Exploiting the Proteome to Improve the Genome-Wide Genetic Analysis of Epistasis in Common Human Diseases

PubMed Central

Pattin, Kristine A.; Moore, Jason H.

2009-01-01

One of the central goals of human genetics is the identification of loci with alleles or genotypes that confer increased susceptibility. The availability of dense maps of single-nucleotide polymorphisms (SNPs) along with high-throughput genotyping technologies has set the stage for routine genome-wide association studies that are expected to significantly improve our ability to identify susceptibility loci. Before this promise can be realized, there are some significant challenges that need to be addressed. We address here the challenge of detecting epistasis or gene-gene interactions in genome-wide association studies. Discovering epistatic interactions in high dimensional datasets remains a challenge due to the computational complexity resulting from the analysis of all possible combinations of SNPs. One potential way to overcome the computational burden of a genome-wide epistasis analysis would be to devise a logical way to prioritize the many SNPs in a dataset so that the data may be analyzed more efficiently and yet still retain important biological information. One of the strongest demonstrations of the functional relationship between genes is protein-protein interaction. Thus, it is plausible that the expert knowledge extracted from protein interaction databases may allow for a more efficient analysis of genome-wide studies as well as facilitate the biological interpretation of the data. In this review we will discuss the challenges of detecting epistasis in genome-wide genetic studies and the means by which we propose to apply expert knowledge extracted from protein interaction databases to facilitate this process. We explore some of the fundamentals of protein interactions and the databases that are publicly available. PMID:18551320

Effect of inter- and intragenic epistasis on the heritability of oil content in rapeseed (Brassica napus L.).

PubMed

Würschum, Tobias; Maurer, Hans Peter; Dreyer, Felix; Reif, Jochen C

2013-02-01

The loci detected by association mapping which are involved in the expression of important agronomic traits in crops often explain only a small proportion of the total genotypic variance. Here, 17 SNPs derived from 9 candidate genes from the triacylglycerol biosynthetic pathway were studied in an association analysis in a population of 685 diverse elite rapeseed inbred lines. The 685 lines were evaluated for oil content, as well as for glucosinolates, yield, and thousand-kernel weight in field trials at 4 locations. We detected main effects for most of the studied genes illustrating that genetic diversity for oil content can be exploited by the selection of favorable alleles. In addition to main effects, both intergenic and intragenic epistasis was detected that contributes to a considerable amount to the genotypic variance observed for oil content. The proportion of explained genotypic variance was doubled when in addition to main effects epistasis was considered. Therefore, a knowledge-based improvement of oil content in rapeseed should also take such favorable epistatic interactions into account. Our results suggest, that the observed high contribution of epistasis may to some extent explain the missing heritability in genome-wide association studies.

REVIEW: Epistasis and dominance in the emergence of catalytic function as exemplified by the evolution of plant terpene synthases.

PubMed

Cheema, Jitender; Faraldos, Juan A; O'Maille, Paul E

2017-02-01

Epistasis, the interaction between mutations and the genetic background, is a pervasive force in evolution that is difficult to predict yet derives from a simple principle - biological systems are interconnected. Therefore, one effect may be intimately linked to another, hence interdependent. Untangling epistatic interactions between and within genes is a vibrant area of research. Deriving a mechanistic understanding of epistasis is a major challenge. Particularly, elucidating how epistasis can attenuate the effects of otherwise dominant mutations that control phenotypes. Using the emergence of terpene cyclization in specialized metabolism as an excellent example, this review describes the process of discovery and interpretation of dominance and epistasis in relation to current efforts. Specifically, we outline experimental approaches to isolating epistatic networks of mutations in protein structure, formally quantifying epistatic interactions, then building biochemical models with chemical mechanisms in efforts to achieve an understanding of the physical basis for epistasis. From these models we describe informed conjectures about past evolutionary events that underlie the emergence, divergence and specialization of terpene synthases to illustrate key principles of the constraining forces of epistasis in enzyme function. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Deep epistasis in human metabolism

NASA Astrophysics Data System (ADS)

Imielinski, Marcin; Belta, Calin

2010-06-01

We extend and apply a method that we have developed for deriving high-order epistatic relationships in large biochemical networks to a published genome-scale model of human metabolism. In our analysis we compute 33 328 reaction sets whose knockout synergistically disables one or more of 43 important metabolic functions. We also design minimal knockouts that remove flux through fumarase, an enzyme that has previously been shown to play an important role in human cancer. Most of these knockout sets employ more than eight mutually buffering reactions, spanning multiple cellular compartments and metabolic subsystems. These reaction sets suggest that human metabolic pathways possess a striking degree of parallelism, inducing "deep" epistasis between diversely annotated genes. Our results prompt specific chemical and genetic perturbation follow-up experiments that could be used to query in vivo pathway redundancy. They also suggest directions for future statistical studies of epistasis in genetic variation data sets.

Role of epistasis on the fixation probability of a non-mutator in an adapted asexual population.

PubMed

James, Ananthu

2016-10-21

The mutation rate of a well adapted population is prone to reduction so as to have a lower mutational load. We aim to understand the role of epistatic interactions between the fitness affecting mutations in this process. Using a multitype branching process, the fixation probability of a single non-mutator emerging in a large asexual mutator population is analytically calculated here. The mutator population undergoes deleterious mutations at constant, but at a much higher rate than that of the non-mutator. We find that antagonistic epistasis lowers the chances of mutation rate reduction, while synergistic epistasis enhances it. Below a critical value of epistasis, the fixation probability behaves non-monotonically with variation in the mutation rate of the background population. Moreover, the variation of this critical value of the epistasis parameter with the strength of the mutator is discussed in the appendix. For synergistic epistasis, when selection is varied, the fixation probability reduces overall, with damped oscillations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Extensive epistasis for olfactory behaviour, sleep and waking activity in Drosophila melanogaster.

PubMed

Swarup, Shilpa; Harbison, Susan T; Hahn, Lauren E; Morozova, Tatiana V; Yamamoto, Akihiko; Mackay, Trudy F C; Anholt, Robert R H

2012-02-01

Epistasis is an important feature of the genetic architecture of quantitative traits, but the dynamics of epistatic interactions in natural populations and the relationship between epistasis and pleiotropy remain poorly understood. Here, we studied the effects of epistatic modifiers that segregate in a wild-derived Drosophila melanogaster population on the mutational effects of P-element insertions in Semaphorin-5C (Sema-5c) and Calreticulin (Crc), pleiotropic genes that affect olfactory behaviour and startle behaviour and, in the case of Crc, sleep phenotypes. We introduced Canton-S B (CSB) third chromosomes with or without a P-element insertion at the Crc or Sema-5c locus in multiple wild-derived inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and assessed the effects of epistasis on the olfactory response to benzaldehyde and, for Crc, also on sleep. In each case, we found substantial epistasis and significant variation in the magnitude of epistasis. The predominant direction of epistatic effects was to suppress the mutant phenotype. These observations support a previous study on startle behaviour using the same D. melanogaster chromosome substitution lines, which concluded that suppressing epistasis may buffer the effects of new mutations. However, epistatic effects are not correlated among the different phenotypes. Thus, suppressing epistasis appears to be a pervasive general feature of natural populations to protect against the effects of new mutations, but different epistatic interactions modulate different phenotypes affected by mutations at the same pleiotropic gene.

Evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family.

PubMed

Redondo, Rodrigo A F; de Vladar, Harold P; Włodarski, Tomasz; Bollback, Jonathan P

2017-01-01

Viral capsids are structurally constrained by interactions among the amino acids (AAs) of their constituent proteins. Therefore, epistasis is expected to evolve among physically interacting sites and to influence the rates of substitution. To study the evolution of epistasis, we focused on the major structural protein of the ϕX174 phage family by first reconstructing the ancestral protein sequences of 18 species using a Bayesian statistical framework. The inferred ancestral reconstruction differed at eight AAs, for a total of 256 possible ancestral haplotypes. For each ancestral haplotype and the extant species, we estimated, in silico, the distribution of free energies and epistasis of the capsid structure. We found that free energy has not significantly increased but epistasis has. We decomposed epistasis up to fifth order and found that higher-order epistasis sometimes compensates pairwise interactions making the free energy seem additive. The dN/dS ratio is low, suggesting strong purifying selection, and that structure is under stabilizing selection. We synthesized phages carrying ancestral haplotypes of the coat protein gene and measured their fitness experimentally. Our findings indicate that stabilizing mutations can have higher fitness, and that fitness optima do not necessarily coincide with energy minima. © 2017 The Authors.

Epistasis interaction of QTL effects as a genetic parameter influencing estimation of the genetic additive effect.

PubMed

Bocianowski, Jan

2013-03-01

Epistasis, an additive-by-additive interaction between quantitative trait loci, has been defined as a deviation from the sum of independent effects of individual genes. Epistasis between QTLs assayed in populations segregating for an entire genome has been found at a frequency close to that expected by chance alone. Recently, epistatic effects have been considered by many researchers as important for complex traits. In order to understand the genetic control of complex traits, it is necessary to clarify additive-by-additive interactions among genes. Herein we compare estimates of a parameter connected with the additive gene action calculated on the basis of two models: a model excluding epistasis and a model with additive-by-additive interaction effects. In this paper two data sets were analysed: 1) 150 barley doubled haploid lines derived from the Steptoe × Morex cross, and 2) 145 DH lines of barley obtained from the Harrington × TR306 cross. The results showed that in cases when the effect of epistasis was different from zero, the coefficient of determination was larger for the model with epistasis than for the one excluding epistasis. These results indicate that epistatic interaction plays an important role in controlling the expression of complex traits.

Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis.

PubMed

Moore, Jason H; Williams, Scott M

2005-06-01

Epistasis plays an important role in the genetic architecture of common human diseases and can be viewed from two perspectives, biological and statistical, each derived from and leading to different assumptions and research strategies. Biological epistasis is the result of physical interactions among biomolecules within gene regulatory networks and biochemical pathways in an individual such that the effect of a gene on a phenotype is dependent on one or more other genes. In contrast, statistical epistasis is defined as deviation from additivity in a mathematical model summarizing the relationship between multilocus genotypes and phenotypic variation in a population. The goal of this essay is to review definitions and examples of biological and statistical epistasis and to explore the relationship between the two. Specifically, we present and discuss the following two questions in the context of human health and disease. First, when does statistical evidence of epistasis in human populations imply underlying biomolecular interactions in the etiology of disease? Second, when do biomolecular interactions produce patterns of statistical epistasis in human populations? Answers to these two reciprocal questions will provide an important framework for using genetic information to improve our ability to diagnose, prevent and treat common human diseases. We propose that systems biology will provide the necessary information for addressing these questions and that model systems such as bacteria, yeast and digital organisms will be a useful place to start.

A Computationally Efficient Hypothesis Testing Method for Epistasis Analysis using Multifactor Dimensionality Reduction

PubMed Central

Pattin, Kristine A.; White, Bill C.; Barney, Nate; Gui, Jiang; Nelson, Heather H.; Kelsey, Karl R.; Andrew, Angeline S.; Karagas, Margaret R.; Moore, Jason H.

2008-01-01

Multifactor dimensionality reduction (MDR) was developed as a nonparametric and model-free data mining method for detecting, characterizing, and interpreting epistasis in the absence of significant main effects in genetic and epidemiologic studies of complex traits such as disease susceptibility. The goal of MDR is to change the representation of the data using a constructive induction algorithm to make nonadditive interactions easier to detect using any classification method such as naïve Bayes or logistic regression. Traditionally, MDR constructed variables have been evaluated with a naïve Bayes classifier that is combined with 10-fold cross validation to obtain an estimate of predictive accuracy or generalizability of epistasis models. Traditionally, we have used permutation testing to statistically evaluate the significance of models obtained through MDR. The advantage of permutation testing is that it controls for false-positives due to multiple testing. The disadvantage is that permutation testing is computationally expensive. This is in an important issue that arises in the context of detecting epistasis on a genome-wide scale. The goal of the present study was to develop and evaluate several alternatives to large-scale permutation testing for assessing the statistical significance of MDR models. Using data simulated from 70 different epistasis models, we compared the power and type I error rate of MDR using a 1000-fold permutation test with hypothesis testing using an extreme value distribution (EVD). We find that this new hypothesis testing method provides a reasonable alternative to the computationally expensive 1000-fold permutation test and is 50 times faster. We then demonstrate this new method by applying it to a genetic epidemiology study of bladder cancer susceptibility that was previously analyzed using MDR and assessed using a 1000-fold permutation test. PMID:18671250

Examination of Csr regulatory circuitry using epistasis analysis with RNA-seq (Epi-seq) confirms that CsrD affects gene expression via CsrA, CsrB and CsrC.

PubMed

Potts, Anastasia H; Leng, Yuanyuan; Babitzke, Paul; Romeo, Tony

2018-03-29

The Csr global regulatory system coordinates gene expression in response to metabolic status. This system utilizes the RNA binding protein CsrA to regulate gene expression by binding to transcripts of structural and regulatory genes, thus affecting their structure, stability, translation, and/or transcription elongation. CsrA activity is controlled by sRNAs, CsrB and CsrC, which sequester CsrA away from other transcripts. CsrB/C levels are partly determined by their rates of turnover, which requires CsrD to render them susceptible to RNase E cleavage. Previous epistasis analysis suggested that CsrD affects gene expression through the other Csr components, CsrB/C and CsrA. However, those conclusions were based on a limited analysis of reporters. Here, we reassessed the global behavior of the Csr circuitry using epistasis analysis with RNA seq (Epi-seq). Because CsrD effects on mRNA levels were entirely lost in the csrA mutant and largely eliminated in a csrB/C mutant under our experimental conditions, while the majority of CsrA effects persisted in the absence of csrD, the original model accounts for the global behavior of the Csr system. Our present results also reflect a more nuanced role of CsrA as terminal regulator of the Csr system than has been recognized.

The Influence of Higher-Order Epistasis on Biological Fitness Landscape Topography

NASA Astrophysics Data System (ADS)

Weinreich, Daniel M.; Lan, Yinghong; Jaffe, Jacob; Heckendorn, Robert B.

2018-07-01

The effect of a mutation on the organism often depends on what other mutations are already present in its genome. Geneticists refer to such mutational interactions as epistasis. Pairwise epistatic effects have been recognized for over a century, and their evolutionary implications have received theoretical attention for nearly as long. However, pairwise epistatic interactions themselves can vary with genomic background. This is called higher-order epistasis, and its consequences for evolution are much less well understood. Here, we assess the influence that higher-order epistasis has on the topography of 16 published, biological fitness landscapes. We find that on average, their effects on fitness landscape declines with order, and suggest that notable exceptions to this trend may deserve experimental scrutiny. We conclude by highlighting opportunities for further theoretical and experimental work dissecting the influence that epistasis of all orders has on fitness landscape topography and on the efficiency of evolution by natural selection.

The Influence of Higher-Order Epistasis on Biological Fitness Landscape Topography

NASA Astrophysics Data System (ADS)

Weinreich, Daniel M.; Lan, Yinghong; Jaffe, Jacob; Heckendorn, Robert B.

2018-02-01

The effect of a mutation on the organism often depends on what other mutations are already present in its genome. Geneticists refer to such mutational interactions as epistasis. Pairwise epistatic effects have been recognized for over a century, and their evolutionary implications have received theoretical attention for nearly as long. However, pairwise epistatic interactions themselves can vary with genomic background. This is called higher-order epistasis, and its consequences for evolution are much less well understood. Here, we assess the influence that higher-order epistasis has on the topography of 16 published, biological fitness landscapes. We find that on average, their effects on fitness landscape declines with order, and suggest that notable exceptions to this trend may deserve experimental scrutiny. We conclude by highlighting opportunities for further theoretical and experimental work dissecting the influence that epistasis of all orders has on fitness landscape topography and on the efficiency of evolution by natural selection.

The effect of epistasis on sexually antagonistic genetic variation

PubMed Central

Arnqvist, Göran; Vellnow, Nikolas; Rowe, Locke

2014-01-01

There is increasing evidence of segregating sexually antagonistic (SA) genetic variation for fitness in laboratory and wild populations, yet the conditions for the maintenance of such variation can be restrictive. Epistatic interactions between genes can contribute to the maintenance of genetic variance in fitness and we suggest that epistasis between SA genes should be pervasive. Here, we explore its effect on SA genetic variation in fitness using a two locus model with negative epistasis. Our results demonstrate that epistasis often increases the parameter space showing polymorphism for SA loci. This is because selection in one locus is affected by allele frequencies at the other, which can act to balance net selection in males and females. Increased linkage between SA loci had more marginal effects. We also show that under some conditions, large portions of the parameter space evolve to a state where male benefit alleles are fixed at one locus and female benefit alleles at the other. This novel effect of epistasis on SA loci, which we term the ‘equity effect’, may have important effects on population differentiation and may contribute to speciation. More generally, these results support the suggestion that epistasis contributes to population divergence. PMID:24870040

Capturing pair-wise epistatic effects associated with three agronomic traits in barley.

PubMed

Xu, Yi; Wu, Yajun; Wu, Jixiang

2018-04-01

Genetic association mapping has been widely applied to determine genetic markers favorably associated with a trait of interest and provide information for marker-assisted selection. Many association mapping studies commonly focus on main effects due to intolerable computing intensity. This study aims to select several sets of DNA markers with potential epistasis to maximize genetic variations of some key agronomic traits in barley. By doing so, we integrated a MDR (multifactor dimensionality reduction) method with a forward variable selection approach. This integrated approach was used to determine single nucleotide polymorphism pairs with epistasis effects associated with three agronomic traits: heading date, plant height, and grain yield in barley from the barley Coordinated Agricultural Project. Our results showed that four, seven, and five SNP pairs accounted for 51.06, 45.66 and 40.42% for heading date, plant height, and grain yield, respectively with epistasis being considered, while corresponding contributions to these three traits were 45.32, 31.39, 31.31%, respectively without epistasis being included. The results suggested that epistasis model was more effective than non-epistasis model in this study and can be more preferred for other applications.

Epistasis analysis using artificial intelligence.

PubMed

Moore, Jason H; Hill, Doug P

2015-01-01

Here we introduce artificial intelligence (AI) methodology for detecting and characterizing epistasis in genetic association studies. The ultimate goal of our AI strategy is to analyze genome-wide genetics data as a human would using sources of expert knowledge as a guide. The methodology presented here is based on computational evolution, which is a type of genetic programming. The ability to generate interesting solutions while at the same time learning how to solve the problem at hand distinguishes computational evolution from other genetic programming approaches. We provide a general overview of this approach and then present a few examples of its application to real data.

