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PubMed1983

The effect of two chemical mutagens ENU and MMS on MR-mediated reversion of an insertion-sequence mutation in Drosophila melanogaster.

The effects of two mutagens ENU and MMS characterized by different alkylation patterns have been studied on the reversion of an MR-induced singed mutation to wild-type. Reversion of this unstable singed mutation under the influence of MR is assumed to represent the removal or transposition of an insertion element. Since MR acts primarily in spermatogonia, the mutagens were fed to 1st instar larvae. Recessive lethal tests were carried out simultaneously to calibrate for the mutagenic effectiveness of the chemicals. For both powerful mutagens, it was observed that the frequency of reversion remained far below of what would have been expected on the basis of the mutagenic effectiveness, as registered in the lethal tests. Thus 1 mM ENU, 5 mM and 10 mM MMS did not affect the reversion frequency at all, and with 3 mM ENU only a doubling of the reversion frequency was observed, despite a 5-fold increase in the lethal frequency. The threshold at 1 mM EMU and the low effectiveness of 3 mM on the reversion process are taken as an indication that ENU affected the transposition process in an indirect manner, rather than the excision events themselves. The data obtained with Drosophila are consistent with the microbial observations in that mutation involving removal or transposition of an insertion element is not affected by mutagenic treatments. This finding may have consequences for the evaluation of induced genetic damage on the basis of the spontaneous load of genetic detriment in man. An incidental observation was that non-MR Cy larvae exhibited greater sensitivity to the induction of recessive lethals by MMS than MR-individuals.

Animals↗
PubMed1993

[Detection of risk factors for hemodynamic dysadaptation under physical loading by data of genetic studies (echocardiography data) (Part 2)].

Examination in 28 pairs of twins who were studied by echocardiography just after their performance of exercise (Stage I) and at the peak of effects produced by oral anapriline (Stage II) have shown that at rest such parameters as end-systolic volume, ejection fraction, relative changes in the internal dimension of the left ventricular cavity during a cardiac cycle, show moderate-to-high genetic predisposition. At the same time, a persistent contribution of heredity to myocardial contractility is found only for end-systolic volume when the conditions of the examination were changed. The lesser extent to which contractility parameters had hereditable signs, the more intensively they varied under different conditions. It is assumed that the contraction rate of circulatory myocardial fibers is less resistant to environmental factors. A significant decrease in this parameter during anapriline administration allows one to suppose that cardiac decompensation in patients with coronary heart disease starts with damages to the very myocardial circulatory muscles.

Adaptation, Physiological↗
PubMed1993

[Detection of risk factors for hemodynamic dysadaptation under physical loading by data of genetic studies (the beta-adrenoreceptor blockade test) (Part 3)].

Examinations in 28 pairs of twins who were studied by bicycle ergometry during a "pure" graded exercise and an exercise during oral administration of anapriline have shown that the functional features of the heart make some contribution to cardiovascular implementation of the "pure" graded exercise. When given exercise and anapriline, energy processes play a role in its implementation. It is suggested that exercise + anapriline will cause substantial metabolic changes which can be essential in cardiac decompensation if exercise is not limited in the use of beta-blockers.

Adaptation, Physiological↗
PubMed2003

Vascular risk and genetics of sporadic late-onset Alzheimer's disease.

In recent years, it is becoming apparent that genes may play an important role in the development of late-onset Alzheimer's disease (LOAD), and genetic studies could unravel new clues. Based on a growing vascular hypothesis for the pathogenesis of LOAD and other dementias, there is increasing interest for environmental and genetic vascular factors. Polymorphisms in different susceptibility genes already implicated in vascular disease risk are now also being suggested as possible genetic markers for increased risk of developing LOAD; however, many of these studies have shown conflicting results. Thus far, the apolipoprotein E (APOE) gene seems to be the only vascular susceptibility factor that is agreed to play a role in the multifactorial pathogenesis of AD although emerging genetic and biological evidence is now strengthening the case for additional inclusion of angiotensin I-converting enzyme 1 (ACE1) into this category. This review will focus on the current knowledge on genetic and nongenetic vascular factors likely to be involved in LOAD, with special emphasis placed on the APOE and ACE1 genes.

