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At least 1,117 records · Page 62Linked to original sources
PubMed2006

Chemical genetic algorithms--evolutionary optimization of binary-to-real-value translation in genetic algorithms.

A chemical genetic algorithm (CGA) in which several types of molecules (information units) react with each other in a cell is proposed. Not only the information in DNA, but also smaller molecules responsible for the transcription and translation of DNA into amino acids, are adaptively changed during evolution, which optimizes the fundamental mapping from binary substrings in DNA ( genotype) to real values for a parameter set (phenotype). Through the struggle between cells containing a DNA unit and small molecular units, the codes (DNA) and the interpreter (the small molecular units) coevolve, and a specific output function, from which a cell's fitness is evaluated, is optimized. To demonstrate the effectiveness of the CGA, it is applied to a set of variable-separable and variable-inseparable problems, and it is shown that the CGA can robustly solve a wide range of optimization problems regardless of their fitness characteristics. To ascertain the optimization of the genotype-to-phenotype mapping by the CGA, we also conduct analytical experiments for some problems while observing the basin size of a global optimum solution in the binary genotype space. The results show that the CGA effectively augments the basin size, makes it easier for evolution to find a path to the global optimum solution, and enhances the GA's evolvability during evolution.

Algorithms↗
PubMed1996

Asthma on Tristan da Cunha: looking for the genetic link. The University of Toronto Genetics of Asthma Research Group.

Although asthma has a significant heritable component, the mode of inheritance remains controversial because of the complexity of the disease and the influence of environmental factors. Isolated, inbred populations serve to reduce variability, thus increasing the probability of gene localization. We studied the inbred population of the remote island of Tristan da Cunha to document asthma prevalence for the purpose of genetic linkage analysis. Medical histories and skin atopy were determined on 282 islanders, representing 97% of the population, and airway responsiveness was measured in 254; 226 by methacholine challenge (tidal breathing method) and 28 by bronchodilator response (400 micrograms salbutamol aerosol). Blood samples were collected from 275 islanders. Participants ranged in age from 3 to 94 yr. Asthma was defined as increased airway responsiveness (AR+: PC20 < 4 mg/ml or > or = 15% increase in FEV1 postbronchodilator) combined with a positive history (Hx+). Fifty-seven percent of the islanders had at least partial evidence of asthma (Hx+ and/or AR+) and 23% had a definitive diagnosis of asthma (AR+ with Hx+). Overall 47% of the population were atopic, atopy was proportionally higher in asthmatics (74%) than nonasthmatics (32%; p < 0.01). Analysis of the methacholine dose-response curves demonstrated that asthmatics were significantly (p < 0.01) more responsive than those with AR+ only, and nonasthmatics (AR-, Hx-) were more responsive than laboratory control subjects (p < 0.05), suggesting that these islanders may also carry an airway hyperresponsiveness gene. A frequency plot of the percent fall in FEV1 for all Hx- subjects compared with control data suggests a bimodal distribution consistent with a major gene mechanism for airway responsiveness. Genealogy mapping revealed that the islanders are direct descendants of the 15 original settlers, and historical records suggest at least two founders may have been asthmatic. The data confirm previous reports of a high asthma prevalence on Tristan and support the postulate that this prevalence is a result of gene enrichment occurring in isolated populations by virtue of extensive inbreeding and a probable founder effect.

Adolescent↗
PubMed2004

Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing.

Hypertrophic cardiomyopathy is a Mendelian disease characterized by cardiac hypertrophy. It has a prevalence of 1:500 individuals and is the most common cause of sudden death in the young. Other complications include heart failure and the need for heart transplantation. Hypertrophic cardiomyopathy is due to sarcomeric gene mutations, however, phenocopies with myocardial hypertrophy can be due to triplet-repeat syndromes (Friedreich ataxia and myotonic dystrophy), mitochondrial and metabolic diseases. In a peculiar form associated with Wolf-Parkinson-White syndrome, the disease is caused by mutations in the gamma2 regulatory subunit of the AMP-activated protein kinase gene, leading to a glycogen storage cardiomyopathy. In spite of the growing knowledge about the molecular basis of hypertrophic cardiomyopathy, very little is still known about the genotype-phenotype correlations and their clinical implications. In this review, the clinical and molecular genetics of hypertrophic cardiomyopathy are described.