Combining growth-promoting genes leads to positive epistasis in Arabidopsis thaliana

PubMed Central

Vanhaeren, Hannes; Gonzalez, Nathalie; Coppens, Frederik; De Milde, Liesbeth; Van Daele, Twiggy; Vermeersch, Mattias; Eloy, Nubia B; Storme, Veronique; Inzé, Dirk

2014-01-01

Several genes positively influence final leaf size in Arabidopsis when mutated or overexpressed. The connections between these growth regulators are still poorly understood although such knowledge would further contribute to understand the processes driving leaf growth. In this study, we performed a combinatorial screen with 13 transgenic Arabidopsis lines with an increased leaf size. We found that from 61 analyzed combinations, 39% showed an additional increase in leaf size and most resulted from a positive epistasis on growth. Similar to what is found in other organisms in which such an epistasis assay was performed, only few genes were highly connected in synergistic combinations as we observed a positive epistasis in the majority of the combinations with samba, BRI1OE or SAUR19OE. Furthermore, positive epistasis was found with combinations of genes with a similar mode of action, but also with genes which affect distinct processes, such as cell proliferation and cell expansion. DOI: http://dx.doi.org/10.7554/eLife.02252.001 PMID:24843021

Ant Species Differences Determined by Epistasis between Brood and Worker Genomes

PubMed Central

Linksvayer, Timothy A.

2007-01-01

Epistasis arising from physiological interactions between gene products often contributes to species differences, particularly those involved in reproductive isolation. In social organisms, phenotypes are influenced by the genotypes of multiple interacting individuals. In theory, social interactions can give rise to an additional type of epistasis between the genomes of social partners that can contribute to species differences. Using a full-factorial cross-fostering design with three species of closely related Temnothorax ants, I found that adult worker size was determined by an interaction between the genotypes of developing brood and care-giving workers, i.e. intergenomic epistasis. Such intergenomic social epistasis provides a strong signature of coevolution between social partners. These results demonstrate that just as physiologically interacting genes coevolve, diverge, and contribute to species differences, so do socially interacting genes. Coevolution and conflict between social partners, especially relatives such as parents and offspring, has long been recognized as having widespread evolutionary effects. This coevolutionary process may often result in coevolved socially-interacting gene complexes that contribute to species differences. PMID:17912371

Detecting epistasis with the marginal epistasis test in genetic mapping studies of quantitative traits

PubMed Central

Zeng, Ping; Mukherjee, Sayan; Zhou, Xiang

2017-01-01

Epistasis, commonly defined as the interaction between multiple genes, is an important genetic component underlying phenotypic variation. Many statistical methods have been developed to model and identify epistatic interactions between genetic variants. However, because of the large combinatorial search space of interactions, most epistasis mapping methods face enormous computational challenges and often suffer from low statistical power due to multiple test correction. Here, we present a novel, alternative strategy for mapping epistasis: instead of directly identifying individual pairwise or higher-order interactions, we focus on mapping variants that have non-zero marginal epistatic effects—the combined pairwise interaction effects between a given variant and all other variants. By testing marginal epistatic effects, we can identify candidate variants that are involved in epistasis without the need to identify the exact partners with which the variants interact, thus potentially alleviating much of the statistical and computational burden associated with standard epistatic mapping procedures. Our method is based on a variance component model, and relies on a recently developed variance component estimation method for efficient parameter inference and p-value computation. We refer to our method as the “MArginal ePIstasis Test”, or MAPIT. With simulations, we show how MAPIT can be used to estimate and test marginal epistatic effects, produce calibrated test statistics under the null, and facilitate the detection of pairwise epistatic interactions. We further illustrate the benefits of MAPIT in a QTL mapping study by analyzing the gene expression data of over 400 individuals from the GEUVADIS consortium. PMID:28746338

Investigating the Association between Flowering Time and Defense in the Arabidopsis thaliana-Fusarium oxysporum Interaction.

PubMed

Lyons, Rebecca; Rusu, Anca; Stiller, Jiri; Powell, Jonathan; Manners, John M; Kazan, Kemal

2015-01-01

Plants respond to pathogens either by investing more resources into immunity which is costly to development, or by accelerating reproductive processes such as flowering time to ensure reproduction occurs before the plant succumbs to disease. In this study we explored the link between flowering time and pathogen defense using the interaction between Arabidopsis thaliana and the root infecting fungal pathogen Fusarium oxysporum. We report that F. oxysporum infection accelerates flowering time and regulates transcription of a number of floral integrator genes, including FLOWERING LOCUS C (FLC), FLOWERING LOCUS T (FT) and GIGANTEA (GI). Furthermore, we observed a positive correlation between late flowering and resistance to F. oxysporum in A. thaliana natural ecotypes. Late-flowering gi and autonomous pathway mutants also exhibited enhanced resistance to F. oxysporum, supporting the association between flowering time and defense. However, epistasis analysis showed that accelerating flowering time by deletion of FLC in fve-3 or fpa-7 mutants did not alter disease resistance, suggesting that the effect of autonomous pathway on disease resistance occurs independently from flowering time. Indeed, RNA-seq analyses suggest that fve-3 mediated resistance to F. oxysporum is most likely a result of altered defense-associated gene transcription. Together, our results indicate that the association between flowering time and pathogen defense is complex and can involve both pleiotropic and direct effects.

Investigating the Association between Flowering Time and Defense in the Arabidopsis thaliana-Fusarium oxysporum Interaction

PubMed Central

Lyons, Rebecca; Rusu, Anca; Stiller, Jiri; Powell, Jonathan; Manners, John M.; Kazan, Kemal

2015-01-01

Plants respond to pathogens either by investing more resources into immunity which is costly to development, or by accelerating reproductive processes such as flowering time to ensure reproduction occurs before the plant succumbs to disease. In this study we explored the link between flowering time and pathogen defense using the interaction between Arabidopsis thaliana and the root infecting fungal pathogen Fusarium oxysporum. We report that F. oxysporum infection accelerates flowering time and regulates transcription of a number of floral integrator genes, including FLOWERING LOCUS C (FLC), FLOWERING LOCUS T (FT) and GIGANTEA (GI). Furthermore, we observed a positive correlation between late flowering and resistance to F. oxysporum in A. thaliana natural ecotypes. Late-flowering gi and autonomous pathway mutants also exhibited enhanced resistance to F. oxysporum, supporting the association between flowering time and defense. However, epistasis analysis showed that accelerating flowering time by deletion of FLC in fve-3 or fpa-7 mutants did not alter disease resistance, suggesting that the effect of autonomous pathway on disease resistance occurs independently from flowering time. Indeed, RNA-seq analyses suggest that fve-3 mediated resistance to F. oxysporum is most likely a result of altered defense-associated gene transcription. Together, our results indicate that the association between flowering time and pathogen defense is complex and can involve both pleiotropic and direct effects. PMID:26034991

Epistasis in intra- and inter-gene pool crosses of the common bean.

PubMed

Borel, J C; Ramalho, M A P; Abreu, A F B

2016-02-26

Epistasis has been shown to have an important role in the genetic control of several quantitative traits in the common bean. This study aimed to investigate the occurrence of epistasis in intra- and inter-pool gene crosses of the common bean. Four elite lines adapted to Brazilian conditions were used as parents, two from the Andean gene pool (ESAL 686; BRS Radiante) and two from the Mesoamerican gene pool (BRSMG Majestoso; BRS Valente). Four F2 populations were obtained: "A" (ESAL 686 x BRS Radiante), "B" (BRSMG Majestoso x BRS Valente), "C" (BRS Radiante x BRSMG Majestoso), and "D" (BRS Valente x ESAL 686). A random sample of F2 plants from each population was backcrossed to parents and F1 individuals, according to the triple test cross. Three types of progenies from each population were evaluated in contiguous trials. Seed yield and 100-seed weight were evaluated. Dominance genetic variance was predominant in most cases. However, the estimates of genetic variance may be biased by the occurrence of linkage disequilibrium and epistasis. Epistasis was detected for both traits; however, the occurrence differed among the populations and between the two traits. The results of this study reinforce the hypothesis that epistasis is present in the genetic control of traits in the common bean and suggest that the phenomenon is more frequent in inter-gene pool crosses than in intra-gene pool crosses.

The evolution of recombination in a heterogeneous environment.

PubMed Central

Lenormand, T; Otto, S P

2000-01-01

Most models describing the evolution of recombination have focused on the case of a single population, implicitly assuming that all individuals are equally likely to mate and that spatial heterogeneity in selection is absent. In these models, the evolution of recombination is driven by linkage disequilibria generated either by epistatic selection or drift. Models based on epistatic selection show that recombination can be favored if epistasis is negative and weak compared to directional selection and if the recombination modifier locus is tightly linked to the selected loci. In this article, we examine the joint effects of spatial heterogeneity in selection and epistasis on the evolution of recombination. In a model with two patches, each subject to different selection regimes, we consider the cases of mutation-selection and migration-selection balance as well as the spread of beneficial alleles. We find that including spatial heterogeneity extends the range of epistasis over which recombination can be favored. Indeed, recombination can be favored without epistasis, with negative and even with positive epistasis depending on environmental circumstances. The selection pressure acting on recombination-modifier loci is often much stronger with spatial heterogeneity, and even loosely linked modifiers and free linkage may evolve. In each case, predicting whether recombination is favored requires knowledge of both the type of environmental heterogeneity and epistasis, as none of these factors alone is sufficient to predict the outcome. PMID:10978305

Computational analysis of gene-gene interactions using multifactor dimensionality reduction.

PubMed

Moore, Jason H

2004-11-01

Understanding the relationship between DNA sequence variations and biologic traits is expected to improve the diagnosis, prevention and treatment of common human diseases. Success in characterizing genetic architecture will depend on our ability to address nonlinearities in the genotype-to-phenotype mapping relationship as a result of gene-gene interactions, or epistasis. This review addresses the challenges associated with the detection and characterization of epistasis. A novel strategy known as multifactor dimensionality reduction that was specifically designed for the identification of multilocus genetic effects is presented. Several case studies that demonstrate the detection of gene-gene interactions in common diseases such as atrial fibrillation, Type II diabetes and essential hypertension are also discussed.

Epistasis in protein evolution

PubMed Central

Starr, Tyler N.

2016-01-01

Abstract The structure, function, and evolution of proteins depend on physical and genetic interactions among amino acids. Recent studies have used new strategies to explore the prevalence, biochemical mechanisms, and evolutionary implications of these interactions—called epistasis—within proteins. Here we describe an emerging picture of pervasive epistasis in which the physical and biological effects of mutations change over the course of evolution in a lineage‐specific fashion. Epistasis can restrict the trajectories available to an evolving protein or open new paths to sequences and functions that would otherwise have been inaccessible. We describe two broad classes of epistatic interactions, which arise from different physical mechanisms and have different effects on evolutionary processes. Specific epistasis—in which one mutation influences the phenotypic effect of few other mutations—is caused by direct and indirect physical interactions between mutations, which nonadditively change the protein's physical properties, such as conformation, stability, or affinity for ligands. In contrast, nonspecific epistasis describes mutations that modify the effect of many others; these typically behave additively with respect to the physical properties of a protein but exhibit epistasis because of a nonlinear relationship between the physical properties and their biological effects, such as function or fitness. Both types of interaction are rampant, but specific epistasis has stronger effects on the rate and outcomes of evolution, because it imposes stricter constraints and modulates evolutionary potential more dramatically; it therefore makes evolution more contingent on low‐probability historical events and leaves stronger marks on the sequences, structures, and functions of protein families. PMID:26833806

A Systematic Survey of an Intragenic Epistatic Landscape

PubMed Central

Bank, Claudia; Hietpas, Ryan T.; Jensen, Jeffrey D.; Bolon, Daniel N.A.

2015-01-01

Mutations are the source of evolutionary variation. The interactions of multiple mutations can have important effects on fitness and evolutionary trajectories. We have recently described the distribution of fitness effects of all single mutations for a nine-amino-acid region of yeast Hsp90 (Hsp82) implicated in substrate binding. Here, we report and discuss the distribution of intragenic epistatic effects within this region in seven Hsp90 point mutant backgrounds of neutral to slightly deleterious effect, resulting in an analysis of more than 1,000 double mutants. We find negative epistasis between substitutions to be common, and positive epistasis to be rare—resulting in a pattern that indicates a drastic change in the distribution of fitness effects one step away from the wild type. This can be well explained by a concave relationship between phenotype and genotype (i.e., a concave shape of the local fitness landscape), suggesting mutational robustness intrinsic to the local sequence space. Structural analyses indicate that, in this region, epistatic effects are most pronounced when a solvent-inaccessible position is involved in the interaction. In contrast, all 18 observations of positive epistasis involved at least one mutation at a solvent-exposed position. By combining the analysis of evolutionary and biophysical properties of an epistatic landscape, these results contribute to a more detailed understanding of the complexity of protein evolution. PMID:25371431

Of Mice and Men: Empirical Support for the Population-Based Social Epistasis Amplification Model (a Comment on ).

PubMed

Sarraf, Matthew Alexandar; Woodley Of Menie, Michael Anthony

2017-01-01

This commentary article offers new perspective on recent research investigating the behavioral and social ecological effects of a mutation related to autism spectrum disorders in mice. The authors explain the consistency of this research on mice with predictions advanced by a theory of the role of mutations in altering interorganismal gene-gene interactions (social epistasis) in social species including humans, known as the social epistasis amplification model. The potential significance of the mouse research for understanding contemporary human behavioral trends is explored.

Shadows of complexity: what biological networks reveal about epistasis and pleiotropy

PubMed Central

Tyler, Anna L.; Asselbergs, Folkert W.; Williams, Scott M.; Moore, Jason H.

2011-01-01

Pleiotropy, in which one mutation causes multiple phenotypes, has traditionally been seen as a deviation from the conventional observation in which one gene affects one phenotype. Epistasis, or gene-gene interaction, has also been treated as an exception to the Mendelian one gene-one phenotype paradigm. This simplified perspective belies the pervasive complexity of biology and hinders progress toward a deeper understanding of biological systems. We assert that epistasis and pleiotropy are not isolated occurrences, but ubiquitous and inherent properties of biomolecular networks. These phenomena should not be treated as exceptions, but rather as fundamental components of genetic analyses. A systems level understanding of epistasis and pleiotropy is, therefore, critical to furthering our understanding of human genetics and its contribution to common human disease. Finally, graph theory offers an intuitive and powerful set of tools with which to study the network bases of these important genetic phenomena. PMID:19204994

Cancer type-dependent genetic interactions between cancer driver alterations indicate plasticity of epistasis across cell types

PubMed Central

Park, Solip; Lehner, Ben

2015-01-01

Cancers, like many diseases, are normally caused by combinations of genetic alterations rather than by changes affecting single genes. It is well established that the genetic alterations that drive cancer often interact epistatically, having greater or weaker consequences in combination than expected from their individual effects. In a stringent statistical analysis of data from > 3,000 tumors, we find that the co-occurrence and mutual exclusivity relationships between cancer driver alterations change quite extensively in different types of cancer. This cannot be accounted for by variation in tumor heterogeneity or unrecognized cancer subtypes. Rather, it suggests that how genomic alterations interact cooperatively or partially redundantly to driver cancer changes in different types of cancers. This re-wiring of epistasis across cell types is likely to be a basic feature of genetic architecture, with important implications for understanding the evolution of multicellularity and human genetic diseases. In addition, if this plasticity of epistasis across cell types is also true for synthetic lethal interactions, a synthetic lethal strategy to kill cancer cells may frequently work in one type of cancer but prove ineffective in another. PMID:26227665

Detection of Epistasis for Flowering Time Using Bayesian Multilocus Estimation in a Barley MAGIC Population

PubMed Central

Mathew, Boby; Léon, Jens; Sannemann, Wiebke; Sillanpää, Mikko J.

2018-01-01

Gene-by-gene interactions, also known as epistasis, regulate many complex traits in different species. With the availability of low-cost genotyping it is now possible to study epistasis on a genome-wide scale. However, identifying genome-wide epistasis is a high-dimensional multiple regression problem and needs the application of dimensionality reduction techniques. Flowering Time (FT) in crops is a complex trait that is known to be influenced by many interacting genes and pathways in various crops. In this study, we successfully apply Sure Independence Screening (SIS) for dimensionality reduction to identify two-way and three-way epistasis for the FT trait in a Multiparent Advanced Generation Inter-Cross (MAGIC) barley population using the Bayesian multilocus model. The MAGIC barley population was generated from intercrossing among eight parental lines and thus, offered greater genetic diversity to detect higher-order epistatic interactions. Our results suggest that SIS is an efficient dimensionality reduction approach to detect high-order interactions in a Bayesian multilocus model. We also observe that many of our findings (genomic regions with main or higher-order epistatic effects) overlap with known candidate genes that have been already reported in barley and closely related species for the FT trait. PMID:29254994

Are Interactions between cis-Regulatory Variants Evidence for Biological Epistasis or Statistical Artifacts?

PubMed

Fish, Alexandra E; Capra, John A; Bush, William S

2016-10-06

The importance of epistasis-or statistical interactions between genetic variants-to the development of complex disease in humans has been controversial. Genome-wide association studies of statistical interactions influencing human traits have recently become computationally feasible and have identified many putative interactions. However, statistical models used to detect interactions can be confounded, which makes it difficult to be certain that observed statistical interactions are evidence for true molecular epistasis. In this study, we investigate whether there is evidence for epistatic interactions between genetic variants within the cis-regulatory region that influence gene expression after accounting for technical, statistical, and biological confounding factors. We identified 1,119 (FDR = 5%) interactions that appear to regulate gene expression in human lymphoblastoid cell lines, a tightly controlled, largely genetically determined phenotype. Many of these interactions replicated in an independent dataset (90 of 803 tested, Bonferroni threshold). We then performed an exhaustive analysis of both known and novel confounders, including ceiling/floor effects, missing genotype combinations, haplotype effects, single variants tagged through linkage disequilibrium, and population stratification. Every interaction could be explained by at least one of these confounders, and replication in independent datasets did not protect against some confounders. Assuming that the confounding factors provide a more parsimonious explanation for each interaction, we find it unlikely that cis-regulatory interactions contribute strongly to human gene expression, which calls into question the relevance of cis-regulatory interactions for other human phenotypes. We additionally propose several best practices for epistasis testing to protect future studies from confounding. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Recombination and the evolution of coordinated phenotypic expression in a frequency-dependent game

PubMed Central

Arbilly, Michal; Motro, Uzi; Feldman, Marcus W.; Lotem, Arnon

2011-01-01

A long standing question in evolutionary biology concerns the maintenance of adaptive combinations of traits in the presence of recombination. This problem may be solved if positive epistasis selects for reducing the rate of recombination between such traits, but this requires sufficiently strong epistasis. Here we use a model that we developed previously to analyze a frequency-dependent strategy game in asexual populations, to study how adaptive combinations of traits may be maintained in the presence of recombination when epistasis is too weak to select for genetic linkage. Previously, in the asexual case, our model demonstrated the evolution of adaptive associations between social foraging strategies and learning rules. We verify that these adaptive associations, which are represented by different two-locus haplotypes, can easily be broken by genetic recombination. We also confirm that a modifier allele that reduces the rate of recombination fails to evolve (due to weak epistasis). However, we find that under the same conditions of weak epistasis, there is an alternative mechanism that allows association between traits to evolve. This is based on a genetic switch that responds to the presence of one social foraging allele by activating one of two alternative learning alleles that are carried by all individuals. We suggest that such coordinated phenotypic expression by genetic switches offers a general and robust mechanism for the evolution of adaptive combinations of traits in the presence of recombination. PMID:21945887

GxG epistasis in growth and condition and the maintenance of genetic polymorphism in Gambusia holbrooki.

