~1100 microsatellites were generated, collected, and error checked in one or more RI sets. Consensus RI maps that integrate genotypes of ~1600 microsatellite loci were assembled. The genomes of individual strains typically incorporate 45-55 recombination breakpoints. The collected RI set - termed the BXN set - contains approximately 5000 breakpoints. The distribution of recombinations approximates a Poisson distribution and distances between breakpoints average about 0.5 cM. Locations of most breakpoints have been defined with a precision of < 2 cM. Genotypes deviate from Hardy-Weinberg equilibrium in only a small number of intervals.

Conclusions

Consensus maps derived from RI strains conform almost precisely with theoretical expectation and are close to the length predicted by the Haldane-Waddington equation (X3.6 for a 2-3 cM interval between markers). Non-syntenic associations among different chromosomes introduce predictable distortions in QTL data sets that can be partly corrected using two-locus correlation matrices.