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The genetics of aging in Drosophila are reviewed under the separate headings of population genetics, physiological genetics, and molecular genetics. However, connections between these sub-fields are brought forward for discussion.
Myopia is the most common disorder of visual function in many literate populations, affecting 70% of some specific groups. The causes may lie in genetic or environmental factors. This article discusses the arguments put forward to support of the biological and environmental theories of the cause of myopia. It is argued that the biological theory has never been proven empirically and that the evidence clearly points to the role of close-range work in the prevalence of myopia as a massdisease. Primary prevention is difficult in this situation and compensatory strategies (relaxation, eye exercises) are rather ineffective. Prevention strategies are discussed and a research program to evaluate their effectiveness and efficiency is proposed.
As the 21st century moves forward, it is becoming more and more apparent that the genetic makeup of any individual strongly influences the way they metabolise nutrients. It is very important, therefore, to understand the techniques and technologies used to assess the contribution genes make to the physiology of an individual. Clearly, it is not possible to provide a comprehensive overview, but in the present review an attempt will be made to show, using examples from the authors' research, how these methods have contributed to this understanding. Studies are being undertaken into Fe transport across the placenta, from the mother to the fetus, and the consequences of maternal anaemia on pregnancy outcome. Levels of gene transcript and protein have been measured using Northern and Western blotting respectively. During the course of this work a new protein has been identified using the available human genome database. Following this 'in silico' or 'cyber biology', techniques such as real-time RT-PCR and RNA interference have been used to examine expression of this gene and its protein. The methods used, briefly how they work and some of their limitations will be explained. The objective of the present review is primarily to give a better perception of how molecular biology can be used in research and to help gain a clearer understanding of some of the techniques used.
This paper describes a mutator system in the nematode Caenorhabditis elegans var. Bergerac for the gene unc-22. Of nine C. elegans and two C. briggsae strains tested only the Bergerac BO strain yielded mutant animals at a high frequency and the unc-22 IV gene is a preferred mutational target. The forward spontaneous mutation frequency at the unc-22 locus in Bergerac BO is about 1 X 10(-4), and most of these spontaneous unc-22 mutations revert at frequencies between 2 X 10(-3) and 2 X 10(-4). Both the forward mutation frequency and the reversion frequency are sensitive to genetic background. Spontaneous unc-22 mutations derived in a Bergerac background and placed in a primarily Bristol background revert at frequencies of less than 10(-6). When reintroduced into a Bergerac/Bristol hybrid background the mutations once again become unstable. The mutator activity could not be localized to a discrete site in the Bergerac genome. Nor did mutator activity require the Bergerac unc-22 gene as a target since the Bristol unc-22 homolog placed in a Bergerac background also showed high mutation frequency. Intragenic mapping of two spontaneous unc-22 alleles, st136 and st137, place both mutations in the central region of the known unc-22 map. However, these mutations probably recombine with one another, suggesting that the unstable mutations can occur in more than one site in unc-22. Examination of the phenotypic effect of these mutations on muscle structure indicates that they are less severe in their effect than a known amber allele. We suggest that this mutator system is polygenic and dispersed over the nematode genome and could represent activity of the transposable element Tc1.
The description of the chemoreception pathway in Paramecium is incomplete, but the technical means are available to study these pathways at the molecular level. The hallmark of ciliates is their versatility and their most important attribute is the availability of useful mutants. It is just this versatility and amenability to genetic manipulation that will move the study of Paramecium chemoreception forward and provide useful information for chemoreceptor cell function in general.
The objective of this work was to apply artificial neural networks (ANNs) to examine the relative importance of various factors, both formulation and process, governing the in-vitro dissolution from enteric-coated sustained release (SR) minitablets. Input feature selection (IFS) algorithms were used in order to give an estimate of the relative importance of the various formulation and processing variables in determining minitablet dissolution rate. Both forward and backward stepwise algorithms were used as well as genetic algorithms. Networks were subsequently trained using the back propagation algorithm in order to check whether or not the IFS process had correctly located any unimportant inputs. IFS gave consistent rankings for the importance of the various formulation and processing variables in determining the release of drug from minitablets. Consistent ranking was achieved for both indices of the release process; ie, the time taken for release to commence through the enteric coat (T(lag)) and that for the drug to diffuse through the SR matrix of the minitablet into the dissolution medium (T9(0-10)). In the case of the T(lag) phase, the main coating parameters, along with the original batch blend size and the blend time with lubricant, were found to have most influence. By contrast, with the T(90-10 phase), the amounts of matrix forming polymer and direct compression filler were most important. In the subsequent training of the ANNs, removal of inputs regarded as less important led to improved network performance. ANNs were capable of ranking the relative importance of the various formulations and processing variables that influenced the release rate of the drug from minitablets. This could be done for all main stages of the release process. Subsequent training of the ANN verified that removal of less relevant inputs from the training process led to an improved performance from the ANN.
