A mother-child combination analysis for AB0-Hp interaction

Summary Tests for interaction between AB0 and Hp were performed in 1824 mother-child pairs. There was no significant difference in the Hp distribution between mothers and children. When the children were divided into AB0-compatible and AB0-incompatible with their mothers there was an excess of the Hp ¹ gene in the incompatible group. The results are discussed.

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Zusammenfassung An 1824 Mutter-Kind-Paaren wurden vermutete AB0-Hp-Interaktionen untersucht. In der Verteilung der Hp-Phänotypen lag keine signifikante Differenz zwischen Müttern und Kindern vor. Dagegen konnte ein Überschuß des Hp¹-Allels beobachtet werden, wenn die Kinder in die Gruppen mit der Mutter AB0-verträglich bzw. mit der Mutter AB0-unverträglich gegliedert wurden. Die Ergebnisse werden diskutiert.

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Alexander von Humboldt Fellow.     

PreSPI: a domain combination based prediction system for protein-protein interaction

With the accumulation of protein and its related data on the Internet, many domain-based computational techniques to predict protein interactions have been developed. However, most techniques still have many limitations when used in real fields. They usually suffer from low accuracy in prediction and do not provide any interaction possibility ranking method for multiple protein pairs. In this paper, we propose a probabilistic framework to predict the interaction probability of proteins and develop an interaction possibility ranking method for multiple protein pairs. Using the ranking method, one can discern the protein pairs that are more likely to interact with each other in multiple protein pairs. The validity of the prediction model was evaluated using an interacting set of protein pairs in yeast and an artificially generated non-interacting set of protein pairs. When 80% of the set of interacting protein pairs in the DIP (Database of Interacting Proteins) was used as a learning set of interacting protein pairs, high sensitivity (77%) and specificity (95%) were achieved for the test groups containing common domains with the learning set of proteins within our framework. The stability of the prediction model was also evident when tested over DIP CORE, HMS-PCI and TAP data. In the validation of the ranking method, we reveal that some correlations exist between the interacting probability and the accuracy of the prediction.     

papa (package for the analysis of parental allocation): a computer program for simulated and real parental allocation

papa is a parental pair allocation and simulator program. The allocation method is based on the likelihood of a parental pair producing the multilocus genotype found in the offspring being tested, which will be referred to as the breeding likelihood. Estimated level and structure of allele transmission errors in offspring are parameters fed into the allocation procedure. The embodied Monte‐Carlo simulator also allows modelling of many allocation conditions, including transmission error and the estimated proportion of missing parents. Simulations may be run prior to the collection of real parents in order to define the minimal set of loci that is necessary to reach a desired level of allocation success. Post‐collection simulations aim at statistically assessing the reliability of nonsimulated allocations. Simulations output values for several random variables.     

Selection on parental performance opposes selection for larger body mass in a wild population of blue tits

There is abundant evidence in many taxa for positive directional selection on body size, and yet little evidence for microevolutionary change. In many species, variation in body size is partly determined by the actions of parents, so a proposed explanation for stasis is the presence of a negative genetic correlation between direct and parental effects. Consequently, selecting genes for increased body size would result in a correlated decline in parental effects, reducing body size in the following generation. We show that these arguments implicitly assume that parental care is cost free, and that including a cost alters the predicted genetic architectures needed to explain stasis. Using a large cross‐fostered population of blue tits, we estimate direct selection on parental effects for body mass, and show it is negative. Negative selection is consistent with a cost to parental care, mainly acting through a reduction in current fecundity rather than survival. Under these conditions, evolutionary stasis is possible for moderately negative genetic correlations between direct and parental effects. This is in contrast to the implausibly extreme correlations needed when care is assumed to be cost‐free. Thus, we highlight the importance of accounting correctly for complete selection acting on traits across generations.     