Animals↗
PubMed1993

Genetic survey of a group of children with clefting: implications for genetic counseling.

A cleft lip, cleft palate, or both are associated with a high frequency of other anomalies. This study gives an inventory of associated anomalies in a consecutive group of children (n = 36) with clefts, referred to a local multidisciplinary cleft team in the Netherlands. In 47.2% of cleft patients associated anomalies were found, allowing diagnosis of provisionally unique syndromes or known entities. In 17 patients family history was positive for clefting; in five patients (13.9%) this influenced the occurrence risks for siblings. Both findings had an effect on genetic counseling of the parents of these children. Additional evidence is provided that all children with clefting should be carefully evaluated by a trained clinician for additional anomalies, including dysmorphic features.

Abnormalities, Multiple↗
PubMed2004

Genetically engineered mouse models for drug discovery: new chemical genetic approaches.

While standard transgenic and knockout mouse technologies have provided a wealth of information for target selection and validation, there have been great advances in using more sophisticated modeling techniques to achieve temporal and spatial regulation of individual genes in adult animals. Recent developments in RNA interference (RNAi) technology in in vivo models promise to further improve upon the static and irreversible features of gene knockouts. Chemical genetic approaches create novel functional alleles of targets and allow fine modulation of protein function in vivo by small molecules, providing the most pharmacologically relevant target validation. Using these advanced models, one can not only ask whether the function of the target is critical for the initiation and maintenance of the disease, but also whether therapies designed to alter the function of the target would be safe and efficacious. In this review, we describe various in vivo tools for target validation in mouse models, discuss advantages and disadvantages of each approach, and give examples of their impact on drug discovery.

Animals↗
PubMed2000

Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group.

Type 1 diabetes is considered to be a T-cell-mediated autoimmune disease in which insulin-producing beta-cells are destroyed. Immunity to insulin has been suggested to be one of the primary autoimmune mechanisms leading to islet cell destruction. We have previously shown that the first immunization to insulin occurs by exposure to bovine insulin (BI) in cow's milk (CM) formula. In this study, we analyzed the development of insulin-specific T-cell responses by proliferation test, emergence of insulin-binding antibodies by enzyme immunoassay, and insulin autoantibodies by radioimmunoassay in relation to CM exposure and family history of type 1 diabetes in infants with a first-degree relative with type 1 diabetes and increased genetic risk for the disease. The infants were randomized to receive either an adapted CM-based formula or a hydrolyzed casein (HC)-based formula after breast-feeding for the first 6-8 months of life. At the age of 3 months, both cellular and humoral responses to BI were higher in infants exposed to CM formula than in infants fully breast-fed (P = 0.015 and P = 0.007). IgG antibodies to BI were higher in infants who received CM formula than in infants who received HC formula at 3 months of age (P = 0.01), but no difference in T-cell responses was seen between the groups. T-cell responses to BI at 9 months of age (P = 0.05) and to human insulin at 12 (P = 0.014) and 24 months of age (P = 0.009) as well as IgG antibodies to BI at 24 months of age (P = 0.05) were lower in children with a diabetic mother than in children with a diabetic father or a sibling, suggesting possible tolerization to insulin by maternal insulin therapy. The priming of insulin-specific humoral and T-cell immunity occurs in early infancy by dietary insulin, and this phenomenon is influenced by maternal type 1 diabetes.

Animals↗
PubMed1988

Genetic variation of plasma growth hormone and its genetic association with growth traits in young chickens.

A pedigreed, randomly mated population of 25 sire families was assessed for genetic variation in body weight, gain, and plasma growth hormone (GH) under conditions of reduced temperature brooding (26.7 C) from day of hatch to 7 days of age. Heritability estimates (h2) for 7-day body weight and gain were moderate to high. The calculated h2 for GH was moderate. Plasma levels of GH were not phenotypically or genotypically correlated with body weight or gain.