The success of mapping genes involved in complex diseases, using association or linkage disequilibrium methods, depends heavily on the number and frequency of susceptibility alleles of these genes. These methods will be economically and statistically feasible if common diseases are usually influenced by one or a few susceptibility alleles at each locus (common disease-common variant, CDCV, hypothesis), but not so if there is a high degree of allelic heterogeneity. Here, we use forward-time population simulations to investigate the impact of various genetic and demographic factors on the allelic spectra of human diseases, on the basis of two models proposed by Reich and Lander and by Pritchard. Factors considered are more complex demographies, a finite-allele mutation model, population structure and migration, and interaction between disease susceptibility loci. The conclusion is that the CDCV hypothesis holds and that the phenomenon is caused by transient effects of demography (population expansion). As a result, we devise a multilocus generalization of the Reich and Lander model and demonstrate how interaction between loci with respect to their response to selection may lead to complex effects. We discuss the implications for mapping of complex diseases.
To investigate the generation of an abnormally long HIV-1 env PCR DNA product the latter was cloned and sequenced followed by sequence analysis of HIV-1 primer binding sites. We found that the formation of an abnormally long PCR product was due to HIV-1 env sequence alteration (a) in the reverse primer binding site resulting in faulty primer binding and (b) downstream from the forward primer sequence resulting in a new binding site with reverse complementary sequence with respect to the forward primer at the opposite end of the PCR product. Both changes led to amplification of a longer PCR product with forward primer alone. Our results indicate that the HIV-1 genetic diversity in the env gene can lead to amplification of a specific PCR product of unexpected size which can be disregarded in the absence of its cross-validation.
In this study, a controlled experiment of winter wheat under water stress at the seedling stage was conducted in soil columns in greenhouse. Based on the data gotten from the experiment, a model to estimate root length density distribution was developed through optimizing the weights of neural network by genetic algorithm. The neural network model was constructed by using forward neural network framework, by applying the strategy of the roulette wheel selection and reserving the most optimizing series of weights, which were composed by real codes. This model was applied to predict the root length density distribution of winter wheat, and the predicted root length density had good agreement with experiment data. The way could save a lot of manpower and material resources for determining the root length density distribution of winter wheat.
Although important cell biological questions concerning the compartmental organization of the secretory pathway still remain, enough is now known to permit a meaningful dissection of the molecular machinery of individual segments. It is both fortunate and remarkable that these kinds of pathways, whose essential purpose is to propagate the three-dimensional organization of the cytoplasm, can nonetheless be faithfully reproduced in dispersed cell-free systems without the benefit (or constraint) of preexisting spatial arrangements. This has opened the door to biochemistry, and superficial outlines of the steps involved in vesicle budding and fusion are now emerging. Crucial points remain. Among them, how, in step-by-step fashion, do coats assemble on membranes to yield a vesicle? What is the targeting signal that triggers uncoating and attachment of a vesicle? How can a protein machine fuse two lipid layers? Answers to questions of molecular mechanism at this level have and will necessarily continue to emerge from cell-free systems, and thus need in one way or another to be confirmed in vivo. Since so little is known, or can be learned, at this level from studies in whole cells, how can this be done? The answer is that the molecules discovered with cell-free systems, putatively performing the same roles in living cells, will provide the very tools to make the assessment of authenticity. As genes encoding these purified transport components are manipulated, and antibodies microinjected, the predicted effects on cellular physiology can be scrutinized. This has already begun by synthesizing the results from animal cell-free biochemistry with those from yeast genetics, and the results are encouraging. We can now look forward to a rapid fleshing out of the secretory pathway so that, in the not too distant future, we will be able to discuss these complex events of macromolecular targeting with the same kind of sophistication with which we now describe the biosynthesis of macromolecules like proteins and nucleic acids, and will be able to do so in a common language, that of protein biochemistry.
Analysis of sampling data from Chinese people in 1987 showed prevalence of visual disability was 10.08/1000. Major factors causing visual disability were congenital or hereditary defects, ametropia, amblyopia and corneal disease in children aged 0-14 years; senile cataract, trachoma and corneal disease in the elderly people aged 60 and over; and ametropia, amblyopia, cataract and corneal disease in the other people. Glaucoma and eye trauma were two major causes leading to severe visual disability. Suggestion of three-level prevention for visual disability in the country was put forward by the authors with focus on primary prevention, including genetic counselling and health care in pregnancy, preventing from eye infection and trauma, and active treatment of primary diseases, such as diabetes.