A key factor analysis of a sparrowhawk population

Summary During 1972–86, the Sparrowhawk breeding population in Eskdale, southern Scotland, remained fairly stable, with nest numbers fluctuating between 29 and 39 in different years. The annual production of young varied rather more, between 44 and 86 in different years. In a key factor analysis, the overwinter loss operating in the period between the fledging of young and subsequent recruitment to the breeding population, emerged as the key factor, explaining 77% of the variance in total annual loss, and largely accounting for the pattern of change in breeding numbers. Overwinter loss in each new cohort was also the only form of loss which was density dependent. In a simulation model this loss was found to be capable, on its own, of stabilising the nesting population at the mean level observed. Losses during the breeding season were inversely correlated with losses over the ensuing winter. Thus, good breeding seasons, when many young were produced, were followed by high losses over winter, while poor breeding seasons were followed by reduced losses over winter. No density dependence was detected at any stage of breeding, or in the annual mortality of established breeders.     

Heterozygosity–fitness correlations in a wild mammal population: accounting for parental and environmental effects

HFCs (heterozygosity–fitness correlations) measure the direct relationship between an individual's genetic diversity and fitness. The effects of parental heterozygosity and the environment on HFCs are currently under‐researched. We investigated these in a high‐density U.K. population of European badgers (Meles meles), using a multimodel capture–mark–recapture framework and 35 microsatellite loci. We detected interannual variation in first‐year, but not adult, survival probability. Adult females had higher annual survival probabilities than adult males. Cubs with more heterozygous fathers had higher first‐year survival, but only in wetter summers; there was no relationship with individual or maternal heterozygosity. Moist soil conditions enhance badger food supply (earthworms), improving survival. In dryer years, higher indiscriminate mortality rates appear to mask differential heterozygosity‐related survival effects. This paternal interaction was significant in the most supported model; however, the model‐averaged estimate had a relative importance of 0.50 and overlapped zero slightly. First‐year survival probabilities were not correlated with the inbreeding coefficient (f); however, small sample sizes limited the power to detect inbreeding depression. Correlations between individual heterozygosity and inbreeding were weak, in line with published meta‐analyses showing that HFCs tend to be weak. We found support for general rather than local heterozygosity effects on first‐year survival probability, and g2 indicated that our markers had power to detect inbreeding. We emphasize the importance of assessing how environmental stressors can influence the magnitude and direction of HFCs and of considering how parental genetic diversity can affect fitness‐related traits, which could play an important role in the evolution of mate choice.     

Nonlinear response surface in the study of interaction analysis of three combination drugs

Few articles have been written on analyzing three‐way interactions between drugs. It may seem to be quite straightforward to extend a statistical method from two‐drugs to three‐drugs. However, there may exist more complex nonlinear response surface of the interaction index () with more complex local synergy and/or local antagonism interspersed in different regions of drug combinations in a three‐drug study, compared in a two‐drug study. In addition, it is not possible to obtain a four‐dimensional (4D) response surface plot for a three‐drug study. We propose an analysis procedure to construct the dose combination regions of interest (say, the synergistic areas with ). First, use the model robust regression method (MRR), a semiparametric method, to fit the entire response surface of the , which allows to fit a complex response surface with local synergy/antagonism. Second, we run a modified genetic algorithm (MGA), a stochastic optimization method, many times with different random seeds, to allow to collect as many feasible points as possible that satisfy the estimated values of . Last, all these feasible points are used to construct the approximate dose regions of interest in a 3D. A case study with three anti‐cancer drugs in an in vitro experiment is employed to illustrate how to find the dose regions of interest.     

Adjustment of parental frequencies to maximize the diversity of a synthetic population

Summary A method is outlined for maximizing the mean genetic distance among plants in a synthetic population by adjusting the relative contributions of the population's parents. The largest latent vector of the genetic distance matrix is used to find relative parental frequencies. The largest increases in the diversity of a synthetic will be achieved when there are different-sized clusters of parents, with considerably larger distances between than within clusters. The method may have application in maximizing the yields of synthetic cultivars or the resistance of multi-line cultivars.Joint contribution of the USDA-ARS and Department of Agronomy, Kansas Agricultural Experiment Station. Contribution No. 87-435-J     

