Inherited differences in blood group A subtypes in Caucasians and Negroes.
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ABO Blood-Group System↗
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Results for “statistical genetics”
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Effect of age on chiasma number in man.
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Aging↗
Exact significance levels of goodness-of-fit tests for the Hardy-Weinberg equilibrium.
The aim of this work is to examine the validity of several chi2 criteria, when used to test the fit of genotypic frequencies to the Hardy-Weinberg law. The exact type I error probabilities were compared to the nominal significance levels for two genetic models. The Pearson's chi2 test usually provided the best approximations. This test was found to be remarkably robust, when in situations involving very small expected frequencies.
ABO Blood-Group System↗
Properties of the major gene index and related functions.
Two recent methods for detecting major genes under continuous variation are investigated, by analysis of both simulated and real data. The major gene index of Karlin is shown to be sensitive to the distribution of gene effects in such a way that it may not detect major genes in certain cases. The intrafamily correlations of Matthysse et al. are shown to yield values difficult to reconcile with established patterns of inheritance for certain traits.
Gene Pool↗
R3531C mutation in the apolipoprotein B gene is not sufficient to cause hypercholesterolemia.
Familial hypercholesterolemia and familial ligand-defective apolipoprotein B-100 (FDB) are dominantly inherited disorders leading to impaired low-density lipoprotein receptor (LDLR) and apolipoprotein B-100 (APOB) interaction, plasma LDL elevation, and hypercholesterolemia. We previously identified the first French FDB-R3531C proband, a woman with very high total cholesterol, in a group of type IIa hypercholesterolemic families. We report here the investigation of her family at large that revealed the total absence of cosegregation with hypercholesterolemia. Six of the 10 subjects heterozygous for the R3531C mutation had plasma cholesterol lower than the 97.5th percentile for their age and gender, and mean cholesterol levels were not significantly different between affected and unaffected persons. Furthermore, 2 family members with similar high LDL-cholesterol levels were not carriers of the R3531C substitution, suggesting the implication of another mutation. Segregation analysis of the LDLR gene revealed statistically significant genetic linkage with hypercholesterolemia, and analysis of the proband LDLR gene led to the identification of the 664 proline to leucine defective mutation and its detection in all 6 hypercholesterolemic-related members of this family. Therefore, our results show that the family presents with familial hypercholesterolemia and give evidence that the R3531C substitution in the APOB gene is not an allelic variant leading to FDB. Furthermore, thorough analysis of our data suggests that the APOB-R3531C mutation enhances the hypercholesterolemic effect of the LDLR-P664L defect, suggesting that it is a susceptibility mutation.
Adolescent↗
Comment on the phosphodiesterase 4D replication study by Bevan et al.
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3',5'-Cyclic-AMP Phosphodiesterases↗
Protein Z levels, protein Z G79A polymorphism, and prothrombotic conditions.
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Alleles↗
Genotype at the -174G/C polymorphism of the interleukin-6 gene is associated with common carotid artery intimal-medial thickness: family study and meta-analysis.
BACKGROUND AND PURPOSE: Studies in unrelated individuals have produced conflicting findings concerning the putative association between the interleukin-6 (IL-6) -174G/C polymorphism and carotid intimal-medial thickness (IMT). We have used a family-based genetic association design to assess the heritability of carotid IMT and to investigate the hypothesized association of carotid IMT with the IL-6 to -174G/C polymorphism. METHODS: We studied 854 members of 224 white British families. The heritability of carotid IMT was determined using Multipoint Engine for Rapid Likelihood Inference. Genetic association analyses were carried out using ANOVA and family-based tests of association implemented in Quantitative Transmission Disequilibrium Test. A meta-analysis of previous studies of the association was conducted to place our result in context. RESULTS: The heritability of carotid IMT was 24%. Under a recessive model (GG+GC versus CC), there was significant evidence of association between IL-6 to the -174G/C genotype and adjusted log(e) maximal carotid IMT (F=5.469; P=0.02). Family-based analyses using Quantitative Transmission Disequilibrium Test showed no evidence of population stratification as a cause of the observed association (chi2(1)=0.469; P=0.4934). The CC genotype was associated with a 4.8% increase in maximal carotid IMT and accounted for 0.6% of the observed variation in the trait, which is equivalent to 2.5% of the heritable component. A meta-analysis of the present and 2 previous large studies, which enrolled a total of 2930 subjects, confirmed the recessive effect of the C allele on carotid IMT (P=0.0014). CONCLUSIONS: The genotype at the IL-6 to -174G/C polymorphism is associated with common carotid artery IMT, although the size of the genetic effect is small.