Age of Onset↗
PubMed2003

Epistasis in polygenic traits and the evolution of genetic architecture under stabilizing selection.

We consider the effects of epistasis in a polygenic trait in the balance of mutation and stabilizing selection. The main issues are the genetic variation maintained in equilibrium and the evolution of the mutational effect distribution. The model assumes symmetric mutation and a continuum of alleles at all loci. Epistasis is modeled proportional to pairwise products of the single-locus effects. A general analytical formalism is developed. Assuming linkage equilibrium, we derive results for the equilibrium mutation load and the genetic and mutational variance in the house of cards and the Gaussian approximation. The additive genetic variation maintained in mutation-selection balance is reduced by any pattern of the epistatic interactions. The mutational variance, in contrast, is often increased. Large differences in mutational effects among loci emerge, and a negative correlation among (standard mean) locus mutation effects and mutation rates is predicted. Contrary to the common view since Waddington, we find that stabilizing selection in general does not lead to canalization of the trait. We propose that canalization as a target of selection instead occurs at the genic level. Here, primarily genes with a high mutation rate are buffered, often at the cost of decanalization of other genes. An intuitive interpretation of this view is given in the discussion.

Epistasis, Genetic↗
PubMed1992

[Hereditary pathology load of the population and regional medical-genetic counseling].

Analysis of hereditary disease load of the populations with different genetic structure has demonstrated the necessity of a regional approach to the organization of the medico-genetic aid to the community. It has been shown that in Central Asia, the requirement of the medico-genetic aid is almost 2 times higher than in the Russian Federation. Bearing in mind the age-associated reproduction data, those differences are three times as higher. To make the work of the medico-genetic consultations more efficient, it is necessary to increase the portion of prospective counselling at the expense of an active approach to identifying patients in the populations.

Adult↗
PubMed2002

Molecular characterization of cytoplasmic and nuclear genomes in phenotypically abnormal Valencia orange (Citrus sinensis) + Meiwa kumquat (Fortunella crassifolia) intergeneric somatic hybrids.

Organelle DNA inheritance of four 10-year-old somatic hybrid trees between Valencia orange [Citrus sinensis (L.) Osbeck] and Meiwa kumquat (Fortunella crassifolia Swingle) was analyzed by cleaved amplified polymorphic sequence (CAPS) and restriction fragment length polymorphisms (RFLPs). Five chloroplast (cp) and three mitochondrial (mt) universal primer pairs were amplified, but no polymorphisms were detected. When the polymerase chain reaction products were digested by 15 restriction enzymes, four polymorphic cpDNA-CAPS and two mtDNA-CAPS markers were found. Both the cpDNA and mtDNA in the somatic hybrids were derived from Valencia orange (the embryogenic suspension parent). Genomic DNA of the somatic hybrids and corresponding parents was digested by five restriction endonucleases and hybridized with one chloroplast probe (RbcL- RbcL) and nine mitochondrial probes (coxI, coxII, c oxIII, c ob, atpA, tyr, proI, atp6 and atp9). The results indicated that three hybrid plants shared one strong cpDNA band with both parents and that the remaining one plant had two additional novel bands besides the shared band, while their mtDNA was identical to that of Valencia orange plus non-parental bands. When data on the mtDNA banding patterns were combined with observations on phenotypic performance in the field, it was found that the more complex mtDNA banding pattern coincided with increased vigor of the plant. The stability of the organelle genomes was studied by extracting the genomic DNA of one hybrid plant at monthly intervals for 1 year and then analyzing it using RFLPs. Before the dieback of the shoots, two fragments of the mtDNA were lost while the cpDNAs remained stable. Ploidy analysis by flow cytometry showed that all of the hybrids were stable tetraploids. Four simple sequence repeat primer pairs were applied to detect microsatellite alleles of the four hybrid plants, both parents and the 12 DNA samples from one plant. The results showed that all hybrids had biparental bands uniformly, which indicated that they had the same nuclear background. These results suggest that the mtDNA pattern is correlated with the phenotypic abnormality of Valencia and kumquat somatic hybrid plants and that nuclear-cytoplasm incompatibility may be the cause of dieback.