Animals↗
PubMedDate not supplied

Genetic counselling. Alzheimer's disease: advances in genetics.

Recent advances in DNA technology have allowed identification of those carrying the gene mutation for early onset Alzheimer's disease in some families, and provide the prospect of an effective treatment or cure in the future. While last week's article questioned the existence of late onset Alzheimer's as a distinct disease entity, this one illustrates how and why these scientific advances may have far-reaching psychosocial consequences for some family members. It suggests why there is likely to be an increase in demand for the kind of information and support which can be offered by a genetic counselling service.

Alzheimer Disease↗
PubMed1976

[Problems in the genetics of stress. II. Genetic analysis of endocrine gland weight in mice under normal conditions and during exposure to stress].

Relative weight of adrenals, thymus, hypophysis and gonads was studied in female mice after 21 days after parturition and in intact males. One group of females was stressed during pregnancy, and another group was intact. All these animals were a progeny of the full diallele cross of 4 inbred mice strains (BALB/c, C3H/He, C57BL/6, AKR/J). On the basis of analysis of general and specific combining ability the conclusion is drawn that the relative weight of the endocrine glands is inherited additively in females of both experimental groups. However, it was found that the size of additive genetic variation for these characters in the population of females, which had been stressed during their pregnancy was larger, than in the control population. A significant role of non-additive genes in the determination of these characters was observed in males. The degree of hypertrophy of adrenals and lysis of thymus in stressed females corresponded to their emotional reactivity. Significant genotypic correlations between the weight of some endocrine glands, on one hand, and the emotional reactivity and the rate of sexual maturation, on the other hand, were found in both experimental groups of females. In the stressed group these correlations were higher.

Adrenal Glands↗
PubMed1999

Genetic effects of exocyclic DNA adducts in vivo: heritable genetic damage in comparison with loss of heterozygosity in somatic cells.

Etheno adducts are promutagenic lesions which generate point mutations, deletions, homologous recombination and gross structural DNA aberrations. High ratios of chromosome loss to forward mutations characterize vinyl bromide, vinyl chloride, ethyl carbamate, vinyl carbamate and its epoxide as effective clastogens in postmeiotic germ cells of Drosophila melanogaster. Of the mutants induced by vinyl carbamate at the vermilion gene, 68% were intra-locus or multi-locus deletions. In view of the far-reaching concordance between mutation spectra in mice and Drosophila observed in specific-locus tests with genotoxic agents, etheno bases are expected to generate mainly deletions in male mammals in the postmeiotic germ-cell stages. Twenty-two of 23 base substitutions induced in the vermilion gene after treatment of postmeiotic stages with vinyl carbamate or vinyl bromide fall into four categories of mutations expected from etheno bases: GC-->AT, AT-->GC, GC-->TA and AT-->TA base-pair changes. These types of point mutations occurred in mutated proto-oncogenes of tumours induced in rodents by vinyl chloride, ethyl carbamate or their metabolites. Of interest is the ability of vinyl carbamate to produce persistent lesions in otherwise highly repair-active premeiotic cells of Drosophila, leading to mutations of yet unknown nature. Etheno bases are also potent pro-clastogenic lesions in somatic cells in vivo. Strongly positive responses were reported for ethyl carbamate and vinyl carbamate in assays for micronucleus formation in mouse bone marrow and in the Drosophila white+/white eye mosaic test. Loss of heterozygosity in somatic cells of Drosophila was due primarily to ring-X chromosome loss, followed by homologous mitotic recombination. Particularly striking is the near failure of ethyl carbamate and vinyl carbamate to generate significant frequencies of intrachromosomal recombination. The overall genetic activity profiles of etheno adduct-forming chemicals in mice and in Drosophila support the hypothesis that vinyl carbamate is the proximate mutagen of ethyl carbamate, and vinyl carbamate epoxide is the ultimate electrophilic mutagen and carcinogen.