Adult↗
Analysis of the (mu/mu, lambda)-ES on the parabolic ridge.
The progress behavior of evolution strategies (ES) using recombination is analyzed in this paper on the parabolic ridge. This test function represents landscapes far from the optimum. The ES algorithms with intermediate and dominant recombination are considered in the analysis. The derivations are presented for intermediate recombination. Thereafter, the formulae for dominant recombination are obtained using the so-called surrogate mutation model. In the analysis, the formulae are derived for the progress rate psi and for the stationary distance R(infinity) to the ridge axis. As a result, it will be shown that the progress rate psi can increase if recombination is applied. Simulations are used to show the appropriateness of the formulae derived.
Algorithms↗
Scalability problems of simple genetic algorithms.
Scalable evolutionary computation has become an intensively studied research topic in recent years. The issue of scalability is predominant in any field of algorithmic design, but it became particularly relevant for the design of competent genetic algorithms once the scalability problems of simple genetic algorithms were understood. Here we present some of the work that has aided in getting a clear insight in the scalability problems of simple genetic algorithms. Particularly, we discuss the important issue of building block mixing. We show how the need for mixing places a boundary in the GA parameter space that, together with the boundary from the schema theorem, delimits the region where the GA converges reliably to the optimum in problems of bounded difficulty. This region shrinks rapidly with increasing problem size unless the building blocks are tightly linked in the problem coding structure. In addition, we look at how straightforward extensions of the simple genetic algorithm-namely elitism, niching, and restricted mating are not significantly improving the scalability problems.
Algorithms↗
Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene.
Patients with cystic fibrosis (CF) have decreased concentrations of expired nitric oxide (FENO) as compared with healthy individuals. A number of factors, including viscous mucus as a diffusion barrier for airway NO, consumption of NO by bacterial enzymes, and decreased NO production have been hypothesized to account for these low levels of FENO. We examined the relationship between the size of an AAT repeat polymorphism in intron 20 of the NOS1 gene and FENO in 75 patients with CF. Mean FENO was significantly (p = 0.027) lower in CF patients who harbored two alleles with a high number of repeats (>/= 12) than in those who harbored alleles with fewer repeats at this locus (4.0 +/- 0.8 [mean +/- SEM] ppb versus 6.4 +/- 0.9 ppb). Colonization of the airways with Pseudomonas aeruginosa was significantly (p = 0.0358) more common in CF patients with high numbers of AAT repeats in the NOS1 gene. Significant differences between NOS1 genotypes were also observed among patients homozygous for the cystic fibrosis transmembrane regulator delta F508 mutation for FENO (2.3 +/- 0.4 ppb versus 5.3 +/- 0.7 ppb, p = 0.0006), and this was also true for colonization of the airways with P. aeruginosa (p = 0.0147) and Aspergillus fumigatus (p = 0.0221). These data provide evidence that the NOS1 gene is not only associated with the variability of FENO, but also with P. aeruginosa colonization of airways in CF patients.
Adolescent↗
Monogenic control of variations in antipyrine metabolite formation. New polymorphism of hepatic drug oxidation.