Cell Nucleus↗
PubMed1987

Genetic polymorphism and high detrimental load in natural populations of Drosophila melanogaster from cellar and vineyard.

Two Spanish natural populations of Drosophila melanogaster have been analysed with respect to genetic variability in third chromosome viability. The two populations, although from the same locality, belong to relatively different habitats: the inside of a cellar and a vineyard. The patterns of homozygote and heterozygote viability are similar in both populations. The homozygous detrimental loads estimated are very high and the values for the D:L (detrimental/lethal) ratio close to 2.5, which is higher than any previously found. The environmental variance of viability, average degrees of dominance of lethal genes and of viability polygenes and effective population sizes were estimated in each population. The mechanisms which could maintain variability in these populations, the causes of the high detrimental loads and the possibility that cellar and vineyard could be two subpopulations of a larger population are discussed.

Animals↗
PubMed2002

Deleterious mutations in a hybrid zone: can mutational load decrease the barrier to gene flow?

The aim of this paper is to investigate the effect of deleterious mutations in a hybrid zone maintained by selection against hybrids. In such zones, linkage disequilibria among hybrid depression loci, resulting from a balance between migration and selection, are crucial in maintaining the barrier because they allow each locus, in addition to its own selection coefficient, to cumulate indirect selective effects from other loci. Deleterious alleles produce heterosis and increase by this means the effective migration rate in structured populations. In a hybrid zone, they therefore contribute to decrease linkage disequilibria as well as the barrier to gene flow imposed by hybrid depression. However, deleterious mutations have no effect: (i) when selection against hybrids is weak, because linkage disequilibria are small even without heterosis in this case, or (ii) when selection against hybrids is so strong that it overwhelms heterosis. On the other hand, with moderate selection against hybrids, the decrease in the strength of the barrier due to heterosis may reach detectable levels, although it requires relatively small population sizes and/or migration rates. The effect is expected to be small and only within small genomes where loci are tightly linked can it become strong. Nevertheless, neglecting mutational load may to some extent obscure the estimations of selective parameters based either on artificial F1 crosses or on cline characteristics.

Computer Simulation↗
PubMed2006

Error processing in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a genetic disorder expressed by a degeneration of the basal ganglia inter alia accompanied with dopaminergic alterations. These dopaminergic alterations are related to genetic factors i.e., CAG-repeat expansion. The error (related) negativity (Ne/ERN), a cognitive event-related potential related to performance monitoring, is generated in the anterior cingulate cortex (ACC) and supposed to depend on the dopaminergic system. The Ne is reduced in Parkinson's Disease (PD). Due to a dopaminergic deficit in HD, a reduction of the Ne is also likely. Furthermore it is assumed that movement dysfunction emerges as a consequence of dysfunctional error-feedback processing. Since dopaminergic alterations are related to the CAG-repeat, a Ne reduction may furthermore also be related to the genetic disease load. METHODOLOGY/PRINCIPLE FINDINGS: We assessed the error negativity (Ne) in a speeded reaction task under consideration of the underlying genetic abnormalities. HD patients showed a specific reduction in the Ne, which suggests impaired error processing in these patients. Furthermore, the Ne was closely related to CAG-repeat expansion. CONCLUSIONS/SIGNIFICANCE: The reduction of the Ne is likely to be an effect of the dopaminergic pathology. The result resembles findings in Parkinson's Disease. As such the Ne might be a measure for the integrity of striatal dopaminergic output function. The relation to the CAG-repeat expansion indicates that the Ne could serve as a gene-associated "cognitive" biomarker in HD.

Adult↗
PubMed2004

Sheltered load associated with S-alleles in Solanum carolinense.

Bud pollinations allowed me to examine the effects of homozygosity at loci in the area of suppressed recombination around the S-locus in Solanum carolinense, whose S-alleles show surprisingly low diversification rates. The total number of seeds produced was lower for incompatible than compatible pollinations, revealing that self-incompatibility was only somewhat overcome by bud pollination. However, low seed set in incompatible crosses was not due solely to the incompatibility response; crosses between distinct plants sharing the same alleles at the S-locus led to dramatically high seed abortion, nearly equal to that found upon selfing. An excess of heterozygotes in the surviving progeny supports the supposition that these high abortion rates are due to sheltered load, that is, previously unexpressed load accumulated due to enforced heterozygosity and recombination suppression around the S-locus. Of the seven alleles examined in total, two showed evidence of severe load and five did not. The magnitude of load was consistent with terminal branch length in some, but not all, cases.