PubMed

Culumber, Zachary W; Kraft, Brittany; Lemakos, Valerie; Hoffner, Erika; Travis, Joseph; Hughes, Kimberly A

2018-05-01

Theory on indirect genetic effects (IGEs) indicates that variation in the genetic composition of social groups can generate GxG epistasis that may promote the evolution of stable polymorphisms. Using a livebearing fish with a genetic polymorphism in coloration and associated behavioral differences, we tested whether genotypes of social partners interacted with focal individual genotypes to influence growth and condition over 16 weeks of development. We found that IGEs had a significant influence on patterns of feeding, regardless of focal fish genotype. There was no influence of social environment on juvenile length, but there was significant GxG epistasis for body condition. Each focal juvenile was in better condition when its own genotype was not present in adult social partners. These data are consistent with negative frequency-dependent selection in which each morph performs better when it is rare. Neither variation in feeding nor activity-related behaviors explained variation in body condition, suggesting that GxG epistasis for condition was caused by physiological differences between the two genotypes. These findings indicate that GxG epistasis in a given polymorphism can generate fitness landscapes that contribute to the maintenance of that polymorphism and to maintenance of genetic variation for additional fitness-related traits. © 2018 The Author(s). Evolution © 2018 The Society for the Study of Evolution.

The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project.

PubMed

Medway, Christopher; Combarros, Onofre; Cortina-Borja, Mario; Butler, Helen T; Ibrahim-Verbaas, Carla A; de Bruijn, Renée F A G; Koudstaal, Peter J; van Duijn, Cornelia M; Ikram, M Arfan; Mateo, Ignacio; Sánchez-Juan, Pascual; Lehmann, Michael G; Heun, Reinhard; Kölsch, Heike; Deloukas, Panos; Hammond, Naomi; Coto, Eliecer; Alvarez, Victoria; Kehoe, Patrick G; Barber, Rachel; Wilcock, Gordon K; Brown, Kristelle; Belbin, Olivia; Warden, Donald R; Smith, A David; Morgan, Kevin; Lehmann, Donald J

2014-02-01

Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.

SuperDCA for genome-wide epistasis analysis.

PubMed

Puranen, Santeri; Pesonen, Maiju; Pensar, Johan; Xu, Ying Ying; Lees, John A; Bentley, Stephen D; Croucher, Nicholas J; Corander, Jukka

2018-05-29

The potential for genome-wide modelling of epistasis has recently surfaced given the possibility of sequencing densely sampled populations and the emerging families of statistical interaction models. Direct coupling analysis (DCA) has previously been shown to yield valuable predictions for single protein structures, and has recently been extended to genome-wide analysis of bacteria, identifying novel interactions in the co-evolution between resistance, virulence and core genome elements. However, earlier computational DCA methods have not been scalable to enable model fitting simultaneously to 10 4 -10 5 polymorphisms, representing the amount of core genomic variation observed in analyses of many bacterial species. Here, we introduce a novel inference method (SuperDCA) that employs a new scoring principle, efficient parallelization, optimization and filtering on phylogenetic information to achieve scalability for up to 10 5 polymorphisms. Using two large population samples of Streptococcus pneumoniae, we demonstrate the ability of SuperDCA to make additional significant biological findings about this major human pathogen. We also show that our method can uncover signals of selection that are not detectable by genome-wide association analysis, even though our analysis does not require phenotypic measurements. SuperDCA, thus, holds considerable potential in building understanding about numerous organisms at a systems biological level.

What’s Downstream? A Set of Classroom Exercises to Help Students Understand Recessive Epistasis †

PubMed Central

Knight, Jennifer K.; Wood, William B.; Smith, Michelle K.

2013-01-01

Undergraduate students in genetics and developmental biology courses often struggle with the concept of epistasis because they are unaware that the logic of gene interactions differs between enzymatic pathways and signaling pathways. If students try to develop and memorize a single simple rule for predicting epistatic relationships without taking into account the nature of the pathway under consideration, they can become confused by cases where the rule does not apply. To remedy this problem, we developed a short pre-/post-test, an in-class activity for small groups, and a series of clicker questions about recessive epistasis in the context of a signaling pathway that intersects with an enzymatic pathway. We also developed a series of homework problems that provide deliberate practice in applying concepts in epistasis to different pathways and experimental situations. Students show significant improvement from pretest to posttest, and perform well on homework and exam questions following this activity. Here we describe these materials, as well as the formative and summative assessment results from one group of students to show how the activities impact student learning. PMID:24358383

Epistasis and the selective advantage of sex and recombination

NASA Astrophysics Data System (ADS)

de Oliveira, Viviane M.; da Silva, Juliana K.; Campos, Paulo R. A.

2008-09-01

The understanding of the central mechanisms favoring sex and recombination in real populations is one of the fundamental issues in evolutionary biology. Based on a previous stochastic formulation for the study of sex, here we aim to investigate the conditions under which epistasis favors the fixation of the sexual mode of reproduction in a given population. In addition, we try to identify the evolutionary forces which contribute to this process. One considers a finite population model which assumes the existence of a recombination modifier allele that can activate the recombination mechanism. We have found that sex is very little favored in a scenario of antagonistic epistasis, and this advantage only occurs in a narrow range of values of the selection coefficient sd . On the other hand, synergistic epistasis favors recombination in a very broad domain. However, the major mechanism contributing to the spreading of the modifier allele depends on the range of values of sd . At large sd , background selection favors recombination since it increases the efficacy of selection, while at low sd Muller’s ratchet is the leading mechanism.

Epistasis and Its Implications for Personal Genetics

PubMed Central

Moore, Jason H.; Williams, Scott M.

2009-01-01

The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis can affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity. PMID:19733727

Epistasis and its implications for personal genetics.

PubMed

Moore, Jason H; Williams, Scott M

2009-09-01

The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis can affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity.

JBASE: Joint Bayesian Analysis of Subphenotypes and Epistasis.

PubMed

Colak, Recep; Kim, TaeHyung; Kazan, Hilal; Oh, Yoomi; Cruz, Miguel; Valladares-Salgado, Adan; Peralta, Jesus; Escobedo, Jorge; Parra, Esteban J; Kim, Philip M; Goldenberg, Anna

2016-01-15

Rapid advances in genotyping and genome-wide association studies have enabled the discovery of many new genotype-phenotype associations at the resolution of individual markers. However, these associations explain only a small proportion of theoretically estimated heritability of most diseases. In this work, we propose an integrative mixture model called JBASE: joint Bayesian analysis of subphenotypes and epistasis. JBASE explores two major reasons of missing heritability: interactions between genetic variants, a phenomenon known as epistasis and phenotypic heterogeneity, addressed via subphenotyping. Our extensive simulations in a wide range of scenarios repeatedly demonstrate that JBASE can identify true underlying subphenotypes, including their associated variants and their interactions, with high precision. In the presence of phenotypic heterogeneity, JBASE has higher Power and lower Type 1 Error than five state-of-the-art approaches. We applied our method to a sample of individuals from Mexico with Type 2 diabetes and discovered two novel epistatic modules, including two loci each, that define two subphenotypes characterized by differences in body mass index and waist-to-hip ratio. We successfully replicated these subphenotypes and epistatic modules in an independent dataset from Mexico genotyped with a different platform. JBASE is implemented in C++, supported on Linux and is available at http://www.cs.toronto.edu/∼goldenberg/JBASE/jbase.tar.gz. The genotype data underlying this study are available upon approval by the ethics review board of the Medical Centre Siglo XXI. Please contact Dr Miguel Cruz at mcruzl@yahoo.com for assistance with the application. anna.goldenberg@utoronto.ca Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

TEAM: efficient two-locus epistasis tests in human genome-wide association study.

PubMed

Zhang, Xiang; Huang, Shunping; Zou, Fei; Wang, Wei

2010-06-15

As a promising tool for identifying genetic markers underlying phenotypic differences, genome-wide association study (GWAS) has been extensively investigated in recent years. In GWAS, detecting epistasis (or gene-gene interaction) is preferable over single locus study since many diseases are known to be complex traits. A brute force search is infeasible for epistasis detection in the genome-wide scale because of the intensive computational burden. Existing epistasis detection algorithms are designed for dataset consisting of homozygous markers and small sample size. In human study, however, the genotype may be heterozygous, and number of individuals can be up to thousands. Thus, existing methods are not readily applicable to human datasets. In this article, we propose an efficient algorithm, TEAM, which significantly speeds up epistasis detection for human GWAS. Our algorithm is exhaustive, i.e. it does not ignore any epistatic interaction. Utilizing the minimum spanning tree structure, the algorithm incrementally updates the contingency tables for epistatic tests without scanning all individuals. Our algorithm has broader applicability and is more efficient than existing methods for large sample study. It supports any statistical test that is based on contingency tables, and enables both family-wise error rate and false discovery rate controlling. Extensive experiments show that our algorithm only needs to examine a small portion of the individuals to update the contingency tables, and it achieves at least an order of magnitude speed up over the brute force approach.

Evolution and polymorphism in the multilocus Levene model with no or weak epistasis.

PubMed

Bürger, Reinhard

2010-09-01

Evolution and the maintenance of polymorphism under the multilocus Levene model with soft selection are studied. The number of loci and alleles, the number of demes, the linkage map, and the degree of dominance are arbitrary, but epistasis is absent or weak. We prove that, without epistasis and under mild, generic conditions, every trajectory converges to a stationary point in linkage equilibrium. Consequently, the equilibrium and stability structure can be determined by investigating the much simpler gene-frequency dynamics on the linkage-equilibrium manifold. For a haploid species an analogous result is shown. For weak epistasis, global convergence to quasi-linkage equilibrium is established. As an application, the maintenance of multilocus polymorphism is explored if the degree of dominance is intermediate at every locus and epistasis is absent or weak. If there are at least two demes, then arbitrarily many multiallelic loci can be maintained polymorphic at a globally asymptotically stable equilibrium. Because this holds for an open set of parameters, such equilibria are structurally stable. If the degree of dominance is not only intermediate but also deme independent, and loci are diallelic, an open set of parameters yielding an internal equilibrium exists only if the number of loci is strictly less than the number of demes. Otherwise, a fully polymorphic equilibrium exists only nongenerically, and if it exists, it consists of a manifold of equilibria. Its dimension is determined. In the absence of genotype-by-environment interaction, however, a manifold of equilibria occurs for an open set of parameters. In this case, the equilibrium structure is not robust to small deviations from no genotype-by-environment interaction. In a quantitative-genetic setting, the assumptions of no epistasis and intermediate dominance are equivalent to assuming that in every deme directional selection acts on a trait that is determined additively, i.e., by nonepistatic loci with dominance. Some of our results are exemplified in this quantitative-genetic context. Copyright 2010 Elsevier Inc. All rights reserved.

Comparing GWAS Results of Complex Traits Using Full Genetic Model and Additive Models for Revealing Genetic Architecture

PubMed Central

Monir, Md. Mamun; Zhu, Jun

2017-01-01

Most of the genome-wide association studies (GWASs) for human complex diseases have ignored dominance, epistasis and ethnic interactions. We conducted comparative GWASs for total cholesterol using full model and additive models, which illustrate the impacts of the ignoring genetic variants on analysis results and demonstrate how genetic effects of multiple loci could differ across different ethnic groups. There were 15 quantitative trait loci with 13 individual loci and 3 pairs of epistasis loci identified by full model, whereas only 14 loci (9 common loci and 5 different loci) identified by multi-loci additive model. Again, 4 full model detected loci were not detected using multi-loci additive model. PLINK-analysis identified two loci and GCTA-analysis detected only one locus with genome-wide significance. Full model identified three previously reported genes as well as several new genes. Bioinformatics analysis showed some new genes are related with cholesterol related chemicals and/or diseases. Analyses of cholesterol data and simulation studies revealed that the full model performs were better than the additive-model performs in terms of detecting power and unbiased estimations of genetic variants of complex traits. PMID:28079101

Survival dimensionality reduction (SDR): development and clinical application of an innovative approach to detect epistasis in presence of right-censored data.

PubMed

Beretta, Lorenzo; Santaniello, Alessandro; van Riel, Piet L C M; Coenen, Marieke J H; Scorza, Raffaella

2010-08-06

Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%). The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the Fc gamma RIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. http://sourceforge.net/projects/sdrproject/.

An information-gain approach to detecting three-way epistatic interactions in genetic association studies

PubMed Central

Hu, Ting; Chen, Yuanzhu; Kiralis, Jeff W; Collins, Ryan L; Wejse, Christian; Sirugo, Giorgio; Williams, Scott M; Moore, Jason H

2013-01-01

Background Epistasis has been historically used to describe the phenomenon that the effect of a given gene on a phenotype can be dependent on one or more other genes, and is an essential element for understanding the association between genetic and phenotypic variations. Quantifying epistasis of orders higher than two is very challenging due to both the computational complexity of enumerating all possible combinations in genome-wide data and the lack of efficient and effective methodologies. Objectives In this study, we propose a fast, non-parametric, and model-free measure for three-way epistasis. Methods Such a measure is based on information gain, and is able to separate all lower order effects from pure three-way epistasis. Results Our method was verified on synthetic data and applied to real data from a candidate-gene study of tuberculosis in a West African population. In the tuberculosis data, we found a statistically significant pure three-way epistatic interaction effect that was stronger than any lower-order associations. Conclusion Our study provides a methodological basis for detecting and characterizing high-order gene-gene interactions in genetic association studies. PMID:23396514

PEPIS: A Pipeline for Estimating Epistatic Effects in Quantitative Trait Locus Mapping and Genome-Wide Association Studies.

PubMed

Zhang, Wenchao; Dai, Xinbin; Wang, Qishan; Xu, Shizhong; Zhao, Patrick X

2016-05-01

The term epistasis refers to interactions between multiple genetic loci. Genetic epistasis is important in regulating biological function and is considered to explain part of the 'missing heritability,' which involves marginal genetic effects that cannot be accounted for in genome-wide association studies. Thus, the study of epistasis is of great interest to geneticists. However, estimating epistatic effects for quantitative traits is challenging due to the large number of interaction effects that must be estimated, thus significantly increasing computing demands. Here, we present a new web server-based tool, the Pipeline for estimating EPIStatic genetic effects (PEPIS), for analyzing polygenic epistatic effects. The PEPIS software package is based on a new linear mixed model that has been used to predict the performance of hybrid rice. The PEPIS includes two main sub-pipelines: the first for kinship matrix calculation, and the second for polygenic component analyses and genome scanning for main and epistatic effects. To accommodate the demand for high-performance computation, the PEPIS utilizes C/C++ for mathematical matrix computing. In addition, the modules for kinship matrix calculations and main and epistatic-effect genome scanning employ parallel computing technology that effectively utilizes multiple computer nodes across our networked cluster, thus significantly improving the computational speed. For example, when analyzing the same immortalized F2 rice population genotypic data examined in a previous study, the PEPIS returned identical results at each analysis step with the original prototype R code, but the computational time was reduced from more than one month to about five minutes. These advances will help overcome the bottleneck frequently encountered in genome wide epistatic genetic effect analysis and enable accommodation of the high computational demand. The PEPIS is publically available at http://bioinfo.noble.org/PolyGenic_QTL/.

Genome-wide analysis of epistasis in body mass index using multiple human populations.

PubMed

Wei, Wen-Hua; Hemani, Gib; Gyenesei, Attila; Vitart, Veronique; Navarro, Pau; Hayward, Caroline; Cabrera, Claudia P; Huffman, Jennifer E; Knott, Sara A; Hicks, Andrew A; Rudan, Igor; Pramstaller, Peter P; Wild, Sarah H; Wilson, James F; Campbell, Harry; Hastie, Nicholas D; Wright, Alan F; Haley, Chris S

2012-08-01

We surveyed gene-gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E-08) and a Bonferroni corrected threshold (P=1.1E-12), respectively. Next we compared sub genome-wide significant SNP interactions (P<5.0E-08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E-08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.

ViSEN: methodology and software for visualization of statistical epistasis networks

PubMed Central

Hu, Ting; Chen, Yuanzhu; Kiralis, Jeff W.; Moore, Jason H.

2013-01-01

The non-linear interaction effect among multiple genetic factors, i.e. epistasis, has been recognized as a key component in understanding the underlying genetic basis of complex human diseases and phenotypic traits. Due to the statistical and computational complexity, most epistasis studies are limited to interactions with an order of two. We developed ViSEN to analyze and visualize epistatic interactions of both two-way and three-way. ViSEN not only identifies strong interactions among pairs or trios of genetic attributes, but also provides a global interaction map that shows neighborhood and clustering structures. This visualized information could be very helpful to infer the underlying genetic architecture of complex diseases and to generate plausible hypotheses for further biological validations. ViSEN is implemented in Java and freely available at https://sourceforge.net/projects/visen/. PMID:23468157

Survival dimensionality reduction (SDR): development and clinical application of an innovative approach to detect epistasis in presence of right-censored data

PubMed Central

2010-01-01

Background Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. Results The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%). The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the FcγRIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. Conclusions Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. Availability: http://sourceforge.net/projects/sdrproject/ PMID:20691091

Mitochondrial Recombination Reveals Mito-Mito Epistasis in Yeast.

PubMed

Wolters, John F; Charron, Guillaume; Gaspary, Alec; Landry, Christian R; Fiumera, Anthony C; Fiumera, Heather L

2018-05-01

Genetic variation in mitochondrial DNA (mtDNA) provides adaptive potential although the underlying genetic architecture of fitness components within mtDNAs is not known. To dissect functional variation within mtDNAs, we first identified naturally occurring mtDNAs that conferred high or low fitness in Saccharomyces cerevisiae by comparing growth in strains containing identical nuclear genotypes but different mtDNAs. During respiratory growth under temperature and oxidative stress conditions, mitotype effects were largely independent of nuclear genotypes even in the presence of mito-nuclear interactions. Recombinant mtDNAs were generated to determine fitness components within high- and low-fitness mtDNAs. Based on phenotypic distributions of isogenic strains containing recombinant mtDNAs, we found that multiple loci contributed to mitotype fitness differences. These mitochondrial loci interacted in epistatic, nonadditive ways in certain environmental conditions. Mito-mito epistasis ( i.e. , nonadditive interactions between mitochondrial loci) influenced fitness in progeny from four different crosses, suggesting that mito-mito epistasis is a widespread phenomenon in yeast and other systems with recombining mtDNAs. Furthermore, we found that interruption of coadapted mito-mito interactions produced recombinant mtDNAs with lower fitness. Our results demonstrate that mito-mito epistasis results in functional variation through mitochondrial recombination in fungi, providing modes for adaptive evolution and the generation of mito-mito incompatibilities. Copyright © 2018 by the Genetics Society of America.

Analysis of recombination QTLs, segregation distortion, and epistasis for fitness in maize multiple populations using ultra-high-density markers

USDA-ARS?s Scientific Manuscript database

Understanding the maize genomic features would be useful for the study of genetic diversity and evolution and for maize breeding. Here, we used two maize nested association mapping (NAM) populations separately derived in China (CN-NAM) and the US (US-NAM) to explore the maize genomic features. The t...