Strain BALB/c and DBA/2 mice were chosen to investigate the effects of genetic background on the radiation-induced mutation rate since they exhibit differences in their radiation sensitivity. Males were exposed to 3 + 3-Gy X-irradiation and mated to untreated specific locus Test-stock females. Offspring resulting from treated spermatogonia were screened for induced specific locus forward and reverse mutations and dominant cataract mutations. Since BALB/c mice are homozygous brown and albino, specific locus forward mutations could be screened at 5 of the 7 specific loci (a, d, se, p, s), while reverse mutations could be screened at the b and c loci. Strain DBA/2 is homozygous non-agouti, brown and dilute. Therefore, specific locus forward mutations could be screened at 4 loci (c, se, p, s) and reverse mutations were screened at the a, b and d loci. Results indicate no effect of genetic background on the sensitivity to mutation induction of specific locus forward mutations, while for the dominant cataract alleles strain DBA/2 exhibited a higher mutation rate than either strain BALB/c or similarly treated (101/El X C3H/El)F1 mice. If, by confirmation, these differences should be demonstrated to be real, it is interesting that strain DBA/2 should exhibit a greater sensitivity to radiation-induced dominant mutations. First, strain DBA/2 was chosen as radiation resistant or repair competent. The observation that DBA/2 exhibited a higher sensitivity to radiation-induced mutation may indicate a role for repair, albeit misrepair, in the mutation process. Second, that the effect of genotype was only observed for the mutation rate to dominant cataract alleles may reflect a difference in the spectrum of DNA alterations which result in dominant or recessive alleles. A dominant allele is more likely misinformation, such that as heterozygote it interferes with the wild-type allele. By comparison, a recessive allele may result from any DNA alteration leading to the loss of a functional gene product. One reverse mutation at each of the a and d loci was recovered in the present experiments. The similarities of the present results for radiation-induced reverse mutations with the extensive data on the spontaneous reverse mutation rates are interesting. Reverse mutations were recovered only at the a and d loci. Further, the reverse mutations recovered at the a locus were to alternate alleles (at, Aw or Asy) while true reverse mutations were apparently recovered at the d locus.
Packet routing in networks requires knowledge about available paths, which can be either acquired dynamically while the traffic is being forwarded, or statically (in advance) based on prior information of a network's topology. This paper describes an experimental investigation of path discovery using genetic algorithms (GAs). We start with the quality-of-service (QoS)-driven routing protocol called "cognitive packet network" (CPN), which uses smart packets (SPs) to dynamically select routes in a distributed autonomic manner based on a user's QoS requirements. We extend it by introducing a GA at the source routers, which modifies and filters the paths discovered by the CPN. The GA can combine the paths that were previously discovered to create new untested but valid source-to-destination paths, which are then selected on the basis of their "fitness." We present an implementation of this approach, where the GA runs in background mode so as not to overload the ingress routers. Measurements conducted on a network test bed indicate that when the background-traffic load of the network is light to medium, the GA can result in improved QoS. When the background-traffic load is high, it appears that the use of the GA may be detrimental to the QoS experienced by users as compared to CPN routing because the GA uses less timely state information in its decision making.
The genetic effects of MNNG, 4NQO and ICR-170 have been compared on 5 different UV-sensitive strains and a standard wild-type strain of Neurospora crassa with regard to inactivation and the induction of forward-mutations at the ad-3A and ad-3B loci. Whereas all UV-sensitive strains (upr-1, uvs-2, uvs-3, uvs-5 and uvs-6) are more sensitive to inactivation by MNNG and ICR-170 than wild-type, only uvs-5 shows survival comparable to wild-type after 4NQO treatment, all other strains are more sensitive to 4NQO. In contrast to the effects on inactivation, a wide variety of effects were found for the induction of ad-3A and ad-3B mutations: higher forward-mutation frequencies than were found in wild-type were obtained after treatment with MNNG or 4NQO for upr-1 and uvs-2, no significant increase over the spontaneous mutation frequency was found with uvs-3 after MNNG, 4NQO or ICR-170 treatment; mutation frequencies comparable to that found in wild-type were obtained with uvs-6 after MNNG, 4NQO or ICR-170 treatment and with upr-1 after ICR-170 treatment. Lower forward-mutation frequencies than were found in wild-type were obtained with uvs-2 after ICR-170 treatment and with uvs-5 after MNNG, 4NQO or ICR-170 treatment. These data clearly show that the process of forward-mutation at the ad-3A and ad-3B loci is under genetic control by mutations at other loci (e.g. upr-1, uvs-2, uvs-3, uvs-5 and uvs-6) and that the effect is markedly mutagen-dependent.
