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Intracellular recordings were made from neurones of the rat locus coeruleus (LC) which were located in a slice of pons superfused in vitro. Opioid agonists and antagonists were applied by adding them to the superfusing solution; normorphine and enkephalin analogues were also applied by ejecting a few nanoliters of a solution which contained the drugs from a pipette situated above the tissue slice. Opioid agonists hyperpolarized LC neurones. This has been shown previously to result from an increase in the membrane potassium conductance. The lowest concentration of normorphine which was effective was 30 nM, the EC50 was 1 microM, and the maximum effect was observed with 30 microM. The irreversible antagonist beta-funaltrexamine (beta-FNA) was used to estimate the dissociation equilibrium constants; these ranged from 9-16 microM for normorphine and [Met5]enkephalin and was about 2 microM for [D-Ala2,D-Leu5]enkephalin. beta-FNA also blocked the hyperpolarization caused by [D-Ala2,D-Leu5]enkephalin, ethylketacyclazocine, and [D-Ser2,D-Leu5] enkephalin-Thr. Naloxone reversibly antagonized the hyperpolarizations caused by normorphine and [D-Ala2,D-Leu5]enkephalin, with a dissociation equilibrium constant of 2 nM. It is suggested that the opioid hyperpolarization of LC neurones is mediated by a receptor having a high affinity for naloxone, previously termed a mu-receptor. The affinity of this receptor for normorphine appears to be 3 to 4 orders or magnitude lower than its affinity for naloxone.
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Specific features of serotonin (5-hydroxytryptamine, 5-HT) metabolism were studied in the brain of mutant sapphire minks, homozygous at genes determining silver-blue and Aleutian fur color (ppaa), and silver-blue minks (pp) in comparison with the standard-colored minks (++/++). In the midbrain of sapphire mutants, the activities of tryptophan hydroxylase (TPH) and monoamine oxidase (MAO), key enzymes of 5-HT biosynthesis and catabolism, were significantly higher; an increase in the 5-HT level was statistically nonsignificant due to considerable variation in this parameter; and the level of 5-hydroxyindole-3-acetic acid remained unchanged. A similar increase in TPH and MAO activities was also found in the midbrain of silver-blue pp minks, suggesting that activation of key enzymes of 5-HT metabolism in sapphire aapp minks is associated with the mutant alleles pp.
Individuals genetically predisposed to cancer may be more sensitive to cancers induced by ionizing radiation than those who are not so predisposed. Should this be true, under conditions of radiation exposure, a population consisting of cancer-predisposed and non-predisposed individuals will be expected to respond with a higher total frequency of induced cancers than one in which all the individuals are assumed to have the same sensitivity to radiation-induced cancers. To study this problem quantitatively, we have developed a Mendelian autosomal one-locus, two-allele model; this model assumes that one of the alleles is mutant and the genotypes carrying the mutant allele(s) are cancer-predisposed and are also more sensitive to radiation-induced cancer. Formal analytical predictions as well as numerical illustrations of this model show that: (1) when such heterogeneity with respect to cancer predisposition and radiosensitivity is present in the population, irradiation results in a greater increase in the frequency of induced cancers than when it is absent; (2) this increase is detectable only when the proportion of cancers due to genetic predisposition is large and when the degree of predisposition is considerable; and (3) even when the effect is small, most of the radiation-induced cancers will occur in predisposed individuals. These conclusions are valid for models of cancer when predisposition and radiosensitivity may be either dominant or recessive. The published data on breast cancers in Japanese A-bomb survivors show that at 1 Sv, the radiation-related excess relative risk in women irradiated before age 20 is 13 compared to about 2 for those irradiated at later ages. We examined the application of our model to the above data using two assumptions, namely, that the proportion of cancers due to genetic susceptibility at the BRCA1 locus (1/200) and the frequency of the mutant allele (0.0033) estimated for Western populations are valid for Japanese women. With our model, these results can be explained only if there are very large differences in cancer susceptibility (> 1000-fold) and radiosensitivity (> 100-fold) of the heterozygotes.
The aim of the work was to analyse some regularities of correlative variability of qualitative and quantitative characters. The simplest classical model of quantitative character was used for study of the dependence of mean (X) and variance (V) of quantitative character on the genotypic composition of the group, on peculiarities of alleles relations with quantitative character and on the allele frequencies (q). Two types of the genotypic groups were discriminated: homogeneous and heterogeneous ones. In homogeneous groups V = 0; X and V are independent of the q. In heterogeneous ones V > 0 and both of X and V depend of the q. Specific contribution of additive and dominant allelic effect on the group genotypic composition and also on the q. It is possible to determine the expected value of X and V for any group of known genotypic composition on the base of data calculated from direct measures of individuals in the sample. The expected differences of variances in homogeneous group of heterozygotes and heterogeneous ones of homozygotes (1/1 + 2/2) become significant since expected genotypic variance of last group is equal or more than 0.4VE, where VE--nongenotypic variance. The need of taking into consideration expected X and V under comparing quantitative character in groups with different genotypic compositions is discussed.