Estimation and interpretation of genetic effects with epistasis using the NOIA model.

PubMed

Alvarez-Castro, José M; Carlborg, Orjan; Rönnegård, Lars

2012-01-01

We introduce this communication with a brief outline of the historical landmarks in genetic modeling, especially concerning epistasis. Then, we present methods for the use of genetic modeling in QTL analyses. In particular, we summarize the essential expressions of the natural and orthogonal interactions (NOIA) model of genetic effects. Our motivation for reviewing that theory here is twofold. First, this review presents a digest of the expressions for the application of the NOIA model, which are often mixed with intermediate and additional formulae in the original articles. Second, we make the required theory handy for the reader to relate the genetic concepts to the particular mathematical expressions underlying them. We illustrate those relations by providing graphical interpretations and a diagram summarizing the key features for applying genetic modeling with epistasis in comprehensive QTL analyses. Finally, we briefly review some examples of the application of NOIA to real data and the way it improves the interpretability of the results.

How does epistasis influence the response to selection?

PubMed Central

Barton, N H

2017-01-01

Much of quantitative genetics is based on the ‘infinitesimal model', under which selection has a negligible effect on the genetic variance. This is typically justified by assuming a very large number of loci with additive effects. However, it applies even when genes interact, provided that the number of loci is large enough that selection on each of them is weak relative to random drift. In the long term, directional selection will change allele frequencies, but even then, the effects of epistasis on the ultimate change in trait mean due to selection may be modest. Stabilising selection can maintain many traits close to their optima, even when the underlying alleles are weakly selected. However, the number of traits that can be optimised is apparently limited to ~4Ne by the ‘drift load', and this is hard to reconcile with the apparent complexity of many organisms. Just as for the mutation load, this limit can be evaded by a particular form of negative epistasis. A more robust limit is set by the variance in reproductive success. This suggests that selection accumulates information most efficiently in the infinitesimal regime, when selection on individual alleles is weak, and comparable with random drift. A review of evidence on selection strength suggests that although most variance in fitness may be because of alleles with large Nes, substantial amounts of adaptation may be because of alleles in the infinitesimal regime, in which epistasis has modest effects. PMID:27901509

How does epistasis influence the response to selection?

PubMed

Barton, N H

2017-01-01

Much of quantitative genetics is based on the 'infinitesimal model', under which selection has a negligible effect on the genetic variance. This is typically justified by assuming a very large number of loci with additive effects. However, it applies even when genes interact, provided that the number of loci is large enough that selection on each of them is weak relative to random drift. In the long term, directional selection will change allele frequencies, but even then, the effects of epistasis on the ultimate change in trait mean due to selection may be modest. Stabilising selection can maintain many traits close to their optima, even when the underlying alleles are weakly selected. However, the number of traits that can be optimised is apparently limited to ~4N e by the 'drift load', and this is hard to reconcile with the apparent complexity of many organisms. Just as for the mutation load, this limit can be evaded by a particular form of negative epistasis. A more robust limit is set by the variance in reproductive success. This suggests that selection accumulates information most efficiently in the infinitesimal regime, when selection on individual alleles is weak, and comparable with random drift. A review of evidence on selection strength suggests that although most variance in fitness may be because of alleles with large N e s, substantial amounts of adaptation may be because of alleles in the infinitesimal regime, in which epistasis has modest effects.

The effect of gene interactions on the long-term response to selection.

PubMed

Paixão, Tiago; Barton, Nicholas H

2016-04-19

The role of gene interactions in the evolutionary process has long been controversial. Although some argue that they are not of importance, because most variation is additive, others claim that their effect in the long term can be substantial. Here, we focus on the long-term effects of genetic interactions under directional selection assuming no mutation or dominance, and that epistasis is symmetrical overall. We ask by how much the mean of a complex trait can be increased by selection and analyze two extreme regimes, in which either drift or selection dominate the dynamics of allele frequencies. In both scenarios, epistatic interactions affect the long-term response to selection by modulating the additive genetic variance. When drift dominates, we extend Robertson's [Robertson A (1960)Proc R Soc Lond B Biol Sci153(951):234-249] argument to show that, for any form of epistasis, the total response of a haploid population is proportional to the initial total genotypic variance. In contrast, the total response of a diploid population is increased by epistasis, for a given initial genotypic variance. When selection dominates, we show that the total selection response can only be increased by epistasis when some initially deleterious alleles become favored as the genetic background changes. We find a simple approximation for this effect and show that, in this regime, it is the structure of the genotype-phenotype map that matters and not the variance components of the population.

Translational regulation of ribosomal protein S15 drives characteristic patterns of protein-mRNA epistasis.

PubMed

Mallik, Saurav; Basu, Sudipto; Hait, Suman; Kundu, Sudip

2018-04-21

Do coding and regulatory segments of a gene co-evolve with each-other? Seeking answers to this question, here we analyze the case of Escherichia coli ribosomal protein S15, that represses its own translation by specifically binding its messenger RNA (rpsO mRNA) and stabilizing a pseudoknot structure at the upstream untranslated region, thus trapping the ribosome into an incomplete translation initiation complex. In the absence of S15, ribosomal protein S1 recognizes rpsO and promotes translation by melting this very pseudoknot. We employ a robust statistical method to detect signatures of positive epistasis between residue site pairs and find that biophysical constraints of translational regulation (S15-rpsO and S1-rpsO recognition, S15-mediated rpsO structural rearrangement, and S1-mediated melting) are strong predictors of positive epistasis. Transforming the epistatic pairs into a network, we find that signatures of two different, but interconnected regulatory cascades are imprinted in the sequence-space and can be captured in terms of two dense network modules that are sparsely connected to each other. This network topology further reflects a general principle of how functionally coupled components of biological networks are interconnected. These results depict a model case, where translational regulation drives characteristic residue-level epistasis-not only between a protein and its own mRNA but also between a protein and the mRNA of an entirely different protein. © 2018 Wiley Periodicals, Inc.

EPIBLASTER-fast exhaustive two-locus epistasis detection strategy using graphical processing units

PubMed Central

Kam-Thong, Tony; Czamara, Darina; Tsuda, Koji; Borgwardt, Karsten; Lewis, Cathryn M; Erhardt-Lehmann, Angelika; Hemmer, Bernhard; Rieckmann, Peter; Daake, Markus; Weber, Frank; Wolf, Christiane; Ziegler, Andreas; Pütz, Benno; Holsboer, Florian; Schölkopf, Bernhard; Müller-Myhsok, Bertram

2011-01-01

Detection of epistatic interaction between loci has been postulated to provide a more in-depth understanding of the complex biological and biochemical pathways underlying human diseases. Studying the interaction between two loci is the natural progression following traditional and well-established single locus analysis. However, the added costs and time duration required for the computation involved have thus far deterred researchers from pursuing a genome-wide analysis of epistasis. In this paper, we propose a method allowing such analysis to be conducted very rapidly. The method, dubbed EPIBLASTER, is applicable to case–control studies and consists of a two-step process in which the difference in Pearson's correlation coefficients is computed between controls and cases across all possible SNP pairs as an indication of significant interaction warranting further analysis. For the subset of interactions deemed potentially significant, a second-stage analysis is performed using the likelihood ratio test from the logistic regression to obtain the P-value for the estimated coefficients of the individual effects and the interaction term. The algorithm is implemented using the parallel computational capability of commercially available graphical processing units to greatly reduce the computation time involved. In the current setup and example data sets (211 cases, 222 controls, 299468 SNPs; and 601 cases, 825 controls, 291095 SNPs), this coefficient evaluation stage can be completed in roughly 1 day. Our method allows for exhaustive and rapid detection of significant SNP pair interactions without imposing significant marginal effects of the single loci involved in the pair. PMID:21150885

Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus.

PubMed

Hughes, Travis; Adler, Adam; Kelly, Jennifer A; Kaufman, Kenneth M; Williams, Adrienne H; Langefeld, Carl D; Brown, Elizabeth E; Alarcón, Graciela S; Kimberly, Robert P; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle; Boackle, Susan A; Stevens, Anne M; Reveille, John D; Sanchez, Elena; Martín, Javier; Niewold, Timothy B; Vilá, Luis M; Scofield, R Hal; Gilkeson, Gary S; Gaffney, Patrick M; Criswell, Lindsey A; Moser, Kathy L; Merrill, Joan T; Jacob, Chaim O; Tsao, Betty P; James, Judith A; Vyse, Timothy J; Alarcón-Riquelme, Marta E; Harley, John B; Richardson, Bruce C; Sawalha, Amr H

2012-02-01

Several confirmed genetic susceptibility loci for lupus have been described. To date, no clear evidence for genetic epistasis in lupus has been established. The aim of this study was to test for gene-gene interactions in a number of known lupus susceptibility loci. Eighteen single-nucleotide polymorphisms tagging independent and confirmed lupus susceptibility loci were genotyped in a set of 4,248 patients with lupus and 3,818 normal healthy control subjects of European descent. Epistasis was tested by a 2-step approach using both parametric and nonparametric methods. The false discovery rate (FDR) method was used to correct for multiple testing. We detected and confirmed gene-gene interactions between the HLA region and CTLA4, IRF5, and ITGAM and between PDCD1 and IL21 in patients with lupus. The most significant interaction detected by parametric analysis was between rs3131379 in the HLA region and rs231775 in CTLA4 (interaction odds ratio 1.19, Z = 3.95, P = 7.8 × 10(-5) [FDR ≤0.05], P for multifactor dimensionality reduction = 5.9 × 10(-45)). Importantly, our data suggest that in patients with lupus, the presence of the HLA lupus risk alleles in rs1270942 and rs3131379 increases the odds of also carrying the lupus risk allele in IRF5 (rs2070197) by 17% and 16%, respectively (P = 0.0028 and P = 0.0047, respectively). We provide evidence for gene-gene epistasis in systemic lupus erythematosus. These findings support a role for genetic interaction contributing to the complexity of lupus heritability. Copyright © 2012 by the American College of Rheumatology.

Genetics of hybrid male sterility between drosophila sibling species: a complex web of epistasis is revealed in interspecific studies.

PubMed

Palopoli, M F; Wu, C I

1994-10-01

To study the genetic differences responsible for the sterility of their male hybrids, we introgressed small segments of an X chromosome from Drosophila simulans into a pure Drosophila mauritiana genetic background, then assessed the fertility of males carrying heterospecific introgressions of varying size. Although this analysis examined less than 20% of the X chromosome (roughly 5% of the euchromatic portion of the D. simulans genome), and the segments were introgressed in only one direction, a minimum of four factors that contribute to hybrid male sterility were revealed. At least two of the factors exhibited strong epistasis: males carrying either factor alone were consistently fertile, whereas males carrying both factors together were always sterile. Distinct spermatogenic phenotypes were observed for sterile introgressions of different lengths, and it appeared that an interaction between introgressed segments also influenced the stage of spermatogenic defect. Males with one category of introgression often produced large quantities of motile sperm and were observed copulating, but never inseminated females. Evidently these two species have diverged at a large number of loci which have varied effects on hybrid male fertility. By extrapolation, we estimate that there are at least 40 such loci on the X chromosome alone. Because these species exhibit little DNA-sequence divergence at arbitrarily chosen loci, it seems unlikely that the extensive functional divergence observed could be due mainly to random genetic drift. Significant epistasis between conspecific genes appears to be a common component of hybrid sterility between recently diverged species of Drosophila. The linkage relationships of interacting factors could shed light on the role played by epistatic selection in the dynamics of the allele substitutions responsible for reproductive barriers between species.

Genetics of Hybrid Male Sterility between Drosophila Sibling Species: A Complex Web of Epistasis Is Revealed in Interspecific Studies

PubMed Central

Palopoli, M. F.; Wu, C. I.

1994-01-01

To study the genetic differences responsible for the sterility of their male hybrids, we introgressed small segments of an X chromosome from Drosophila simulans into a pure Drosophila mauritiana genetic background, then assessed the fertility of males carrying heterospecific introgressions of varying size. Although this analysis examined less than 20% of the X chromosome (roughly 5% of the euchromatic portion of the D. simulans genome), and the segments were introgressed in only one direction, a minimum of four factors that contribute to hybrid male sterility were revealed. At least two of the factors exhibited strong epistasis: males carrying either factor alone were consistently fertile, whereas males carrying both factors together were always sterile. Distinct spermatogenic phenotypes were observed for sterile introgressions of different lengths, and it appeared that an interaction between introgressed segments also influenced the stage of spermatogenic defect. Males with one category of introgression often produced large quantities of motile sperm and were observed copulating, but never inseminated females. Evidently these two species have diverged at a large number of loci which have varied effects on hybrid male fertility. By extrapolation, we estimate that there are at least 40 such loci on the X chromosome alone. Because these species exhibit little DNA-sequence divergence at arbitrarily chosen loci, it seems unlikely that the extensive functional divergence observed could be due mainly to random genetic drift. Significant epistasis between conspecific genes appears to be a common component of hybrid sterility between recently diverged species of Drosophila. The linkage relationships of interacting factors could shed light on the role played by epistatic selection in the dynamics of the allele substitutions responsible for reproductive barriers between species. PMID:7828817

An Analysis of the Mode of Gene Action Affecting Pupa Weight in TRIBOLIUM CASTANEUM

PubMed Central

Goodwill, R.

1975-01-01

Triple-testcross experiments (Kearsey and Jinks 1968) were employed to investigate the mode of gene action affecting pupa weight in Tribolium castaneum. Their experimental design involves two inbred lines, the F1 progeny and a segregating population derived from the cross of the inbred lines. In the present experiments, four segregating populations were used. These populations included the F2 generation, a select line (SEL) and two relaxed select lines (RSI and RSII). In addition, all possible reciprocal crosses were made among the RSI, RSII, and SEL populations. It was observed that: (1) additive, dominant and epistatic gene effects all made significant contributions to the pupa weight of the progeny from all four segregating populations; (2) there was no evidence of either accumulation of epistasis as a result of selection in the SEL population or decline in epistasis as a result of removing selection pressure from the RSI and RSII populations; and (3) significant negative heterosis and maternal effects contributed to the pupa weight of the crossbred progeny of the RSI, RSII and SEL populations. PMID:1132679

Leveraging population admixture to characterize the heritability of complex traits.

PubMed

Zaitlen, Noah; Pasaniuc, Bogdan; Sankararaman, Sriram; Bhatia, Gaurav; Zhang, Jianqi; Gusev, Alexander; Young, Taylor; Tandon, Arti; Pollack, Samuela; Vilhjálmsson, Bjarni J; Assimes, Themistocles L; Berndt, Sonja I; Blot, William J; Chanock, Stephen; Franceschini, Nora; Goodman, Phyllis G; He, Jing; Hennis, Anselm J M; Hsing, Ann; Ingles, Sue A; Isaacs, William; Kittles, Rick A; Klein, Eric A; Lange, Leslie A; Nemesure, Barbara; Patterson, Nick; Reich, David; Rybicki, Benjamin A; Stanford, Janet L; Stevens, Victoria L; Strom, Sara S; Whitsel, Eric A; Witte, John S; Xu, Jianfeng; Haiman, Christopher; Wilson, James G; Kooperberg, Charles; Stram, Daniel; Reiner, Alex P; Tang, Hua; Price, Alkes L

2014-12-01

Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2).

Both Epistasis and Diversifying Selection Drive the Structural Evolution of the Ebola Virus Glycoprotein Mucin-Like Domain.

PubMed

Ibeh, Neke; Nshogozabahizi, Jean Claude; Aris-Brosou, Stéphane

2016-06-01

Throughout the last 3 decades, Ebola virus (EBOV) outbreaks have been confined to isolated areas within Central Africa; however, the 2014 variant reached unprecedented transmission and mortality rates. While the outbreak was still under way, it was reported that the variant leading up to this outbreak evolved faster than previous EBOV variants, but evidence for diversifying selection was undetermined. Here, we test this selection hypothesis and show that while previous EBOV outbreaks were preceded by bursts of diversification, evidence for site-specific diversifying selection during the emergence of the 2014 EBOV clade is weak. However, we show strong evidence supporting an interplay between selection and correlated evolution (epistasis), particularly in the mucin-like domain (MLD) of the EBOV glycoprotein. By reconstructing ancestral structures of the MLD, we further propose a structural mechanism explaining how the substitutions that accumulated between 1918 and 1969 distorted the MLD, while more recent epistatic substitutions restored part of the structure, with the most recent substitution being adaptive. We suggest that it is this complex interplay between weak selection, epistasis, and structural constraints that has shaped the evolution of the 2014 EBOV variant. The role that selection plays in the emergence of viral epidemics remains debated, particularly in the context of the 2014 EBOV outbreak. Most critically, should such evidence exist, it is generally unclear how this relates to function and increased virulence. Here, we show that the viral lineage leading up to the 2014 outbreak underwent a complex interplay between selection and correlated evolution (epistasis) in a protein region that is critical for immune evasion. We then reconstructed the three-dimensional structure of this domain and showed that the initial mutations in this lineage deformed the structure, while subsequent mutations restored part of the structure. Along this mutational path, the first and last mutations were adaptive, while the intervening ones were epistatic. Altogether, we provide a mechanistic model that explains how selection and epistasis acted on the structural constraints that materialized during the 2014 EBOV outbreak. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

The Nonstationary Dynamics of Fitness Distributions: Asexual Model with Epistasis and Standing Variation

PubMed Central

Martin, Guillaume; Roques, Lionel

2016-01-01

Various models describe asexual evolution by mutation, selection, and drift. Some focus directly on fitness, typically modeling drift but ignoring or simplifying both epistasis and the distribution of mutation effects (traveling wave models). Others follow the dynamics of quantitative traits determining fitness (Fisher’s geometric model), imposing a complex but fixed form of mutation effects and epistasis, and often ignoring drift. In all cases, predictions are typically obtained in high or low mutation rate limits and for long-term stationary regimes, thus losing information on transient behaviors and the effect of initial conditions. Here, we connect fitness-based and trait-based models into a single framework, and seek explicit solutions even away from stationarity. The expected fitness distribution is followed over time via its cumulant generating function, using a deterministic approximation that neglects drift. In several cases, explicit trajectories for the full fitness distribution are obtained for arbitrary mutation rates and standing variance. For nonepistatic mutations, especially with beneficial mutations, this approximation fails over the long term but captures the early dynamics, thus complementing stationary stochastic predictions. The approximation also handles several diminishing returns epistasis models (e.g., with an optimal genotype); it can be applied at and away from equilibrium. General results arise at equilibrium, where fitness distributions display a “phase transition” with mutation rate. Beyond this phase transition, in Fisher’s geometric model, the full trajectory of fitness and trait distributions takes a simple form; robust to the details of the mutant phenotype distribution. Analytical arguments are explored regarding why and when the deterministic approximation applies. PMID:27770037

Epistasis modifies the dominance of loci causing hybrid male sterility in the Drosophila pseudoobscura species group

PubMed Central

Chang, Audrey S.; Noor, Mohamed A. F.