To investigate mechanisms that control large variations among normal uninduced subjects in the elimination of the model compound antipyrine (AP) and other drugs, AP was administered to 144 subjects (83 unrelated adults and 61 members of 13 families). Thereafter, at regular intervals for 72 h, the urine of each subject was collected and concentrations of AP and its three main metabolites measured. From these urinary concentrations, rate constants for formation of each AP metabolite were calculated. Trimodal curves were observed when values for each AP rate constant were plotted in 83 unrelated subjects; probit plots of these values showed inflections at the two antimodes of each trimodal distribution. All members of our 13 families were assigned one of three phenotypes determined by where their AP metabolite rate constant placed them in the trimodal distributions derived from the 83 unrelated subjects. In each family, pedigree analysis to identify the mode of transmission of these three phenotypes was consistent with their monogenic control. These results provide evidence for a new polymorphism of drug oxidation in man.
Adolescent↗
Regulation of TNF-alpha-induced IL-6 production in MG-63 human osteoblast-like cells.
Tumor necrosis factor-alpha (TNF-alpha) stimulates osteoblast production of interleukin-6 (IL-6), an inflammatory cytokine implicated in osteoclastic bone resorption. Therefore, we tested the hypothesis that TNF-alpha-induced IL-6 production in MG-63 osteosarcoma cells occurs via the p38 mitogen-activated protein kinase (MAPK) pathway. TNF-alpha activated p38 MAPK and stimulated IL-6 secretion by MG-63 cells, and pre-incubation of cells with the p38 MAPK inhibitor abrogated TNF-alpha-dependent IL-6 secretion. Transfection of IL-6 full-length and 5-deletion gene promoter reporter constructs indicated that p38 MAPK activation by TNF-alpha enhanced IL-6 gene expression, and that the p38 MAPK-responsive region resided in the proximal 260-bp segment. Transfection of NFkappaB and C/EBPbeta-sensitive reporter promoter constructs demonstrated that NFkappaB activity was enhanced and that constitutive C/EBPbeta was inhibited by TNF-alpha, with both effects being p38 MAPK-dependent. In conclusion, although p38 MAPK activation by TNF-alpha stimulates IL-6 secretion by MG-63 cells, it has opposing effects on c/EBPbeta and NFkappaB activity.
Analysis of Variance↗
Lack of evidence for association between endothelial nitric oxide synthase gene polymorphisms and coronary artery disease in the Australian Caucasian population.
BACKGROUND: Genetic polymorphism in the gene for endothelial nitric oxide synthase (eNOS) has been identified as a potential risk factor for the development of premature coronary artery disease (CAD). We determined whether the eNOS 4ab, G894T, and T-786C polymorphisms are associated with premature coronary artery disease. DESIGN: A case-control study. METHODS: PCR-based assays were used to compare the frequency of eNOS gene polymorphisms in 573 Caucasian subjects aged under 50 years presenting with symptomatic CAD and documented by coronary angiography, with or without myocardial infarction, to that of 624 similarly aged community controls without a history of symptomatic CAD. RESULTS: We found no difference in the frequency of 4ab genotypes between cases and controls: in the CAD subjects, the 4aa, 4ab, and 4bb genotype frequencies were 1.9%, 24.3% and 73.8% respectively, compared to 2.2%, 25.5% and 72.3% respectively for the controls. There was also no significant difference between cases and controls in the frequency of any allele (4a/4b, 894G/894T, -786C/-786T), or genotype for any of the polymorphisms. Similarly, logistic regression analysis showed no evidence for an association of the polymorphisms with premature CAD or myocardial infarction or any indication of an interaction between the polymorphisms and other CAD risk factors, including smoking. CONCLUSIONS: In a large case-control study, and in contrast to some earlier positive findings by others, we have found no evidence for an association between several eNOS gene polymorphisms and premature CAD in an Australian Caucasian population.
Adult↗
Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations.