Organ transplantation requires lifelong antirejection therapy, which carries the risk of infection and cancer. A revolutionary approach is to transduce the organ graft with immunomodulatory genes to render them tolerated with no need of systemic immunosuppression. Prolonged allograft survival was achieved by adenovirus-mediated transduction of the cold-preserved kidney with sequences encoding CTLA4Ig, a recombinant fusion protein that blocks T cell activation. Organ expression of the transgene was achieved associated with mild infiltration of mononuclear cells in the transfected kidney. Mixed lymphocyte reaction as well as the production of both Thl and Th2 cytokines were reduced. Thus, the gene transfer technique to prolong graft survival is indeed effective and safe and can induce donor-specific unresponsiveness. Pending appropriate large animal testing, ex vivo genetic manipulation of the organ before surgery may hopefully represent a major step forward in human transplant medicine.
Data from experiments on the induction of specific-locus mutations in model systems are utilized in genetic risk assessment to estimate potential adverse effects in the human population. In such assessments with radiation or chemical mutagens, the following information is required: (1) spontaneous and induced forward-mutation frequencies, (2) dose-response curves for the overall induction of specific-locus mutations, (3) genetic characterization of spontaneous and induced mutations, and (4) dose-response curves for the different genotypic classes. Specific-locus assays in most eukaryote assay systems provide only portions of the information required for genetic risk assessment. In recognition of the need for a more comprehensive data base, a model system was developed for specific-locus studies in Neurospora crassa. The adenine-3 (ad-3) specific-locus assay was modeled after the 2 gene, morphological specific-locus assay in the dilute-short-ear region of the mouse, and it detects forward-mutations at two closely linked loci: ad-3A and ad-3B. The ad-3 assay system has provided precise dose-response curves not only for inactivation, but also the overall induction of ad-3 mutations. The utilization of this assay in experiments with radiation or chemical mutagens has provided a data base on the induction and genetic characterization of specific-locus mutations that is unique among eukaryotic organisms. In this assay, gene/point mutations, multilocus deletion mutations, and 3 different classes of multiple-locus mutations can be identified. The latter consist of specific-locus mutations associated with recessive lethal mutations located either closely linked to the ad-3 region or elsewhere in the genome. The overall data base on the heterozygous effects of X-ray-induced ad-3 mutations demonstrates that such effects are allele specific, genotype specific, and locus specific. There are probably a variety of mechanisms by which the heterozygous effects of individual allelic mutations at different genetic loci can be affected. In conclusion, unless the frequencies of all of the different classes of induced specific-locus mutations are determined, and utilized in genetic risk assessment exercises, the risk of human exposure to environmental mutagens may be grossly underestimated.
The potential of actinomycin D for induction of forward mutation (ADE-), reversion (TRP+), gene conversion, and mitotic recombination, was examined using haploid and diploid strains of yeast Saccharomyces cerevisiae. No increase in forward or reverse mutations or gene conversion was detected, but actinomycin D induced up to 13-fold increases in mitotic recombinants and a 2-fold increase in numbers of aberrant colonies, in a non-selective assay for genetic activity. Actinomycin D was non-mutagenic in a fluctuation test using Escherichia coli strain WP2 UvrA-. This furnishes an example of a mutagen which is negative in bacteria but has genetic activity in yeast, emphasizing the need for using a battery of microbial tests for determining the genetic activity of any given chemical.
We have developed an auditory brainstem response (ABR) based method for frequency selective forward masking tuning curve technique. Normative data from CBA/CBA mice are compared with tuning curves (TCs) from heterozygote dancer mice which in most cases initially had a normal ABR threshold. The sharpest tuning in normal mice was obtained at 10 kHz (Q10 = 7.6) and 12 kHz (Q10 = 10.9). With increasing age the mutants showed a broadening of the TC tip before ABR threshold impairment occurred. Morphological analysis of the cochleae from dancer mutants revealed an early disarray of hair cell stereocilia which became increasingly more severely affected with advancing age. We conclude that the broadening of the TC tip is an early finding in the genetically induced cochlear susceptibility which can be correlated to stereociliary dysfunction.