Alleles↗
PubMed2002

Association between the TNFalpha-308 A/G polymorphism and the onset-age of Alzheimer disease.

Local inflammatory processes associated with amyloid plaques would contribute to the progression of late-onset Alzheimer disease (LOAD). Tumor necrosis factors alpha (TNF(alpha)) and beta (LT(alpha)) are inflammatory cytokines involved in the local immune response occurring in the central nervous system of LOAD patients. Genetic variation at these genes could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 315 LOAD patients and 400 healthy controls for DNA-polymorphisms in the genes encoding TNF(alpha) (-308 G/A, -238G/A) and LT(alpha) (Asn26Thr). Carriers of -308A showed a mean age at onset 3 years younger than noncarriers of this allele (P = 0.019). Our data suggest an effect of the TNF(alpha)-308 polymorphism on the age at onset of late AD. This represents additional evidence of the importance of genetic variation at the proinflammatory components in the origin and progression of this common neurodegenerative disease.

Age of Onset↗
PubMed1990

Psychoticism as a dimension of personality: a multivariate genetic test of Eysenck and Eysenck's psychoticism construct.

In this study, we applied multivariate genetic analysis, a generalization of factor analysis and behavior genetic analysis, to responses to items of the Psychoticism scale of the Eysenck Personality Questionnaire by 2,903 adult same-sex Australian twin pairs. Item loadings on genetic, shared environmental, and nonshared environmental common and specific factors were estimated. The genetic factor structure differed considerably from the environmental structures, particularly in men. The genetic correlation between suspiciousness items and items reflecting unconventional or tough-minded attitudes or hostility to others was negative, but the environmental correlation was positive. Thus, conventional behavior genetic studies that have reported significant heritability of psychoticism, on the basis of analyses of scale scores, are misleading as to what trait is being inherited.

Adult↗
PubMed2003

Determinants of increased replicative capacity of serially passaged simian immunodeficiency virus with nef deleted in rhesus monkeys.

Most rhesus macaques infected with simian immunodeficiency virus SIVmac239 with nef deleted (either Delta nef or Delta nef Delta vpr Delta US [Delta 3]) control viral replication and do not progress to AIDS. Some monkeys, however, develop moderate viral load set points and progress to AIDS. When simian immunodeficiency viruses (SIVs) recovered from two such animals (one Delta nef and the other Delta 3) were serially passaged in rhesus monkeys, the SIVs derived from both lineages were found to consistently induce moderate viral loads and disease progression. Analysis of viral sequences in the serially passaged derivatives revealed interesting changes in three regions: (i) an unusually high number of predicted amino acid changes (12 to 14) in the cytoplasmic domain of gp41, most of which were in regions that are usually conserved; these changes were observed in both lineages; (ii) an extreme shortening of nef sequences in the region of overlap with U3; these changes were observed in both lineages; and (iii) duplication of the NF-kappa B binding site in one lineage only. Neither the polymorphic gp41 changes alone nor the U3 deletion alone appeared to be responsible for increased replicative capacity because recombinant SIVmac239 Delta nef, engineered to contain either of these changes, induced moderate viral loads in only one of six monkeys. However, five of six monkeys infected with recombinant SIVmac239 Delta nef containing both TM and U3 changes did develop persisting moderate viral loads. These genetic changes did not increase lymphoid cell-activating properties in the monkey interleukin-2-dependent T-cell line 221, but the gp41 changes did increase the fusogenic activity of the SIV envelope two- to threefold. These results delineate sequence changes in SIV that can compensate for the loss of the nef gene to partially restore replicative and pathogenic potential in rhesus monkeys.

Amino Acid Sequence↗
PubMed1997

Gender-specific regional changes in genetic structure of muscularity in early adolescence.