The peculiarities of dopamine metabolism and dopamine receptors in the brain of homozygous silver-blue (pp) minks were examined in comparison with wild-type (PP) minks. A pp mutation was found to affect the dopamine turnover in corpus striatum, which is one of the major dopaminergic brain structures. In silver-blue minks, increased dopamine catabolic enzyme activity monoamine oxidase type B (MAO B), together with the decreased level of dopamine and the tendency for the level of the metabolite 3,4-dihydrophenyl acetic acid to increase, were demonstrated in this brain region. No significant alterations in the level of another dopamine metabolite, homovanillic acid, or in D1 and D2 receptor density were shown. In the midbrain and hippocampus, an elevated level of MAO B activity was detected. We found no modifications in receptor properties, nor in dopamine turnover in a mesolimbic dopamine structure, the nucleus accumbens. We propose that the primary effect of pp mutation is an increase in MAO B activity resulting in dopamine turnover alterations and probably in dopamine-dependent behavior (pleiotropic cascade).
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BACKGROUND: Essential (multigenic) hypertension is a complex multifactorial disease whose genetic etiology has not been unraveled on a major locus-effect investigative paradigm. As with other complex genetic diseases, applying an interacting loci paradigm could be critical in the elucidation of genetic determinants. Having defined the alpha1 Na,K-ATPase (alpha1NK) as a hypertension susceptibility gene in Dahl salt-sensitive (Dahl S) rats, we determined whether alphaINK interacts with another renal epithelial Na transporter to increase susceptibility to salt-sensitive hypertension. We focused on alpha1NK and Na,K,2Cl-cotransporter (NKC) as an a priori candidate interacting gene pair because they comprise a functionally linked Na transport system in renal thick ascending limb of Henle (TALH) epithelial cells and exhibit altered function in prehypertensive Dahl S rats in contrast to Dahl salt-resistant normotensive (Dahl R) rats. MATERIAL AND METHOD: Cosegregation analysis of alphaNK and NKC loci was done in a (Dahl S x Dahl R) F2 cohort characterized for blood pressure by radiotelemetry using the D2mghII microsatellite marker in the alpha1NK gene and the D3mit3 microsatellite marker close to the NKC gene (NKC/D3mit3 locus). Single locus and digenic analyses were performed to establish the individual and interactive genetic contribution to salt-sensitive hypertension. Molecular analysis was then done to support the NKC gene as the likely candidate gene interacting with alpha1NK in Dahl salt-sensitive hypertension pathogenesis. RESULTS: Compared with respective single locus analysis, digenic analysis of 96 F2 (Dahl S x Dahl R) hybrid male rats revealed cosegregation of alpha1NK and NKC/D3mit3 loci as interacting pair with salt-sensitive hypertension with markedly increased significance for systolic (one-way ANOVA p = 10(-6)), diastolic (p = 10(-5)), and mean arterial (p = 10(-6)) blood pressures. Concordantly, two-way ANOVA detected interaction between alpha1NK and NKC loci in determining the levels of systolic (p = 0.004), diastolic (p = 0.008), and mean arterial (p = 0.006) pressures. To unravel potential NKC molecular dysfunction(s) involved in hypertension pathogenesis, we investigated putative differences between Dahl S and Dahl R rats in nucleotide sequence and isoform gene expression of the renal-specific Na,K,2Cl-cotransporter. Molecular analysis revealed an inversion of alternatively spliced NKC-isoform ratios (4B:4A:4F) between Dahl S and Dahl R prehypertensive kidneys supported by four mutations in intron-3 immediately upstream to alternatively spliced exons 4B, 4A, and 4F. No nucleotide changes were detected within the aminoacid encoding exons of NKC. CONCLUSIONS: Altogether, these current data and previous characterization of the role of the Q276L alpha1NK molecular variant in Dahl S hypertension provide cumulative compelling evidence that alpha1NK and NKC/D3mit3 loci interact to increase susceptibility to hypertension in Dahl S rats and that NKC is the likely candidate gene that interacts with alpha 1NK. More importantly, the data substantiate gene interaction as an operative mechanism in multigenic hypertension.