Animals↗
PubMed1999

Genetics and molecular genetics of the MHC.

The MHC is a well-characterised region of the human genome, containing a high diversity of genes and an apparent clustering of genes involved in the immune response. The genomic sequence of an 8 Mb section, containing the MHC and flanking regions and covering over 300 genes, will soon be available. Since this is a highly polymorphic region, the molecular genetics of the MHC and its relationship with disease have been studied in considerable detail.

Animals↗
PubMed1975

Biochemical, immunological and genetic studies in leprosy. III. Genetic polymorphism of C3 and immunoglobulin profile in leprosy patients, healthy family members and controls.

148 members from 30 families (64 children) from Ethiopia, where one of more persons were affected with leprosy, were investigated for genetic polymorphism of C3, serum concentration of ss1C/ss1A-globulin and immunoglobulins A, G and M using high voltage agarose electrophoresis, immunoelectroassay and single radial immunodiffusion techniques respectively. The results are compared with related healthy controls. No association between C3 phenotypes and leprosy could be established through family studies. C3 concentration was, however, lower in leprosy patients. Difficulties and drawbacks of such studies with small families are discussed.

Adult↗
PubMed2002

[Medico-genetic evaluation of sugar sand, obtained from genetically-modified sugar beet line 77 (toxicologico-biochemical studies)].

The rats were fed with the Suger from the Genetically Modified Suger Beet line 77 (Monsanto Ko, USA) 3 g/rat/day for 3 months. Their blood, urea and liver were investigated to measure total protein and glucose levels, aminotransferase and alkaline phosphatase activities, pH, creatinine level as well as hepatic enzyme activity of the I and II phases of henobiotic metabolism and whole and non-sedimentated lysosomal enzyme activities and activity of antioxidant system.

Alkaline Phosphatase↗
PubMed1975

Population genetic studies in bees (APIDAE, Hymenoptera). I. Genetic load.

Three populations of Apis mellifera each predominantly of a different subspecies (mellifera, ligustica and adansonii) and 7 species of stingless bees (Meliponinae, Apidae) were manipulated for applying the MORTON, CROW & MULLER's methodology in order to estimate the lethal equivalents (B) of each population. A total of 249 queens were used, 27 being meliponids and 222 Apis mellifera. The populations of Apis have a B that does not differ significantly when they are compared to each other (1.29, 1.36, 1.32) and the balanced average equals 1.33. When the x-alleles are not considered, this balanced value is 0.262. The figures for B in the seven species of stingless bees ranged between 0.104 and 0.159 with balanced average of 0.132. The main reason for this smaller load in meliponids may rest in their effective population numbers, which are smaller than those of Apis. The average mortality for diploid females (0.141) and for haploid males (0.163) allows the estimation of the total elimination (sigma E = 0.073). Since for haplo-diploid systems the total mutation rate is sigma mu = 2 sigma E divided by 3 the figure 0.048 is obtained. Since about 15% of the genes in Apis mellifera are sex limited, this value of sigma mu should be added of 0.0072 (that is 0.15 X 0.048) and then, the total mutation rate becomes 0.055. Using a quite different method, the one by MORTON, CROW & MULLER, the figure 0.076 was obtained. If a mutation rate of 10(-5) is assumed, the number of genes in Apis mellifera that can make a contribution to the genetic load would vary between 5,500 and 7,600.

Animals↗
PubMed2004

Genetic factors encoding resistance to late blight caused by Phytophthora infestans (Mont.) de Bary on the potato genetic map.

Late blight, a potato disease caused by Phytophthora infestans (Mont.) de Bary, is of great economic significance, and has been the subject of numerous research projects aimed at both introducing resistance to the disease into potato cultivars, and at unravelling the mechanisms and genes underlying this resistance. This report is on publications about mapping the resistance to P. infestans encoded by major resistance genes or polygenes, introduced into the potato from different sources. Applied methods for resistance evaluation, methods for revealing DNA polymorphisms and for the construction of genetic maps are described and compared, as are results obtained by independent authors working in this field.