2009-01-01

Speciation, the evolution of reproductive isolation between populations, serves as the driving force for generating biodiversity. Postzygotic barriers to gene flow, such as F1 hybrid sterility and inviability, play important roles in the establishment and maintenance of biological species. F1 hybrid incompatibilities in taxa that obey Haldane's rule, the observation that the heterogametic sex suffers greater hybrid fitness problems than the homogametic sex, are thought to often result from interactions between recessive-acting X-linked loci and dominant-acting autosomal loci. Because they play such prominent roles in producing hybrid incompatibilities, we examine the dominance and nature of epistasis between alleles derived from Drosophila persimilis that confer hybrid male sterility in the genetic background of its sister species, D. pseudoobscura bogotana. We show that epistasis elevates the apparent dominance of individually recessive-acting QTL such that they can contribute to F1 hybrid sterility. These results have important implications for assumptions underlying theoretical models of hybrid incompatibilities and may offer a possible explanation for why, to date identification of dominant-acting autosomal “speciation genes” has been challenging. PMID:19686263

Epistasis among Drosophila persimilis factors conferring hybrid male sterility with D. pseudoobscura bogotana.

PubMed

Chang, Audrey S; Bennett, Sarah M; Noor, Mohamed A F

2010-10-27

The Bateson-Dobzhansky-Muller model posits that hybrid incompatibilities result from genetic changes that accumulate during population divergence. Indeed, much effort in recent years has been devoted to identifying genes associated with hybrid incompatibilities, often with limited success, suggesting that hybrid sterility and inviability are frequently caused by complex interactions between multiple loci and not by single or a small number of gene pairs. Our previous study showed that the nature of epistasis between sterility-conferring QTL in the Drosophila persimilis-D. pseudoobscura bogotana species pair is highly specific. Here, we further dissect one of the three QTL underlying hybrid male sterility between these species and provide evidence for multiple factors within this QTL. This result indicates that the number of loci thought to contribute to hybrid dysfunction may have been underestimated, and we discuss how linkage and complex epistasis may be characteristic of the genetics of hybrid incompatibilities. We further pinpoint the location of one locus that confers hybrid male sterility when homozygous, dubbed "mule-like", to roughly 250 kilobases.

Epistasis among Drosophila persimilis Factors Conferring Hybrid Male Sterility with D. pseudoobscura bogotana

PubMed Central

Chang, Audrey S.; Bennett, Sarah M.; Noor, Mohamed A. F.

2010-01-01

The Bateson-Dobzhansky-Muller model posits that hybrid incompatibilities result from genetic changes that accumulate during population divergence. Indeed, much effort in recent years has been devoted to identifying genes associated with hybrid incompatibilities, often with limited success, suggesting that hybrid sterility and inviability are frequently caused by complex interactions between multiple loci and not by single or a small number of gene pairs. Our previous study showed that the nature of epistasis between sterility-conferring QTL in the Drosophila persimilis-D. pseudoobscura bogotana species pair is highly specific. Here, we further dissect one of the three QTL underlying hybrid male sterility between these species and provide evidence for multiple factors within this QTL. This result indicates that the number of loci thought to contribute to hybrid dysfunction may have been underestimated, and we discuss how linkage and complex epistasis may be characteristic of the genetics of hybrid incompatibilities. We further pinpoint the location of one locus that confers hybrid male sterility when homozygous, dubbed “mule-like”, to roughly 250 kilobases. PMID:21060872

Epistasis modifies the dominance of loci causing hybrid male sterility in the Drosophila pseudoobscura species group.

PubMed

Chang, Audrey S; Noor, Mohamed A F

2010-01-01

Speciation, the evolution of reproductive isolation between populations, serves as the driving force for generating biodiversity. Postzygotic barriers to gene flow, such as F(1) hybrid sterility and inviability, play important roles in the establishment and maintenance of biological species. F(1) hybrid incompatibilities in taxa that obey Haldane's rule, the observation that the heterogametic sex suffers greater hybrid fitness problems than the homogametic sex, are thought to often result from interactions between recessive-acting X-linked loci and dominant-acting autosomal loci. Because they play such prominent roles in producing hybrid incompatibilities, we examine the dominance and nature of epistasis between alleles derived from Drosophila persimilis that confer hybrid male sterility in the genetic background of its sister species, D. pseudoobscura bogotana. We show that epistasis elevates the apparent dominance of individually recessive-acting QTL such that they can contribute to F(1) hybrid sterility. These results have important implications for assumptions underlying theoretical models of hybrid incompatibilities and may offer a possible explanation for why, to date, identification of dominant-acting autosomal "speciation genes" has been challenging.

Introduction to Focus Issue: Genetic Interactions

NASA Astrophysics Data System (ADS)

Segrè, Daniel; Marx, Christopher J.

2010-06-01

The perturbation of a gene in an organism's genome often causes changes in the organism's observable properties or phenotypes. It is not obvious a priori whether the simultaneous perturbation of two genes produces a phenotypic change that is easily predictable from the changes caused by individual perturbations. In fact, this is often not the case: the nonlinearity and interdependence between genetic variants in determining phenotypes, also known as epistasis, is a prevalent phenomenon in biological systems. This focus issue presents recent developments in the study of epistasis and genetic interactions, emphasizing the broad implications of this phenomenon in evolutionary biology, functional genomics, and human diseases.

A survey of application: genomics and genetic programming, a new frontier.

PubMed

Khan, Mohammad Wahab; Alam, Mansaf

2012-08-01

The aim of this paper is to provide an introduction to the rapidly developing field of genetic programming (GP). Particular emphasis is placed on the application of GP to genomics. First, the basic methodology of GP is introduced. This is followed by a review of applications in the areas of gene network inference, gene expression data analysis, SNP analysis, epistasis analysis and gene annotation. Finally this paper concluded by suggesting potential avenues of possible future research on genetic programming, opportunities to extend the technique, and areas for possible practical applications. Copyright © 2012 Elsevier Inc. All rights reserved.

Polygenicity and Epistasis Underlie Fitness-Proximal Traits in the Caenorhabditis elegans Multiparental Experimental Evolution (CeMEE) Panel.

PubMed

Noble, Luke M; Chelo, Ivo; Guzella, Thiago; Afonso, Bruno; Riccardi, David D; Ammerman, Patrick; Dayarian, Adel; Carvalho, Sara; Crist, Anna; Pino-Querido, Ania; Shraiman, Boris; Rockman, Matthew V; Teotónio, Henrique

2017-12-01

Understanding the genetic basis of complex traits remains a major challenge in biology. Polygenicity, phenotypic plasticity, and epistasis contribute to phenotypic variance in ways that are rarely clear. This uncertainty can be problematic for estimating heritability, for predicting individual phenotypes from genomic data, and for parameterizing models of phenotypic evolution. Here, we report an advanced recombinant inbred line (RIL) quantitative trait locus mapping panel for the hermaphroditic nematode Caenorhabditis elegans , the C. elegans multiparental experimental evolution (CeMEE) panel. The CeMEE panel, comprising 507 RILs at present, was created by hybridization of 16 wild isolates, experimental evolution for 140-190 generations, and inbreeding by selfing for 13-16 generations. The panel contains 22% of single-nucleotide polymorphisms known to segregate in natural populations, and complements existing C. elegans mapping resources by providing fine resolution and high nucleotide diversity across > 95% of the genome. We apply it to study the genetic basis of two fitness components, fertility and hermaphrodite body size at time of reproduction, with high broad-sense heritability in the CeMEE. While simulations show that we should detect common alleles with additive effects as small as 5%, at gene-level resolution, the genetic architectures of these traits do not feature such alleles. We instead find that a significant fraction of trait variance, approaching 40% for fertility, can be explained by sign epistasis with main effects below the detection limit. In congruence, phenotype prediction from genomic similarity, while generally poor ([Formula: see text]), requires modeling epistasis for optimal accuracy, with most variance attributed to the rapidly evolving chromosome arms. Copyright © 2017 by the Genetics Society of America.

Polygenicity and Epistasis Underlie Fitness-Proximal Traits in the Caenorhabditis elegans Multiparental Experimental Evolution (CeMEE) Panel

PubMed Central

Noble, Luke M.; Chelo, Ivo; Guzella, Thiago; Afonso, Bruno; Riccardi, David D.; Ammerman, Patrick; Dayarian, Adel; Carvalho, Sara; Crist, Anna; Pino-Querido, Ania; Shraiman, Boris; Rockman, Matthew V.; Teotónio, Henrique

2017-01-01

Understanding the genetic basis of complex traits remains a major challenge in biology. Polygenicity, phenotypic plasticity, and epistasis contribute to phenotypic variance in ways that are rarely clear. This uncertainty can be problematic for estimating heritability, for predicting individual phenotypes from genomic data, and for parameterizing models of phenotypic evolution. Here, we report an advanced recombinant inbred line (RIL) quantitative trait locus mapping panel for the hermaphroditic nematode Caenorhabditis elegans, the C. elegans multiparental experimental evolution (CeMEE) panel. The CeMEE panel, comprising 507 RILs at present, was created by hybridization of 16 wild isolates, experimental evolution for 140–190 generations, and inbreeding by selfing for 13–16 generations. The panel contains 22% of single-nucleotide polymorphisms known to segregate in natural populations, and complements existing C. elegans mapping resources by providing fine resolution and high nucleotide diversity across > 95% of the genome. We apply it to study the genetic basis of two fitness components, fertility and hermaphrodite body size at time of reproduction, with high broad-sense heritability in the CeMEE. While simulations show that we should detect common alleles with additive effects as small as 5%, at gene-level resolution, the genetic architectures of these traits do not feature such alleles. We instead find that a significant fraction of trait variance, approaching 40% for fertility, can be explained by sign epistasis with main effects below the detection limit. In congruence, phenotype prediction from genomic similarity, while generally poor (r2<10%), requires modeling epistasis for optimal accuracy, with most variance attributed to the rapidly evolving chromosome arms. PMID:29066469

Immunochip Analyses of Epistasis in Rheumatoid Arthritis Confirm Multiple Interactions within MHC and Suggest Novel Non-MHC Epistatic Signals.

PubMed

Wei, Wen-Hua; Loh, Chia-Yin; Worthington, Jane; Eyre, Stephen

2016-05-01

Studying statistical gene-gene interactions (epistasis) has been limited by the difficulties in performance, both statistically and computationally, in large enough sample numbers to gain sufficient power. Three large Immunochip datasets from cohort samples recruited in the United Kingdom, United States, and Sweden with European ancestry were used to examine epistasis in rheumatoid arthritis (RA). A full pairwise search was conducted in the UK cohort using a high-throughput tool and the resultant significant epistatic signals were tested for replication in the United States and Swedish cohorts. A forward selection approach was applied to remove redundant signals, while conditioning on the preidentified additive effects. We detected abundant genome-wide significant (p < 1.0e-13) epistatic signals, all within the MHC region. These signals were reduced substantially, but a proportion remained significant (p < 1.0e-03) in conditional tests. We identified 11 independent epistatic interactions across the entire MHC, each explaining on average 0.12% of the phenotypic variance, nearly all replicated in both replication cohorts. We also identified non-MHC epistatic interactions between RA susceptible loci LOC100506023 and IRF5 with Immunochip-wide significance (p < 1.1e-08) and between 2 neighboring single-nucleotide polymorphism near PTPN22 that were in low linkage disequilibrium with independent interaction (p < 1.0e-05). Both non-MHC epistatic interactions were statistically replicated with a similar interaction pattern in the US cohort only. There are multiple but relatively weak interactions independent of the additive effects in RA and a larger sample number is required to confidently assign additional non-MHC epistasis.

Multidimensional adaptive evolution of a feed-forward network and the illusion of compensation

PubMed Central

Bullaughey, Kevin

2016-01-01

When multiple substitutions affect a trait in opposing ways, they are often assumed to be compensatory, not only with respect to the trait, but also with respect to fitness. This type of compensatory evolution has been suggested to underlie the evolution of protein structures and interactions, RNA secondary structures, and gene regulatory modules and networks. The possibility for compensatory evolution results from epistasis. Yet if epistasis is widespread, then it is also possible that the opposing substitutions are individually adaptive. I term this possibility an adaptive reversal. Although possible for arbitrary phenotype-fitness mappings, it has not yet been investigated whether such epistasis is prevalent in a biologically-realistic setting. I investigate a particular regulatory circuit, the type I coherent feed-forward loop, which is ubiquitous in natural systems and is accurately described by a simple mathematical model. I show that such reversals are common during adaptive evolution, can result solely from the topology of the fitness landscape, and can occur even when adaptation follows a modest environmental change and the network was well adapted to the original environment. The possibility of adaptive reversals warrants a systems perspective when interpreting substitution patterns in gene regulatory networks. PMID:23289561

Environmental Interactions and Epistasis Are Revealed in the Proteomic Responses to Complex Stimuli

PubMed Central

Samir, Parimal; Rahul; Slaughter, James C.; Link, Andrew J.

2015-01-01

Ultimately, the genotype of a cell and its interaction with the environment determine the cell’s biochemical state. While the cell’s response to a single stimulus has been studied extensively, a conceptual framework to model the effect of multiple environmental stimuli applied concurrently is not as well developed. In this study, we developed the concepts of environmental interactions and epistasis to explain the responses of the S. cerevisiae proteome to simultaneous environmental stimuli. We hypothesize that, as an abstraction, environmental stimuli can be treated as analogous to genetic elements. This would allow modeling of the effects of multiple stimuli using the concepts and tools developed for studying gene interactions. Mirroring gene interactions, our results show that environmental interactions play a critical role in determining the state of the proteome. We show that individual and complex environmental stimuli behave similarly to genetic elements in regulating the cellular responses to stimuli, including the phenomena of dominance and suppression. Interestingly, we observed that the effect of a stimulus on a protein is dominant over other stimuli if the response to the stimulus involves the protein. Using publicly available transcriptomic data, we find that environmental interactions and epistasis regulate transcriptomic responses as well. PMID:26247773

Analysis of IL12B Gene Variants in Inflammatory Bowel Disease

PubMed Central

Wagner, Johanna; Olszak, Torsten; Fries, Christoph; Tillack, Cornelia; Friedrich, Matthias; Beigel, Florian; Stallhofer, Johannes; Steib, Christian; Wetzke, Martin; Göke, Burkhard; Ochsenkühn, Thomas; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

2012-01-01

Background IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. Methodology/Principal Findings We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01–1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99–1.31], p = 0.066) and UC (OR 1.18 [0.97–1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10−5; OR = 2.84, 95% CI 1.66–4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14–0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between IL23R and IL12B variants. Conclusions/Significance The IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of IL23R gene variants. PMID:22479607

Further investigations of the W-test for pairwise epistasis testing.

PubMed

Howey, Richard; Cordell, Heather J

2017-01-01

Background: In a recent paper, a novel W-test for pairwise epistasis testing was proposed that appeared, in computer simulations, to have higher power than competing alternatives. Application to genome-wide bipolar data detected significant epistasis between SNPs in genes of relevant biological function. Network analysis indicated that the implicated genes formed two separate interaction networks, each containing genes highly related to autism and neurodegenerative disorders. Methods: Here we investigate further the properties and performance of the W-test via theoretical evaluation, computer simulations and application to real data. Results: We demonstrate that, for common variants, the W-test is closely related to several existing tests of association allowing for interaction, including logistic regression on 8 degrees of freedom, although logistic regression can show inflated type I error for low minor allele frequencies,  whereas the W-test shows good/conservative type I error control. Although in some situations the W-test can show higher power, logistic regression is not limited to tests on 8 degrees of freedom but can instead be tailored to impose greater structure on the assumed alternative hypothesis, offering a power advantage when the imposed structure matches the true structure. Conclusions: The W-test is a potentially useful method for testing for association - without necessarily implying interaction - between genetic variants disease, particularly when one or more of the genetic variants are rare. For common variants, the advantages of the W-test are less clear, and, indeed, there are situations where existing methods perform better. In our investigations, we further uncover a number of problems with the practical implementation and application of the W-test (to bipolar disorder) previously described, apparently due to inadequate use of standard data quality-control procedures. This observation leads us to urge caution in interpretation of the previously-presented results, most of which we consider are highly likely to be artefacts.

Genetic Interaction Mapping in Schizosaccharomyces pombe Using the Pombe Epistasis Mapper (PEM) System and a ROTOR HDA Colony Replicating Robot in a 1536 Array Format.

PubMed

Roguev, Assen; Xu, Jiewei; Krogan, Nevan

2018-02-01

This protocol describes an optimized high-throughput procedure for generating double deletion mutants in Schizosaccharomyces pombe using the colony replicating robot ROTOR HDA and the PEM (pombe epistasis mapper) system. The method is based on generating high-density colony arrays (1536 colonies per agar plate) and passaging them through a series of antidiploid and mating-type selection (ADS-MTS) and double-mutant selection (DMS) steps. Detailed program parameters for each individual replication step are provided. Using this procedure, batches of 25 or more screens can be routinely performed. © 2018 Cold Spring Harbor Laboratory Press.

Evo-Devo-EpiR: a genome-wide search platform for epistatic control on the evolution of development.

PubMed

Jiang, Libo; Zhang, Miaomiao; Sang, Mengmeng; Ye, Meixia; Wu, Rongling

2017-09-01

Evo-devo is a theory proposed to study how phenotypes evolve by comparing the developmental processes of different organisms or the same organism experiencing changing environments. It has been recognized that nonallelic interactions at different genes or quantitative trait loci, known as epistasis, may play a pivotal role in the evolution of development, but it has proven difficult to quantify and elucidate this role into a coherent picture. We implement a high-dimensional genome-wide association study model into the evo-devo paradigm and pack it into the R-based Evo-Devo-EpiR, aimed at facilitating the genome-wide landscaping of epistasis for the diversification of phenotypic development. By analyzing a high-throughput assay of DNA markers and their pairs simultaneously, Evo-Devo-EpiR is equipped with a capacity to systematically characterize various epistatic interactions that impact on the pattern and timing of development and its evolution. Enabling a global search for all possible genetic interactions for developmental processes throughout the whole genome, Evo-Devo-EpiR provides a computational tool to illustrate a precise genotype-phenotype map at interface between epistasis, development and evolution. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Routine Discovery of Complex Genetic Models using Genetic Algorithms

PubMed Central

Moore, Jason H.; Hahn, Lance W.; Ritchie, Marylyn D.; Thornton, Tricia A.; White, Bill C.

2010-01-01

Simulation studies are useful in various disciplines for a number of reasons including the development and evaluation of new computational and statistical methods. This is particularly true in human genetics and genetic epidemiology where new analytical methods are needed for the detection and characterization of disease susceptibility genes whose effects are complex, nonlinear, and partially or solely dependent on the effects of other genes (i.e. epistasis or gene-gene interaction). Despite this need, the development of complex genetic models that can be used to simulate data is not always intuitive. In fact, only a few such models have been published. We have previously developed a genetic algorithm approach to discovering complex genetic models in which two single nucleotide polymorphisms (SNPs) influence disease risk solely through nonlinear interactions. In this paper, we extend this approach for the discovery of high-order epistasis models involving three to five SNPs. We demonstrate that the genetic algorithm is capable of routinely discovering interesting high-order epistasis models in which each SNP influences risk of disease only through interactions with the other SNPs in the model. This study opens the door for routine simulation of complex gene-gene interactions among SNPs for the development and evaluation of new statistical and computational approaches for identifying common, complex multifactorial disease susceptibility genes. PMID:20948983

A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility.