Genetic and environmental influences on muscle circumference measurements of the extremities were estimated in 105 pairs of twins between 10 and 14 yr of age. Four circumferences, extended upper arm (EAC), forearm (FC), thigh (TC), and calf (CC), were measured. Univariate model fitting revealed that the largest part (87-95%) of the variance for all circumferences at most ages was explained by additive genetic factors. Sex differences were observed for some age categories. Multivariate analyses showed a different pattern evolving according to age and gender. In boys from 10 to 12 yr of age, one general genetic factor influenced all four circumferences. With increasing age, an arm-leg model emerged, one genetic factor influencing the arm and another genetic factor the leg circumferences. In young girls one genetic factor loaded on the proximal (EAC, TC) and another on the distal (FC, CC) circumferences. With subjects at age 14 yr, an arm-leg model was observed. High genetic correlations indicated that genetic factors related to EAC, FC, TC, and CC did not act independently. The age-and gender-specific changes in the genetic structure suggest pubertal influences. This study shows that muscle circumferences are highly heritable characteristics and are therefore a promising starting point at which to locate their genes. Gene mapping could validate the gender-specific change of the genetic structure with age and region.

Adolescent↗
PubMedDate not supplied

HIV viral load quantification, HIV resistance, and antiretroviral therapy.

We are moving rapidly beyond a "black box" understanding of the pathogenesis of HIV. The sites of virus replication, the molecular regulation of virus production in the host, and the dynamics between productive virus infection and immunological and clinical events are areas of intense study using powerful new tools. The quantitation of virus load and genetic characterization of replicating virus has important implications for the development and evaluation of drugs and treatment strategies for HIV. As new compounds are introduced, their ability to reduce virus load in vivo has become a primary consideration in the decision to initiate large efficacy trials and may soon be used, in combination with other markers, in the licensing of new agents. In parallel, rapid molecular evaluation of virus from patients, targeting those who break through drug-induced suppression, provides an explanation for the failure of drugs to sustain an effect on virus load. This approach has compressed the process of drug evaluation and set the stage for the evaluation of complex combinations and sequences of drugs to maintain suppression of virus and prevent the development of drug resistance. The most controversial question for the next few years is whether the measurement of virus load or detection of drug resistance can be incorporated into the practice of medicine and the management of individual patients. There is evidence that changes in virus load are the most proximate markers of drug response and that detection of resistance mutations can predict clinical and immunological decline. However, the window of time between a change in load or the development of drug resistance and a decline in CD4 cells is relatively short. With dideoxynucleoside therapies, a CD4 cell decline follows a rise in virus load or development of resistance within 3-6 months. In early studies with protease inhibitors and nonnucleoside reverse transcriptase inhibitors, the development of resistance and a return to baseline of virus load may occur within 2-3 months, mirrored by a fall in CD4 cells. The challenge to investigators is how to best use these new tools to determine whether changes or additions in therapy, initiated on the basis of virological measurements, result in more effective management of disease.

Antiviral Agents↗
PubMed1998

Regulation of renal alpha 2-adrenoceptor activity in Dahl salt-sensitive rats by dietary sodium changes.

The objective of the study was to evaluate the concept that genetically predisposed salt-sensitivity contributes to an increased adrenergic susceptibility and renal alpha 2-adrenoceptor (A2) abnormality in Dahl salt-sensitive hypertensive rats. The results showed: i) After 2 months of Na-loading (8% NaCl) Dahl salt-sensitive (DSS) rats expressed increased sodium and water retention which paralleled gradual development of diastolic hypertension. Low Na diet (0.5% NaCl) does not prevent hypertension but delays its development. ii) The increased activity of the sympathetic nervous system (SNS), in DSS rats corresponded to the development of hypertension and was stimulated by Na-loading. It was assessed by plasma catecholamine levels and heart rate changes. iii) The increased density of renal A2 by 29% was upregulated by high sodium diet, and coupled with increased norepinephrine level by 53%, only in DSS but not in DSR rats. iv) No strain renal A2 and epinephrine differences between DSS and DSR were found in weanling, prehypertensive rats, or in the adult DSS and DSR on low Na diet. By mediating an enhanced receptor-coupled response, such as increased proximal tubular sodium reabsorption during sodium loading, a genetic abnormality of renal alpha 2-adrenoceptors may contribute to some of the pathophysiologic derangements leading to hypertension in Dahl salt-sensitive rats.

Animals↗