Developmental genetics of red cell indices during puberty: A longitudinal twin study

Red cell number and size increase during puberty, particularly in males. The aim of the present study was to determine whether expression of genes affecting red cell indices varied with age and sex. Haemoglobin, red cell count, and mean cellular volume were measured longitudinally on 578 pairs of twins at twelve, fourteen and sixteen years of age. Data were analysed using a structural equation modeling approach, in which a variety of univariate and longitudinal simplex models were fitted to the data. Significant heritability was demonstrated for all variables across all ages. The genes involved did not differ between the sexes, although there was evidence for sex limitation in the case of haemoglobin at age twelve. Longitudinal analyses indicated that new genes affecting red cell indices were expressed at different stages of puberty. Some of these genes affected the different red cell indices pleiotropically, while others had effects specific to one variable only.

Biometrical Genetics

Biometrical genetics is the science concerned with the inheritance of quantitative traits. In this review we discuss how the analytical methods of biometrical genetics are based upon simple Mendelian principles. We demonstrate how the phenotypic covariance between related individuals provides information on the relative importance of genetic and environmental factors influencing that trait, and how factors such as assortative mating, gene-environment correlation and genotype-environment interaction complicate such interpretations. Twin and adoption studies are discussed as well as their assumptions and limitations. Structural equation modeling (SEM) is introduced and we illustrate how this approach may be applied to genetic problems. In particular, we show how SEM can be used to address complicated issues such as analyzing the causes of correlation between traits or determining the direction of causation (DOC) between variables. (C) 2002 Elsevier Science B.V. All rights reserved.

Genetics of Serum Dehydroepiandrosterone Sulfate and Its Relationship to Insulin in a Population-Based Cohort of Twin Subjects

Previous studies have shown a significant effect of insulin administration on serum dehydroepiandrosterone sulfate (DHEA-S) concentration and its metabolic rate, with evidence for the effect in men, but not in women. This could lead to differences in the sources of variation in serum DHEA-S between men and women and in its covariation with insulin concentration. This study aimed to test whether these hypotheses were supported in a sample of healthy adult twins. Serum DHEA-S (n=2287) and plasma insulin (n=2436) were measured in samples from adult male and female twins recruited through the Australian Twin Registry. Models of genetic and environmental sources of variation and covariation were tested against the data. DHEA-S showed substantial genetic effects in both men and women after adjustment for covariates, including sex, age, body mass index, and time since the last meal. There was no significant phenotypic or genetic correlation between DHEA-S and insulin in either men or women. Despite the experimental evidence for insulin infusion producing a reduction in serum DHEA-S and some effect of meals on the observed DHEA-S concentration, there were no associations between insulin and DHEA-S at the population level. Variations in DHEA-S are due to age, sex, obesity, and substantial polygenic genetic influences.

Using siting algorithms in the design of marine reserve networks

Using benthic habitat data from the Florida Keys (USA), we demonstrate how siting algorithms can help identify potential networks of marine reserves that comprehensively represent target habitat types. We applied a flexible optimization tool-simulated annealing-to represent a fixed proportion of different marine habitat types within a geographic area. We investigated the relative influence of spatial information, planning-unit size, detail of habitat classification, and magnitude of the overall conservation goal on the resulting network scenarios. With this method, we were able to identify many adequate reserve systems that met the conservation goals, e.g., representing at least 20% of each conservation target (i.e., habitat type) while fulfilling the overall aim of minimizing the system area and perimeter. One of the most useful types of information provided by this siting algorithm comes from an irreplaceability analysis, which is a count of the number of, times unique planning units were included in reserve system scenarios. This analysis indicated that many different combinations of sites produced networks that met the conservation goals. While individual 1-km(2) areas were fairly interchangeable, the irreplaceability analysis highlighted larger areas within the planning region that were chosen consistently to meet the goals incorporated into the algorithm. Additionally, we found that reserve systems designed with a high degree of spatial clustering tended to have considerably less perimeter and larger overall areas in reserve-a configuration that may be preferable particularly for sociopolitical reasons. This exercise illustrates the value of using the simulated annealing algorithm to help site marine reserves: the approach makes efficient use of;available resources, can be used interactively by conservation decision makers, and offers biologically suitable alternative networks from which an effective system of marine reserves can be crafted.

Genetics of melanoma predisposition

Predisposition to melanoma is genetically heterogeneous. Two high penetrance susceptibility genes, CDKN2A and CDK4, have so far been identified and mapping is ongoing to localize and identify others. With the advent of a catalogue of millions of potential DNA polymorphisms, attention is now also being focused on identification of genes that confer a more modest contribution to melanoma risk, such as those encoding proteins involved in pigmentation, DNA repair, cell growth and differentiation or detoxification of metabolites. One such pigmentation gene, MC1R, has not only been found to be a low penetrance melanoma gene but has also been shown to act as a genetic modifier of melanoma risk in individuals carrying CDKN2A mutations. Most recently, an environmental agent, ultraviolet radiation, has also been established as a modifier of melanoma risk in CDKN2A mutation carriers. Hence, melanoma is turning out to be an excellent paradigm for studying gene-gene and gene-environment interactions.