A single major locus model of inheritance that incorporates polarity (bipolar-unipolar distinction) and sex effect was applied to family study data on bipolar and unipolar affective disorders. In the model tested, clinical polarity and sex-related thresholds determined a differential liability to major affective illness, whereby unipolar females and bipolar males represented two extremes on a genetic-environmental continuum. Bipolar males were more deviant, and unipolar females were less deviant genetically than bipolar females and unipolar males. The major locus hypothesis did not provide an acceptable fit to the data. The implications of these findings for genetic and biological research in affective disorders are discussed.
The large number (59) of alleles now known at the HLA-A locus is a serious challenge to the existing methods for HLA typing, including many of the DNA based methods. Here, we describe a sequencing-based typing (SBT) protocol for typing of HLA-A alleles using a single A-locus-specific PCR. This reaction amplifies an 824 base pair product from cDNA, prepared from mRNA, covering exons 1-3 and most of exon 4. This product allows identification of all possible combinations of two alleles from this locus. The sequencing strategy used for allele assignment contains several improvements compared to those previously published. The enzyme AmpliTaq DNA Polymerase, FS, used, combines high-quality sequencing, i.e. long reads, low background, and uniform peak heights making the identification of heterozygous positions very reliable in a fast and easy protocol developed by determining the optima for a number of variables. Thus, this strategy meets most of the requirements for the use of sequencing in HLA typing. Furthermore, this method is very flexible. The use of a PCR primer-pair tailed with the recognition sites for two different sequencing primers allows the application of the same sets of fluorescent-labelled sequencing primers regardless of the amplified locus. Thus, the protocol can very easily be extended to cover the B- and C-locus too, simply by adding PCR reactions specific for these loci to the protocol. Using this protocol, we investigated a total of 65 cell lines and clinical samples, many of the latter chosen from samples difficult to type by serology. Our method gave in all cases unambiguous results and proved functional for work requiring the highest resolution.
There are 512 two-locus, two-allele, two-phenotype, fully penetrant disease models. Using the permutation between two alleles, between two loci, and between being affected and unaffected, one model can be considered to be equivalent to another model under the corresponding permutation. These permutations greatly reduce the number of two-locus models in the analysis of complex diseases. This paper determines the number of nonredundant two-locus models (which can be 102, 100, 96, 51, 50, or 58, depending on which permutations are used, and depending on whether zero-locus and single-locus models are excluded). Whenever possible, these nonredundant two-locus models are classified by their property. Besides the familiar features of multiplicative models (logical AND), heterogeneity models (logical OR), and threshold models, new classifications are added or expanded: modifying-effect models, logical XOR models, interference and negative interference models (neither dominant nor recessive), conditionally dominant/recessive models, missing lethal genotype models, and highly symmetric models. The following aspects of two-locus models are studied: the marginal penetrance tables at both loci, the expected joint identity-by-descent (IBD) probabilities, and the correlation between marginal IBD probabilities at the two loci. These studies are useful for linkage analyses using single-locus models while the underlying disease model is two-locus, and for correlation analyses using the linkage signals at different locations obtained by a single-locus model.
Restriction fragment length polymorphisms (RFLPs) have been developed for an adult human skeletal muscle myosin heavy chain gene which was previously mapped to the short arm of human chromosome 17. Using RFLP analysis of DNA from 140 individuals, we have found tight linkage (LOD score of 6.9) between this myosin heavy chain gene and the anonymous DNA probe, D17S1.
A stepwise oligogenic method is developed that can be used to adjust the phenotype of a quantitative trait for the effects of a previously identified single-locus component. This method assumes that a single-locus component can be adequately identified through the use of segregation and/or linkage analysis under a 1-locus model and that the variation due to that locus can be removed from the phenotype leaving a residual that can be parameterized in terms of an additional single-locus component. Segregation and/or linkage analysis can then be used in an attempt to identify an additional single-locus component in the residual phenotype. This stepwise process can be repeated until no further single-locus effects are identified. The method is illustrated using family data on the specific activity of dopamine-beta-hydroxylase (DBH), which a number of studies have suggested may be due either to the combined effects of single-locus and multifactorial components or to the combined effects of 2 loci.
Development of a real-time quantitative TaqMan PCR assay permits the high-quality analysis of DNA or RNA. This study demonstrates the successful detection of single locus genes from single NRBCs, retrieved by micromanipulation of cells on a blood smear slide. Quantitative data in relation to the concentration of a single locus DNA amplified by PEP from a single NRBC are also provided. In summary, a PEP-TaqMan system can potentially be a powerful tool for noninvasive fetal DNA diagnosis through the use of maternal blood.