Chromosome Mapping↗
PubMed1992

Genetic regulation of fatty acid synthetase expression in adipose tissue: overtranscription of the gene in genetically obese rats.

We have investigated the molecular mechanism of the overactivity of fatty acid synthetase (FAS) in adipose tissue from the genetically obese Zucker rat. Purified FAS from lean and obese rat adipose tissues displayed kinetics constants, molecular weight, and immunological properties that were identical. Western blot analysis revealed that FAS overactivity in obese versus lean rat adipose tissue was paralleled by a proportionate increase in FAS mass, i.e., 4-fold increase in suckling normoinsulinemic 16-day-old pups and 25-fold in weaned hyperinsulinemic 30-day-old rats. The determination of absolute FAS mass disclosed that FAS was quantitatively a major protein in obese rat adipose tissue accounting for 13% of cytosolic proteins versus 2% in lean rat at 30 days of age. FAS hyperabundance could be ascribed to an increased relative rate of FAS synthesis that was 6-fold higher in obese than in lean rat adipose tissue. Northern blot analysis demonstrated that FAS mRNA levels in obese rats were increased 4- and 14-fold over those of lean rats at 16 and 30 days of age, respectively, in very close proportion to the 3- and 15-fold increases in FAS gene transcription rates revealed by nuclear run-on assays. Southern analysis of genomic DNA did not allow for detecting amplification or any major structural changes in the FAS gene. It is concluded that FAS overactivity, shown here to be a life-long and general feature of all adipose tissue sites in the obese rat, arises primarily from FAS gene overtranscription.

Adipose Tissue↗
PubMed1991

Genetics of post-hatching survival potential of Australorp chicks infected as embryos by subgroup A Rous sarcoma virus: further support to 4-allele genetic model.

Embryos (II day-old) of Australorp breed were inoculated via chorioallantoic membrane (CAM) with subgroup A Rous sarcoma virus, and hatched subsequently. The post-hatch survival period in chicks was recorded upto the last chick that died by virus-induced liver tumour, which had a range from 3 to 50 days with an average of 13 +/- 8.7 days. The survival potential of progency tested Australorp parents selected on the basis of negative CAM-infection and those selected on uninoculated embryos, differed significantly (P less than 0.01) while maintaining an inverse relationship between liver tumour mortality and degrees of infection of CAMs. The homozygous susceptibles lacking either ar1 or ar2 or both alleles of the tva (tumour virus a) locus died within 7 days of post-hatching, supporting thereby 4-allele genetic model of tva locus recently proposed for the control of LT- and CAM-infection phenotypes.

Alleles↗
PubMed1986

Genetics of antibody responsiveness to bovine serum albumin and rabbit gamma-globulin. I. Genetic analysis of high and low responder lines of mice produced by selective breeding.

The selective breeding for antibody production against bovine serum albumin (BSA) and rabbit gamma-globulin (RGG) induced a large modification in responsiveness in the high (Hv) and low (Lv) responder lines at selection limit. The total response to selection (RT) was 9.0 log2 for BSA and 8.4 log2 for RGG. This gives an interline difference of 500-fold and 337-fold respectively in terms of passive agglutinin titres. For BSA responsiveness, there is, in F1 interline hybrids, an incomplete dominance effect of the low character (-0.41) and a marked maternal effect. Complete dominance effect of high character (1.08) without any maternal effect is observed for responses to RGG. The phenotypical variability of BSA responses in F2 segregants is due 60% to genetic factors and 40% to environmental effects. Such a distribution cannot be achieved for RGG responsiveness. Both responses to BSA and RGG are controlled by the additive effect of several independent loci (polygenic regulation). One of these genes is linked with the H-2 locus. The H-2 linked gene accounts for 29% of the total interline difference for response to BSA and only 11% for response to RGG. Experiments carried out to measure the reciprocal nonspecific effect of BSA and RGG responses failed to give clear-cut results. This important phenomenon will be the subject of the companion article.

Animals↗