PubMed

Moore, Jason H; Gilbert, Joshua C; Tsai, Chia-Ti; Chiang, Fu-Tien; Holden, Todd; Barney, Nate; White, Bill C

2006-07-21

Detecting, characterizing, and interpreting gene-gene interactions or epistasis in studies of human disease susceptibility is both a mathematical and a computational challenge. To address this problem, we have previously developed a multifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension (i.e. constructive induction) thus permitting interactions to be detected in relatively small sample sizes. In this paper, we describe a comprehensive and flexible framework for detecting and interpreting gene-gene interactions that utilizes advances in information theory for selecting interesting single-nucleotide polymorphisms (SNPs), MDR for constructive induction, machine learning methods for classification, and finally graphical models for interpretation. We illustrate the usefulness of this strategy using artificial datasets simulated from several different two-locus and three-locus epistasis models. We show that the accuracy, sensitivity, specificity, and precision of a naïve Bayes classifier are significantly improved when SNPs are selected based on their information gain (i.e. class entropy removed) and reduced to a single attribute using MDR. We then apply this strategy to detecting, characterizing, and interpreting epistatic models in a genetic study (n = 500) of atrial fibrillation and show that both classification and model interpretation are significantly improved.

Epistasis increases the rate of conditionally neutral substitution in an adapting population.

PubMed

Draghi, Jeremy A; Parsons, Todd L; Plotkin, Joshua B

2011-04-01

Kimura observed that the rate of neutral substitution should equal the neutral mutation rate. This classic result is central to our understanding of molecular evolution, and it continues to influence phylogenetics, genomics, and the interpretation of evolution experiments. By demonstrating that neutral mutations substitute at a rate independent of population size and selection at linked sites, Kimura provided an influential justification for the idea of a molecular clock and emphasized the importance of genetic drift in shaping molecular evolution. But when epistasis among sites is common, as numerous empirical studies suggest, do neutral mutations substitute according to Kimura's expectation? Here we study simulated, asexual populations of RNA molecules, and we observe that conditionally neutral mutations--i.e., mutations that do not alter the fitness of the individual in which they arise, but that may alter the fitness effects of subsequent mutations--substitute much more often than expected while a population is adapting. We quantify these effects using a simple population-genetic model that elucidates how the substitution rate at conditionally neutral sites depends on the population size, mutation rate, strength of selection, and prevalence of epistasis. We discuss the implications of these results for our understanding of the molecular clock, and for the interpretation of molecular variation in laboratory and natural populations.

Epistasis Increases the Rate of Conditionally Neutral Substitution in an Adapting Population

PubMed Central

Draghi, Jeremy A.; Parsons, Todd L.; Plotkin, Joshua B.

2011-01-01

Kimura observed that the rate of neutral substitution should equal the neutral mutation rate. This classic result is central to our understanding of molecular evolution, and it continues to influence phylogenetics, genomics, and the interpretation of evolution experiments. By demonstrating that neutral mutations substitute at a rate independent of population size and selection at linked sites, Kimura provided an influential justification for the idea of a molecular clock and emphasized the importance of genetic drift in shaping molecular evolution. But when epistasis among sites is common, as numerous empirical studies suggest, do neutral mutations substitute according to Kimura's expectation? Here we study simulated, asexual populations of RNA molecules, and we observe that conditionally neutral mutations—i.e., mutations that do not alter the fitness of the individual in which they arise, but that may alter the fitness effects of subsequent mutations—substitute much more often than expected while a population is adapting. We quantify these effects using a simple population-genetic model that elucidates how the substitution rate at conditionally neutral sites depends on the population size, mutation rate, strength of selection, and prevalence of epistasis. We discuss the implications of these results for our understanding of the molecular clock, and for the interpretation of molecular variation in laboratory and natural populations. PMID:21288876

The Red Queen lives: Epistasis between linked resistance loci.

PubMed

Metzger, César M J A; Luijckx, Pepijn; Bento, Gilberto; Mariadassou, Mahendra; Ebert, Dieter

2016-02-01

A popular theory explaining the maintenance of genetic recombination (sex) is the Red Queen Theory. This theory revolves around the idea that time-lagged negative frequency-dependent selection by parasites favors rare host genotypes generated through recombination. Although the Red Queen has been studied for decades, one of its key assumptions has remained unsupported. The signature host-parasite specificity underlying the Red Queen, where infection depends on a match between host and parasite genotypes, relies on epistasis between linked resistance loci for which no empirical evidence exists. We performed 13 genetic crosses and tested over 7000 Daphnia magna genotypes for resistance to two strains of the bacterial pathogen Pasteuria ramosa. Results reveal the presence of strong epistasis between three closely linked resistance loci. One locus masks the expression of the other two, while these two interact to produce a single resistance phenotype. Changing a single allele on one of these interacting loci can reverse resistance against the tested parasites. Such a genetic mechanism is consistent with host and parasite specificity assumed by the Red Queen Theory. These results thus provide evidence for a fundamental assumption of this theory and provide a genetic basis for understanding the Red Queen dynamics in the Daphnia-Pasteuria system. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

GAMETES: a fast, direct algorithm for generating pure, strict, epistatic models with random architectures.

PubMed

Urbanowicz, Ryan J; Kiralis, Jeff; Sinnott-Armstrong, Nicholas A; Heberling, Tamra; Fisher, Jonathan M; Moore, Jason H

2012-10-01

Geneticists who look beyond single locus disease associations require additional strategies for the detection of complex multi-locus effects. Epistasis, a multi-locus masking effect, presents a particular challenge, and has been the target of bioinformatic development. Thorough evaluation of new algorithms calls for simulation studies in which known disease models are sought. To date, the best methods for generating simulated multi-locus epistatic models rely on genetic algorithms. However, such methods are computationally expensive, difficult to adapt to multiple objectives, and unlikely to yield models with a precise form of epistasis which we refer to as pure and strict. Purely and strictly epistatic models constitute the worst-case in terms of detecting disease associations, since such associations may only be observed if all n-loci are included in the disease model. This makes them an attractive gold standard for simulation studies considering complex multi-locus effects. We introduce GAMETES, a user-friendly software package and algorithm which generates complex biallelic single nucleotide polymorphism (SNP) disease models for simulation studies. GAMETES rapidly and precisely generates random, pure, strict n-locus models with specified genetic constraints. These constraints include heritability, minor allele frequencies of the SNPs, and population prevalence. GAMETES also includes a simple dataset simulation strategy which may be utilized to rapidly generate an archive of simulated datasets for given genetic models. We highlight the utility and limitations of GAMETES with an example simulation study using MDR, an algorithm designed to detect epistasis. GAMETES is a fast, flexible, and precise tool for generating complex n-locus models with random architectures. While GAMETES has a limited ability to generate models with higher heritabilities, it is proficient at generating the lower heritability models typically used in simulation studies evaluating new algorithms. In addition, the GAMETES modeling strategy may be flexibly combined with any dataset simulation strategy. Beyond dataset simulation, GAMETES could be employed to pursue theoretical characterization of genetic models and epistasis.

A Developmental Systems Perspective on Epistasis: Computational Exploration of Mutational Interactions in Model Developmental Regulatory Networks

PubMed Central

Gutiérrez, Jayson

2009-01-01

The way in which the information contained in genotypes is translated into complex phenotypic traits (i.e. embryonic expression patterns) depends on its decoding by a multilayered hierarchy of biomolecular systems (regulatory networks). Each layer of this hierarchy displays its own regulatory schemes (i.e. operational rules such as +/− feedback) and associated control parameters, resulting in characteristic variational constraints. This process can be conceptualized as a mapping issue, and in the context of highly-dimensional genotype-phenotype mappings (GPMs) epistatic events have been shown to be ubiquitous, manifested in non-linear correspondences between changes in the genotype and their phenotypic effects. In this study I concentrate on epistatic phenomena pervading levels of biological organization above the genetic material, more specifically the realm of molecular networks. At this level, systems approaches to studying GPMs are specially suitable to shed light on the mechanistic basis of epistatic phenomena. To this aim, I constructed and analyzed ensembles of highly-modular (fully interconnected) networks with distinctive topologies, each displaying dynamic behaviors that were categorized as either arbitrary or functional according to early patterning processes in the Drosophila embryo. Spatio-temporal expression trajectories in virtual syncytial embryos were simulated via reaction-diffusion models. My in silico mutational experiments show that: 1) the average fitness decay tendency to successively accumulated mutations in ensembles of functional networks indicates the prevalence of positive epistasis, whereas in ensembles of arbitrary networks negative epistasis is the dominant tendency; and 2) the evaluation of epistatic coefficients of diverse interaction orders indicates that, both positive and negative epistasis are more prevalent in functional networks than in arbitrary ones. Overall, I conclude that the phenotypic and fitness effects of multiple perturbations are strongly conditioned by both the regulatory architecture (i.e. pattern of coupled feedback structures) and the dynamic nature of the spatio-temporal expression trajectories displayed by the simulated networks. PMID:19738908

What can we learn from fitness landscapes?

PubMed

Hartl, Daniel L

2014-10-01

A combinatorially complete data set consists of studies of all possible combinations of a set of mutant sites in a gene or mutant alleles in a genome. Among the most robust conclusions from these studies is that epistasis between beneficial mutations often shows a pattern of diminishing returns, in which favorable mutations are less fit when combined than would be expected. Another robust inference is that the number of adaptive evolutionary paths is often limited to a relatively small fraction of the theoretical possibilities, owing largely to sign epistasis requiring evolutionary steps that would entail a decrease in fitness. Here we summarize these and other results while also examining issues that remain unresolved and future directions that seem promising. Copyright © 2014 Elsevier Ltd. All rights reserved.

Functional Manipulation of Root Endophyte Populations for Feedstock Improvement- Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dangl, Jeffery L.

This study provides a systemic analysis of the influence of the abiotic environment on the assembly of plant microbiomes. We show that under controlled conditions, community assembly cues are robust and predictable across multiple abiotic gradients. Plant colonization patterns are largely driven by phylogeny, and colonization phenotypes are ubiquitous across different specimens of the same phylogenetic class. Subsets of the full synthetic community were shown to induce different root morphologies, and the morphology observed with the full community is an outcome of epistasis between two functional guilds.

Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges

PubMed Central

Marangi, Giuseppe; Traynor, Bryan J.

2018-01-01

The genetic architecture of amyotrophic lateral sclerosis (ALS) is being increasingly understood. In this far-reaching review, we examine what is currently known about ALS genetics and how these genes were initially identified. We also discuss the various types of mutations that might underlie this fatal neurodegenerative condition and outline some of the strategies that might be useful in untangling them. These include expansions of short repeat sequences, common and low-frequency genetic variations, de novo mutations, epigenetic changes, somatic mutations, epistasis, oligogenic and polygenic hypotheses. PMID:25316630

Epistatically Interacting Substitutions Are Enriched during Adaptive Protein Evolution

PubMed Central

Gong, Lizhi Ian; Bloom, Jesse D.

2014-01-01

Most experimental studies of epistasis in evolution have focused on adaptive changes—but adaptation accounts for only a portion of total evolutionary change. Are the patterns of epistasis during adaptation representative of evolution more broadly? We address this question by examining a pair of protein homologs, of which only one is subject to a well-defined pressure for adaptive change. Specifically, we compare the nucleoproteins from human and swine influenza. Human influenza is under continual selection to evade recognition by acquired immune memory, while swine influenza experiences less such selection due to the fact that pigs are less likely to be infected with influenza repeatedly in a lifetime. Mutations in some types of immune epitopes are therefore much more strongly adaptive to human than swine influenza—here we focus on epitopes targeted by human cytotoxic T lymphocytes. The nucleoproteins of human and swine influenza possess nearly identical numbers of such epitopes. However, mutations in these epitopes are fixed significantly more frequently in human than in swine influenza, presumably because these epitope mutations are adaptive only to human influenza. Experimentally, we find that epistatically constrained mutations are fixed only in the adaptively evolving human influenza lineage, where they occur at sites that are enriched in epitopes. Overall, our results demonstrate that epistatically interacting substitutions are enriched during adaptation, suggesting that the prevalence of epistasis is dependent on the underlying evolutionary forces at play. PMID:24811236

No association between apolipoprotein E or N-acetyltransferase 2 gene polymorphisms and age-related hearing loss.

PubMed

Dawes, Piers; Platt, Hazel; Horan, Michael; Ollier, William; Munro, Kevin; Pendleton, Neil; Payton, Antony

2015-01-01

Age-related hearing loss has a genetic component, but there have been limited genetic studies in this field. Both N-acetyltransferase 2 and apolipoprotein E genes have previously been associated. However, these studies have either used small sample sizes, examined a limited number of polymorphisms, or have produced conflicting results. Here we use a haplotype tagging approach to determine association with age-related hearing loss and investigate epistasis between these two genes. Candidate gene association study of a continuous phenotype. We investigated haplotype tagging single nucleotide polymorphisms in the N-acetyltransferase 2 gene and the presence/absence of the apolipoprotein E ε4 allele for association with age-related hearing loss in a cohort of 265 Caucasian elderly volunteers from Greater Manchester, United Kingdom. Hearing phenotypes were generated using principal component analysis of the hearing threshold levels for the better ear (severity, slope, and concavity). Genotype data for the N-acetyltransferase 2 gene was obtained from existing genome-wide association study data from the Illumina 610-Quadv1 chip. Apolipoprotein E genotyping was performed using Sequenom technology. Linear regression analysis was performed using Plink and Stata software. No significant associations (P value, > 0.05) were observed between the N-acetyltransferase 2 or apolipoprotein E gene polymorphisms and any hearing factor. No significant association was observed for epistasis analysis of apolipoprotein E ε4 and the N-acetyltransferase 2 single nucleotide polymorphism rs1799930 (NAT2*6A). We found no evidence to support that either N-acetyltransferase 2 or apolipoprotein E gene polymorphisms are associated with age-related hearing loss in a cohort of 265 elderly volunteers. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

Quantifying the Role of Population Subdivision in Evolution on Rugged Fitness Landscapes

PubMed Central

Bitbol, Anne-Florence; Schwab, David J.

2014-01-01

Natural selection drives populations towards higher fitness, but crossing fitness valleys or plateaus may facilitate progress up a rugged fitness landscape involving epistasis. We investigate quantitatively the effect of subdividing an asexual population on the time it takes to cross a fitness valley or plateau. We focus on a generic and minimal model that includes only population subdivision into equivalent demes connected by global migration, and does not require significant size changes of the demes, environmental heterogeneity or specific geographic structure. We determine the optimal speedup of valley or plateau crossing that can be gained by subdivision, if the process is driven by the deme that crosses fastest. We show that isolated demes have to be in the sequential fixation regime for subdivision to significantly accelerate crossing. Using Markov chain theory, we obtain analytical expressions for the conditions under which optimal speedup is achieved: valley or plateau crossing by the subdivided population is then as fast as that of its fastest deme. We verify our analytical predictions through stochastic simulations. We demonstrate that subdivision can substantially accelerate the crossing of fitness valleys and plateaus in a wide range of parameters extending beyond the optimal window. We study the effect of varying the degree of subdivision of a population, and investigate the trade-off between the magnitude of the optimal speedup and the width of the parameter range over which it occurs. Our results, obtained for fitness valleys and plateaus, also hold for weakly beneficial intermediate mutations. Finally, we extend our work to the case of a population connected by migration to one or several smaller islands. Our results demonstrate that subdivision with migration alone can significantly accelerate the crossing of fitness valleys and plateaus, and shed light onto the quantitative conditions necessary for this to occur. PMID:25122220

Inference of epistatic effects in a key mitochondrial protein

NASA Astrophysics Data System (ADS)

Nelson, Erik D.; Grishin, Nick V.

2018-06-01

We use Potts model inference to predict pair epistatic effects in a key mitochondrial protein—cytochrome c oxidase subunit 2—for ray-finned fishes. We examine the effect of phylogenetic correlations on our predictions using a simple exact fitness model, and we find that, although epistatic effects are underpredicted, they maintain a roughly linear relationship to their true (model) values. After accounting for this correction, epistatic effects in the protein are still relatively weak, leading to fitness valleys of depth 2 N s ≃-5 in compensatory double mutants. Interestingly, positive epistasis is more pronounced than negative epistasis, and the strongest positive effects capture nearly all sites subject to positive selection in fishes, similar to virus proteins evolving under selection pressure in the context of drug therapy.

Genetics of Adverse Reactions to Haloperidol in a Mouse Diallel: A Drug–Placebo Experiment and Bayesian Causal Analysis

PubMed Central

Crowley, James J.; Kim, Yunjung; Lenarcic, Alan B.; Quackenbush, Corey R.; Barrick, Cordelia J.; Adkins, Daniel E.; Shaw, Ginger S.; Miller, Darla R.; de Villena, Fernando Pardo-Manuel; Sullivan, Patrick F.; Valdar, William

2014-01-01

Haloperidol is an efficacious antipsychotic drug that has serious, unpredictable motor side effects that limit its utility and cause noncompliance in many patients. Using a drug–placebo diallel of the eight founder strains of the Collaborative Cross and their F1 hybrids, we characterized aggregate effects of genetics, sex, parent of origin, and their combinations on haloperidol response. Treating matched pairs of both sexes with drug or placebo, we measured changes in the following: open field activity, inclined screen rigidity, orofacial movements, prepulse inhibition of the acoustic startle response, plasma and brain drug level measurements, and body weight. To understand the genetic architecture of haloperidol response we introduce new statistical methodology linking heritable variation with causal effect of drug treatment. Our new estimators, “difference of models” and “multiple-impute matched pairs”, are motivated by the Neyman–Rubin potential outcomes framework and extend our existing Bayesian hierarchical model for the diallel (Lenarcic et al. 2012). Drug-induced rigidity after chronic treatment was affected by mainly additive genetics and parent-of-origin effects (accounting for 28% and 14.8% of the variance), with NZO/HILtJ and 129S1/SvlmJ contributions tending to increase this side effect. Locomotor activity after acute treatment, by contrast, was more affected by strain-specific inbreeding (12.8%). In addition to drug response phenotypes, we examined diallel effects on behavior before treatment and found not only effects of additive genetics (10.2–53.2%) but also strong effects of epistasis (10.64–25.2%). In particular: prepulse inhibition showed additivity and epistasis in about equal proportions (26.1% and 23.7%); there was evidence of nonreciprocal epistasis in pretreatment activity and rigidity; and we estimated a range of effects on body weight that replicate those found in our previous work. Our results provide the first quantitative description of the genetic architecture of haloperidol response in mice and indicate that additive, dominance-like inbreeding and parent-of-origin effects contribute strongly to treatment effect heterogeneity for this drug. PMID:24240528

Improved Statistics for Genome-Wide Interaction Analysis

PubMed Central

Ueki, Masao; Cordell, Heather J.