To assess the prognostic relevance of mutations in the NPM1 gene encoding a nucleocytoplasmic shuttle protein in younger adults with acute myeloid leukemia (AML) and normal cytogenetics, sequencing of NPM1 exon 12 was performed in diagnostic samples from 300 patients entered into 2 consecutive multicenter trials of the AML Study Group (AMLSG). Treatment included intensive double-induction therapy and consolidation therapy with high cumulative doses of high-dose cytarabine. NPM1 mutations were identified in 48% of the patients including 12 novel sequence variants, all leading to a frameshift in the C-terminus of the nucleophosmin 1 (NPM1) protein. Mutant NPM1 was associated with specific clinical, phenotypical, and genetic features. Statistical analysis revealed a significant interaction of NPM1 and FLT3 internal tandem duplications (ITDs). NPM1 mutations predicted for better response to induction therapy and for favorable overall survival (OS) only in the absence of FLT3 ITD. Multivariable analysis for OS revealed combined NPM1-mutated/FLT3 ITD-negative status, CEBPA mutation status, availability of a human leukocyte antigen (HLA)-compatible donor, secondary AML, and lactate dehydrogenase (LDH) as prognostic factors. In conclusion, NPM1 mutations in the absence of FLT3 ITD define a distinct molecular and prognostic subclass of young-adult AML patients with normal cytogenetics.
Acute Disease↗
Simulation analysis to test the influence of model adequacy and data structure on the estimation of genetic parameters for traits with direct and maternal effects.
Simulations were used to study the influence of model adequacy and data structure on the estimation of genetic parameters for traits governed by direct and maternal effects. To test model adequacy, several data sets were simulated according to different underlying genetic assumptions and analysed by comparing the correct and incorrect models. Results showed that omission of one of the random effects leads to an incorrect decomposition of the other components. If maternal genetic effects exist but are neglected, direct heritability is overestimated, and sometimes more than double. The bias depends on the value of the genetic correlation between direct and maternal effects. To study the influence of data structure on the estimation of genetic parameters, several populations were simulated, with different degrees of known paternity and different levels of genetic connectedness between flocks. Results showed that the lack of connectedness affects estimates when flocks have different genetic means because no distinction can be made between genetic and environmental differences between flocks. In this case, direct and maternal heritabilities are under-estimated, whereas maternal environmental effects are overestimated. The insufficiency of pedigree leads to biased estimates of genetic parameters.
Animals↗
Full conjugate analysis of normal multiple traits with missing records using a generalized inverted Wishart distribution.
A Markov chain Monte Carlo (MCMC) algorithm to sample an exchangeable covariance matrix, such as the one of the error terms (R0) in a multiple trait animal model with missing records under normal-inverted Wishart priors is presented. The algorithm (FCG) is based on a conjugate form of the inverted Wishart density that avoids sampling the missing error terms. Normal prior densities are assumed for the 'fixed' effects and breeding values, whereas the covariance matrices are assumed to follow inverted Wishart distributions. The inverted Wishart prior for the environmental covariance matrix is a product density of all patterns of missing data. The resulting MCMC scheme eliminates the correlation between the sampled missing residuals and the sampled R0, which in turn has the effect of decreasing the total amount of samples needed to reach convergence. The use of the FCG algorithm in a multiple trait data set with an extreme pattern of missing records produced a dramatic reduction in the size of the autocorrelations among samples for all lags from 1 to 50, and this increased the effective sample size from 2.5 to 7 times and reduced the number of samples needed to attain convergence, when compared with the 'data augmentation' algorithm.
Algorithms↗
Enhanced individual selection for selecting fast growing fish: the "PROSPER" method, with application on brown trout (Salmo trutta fario).
Growth rate is the main breeding goal of fish breeders, but individual selection has often shown poor responses in fish species. The PROSPER method was developed to overcome possible factors that may contribute to this low success, using (1) a variable base population and high number of breeders (Ne >100), (2) selection within groups with low non-genetic effects and (3) repeated growth challenges. Using calculations, we show that individual selection within groups, with appropriate management of maternal effects, can be superior to mass selection as soon as the maternal effect ratio exceeds 0.15, when heritability is 0.25. Practically, brown trout were selected on length at the age of one year with the PROSPER method. The genetic gain was evaluated against an unselected control line. After four generations, the mean response per generation in length at one year was 6.2% of the control mean, while the mean correlated response in weight was 21.5% of the control mean per generation. At the 4th generation, selected fish also appeared to be leaner than control fish when compared at the same size, and the response on weight was maximal (approximately 130% of the control mean) between 386 and 470 days post fertilisation. This high response is promising, however, the key points of the method have to be investigated in more detail.
Animals↗