A technique for analysis of density dependence in population models

The concept of density-dependent population growth is fundamental to our understanding of how populations persist. While it is generally agreed that negative density dependence must occur at high densities, the direction of density dependence may be negative (pure negative density dependence) or positive (demographic Allee effect) at low densities. In this article, we present a technique to link the direction of density dependence to generic ecological factors. This technique involves exploiting the presence of a particular bifurcation, known as a saddle-node-transcritical interaction. We first provide a method to detect this bifurcation in a given model and then demonstrate its ecological relevance using several existing mechanistic models. With a mathematical framework in place, we are able to identify scenarios in which neither a weak Allee effect nor pure negative density dependence are possible. More generally, we find conditions on parameter values that are necessary for transitions between pure negative density dependence and demographic Allee effects to occur.     

A population dynamics analysis of the interaction between adaptive regulatory T cells and antigen presenting cells

Background

Regulatory T cells are central actors in the maintenance of tolerance of self-antigens or allergens and in the regulation of the intensity of the immune response during infections by pathogens. An understanding of the network of the interaction between regulatory T cells, antigen presenting cells and effector T cells is starting to emerge. Dynamical systems analysis can help to understand the dynamical properties of an interaction network and can shed light on the different tasks that can be accomplished by a network.

Methodology and Principal Findings

We used a mathematical model to describe a interaction network of adaptive regulatory T cells, in which mature precursor T cells may differentiate into either adaptive regulatory T cells or effector T cells, depending on the activation state of the cell by which the antigen was presented. Using an equilibrium analysis of the mathematical model we show that, for some parameters, the network has two stable equilibrium states: one in which effector T cells are strongly regulated by regulatory T cells and another in which effector T cells are not regulated because the regulatory T cell population is vanishingly small. We then simulate different types of perturbations, such as the introduction of an antigen into a virgin system, and look at the state into which the system falls. We find that whether or not the interaction network switches from the regulated (tolerant) state to the unregulated state depends on the strength of the antigenic stimulus and the state from which the network has been perturbed.

Conclusion/Significance

Our findings suggest that the interaction network studied in this paper plays an essential part in generating and maintaining tolerance against allergens and self-antigens.     

Association between childhood atopic disease and parental atopic disease in a population with high consanguinity

The aim of the study was to investigate the association between asthma, allergic rhinitis, and eczema in Qatari schoolchildren with allergic conditions in their parents. A cross-sectional study was conducted among 3500 Qatari schoolchildren aged 6-14 years in period: February, 2003-February, 2004. A questionnaire was used to collect the clinical history of asthma and allergic rhinitis in their parents and siblings. It was found that 21.6% of asthmatic children had mothers with asthma and 18.2% fathers with asthma. This contrasted with 6.8% of non-asthmatic children who had fathers with asthma and 9.4% mothers with asthma. As for allergic rhinitis, 26.5% of asthmatic children had mothers with allergic rhinitis and 25.3% fathers with allergic rhinitis. The frequency of either parent of the asthmatic children having allergic rhinitis was 41.8% and for both parents was 10.0%. The frequency of siblings having asthma was 36.6%, allergic rhinitis 16.4%, and eczema 29.1%. The present study revealed a strong association between respiratory allergies and eczema in parents, and their asthmatic children.     

Medusa: a simple tool for interaction graph analysis

SUMMARY: Medusa is a Java application for visualizing and manipulating graphs of interaction, such as data from the STRING database. It features an intuitive user interface developed with the help of biologists. Medusa is optimized for accessing protein interaction data from STRING, but can be used for any type of graph from any scientific field.     