2012-01-01

Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under the correct model; however, reasons for its superior performance were not fully explored. Here we investigate the theoretical properties and performance of Wu et al.'s proposed statistics and explain why, in some circumstances, they outperform competing approaches. Unfortunately, we find minor errors in the formulae for their statistics, resulting in tests that have higher than nominal type 1 error. We also find minor errors in PLINK's fast-epistasis and case-only statistics, although theory and simulations suggest that these errors have only negligible effect on type 1 error. We propose adjusted versions of all four statistics that, both theoretically and in computer simulations, maintain correct type 1 error rates under the null hypothesis. We also investigate statistics based on correlation coefficients that maintain similar control of type 1 error. Although designed to test specifically for interaction, we show that some of these previously-proposed statistics can, in fact, be sensitive to main effects at one or both loci, particularly in the presence of linkage disequilibrium. We propose two new “joint effects” statistics that, provided the disease is rare, are sensitive only to genuine interaction effects. In computer simulations we find, in most situations considered, that highest power is achieved by analysis under the correct genetic model. Such an analysis is unachievable in practice, as we do not know this model. However, generally high power over a wide range of scenarios is exhibited by our joint effects and adjusted Wu statistics. We recommend use of these alternative or adjusted statistics and urge caution when using Wu et al.'s originally-proposed statistics, on account of the inflated error rate that can result. PMID:22496670

A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region.

PubMed

Olson, Jane M; Goddard, Katrina A B; Dudek, Doreen M

2002-07-01

We used a covariate-based linkage method to reanalyze genome scan data from affected sibships collected by the Alzheimer Disease (AD) Genetics Initiative of the National Institute of Mental Health. As reported in an earlier article, the amyloid-beta precursor protein (APP) region is strongly linked to affected sib pairs of the oldest current age (i.e., age either at last exam or at death) who lack E4 alleles at the apolipoprotein E (ApoE) locus. We now report that a region on 20p shows the same pattern. A model that includes current age and the number of E2 alleles as covariates gives a LOD score of 4.1. The signal on 20p is near the location of the gene coding for cystatin-C, previously shown to be associated with late-onset AD and to codeposit with APP in the brains of patients with AD. Two-locus analysis provides evidence of strong epistasis between 20p and the APP region, limited to the oldest age group and to those lacking ApoE4 alleles. We speculate that high-risk polymorphisms in both regions produce a biological interaction between these two proteins that increases susceptibility to a very-late-onset form of AD.

Fixation Probability in a Two-Locus Model by the Ancestral Recombination–Selection Graph

PubMed Central

Lessard, Sabin; Kermany, Amir R.

2012-01-01

We use the ancestral influence graph (AIG) for a two-locus, two-allele selection model in the limit of a large population size to obtain an analytic approximation for the probability of ultimate fixation of a single mutant allele A. We assume that this new mutant is introduced at a given locus into a finite population in which a previous mutant allele B is already segregating with a wild type at another linked locus. We deduce that the fixation probability increases as the recombination rate increases if allele A is either in positive epistatic interaction with B and allele B is beneficial or in no epistatic interaction with B and then allele A itself is beneficial. This holds at least as long as the recombination fraction and the selection intensity are small enough and the population size is large enough. In particular this confirms the Hill–Robertson effect, which predicts that recombination renders more likely the ultimate fixation of beneficial mutants at different loci in a population in the presence of random genetic drift even in the absence of epistasis. More importantly, we show that this is true from weak negative epistasis to positive epistasis, at least under weak selection. In the case of deleterious mutants, the fixation probability decreases as the recombination rate increases. This supports Muller’s ratchet mechanism to explain the accumulation of deleterious mutants in a population lacking recombination. PMID:22095080

Genetic architecture and the evolution of sex.

PubMed

Lohaus, Rolf; Burch, Christina L; Azevedo, Ricardo B R

2010-01-01

Theoretical investigations of the advantages of sex have tended to treat the genetic architecture of organisms as static and have not considered that genetic architecture might coevolve with reproductive mode. As a result, some potential advantages of sex may have been missed. Using a gene network model, we recently showed that recombination imposes selection for robustness to mutation and that negative epistasis can evolve as a by-product of this selection. These results motivated a detailed exploration of the mutational deterministic hypothesis, a hypothesis in which the advantage of sex depends critically on epistasis. We found that sexual populations do evolve higher mean fitness and lower genetic load than asexual populations at equilibrium, and, under moderate stabilizing selection and large population size, these equilibrium sexual populations resist invasion by asexuals. However, we found no evidence that these long- and short-term advantages to sex were explained by the negative epistasis that evolved in our experiments. The long-term advantage of sex was that sexual populations evolved a lower deleterious mutation rate, but this property was not sufficient to account for the ability of sexual populations to resist invasion by asexuals. The ability to resist asexual invasion was acquired simultaneously with an increase in recombinational robustness that minimized the cost of sex. These observations provide the first direct evidence that sexual reproduction does indeed select for conditions that favor its own maintenance. Furthermore, our results highlight the importance of considering a dynamic view of the genetic architecture to understand the evolution of sex and recombination.

THE EVOLUTION OF CANALIZATION AND THE BREAKING OF VON BAER'S LAWS: MODELING THE EVOLUTION OF DEVELOPMENT WITH EPISTASIS.

PubMed

Rice, Sean H

1998-06-01

Evolution can change the developmental processes underlying a character without changing the average expression of the character itself. This sort of change must occur in both the evolution of canalization, in which a character becomes increasingly buffered against genetic or developmental variation, and in the phenomenon of closely related species that show similar adult phenotypes but different underlying developmental patterns. To study such phenomena, I develop a model that follows evolution on a surface representing adult phenotype as a function of underlying developmental characters. A contour on such a "phenotype landscape" is a set of states of developmental characters that produce the same adult phenotype. Epistasis induces curvature of this surface, and degree of canalization is represented by the slope along a contour. I first discuss the geometric properties of phenotype landscapes, relating epistasis to canalization. I then impose a fitness function on the phenotype and model evolution of developmental characters as a function of the fitness function and the local geometry of the surface. This model shows how canalization evolves as a population approaches an optimum phenotype. It further shows that under some circumstances, "decanalization" can occur, in which the expression of adult phenotype becomes increasingly sensitive to developmental variation. This process can cause very similar populations to diverge from one another developmentally even when their adult phenotypes experience identical selection regimes. © 1998 The Society for the Study of Evolution.

Epistasis and Pleiotropy Affect the Modularity of the Genotype-Phenotype Map of Cross-Resistance in HIV-1.

PubMed

Polster, Robert; Petropoulos, Christos J; Bonhoeffer, Sebastian; Guillaume, Frédéric

2016-12-01

The genotype-phenotype (GP) map is a central concept in evolutionary biology as it describes the mapping of molecular genetic variation onto phenotypic trait variation. Our understanding of that mapping remains partial, especially when trying to link functional clustering of pleiotropic gene effects with patterns of phenotypic trait co-variation. Only on rare occasions have studies been able to fully explore that link and tend to show poor correspondence between modular structures within the GP map and among phenotypes. By dissecting the structure of the GP map of the replicative capacity of HIV-1 in 15 drug environments, we provide a detailed view of that mapping from mutational pleiotropic variation to phenotypic co-variation, including epistatic effects of a set of amino-acid substitutions in the reverse transcriptase and protease genes. We show that epistasis increases the pleiotropic degree of single mutations and provides modularity to the GP map of drug resistance in HIV-1. Moreover, modules of epistatic pleiotropic effects within the GP map match the phenotypic modules of correlated replicative capacity among drug classes. Epistasis thus increases the evolvability of cross-resistance in HIV by providing more drug- and class-specific pleiotropic profiles to the main effects of the mutations. We discuss the implications for the evolution of cross-resistance in HIV. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Epistasis Analysis for Estrogen Metabolic and Signaling Pathway Genes on Young Ischemic Stroke Patients

PubMed Central

Hsieh, Yi-Chen; Jeng, Jiann-Shing; Lin, Huey-Juan; Hu, Chaur-Jong; Yu, Chia-Chen; Lien, Li-Ming; Peng, Giia-Sheun; Chen, Chin-I; Tang, Sung-Chun; Chi, Nai-Fang; Tseng, Hung-Pin; Chern, Chang-Ming; Hsieh, Fang-I; Bai, Chyi-Huey; Chen, Yi-Rhu; Chiou, Hung-Yi; Jeng, Jiann-Shing; Tang, Sung-Chun; Yeh, Shin-Joe; Tsai, Li-Kai; Kong, Shin; Lien, Li-Ming; Chiu, Hou-Chang; Chen, Wei-Hung; Bai, Chyi-Huey; Huang, Tzu-Hsuan; Chi-Ieong, Lau; Wu, Ya-Ying; Yuan, Rey-Yue; Hu, Chaur-Jong; Sheu, Jau- Jiuan; Yu, Jia-Ming; Ho, Chun-Sum; Chen, Chin-I; Sung, Jia-Ying; Weng, Hsing-Yu; Han, Yu-Hsuan; Huang, Chun-Ping; Chung, Wen-Ting; Ke, Der-Shin; Lin, Huey-Juan; Chang, Chia-Yu; Yeh, Poh-Shiow; Lin, Kao-Chang; Cheng, Tain-Junn; Chou, Chih-Ho; Yang, Chun-Ming; Peng, Giia-Sheun; Lin, Jiann-Chyun; Hsu, Yaw-Don; Denq, Jong-Chyou; Lee, Jiunn-Tay; Hsu, Chang-Hung; Lin, Chun-Chieh; Yen, Che-Hung; Cheng, Chun-An; Sung, Yueh-Feng; Chen, Yuan-Liang; Lien, Ming-Tung; Chou, Chung-Hsing; Liu, Chia-Chen; Yang, Fu-Chi; Wu, Yi-Chung; Tso, An-Chen; Lai, Yu- Hua; Chiang, Chun-I; Tsai, Chia-Kuang; Liu, Meng-Ta; Lin, Ying-Che; Hsu, Yu-Chuan; Chen, Chih-Hung; Sung, Pi-Shan; Chern, Chang-Ming; Hu, Han-Hwa; Wong, Wen-Jang; Luk, Yun-On; Hsu, Li-Chi; Chung, Chih-Ping; Tseng, Hung-Pin; Liu, Chin-Hsiung; Lin, Chun-Liang; Lin, Hung-Chih; Hu, Chaur-Jong

2012-01-01

Background Endogenous estrogens play an important role in the overall cardiocirculatory system. However, there are no studies exploring the hormone metabolism and signaling pathway genes together on ischemic stroke, including sulfotransferase family 1E (SULT1E1), catechol-O-methyl-transferase (COMT), and estrogen receptor α (ESR1). Methods A case-control study was conducted on 305 young ischemic stroke subjects aged ≦ 50 years and 309 age-matched healthy controls. SULT1E1 -64G/A, COMT Val158Met, ESR1 c.454−397 T/C and c.454−351 A/G genes were genotyped and compared between cases and controls to identify single nucleotide polymorphisms associated with ischemic stroke susceptibility. Gene-gene interaction effects were analyzed using entropy-based multifactor dimensionality reduction (MDR), classification and regression tree (CART), and traditional multiple regression models. Results COMT Val158Met polymorphism showed a significant association with susceptibility of young ischemic stroke among females. There was a two-way interaction between SULT1E1 -64G/A and COMT Val158Met in both MDR and CART analysis. The logistic regression model also showed there was a significant interaction effect between SULT1E1 -64G/A and COMT Val158Met on ischemic stroke of the young (P for interaction = 0.0171). We further found that lower estradiol level could increase the risk of young ischemic stroke for those who carry either SULT1E1 or COMT risk genotypes, showing a significant interaction effect (P for interaction = 0.0174). Conclusions Our findings support that a significant epistasis effect exists among estrogen metabolic and signaling pathway genes and gene-environment interactions on young ischemic stroke subjects. PMID:23112845

The RAD24 (= Rs1) Gene Product of Saccharomyces cerevisiae Participates in Two Different Pathways of DNA Repair

PubMed Central

Eckardt-Schupp, Friederike; Siede, Wolfram; Game, John C.

1987-01-01

The moderately UV- and X-ray-sensitive mutant of Saccharomyces cerevisiae originally designated rs1 complements all rad and mms mutants available. Therefore, the new nomination rad24-1 according to the RAD nomenclature is suggested. RAD24 maps on chromosome V, close to RAD3 (1.3 cM). In order to associate the RAD24 gene with one of the three repair pathways, double mutants of rad24 and various representative genes of each pathway were constructed. The UV and X-ray sensitivities of the double mutants compared to the single mutants indicate that RAD24 is involved in excision repair of UV damage (RAD3 epistasis group), as well as in recombination repair of UV and X-ray damage (RAD52 epistasis group). Properties of the mutant are discussed which hint at the control of late steps in the pathways. PMID:3549445

Epistasis and the Structure of Fitness Landscapes: Are Experimental Fitness Landscapes Compatible with Fisher’s Geometric Model?

PubMed Central

Blanquart, François; Bataillon, Thomas

2016-01-01

The fitness landscape defines the relationship between genotypes and fitness in a given environment and underlies fundamental quantities such as the distribution of selection coefficient and the magnitude and type of epistasis. A better understanding of variation in landscape structure across species and environments is thus necessary to understand and predict how populations will adapt. An increasing number of experiments investigate the properties of fitness landscapes by identifying mutations, constructing genotypes with combinations of these mutations, and measuring the fitness of these genotypes. Yet these empirical landscapes represent a very small sample of the vast space of all possible genotypes, and this sample is often biased by the protocol used to identify mutations. Here we develop a rigorous statistical framework based on Approximate Bayesian Computation to address these concerns and use this flexible framework to fit a broad class of phenotypic fitness models (including Fisher’s model) to 26 empirical landscapes representing nine diverse biological systems. Despite uncertainty owing to the small size of most published empirical landscapes, the inferred landscapes have similar structure in similar biological systems. Surprisingly, goodness-of-fit tests reveal that this class of phenotypic models, which has been successful so far in interpreting experimental data, is a plausible in only three of nine biological systems. More precisely, although Fisher’s model was able to explain several statistical properties of the landscapes—including the mean and SD of selection and epistasis coefficients—it was often unable to explain the full structure of fitness landscapes. PMID:27052568

The genetic architecture of susceptibility to parasites.

PubMed

Wilfert, Lena; Schmid-Hempel, Paul

2008-06-30

The antagonistic co-evolution of hosts and their parasites is considered to be a potential driving force in maintaining host genetic variation including sexual reproduction and recombination. The examination of this hypothesis calls for information about the genetic basis of host-parasite interactions - such as how many genes are involved, how big an effect these genes have and whether there is epistasis between loci. We here examine the genetic architecture of quantitative resistance in animal and plant hosts by concatenating published studies that have identified quantitative trait loci (QTL) for host resistance in animals and plants. Collectively, these studies show that host resistance is affected by few loci. We particularly show that additional epistatic interactions, especially between loci on different chromosomes, explain a majority of the effects. Furthermore, we find that when experiments are repeated using different host or parasite genotypes under otherwise identical conditions, the underlying genetic architecture of host resistance can vary dramatically - that is, involves different QTLs and epistatic interactions. QTLs and epistatic loci vary much less when host and parasite types remain the same but experiments are repeated in different environments. This pattern of variability of the genetic architecture is predicted by strong interactions between genotypes and corroborates the prevalence of varying host-parasite combinations over varying environmental conditions. Moreover, epistasis is a major determinant of phenotypic variance for host resistance. Because epistasis seems to occur predominantly between, rather than within, chromosomes, segregation and chromosome number rather than recombination via cross-over should be the major elements affecting adaptive change in host resistance.

Genecentric: a package to uncover graph-theoretic structure in high-throughput epistasis data.

PubMed

Gallant, Andrew; Leiserson, Mark D M; Kachalov, Maxim; Cowen, Lenore J; Hescott, Benjamin J

2013-01-18

New technology has resulted in high-throughput screens for pairwise genetic interactions in yeast and other model organisms. For each pair in a collection of non-essential genes, an epistasis score is obtained, representing how much sicker (or healthier) the double-knockout organism will be compared to what would be expected from the sickness of the component single knockouts. Recent algorithmic work has identified graph-theoretic patterns in this data that can indicate functional modules, and even sets of genes that may occur in compensatory pathways, such as a BPM-type schema first introduced by Kelley and Ideker. However, to date, any algorithms for finding such patterns in the data were implemented internally, with no software being made publically available. Genecentric is a new package that implements a parallelized version of the Leiserson et al. algorithm (J Comput Biol 18:1399-1409, 2011) for generating generalized BPMs from high-throughput genetic interaction data. Given a matrix of weighted epistasis values for a set of double knock-outs, Genecentric returns a list of generalized BPMs that may represent compensatory pathways. Genecentric also has an extension, GenecentricGO, to query FuncAssociate (Bioinformatics 25:3043-3044, 2009) to retrieve GO enrichment statistics on generated BPMs. Python is the only dependency, and our web site provides working examples and documentation. We find that Genecentric can be used to find coherent functional and perhaps compensatory gene sets from high throughput genetic interaction data. Genecentric is made freely available for download under the GPLv2 from http://bcb.cs.tufts.edu/genecentric.

Genecentric: a package to uncover graph-theoretic structure in high-throughput epistasis data

PubMed Central

2013-01-01

Background New technology has resulted in high-throughput screens for pairwise genetic interactions in yeast and other model organisms. For each pair in a collection of non-essential genes, an epistasis score is obtained, representing how much sicker (or healthier) the double-knockout organism will be compared to what would be expected from the sickness of the component single knockouts. Recent algorithmic work has identified graph-theoretic patterns in this data that can indicate functional modules, and even sets of genes that may occur in compensatory pathways, such as a BPM-type schema first introduced by Kelley and Ideker. However, to date, any algorithms for finding such patterns in the data were implemented internally, with no software being made publically available. Results Genecentric is a new package that implements a parallelized version of the Leiserson et al. algorithm (J Comput Biol 18:1399-1409, 2011) for generating generalized BPMs from high-throughput genetic interaction data. Given a matrix of weighted epistasis values for a set of double knock-outs, Genecentric returns a list of generalized BPMs that may represent compensatory pathways. Genecentric also has an extension, GenecentricGO, to query FuncAssociate (Bioinformatics 25:3043-3044, 2009) to retrieve GO enrichment statistics on generated BPMs. Python is the only dependency, and our web site provides working examples and documentation. Conclusion We find that Genecentric can be used to find coherent functional and perhaps compensatory gene sets from high throughput genetic interaction data. Genecentric is made freely available for download under the GPLv2 from http://bcb.cs.tufts.edu/genecentric. PMID:23331614

Genetic architecture of natural variation in Drosophila melanogaster aggressive behavior

PubMed Central

Shorter, John; Couch, Charlene; Huang, Wen; Carbone, Mary Anna; Peiffer, Jason; Anholt, Robert R. H.; Mackay, Trudy F. C.