The genetics of coronary heart disease: the contribution of twin studies

Despite the decline in coronary heart disease in many European countries, the disease remains an enormous public health problem. Although we know a great deal about environmental risk factors for coronary heart disease, a heritable component was recognized a long time ago. The earliest and best known examples of how our genetic constitution may determine cardiovascular risk relate to lipoprotein(a), familial hypercholesterolaemia and apolipoprotein E. In the past 20 years a fair number of polymorphisms assessed singly have shown strong associations with the disease but most are subject to poor repeatability. Twins constitute a compelling natural experiment to establish the genetic contribution to coronary heart disease and its risk factors. GenomEUtwin, a recently funded Framework 5 Programme of the European Community, affords the opportunity of comparing the heritability of risk factors in different European Twin Registries. As an illustration we present the heritabilities of systolic and diastolic blood pressure, based on data from over 4000 twin pairs from six different European countries and Australia. Heritabilities for systolic blood pressure are between 52 and 66% and for diastolic blood pressure between 44 and 66%. There is no evidence of sex differences in heritability estimates and very little to no evidence for a significant contribution of shared family environment. A non-twin based prospective case/cohort study of coronary heart disease and stroke (MORGAM) will allow hypotheses relating to cardiovascular disease, generated in the twin cohorts, to be tested prospectively in adult populations. Twin studies have also contributed to our understanding of the life course hypothesis, and GenomEUtwin has the potential to add to this.

Mouse proteome analysis

A general overview of the protein sequence set for the mouse transcriptome produced during the FANTOM2 sequencing project is presented here. We applied different algorithms to characterize protein sequences derived from a nonredundant representative protein set (RPS) and a variant protein set (VPS) of the mouse transcriptome. The functional characterization and assignment of Gene Ontology terms was done by analysis of the proteome using InterPro. The Superfamily database analyses gave a detailed structural classification according to SCOP and provide additional evidence for the functional characterization of the proteome data. The MDS database analysis revealed new domains which are not presented in existing protein domain databases. Thus the transcriptome gives us a unique source of data for the detection of new functional groups. The data obtained for the RPS and VPS sets facilitated the comparison of different patterns of protein expression. A comparison of other existing mouse and human protein sequence sets (e.g., the International Protein Index) demonstrates the common patterns in mammalian proteornes. The analysis of the membrane organization within the transcriptome of multiple eukaryotes provides valuable statistics about the distribution of secretory and transmembrane proteins

Fast, scalable master equation solution algorithms. IV. Lanczos iteration with diffusion approximation preconditioned iterative inversion

In this paper we propose a second linearly scalable method for solving large master equations arising in the context of gas-phase reactive systems. The new method is based on the well-known shift-invert Lanczos iteration using the GMRES iteration preconditioned using the diffusion approximation to the master equation to provide the inverse of the master equation matrix. In this way we avoid the cubic scaling of traditional master equation solution methods while maintaining the speed of a partial spectral decomposition. The method is tested using a master equation modeling the formation of propargyl from the reaction of singlet methylene with acetylene, proceeding through long-lived isomerizing intermediates. (C) 2003 American Institute of Physics.

Fast, scalable master equation solution algorithms. III. Direct time propagation accelerated by a diffusion approximation preconditioned iterative solver

In this paper we propose a novel fast and linearly scalable method for solving master equations arising in the context of gas-phase reactive systems, based on an existent stiff ordinary differential equation integrator. The required solution of a linear system involving the Jacobian matrix is achieved using the GMRES iteration preconditioned using the diffusion approximation to the master equation. In this way we avoid the cubic scaling of traditional master equation solution methods and maintain the low temperature robustness of numerical integration. The method is tested using a master equation modelling the formation of propargyl from the reaction of singlet methylene with acetylene, proceeding through long lived isomerizing intermediates. (C) 2003 American Institute of Physics.

Knowledge-based system on optimum design of liquid retaining structures with genetic algorithms

This paper delineates the development of a prototype hybrid knowledge-based system for the optimum design of liquid retaining structures by coupling the blackboard architecture, an expert system shell VISUAL RULE STUDIO and genetic algorithm (GA). Through custom-built interactive graphical user interfaces under a user-friendly environment, the user is directed throughout the design process, which includes preliminary design, load specification, model generation, finite element analysis, code compliance checking, and member sizing optimization. For structural optimization, GA is applied to the minimum cost design of structural systems with discrete reinforced concrete sections. The design of a typical example of the liquid retaining structure is illustrated. The results demonstrate extraordinarily converging speed as near-optimal solutions are acquired after merely exploration of a small portion of the search space. This system can act as a consultant to assist novice designers in the design of liquid retaining structures.

Primary aldosteronism: From genesis to genetics

The fact that a debate concerning the unexpectedly high prevalence of normokalaemic primary aldosteronism (PAL) attracted a large audience at the 2002 Scientific Meeting of the International Society of Hypertension makes it timely to address this issue. The affirmative case argues that PAL is the most common potentially curable and specifically treatable form of hypertension, itself the most common chronic disorder in Western societies, with significant morbidity and mortality, consuming large proportions of health budgets. Recent discoveries about the genetics of aldosterone production and of its unexpectedly broad effects on the cardiovascular system need to be placed in clinical context.

The genetics of glycosylation in Gram-negative bacteria

In recent years there has been a dramatic increase in reports of glycosylation of proteins in various Gram-negative systems including Neisseria meningitidis, Neisseria gonorrhoeae, Campylobacter jejuni, Pseudomonas aeruginosa, Escherichia coli, Caulobacter crescentus, Aeromonas caviae and Helicobacter pylori. Although this growing list contains many important pathogens (reviewed by Benz and Schmidt [Mol. Microbiol. 45 (2002) 267-276]) and the glycosylations are found on proteins important in pathogenesis such as pili, adhesins and flagella the precise role(s) of the glycosylation of these proteins remains to be determined. Furthermore, the details of the glycosylation biosynthetic process have not been determined in any of these systems. The definition of the precise role of glycosylation and the mechanism of biosynthesis will be facilitated by a detailed understanding of the genes involved. (C) 2002 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.