Gene-gene interaction between tuberculosis candidate genes in a South African population

In a complex disease such as tuberculosis (TB) it is increasingly evident that gene-gene interactions play a far more important role in an individual??s susceptibility to develop the disease than single polymorphisms on their own, as one gene can enhance or hinder the expression of another gene. Gene-gene interaction analysis is a new approach to elucidate susceptibility to TB. The possibility of gene-gene interactions was assessed, focusing on 11 polymorphisms in nine genes (DC-SIGN, IFN-??, IFNGR1, IL-8, IL-1Ra, MBL, NRAMP1, RANTES, and SP-D) that have been associated with TB, some repeatedly. An optimal model, which best describes and predicts TB case?Ccontrol status, was constructed. Significant interactions were detected between eight pairs of variants. The models fitted the observed data extremely well, with p?<?0.0001 for all eight models. A highly significant interaction was detected between INFGR1 and NRAMP1, which is not surprising because macrophage activation is greatly enhanced by IFN-?? and IFN-?? response elements that are present in the human NRAMP1 promoter region, providing further evidence for their interaction. This study enabled us to test the theory that disease outcome may be due to interaction of several gene effects. With eight instances of statistically significant gene-gene interactions, the importance of epistasis is clearly identifiable in this study. Methods for studying gene-gene interactions are based on a multilocus and multigene approach, consistent with the nature of complex-trait diseases, and may provide the paradigm for future genetic studies of TB.     

A multiparent advanced generation inter-cross population for genetic analysis in wheat

We present the first results from a novel multiparent advanced generation inter-cross (MAGIC) population derived from four elite wheat cultivars. The large size of this MAGIC population (1579 progeny), its diverse genetic composition and high levels of recombination all contribute to its value as a genetic resource. Applications of this resource include interrogation of the wheat genome and the analysis of gene-trait association in agronomically important wheat phenotypes. Here, we report the utilization of a MAGIC population for the first time for linkage map construction. We have constructed a linkage map with 1162 DArT, single nucleotide polymorphism and simple sequence repeat markers distributed across all 21 chromosomes. We benchmark this map against a high-density DArT consensus map created by integrating more than 100 biparental populations. The linkage map forms the basis for further exploration of the genetic architecture within the population, including characterization of linkage disequilibrium, founder contribution and inclusion of an alien introgression into the genetic map. Finally, we demonstrate the application of the resource for quantitative trait loci mapping using the complex traits plant height and hectolitre weight as a proof of principle.     

A parental requirement for dual-specificity phosphatase 6 in zebrafish

Background

Signaling cascades, such as the extracellular signal-regulated kinase (ERK) pathway, play vital roles in early vertebrate development. Signals through these pathways are initiated by a growth factor or hormone, are transduced through a kinase cascade, and result in the expression of specific downstream genes that promote cellular proliferation, growth, or differentiation. Tight regulation of these signals is provided by positive or negative modulators at varying levels in the pathway, and is required for proper development and function. Two members of the dual-specificity phosphatase (Dusp) family, dusp6 and dusp2, are believed to be negative regulators of the ERK pathway and are expressed in both embryonic and adult zebrafish, but their specific roles in embryogenesis remain to be fully understood.

Results

Using CRISPR/Cas9 genome editing technology, we generated zebrafish lines harboring germ line deletions in dusp6 and dusp2. We do not detect any overt defects in dusp2 mutants, but we find that approximately 50% of offspring from homozygous dusp6 mutants do not proceed through embryonic development. These embryos are fertilized, but are unable to proceed past the first zygotic mitosis and stall at the 1-cell stage for several hours before dying by 10 h post fertilization. We demonstrate that dusp6 is expressed in gonads of both male and female zebrafish, suggesting that loss of dusp6 causes defects in germ cell production. Notably, the 50% of homozygous dusp6 mutants that complete the first cell division appear to progress through embryogenesis normally and give rise to fertile adults.

Conclusions

The fact that offspring of homozygous dusp6 mutants stall prior to activation of the zygotic genome, suggests that loss of dusp6 affects gametogenesis and/or parentally-directed early development. Further, since only approximately 50% of homozygous dusp6 mutants are affected, we postulate that ERK signaling is tightly regulated and that dusp6 is required to keep ERK signaling within a range that is permissive for proper embryogenesis. Lastly, since dusp6 is expressed throughout zebrafish embryogenesis, but dusp6 mutants do not exhibit defects after the first cell division, it is possible that other regulators of the ERK pathway compensate for loss of dusp6 at later stages.