2015-01-01

Aggression is an evolutionarily conserved complex behavior essential for survival and the organization of social hierarchies. With the exception of genetic variants associated with bioamine signaling, which have been implicated in aggression in many species, the genetic basis of natural variation in aggression is largely unknown. Drosophila melanogaster is a favorable model system for exploring the genetic basis of natural variation in aggression. Here, we performed genome-wide association analyses using the inbred, sequenced lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and replicate advanced intercross populations derived from the most and least aggressive DGRP lines. We identified genes that have been previously implicated in aggressive behavior as well as many novel loci, including gustatory receptor 63a (Gr63a), which encodes a subunit of the receptor for CO2, and genes associated with development and function of the nervous system. Although genes from the two association analyses were largely nonoverlapping, they mapped onto a genetic interaction network inferred from an analysis of pairwise epistasis in the DGRP. We used mutations and RNAi knock-down alleles to functionally validate 79% of the candidate genes and 75% of the candidate epistatic interactions tested. Epistasis for aggressive behavior causes cryptic genetic variation in the DGRP that is revealed by changing allele frequencies in the outbred populations derived from extreme DGRP lines. This phenomenon may pertain to other fitness traits and species, with implications for evolution, applied breeding, and human genetics. PMID:26100892

Dissection of Insertion–Deletion Variants within Differentially Expressed Genes Involved in Wood Formation in Populus

PubMed Central

Gong, Chenrui; Du, Qingzhang; Xie, Jianbo; Quan, Mingyang; Chen, Beibei; Zhang, Deqiang

2018-01-01

Short insertions and deletions (InDels) are one of the major genetic variants and are distributed widely across the genome; however, few investigations of InDels have been conducted in long-lived perennial plants. Here, we employed a combination of RNA-seq and population resequencing to identify InDels within differentially expressed (DE) genes underlying wood formation in a natural population of Populus tomentosa (435 individuals) and utilized InDel-based association mapping to detect the causal variants under additive, dominance, and epistasis underlying growth and wood properties. In the present paper, 5,482 InDels detected from 629 DE genes showed uneven distributions throughout all 19 chromosomes, and 95.9% of these loci were diallelic InDels. Seventy-four InDels (positive false discovery rate q ≤ 0.10) from 68 genes exhibited significant additive/dominant effects on 10 growth and wood-properties, with an average of 14.7% phenotypic variance explained. Potential pleiotropy was observed in one-third of the InDels (representing 24 genes). Seven genes exhibited significantly differential expression among the genotypic classes of associated InDels, indicating possible important roles for these InDels. Epistasis analysis showed that overlapping interacting genes formed unique interconnected networks for each trait, supporting the putative biochemical links that control quantitative traits. Therefore, the identification and utilization of InDels in trees will be recognized as an effective marker system for molecular marker-assisted breeding applications, and further facilitate our understanding of quantitative genomics. PMID:29403506

Causes and Consequences of Genetic Background Effects Illuminated by Integrative Genomic Analysis

PubMed Central

Chandler, Christopher H.; Chari, Sudarshan; Dworkin, Ian

2014-01-01

The phenotypic consequences of individual mutations are modulated by the wild-type genetic background in which they occur. Although such background dependence is widely observed, we do not know whether general patterns across species and traits exist or about the mechanisms underlying it. We also lack knowledge on how mutations interact with genetic background to influence gene expression and how this in turn mediates mutant phenotypes. Furthermore, how genetic background influences patterns of epistasis remains unclear. To investigate the genetic basis and genomic consequences of genetic background dependence of the scallopedE3 allele on the Drosophila melanogaster wing, we generated multiple novel genome-level datasets from a mapping-by-introgression experiment and a tagged RNA gene expression dataset. In addition we used whole genome resequencing of the parental lines—two commonly used laboratory strains—to predict polymorphic transcription factor binding sites for SD. We integrated these data with previously published genomic datasets from expression microarrays and a modifier mutation screen. By searching for genes showing a congruent signal across multiple datasets, we were able to identify a robust set of candidate loci contributing to the background-dependent effects of mutations in sd. We also show that the majority of background-dependent modifiers previously reported are caused by higher-order epistasis, not quantitative noncomplementation. These findings provide a useful foundation for more detailed investigations of genetic background dependence in this system, and this approach is likely to prove useful in exploring the genetic basis of other traits as well. PMID:24504186

Genotypic Complexity of Fisher’s Geometric Model

PubMed Central

Hwang, Sungmin; Park, Su-Chan; Krug, Joachim

2017-01-01

Fisher’s geometric model was originally introduced to argue that complex adaptations must occur in small steps because of pleiotropic constraints. When supplemented with the assumption of additivity of mutational effects on phenotypic traits, it provides a simple mechanism for the emergence of genotypic epistasis from the nonlinear mapping of phenotypes to fitness. Of particular interest is the occurrence of reciprocal sign epistasis, which is a necessary condition for multipeaked genotypic fitness landscapes. Here we compute the probability that a pair of randomly chosen mutations interacts sign epistatically, which is found to decrease with increasing phenotypic dimension n, and varies nonmonotonically with the distance from the phenotypic optimum. We then derive expressions for the mean number of fitness maxima in genotypic landscapes comprised of all combinations of L random mutations. This number increases exponentially with L, and the corresponding growth rate is used as a measure of the complexity of the landscape. The dependence of the complexity on the model parameters is found to be surprisingly rich, and three distinct phases characterized by different landscape structures are identified. Our analysis shows that the phenotypic dimension, which is often referred to as phenotypic complexity, does not generally correlate with the complexity of fitness landscapes and that even organisms with a single phenotypic trait can have complex landscapes. Our results further inform the interpretation of experiments where the parameters of Fisher’s model have been inferred from data, and help to elucidate which features of empirical fitness landscapes can be described by this model. PMID:28450460

[Analysis of genetic models and gene effects on main agronomy characters in rapeseed].

PubMed

Li, J; Qiu, J; Tang, Z; Shen, L

1992-01-01

According to four different genetic models, the genetic patterns of 8 agronomy traits were analysed by using the data of 24 generations which included positive and negative cross of 81008 x Tower, both of the varieties are of good quality. The results showed that none of 8 characters could fit in with additive-dominance models. Epistasis was found in all of these characters, and it has significant effect on generation means. Seed weight/plant and some other main yield characters are controlled by duplicate interaction genes. The interaction between triple genes or multiple genes needs to be utilized in yield heterosis.

A Genome-Wide Association Analysis Reveals Epistatic Cancellation of Additive Genetic Variance for Root Length in Arabidopsis thaliana.

PubMed

Lachowiec, Jennifer; Shen, Xia; Queitsch, Christine; Carlborg, Örjan

2015-01-01

Efforts to identify loci underlying complex traits generally assume that most genetic variance is additive. Here, we examined the genetics of Arabidopsis thaliana root length and found that the genomic narrow-sense heritability for this trait in the examined population was statistically zero. The low amount of additive genetic variance that could be captured by the genome-wide genotypes likely explains why no associations to root length could be found using standard additive-model-based genome-wide association (GWA) approaches. However, as the broad-sense heritability for root length was significantly larger, and primarily due to epistasis, we also performed an epistatic GWA analysis to map loci contributing to the epistatic genetic variance. Four interacting pairs of loci were revealed, involving seven chromosomal loci that passed a standard multiple-testing corrected significance threshold. The genotype-phenotype maps for these pairs revealed epistasis that cancelled out the additive genetic variance, explaining why these loci were not detected in the additive GWA analysis. Small population sizes, such as in our experiment, increase the risk of identifying false epistatic interactions due to testing for associations with very large numbers of multi-marker genotypes in few phenotyped individuals. Therefore, we estimated the false-positive risk using a new statistical approach that suggested half of the associated pairs to be true positive associations. Our experimental evaluation of candidate genes within the seven associated loci suggests that this estimate is conservative; we identified functional candidate genes that affected root development in four loci that were part of three of the pairs. The statistical epistatic analyses were thus indispensable for confirming known, and identifying new, candidate genes for root length in this population of wild-collected A. thaliana accessions. We also illustrate how epistatic cancellation of the additive genetic variance explains the insignificant narrow-sense and significant broad-sense heritability by using a combination of careful statistical epistatic analyses and functional genetic experiments.

Genome-Wide Analysis Reveals Novel Regulators of Growth in Drosophila melanogaster

PubMed Central

Vonesch, Sibylle Chantal; Lamparter, David; Mackay, Trudy F. C.; Bergmann, Sven; Hafen, Ernst

2016-01-01

Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA) analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity. PMID:26751788

Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility.

PubMed

Bossi, G; Mannarino, S; Pietrogrande, M C; Salice, P; Dellepiane, R M; Cremaschi, A L; Corana, G; Tozzo, A; Capittini, C; De Silvestri, A; Tinelli, C; Pasi, A; Martinetti, M

2015-10-01

Kawasaki disease (KD) is a pediatric acute multisystemic vasculitis complicated by development of coronary artery lesions. The breakthrough theory on KD etiopathogenesis points to pathogens/environmental factors triggered by northeastern wind coming from China. Natural Killer cells and T lymphocytes express the inhibitory/activating Killer Immunoglobulin-like Receptors (KIR) to elicit an immune response against pathogens by binding to human leukocyte antigens (HLA) class I epitopes. We first report on the role of KIR/HLA genetic epistasis in a sample of 100 Italian KD children. We genotyped KIR, HLA-A, HLA-B and HLA-C polymorphisms, and compared KD data with those from 270 Italian healthy donors. The HLA-A*11 ligand for KIR2DS2/2DS4/3DL2 was a KD susceptibility marker by itself (odds ratio (OR)=3.85, confidence interval (CI)=1.55-9.53, P=0.004). Although no epistasis between HLA-A*11 and KIR2DS2/S4 emerged, HLA-A*11 also engages KIR3DL2, a framework gene encoding for a pathogen sensor of CpG-oligodeoxynucleotides (CpG-ODN), and KD blood mononuclear cells are actually prone to pathogen CpG-ODN activation in the acute phase. Moreover, carriers of KIR2DS2/HLA-C1 and KIR2DL2/HLA-C1 were more frequent among KD, in keeping with data demonstrating the involvement of these HLA/KIR couples in autoimmune endothelial damage. The highest KD risk factor was observed among carriers of KIR2DL2 and two or more HLA ligands (OR=10.24, CI=1.87-56.28; P=0.007).

Amplified fragment length polymorphism mapping of quantitative trait loci for malaria parasite susceptibility in the yellow fever mosquito Aedes aegypti.

PubMed

Zhong, Daibin; Menge, David M; Temu, Emmanuel A; Chen, Hong; Yan, Guiyun

2006-07-01

The yellow fever mosquito Aedes aegypti has been the subject of extensive genetic research due to its medical importance and the ease with which it can be manipulated in the laboratory. A molecular genetic linkage map was constructed using 148 amplified fragment length polymorphism (AFLP) and six single-strand conformation polymorphism (SSCP) markers. Eighteen AFLP primer combinations were used to genotype two reciprocal F2 segregating populations. Each primer combination generated an average of 8.2 AFLP markers eligible for linkage mapping. The length of the integrated map was 180.9 cM, giving an average marker resolution of 1.2 cM. Composite interval mapping revealed a total of six QTL significantly affecting Plasmodium susceptibility in the two reciprocal crosses of Ae. aegypti. Two common QTL on linkage group 2 were identified in both crosses that had similar effects on the phenotype, and four QTL were unique to each cross. In one cross, the four main QTL accounted for 64% of the total phenotypic variance, and digenic epistasis explained 11.8% of the variance. In the second cross, the four main QTL explained 66% of the variance, and digenic epistasis accounted for 16% of the variance. The actions of these QTL were either dominance or underdominance. Our results indicated that at least three new QTL were mapped on chromosomes 1 and 3. The polygenic nature of susceptibility to P. gallinaceum and epistasis are important factors for significant variation within or among mosquito strains. The new map provides additional information useful for further genetic investigation, such as identification of new genes and positional cloning.

OncoSimulR: genetic simulation with arbitrary epistasis and mutator genes in asexual populations.

PubMed

Diaz-Uriarte, Ramon

2017-06-15

OncoSimulR implements forward-time genetic simulations of biallelic loci in asexual populations with special focus on cancer progression. Fitness can be defined as an arbitrary function of genetic interactions between multiple genes or modules of genes, including epistasis, restrictions in the order of accumulation of mutations, and order effects. Mutation rates can differ among genes, and can be affected by (anti)mutator genes. Also available are sampling from simulations (including single-cell sampling), plotting the genealogical relationships of clones and generating and plotting fitness landscapes. Implemented in R and C ++, freely available from BioConductor for Linux, Mac and Windows under the GNU GPL license. Version 2.5.9 or higher available from: http://www.bioconductor.org/packages/devel/bioc/html/OncoSimulR.html . GitHub repository at: https://github.com/rdiaz02/OncoSimul. ramon.diaz@iib.uam.es. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press.

Fitness benefits in fluoroquinolone-resistant Salmonella Typhi in the absence of antimicrobial pressure

PubMed Central

Baker, Stephen; Duy, Pham Thanh; Nga, Tran Vu Thieu; Dung, Tran Thi Ngoc; Phat, Voong Vinh; Chau, Tran Thuy; Turner, A Keith; Farrar, Jeremy; Boni, Maciej F

2013-01-01

Fluoroquinolones (FQ) are the recommended antimicrobial treatment for typhoid, a severe systemic infection caused by the bacterium Salmonella enterica serovar Typhi. FQ-resistance mutations in S. Typhi have become common, hindering treatment and control efforts. Using in vitro competition experiments, we assayed the fitness of eleven isogenic S. Typhi strains with resistance mutations in the FQ target genes, gyrA and parC. In the absence of antimicrobial pressure, 6 out of 11 mutants carried a selective advantage over the antimicrobial-sensitive parent strain, indicating that FQ resistance in S. Typhi is not typically associated with fitness costs. Double-mutants exhibited higher than expected fitness as a result of synergistic epistasis, signifying that epistasis may be a critical factor in the evolution and molecular epidemiology of S. Typhi. Our findings have important implications for the management of drug-resistant S. Typhi, suggesting that FQ-resistant strains would be naturally maintained even if fluoroquinolone use were reduced. DOI: http://dx.doi.org/10.7554/eLife.01229.001 PMID:24327559

Diminishing-returns epistasis decreases adaptability along an evolutionary trajectory.

PubMed

Wünsche, Andrea; Dinh, Duy M; Satterwhite, Rebecca S; Arenas, Carolina Diaz; Stoebel, Daniel M; Cooper, Tim F

2017-03-01

Populations evolving in constant environments exhibit declining adaptability. Understanding the basis of this pattern could reveal underlying processes determining the repeatability of evolutionary outcomes. In principle, declining adaptability can be due to a decrease in the effect size of beneficial mutations, a decrease in the rate at which they occur, or some combination of both. By evolving Escherichia coli populations started from different steps along a single evolutionary trajectory, we show that declining adaptability is best explained by a decrease in the size of available beneficial mutations. This pattern reflected the dominant influence of negative genetic interactions that caused new beneficial mutations to confer smaller benefits in fitter genotypes. Genome sequencing revealed that starting genotypes that were more similar to one another did not exhibit greater similarity in terms of new beneficial mutations, supporting the view that epistasis acts globally, having a greater influence on the effect than on the identity of available mutations along an adaptive trajectory. Our findings provide support for a general mechanism that leads to predictable phenotypic evolutionary trajectories.

Variability in working memory performance explained by epistasis vs polygenic scores in the ZNF804A pathway.

PubMed

Nicodemus, Kristin K; Hargreaves, April; Morris, Derek; Anney, Richard; Gill, Michael; Corvin, Aiden; Donohoe, Gary

2014-07-01

We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.

SNPassoc: an R package to perform whole genome association studies.

PubMed

González, Juan R; Armengol, Lluís; Solé, Xavier; Guinó, Elisabet; Mercader, Josep M; Estivill, Xavier; Moreno, Víctor

2007-03-01

The popularization of large-scale genotyping projects has led to the widespread adoption of genetic association studies as the tool of choice in the search for single nucleotide polymorphisms (SNPs) underlying susceptibility to complex diseases. Although the analysis of individual SNPs is a relatively trivial task, when the number is large and multiple genetic models need to be explored it becomes necessary a tool to automate the analyses. In order to address this issue, we developed SNPassoc, an R package to carry out most common analyses in whole genome association studies. These analyses include descriptive statistics and exploratory analysis of missing values, calculation of Hardy-Weinberg equilibrium, analysis of association based on generalized linear models (either for quantitative or binary traits), and analysis of multiple SNPs (haplotype and epistasis analysis). Package SNPassoc is available at CRAN from http://cran.r-project.org. A tutorial is available on Bioinformatics online and in http://davinci.crg.es/estivill_lab/snpassoc.

Epistasis-list.org: A Curated Database of Gene-Gene and Gene-Environment Interactions in Human Epidemiology

EPA Science Inventory

The field of human genetics has experienced a paradigm shift in that common diseases are now thought to be due to the complex interactions among numerous genetic and environmental factors. This paradigm shift has prompted the development of myriad novel methods to detect such int...

Hitchhiking and epistasis give rise to cohort dynamics in adapting populations

PubMed Central

Buskirk, Sean W.; Peace, Ryan Emily; Lang, Gregory I.

2017-01-01

Beneficial mutations are the driving force of adaptive evolution. In asexual populations, the identification of beneficial alleles is confounded by the presence of genetically linked hitchhiker mutations. Parallel evolution experiments enable the recognition of common targets of selection; yet these targets are inherently enriched for genes of large target size and mutations of large effect. A comprehensive study of individual mutations is necessary to create a realistic picture of the evolutionarily significant spectrum of beneficial mutations. Here we use a bulk-segregant approach to identify the beneficial mutations across 11 lineages of experimentally evolved yeast populations. We report that nearly 80% of detected mutations have no discernible effects on fitness and less than 1% are deleterious. We determine the distribution of driver and hitchhiker mutations in 31 mutational cohorts, groups of mutations that arise synchronously from low frequency and track tightly with one another. Surprisingly, we find that one-third of cohorts lack identifiable driver mutations. In addition, we identify intracohort synergistic epistasis between alleles of hsl7 and kel1, which arose together in a low-frequency lineage. PMID:28720700

Genotype to Phenotype Mapping of the E. coli lac Promoter

NASA Astrophysics Data System (ADS)

Otwinowski, Jakub; Nemenman, Ilya

2014-03-01

Genotype-to-phenotype maps and the related fitness landscapes that include epistatic interactions are difficult to measure because of their high dimensional structure. Here we construct such a map using the recently collected corpora of high-throughput sequence data from the 75 base pairs long mutagenized E. coli lac promoter region, where each sequence is associated with induced transcriptional activity measured by a fluorescent reporter. We find that the additive (non-epistatic) contributions of individual mutations account for about two-thirds of the explainable phenotype variance, while pairwise epistasis explains about 7% of the variance for the full mutagenized sequence and about 15% for the subsequence associated with protein binding sites. Surprisingly, there is no evidence for third order epistatic contributions, and our inferred fitness landscape is essentially single peaked, with a small amount of antagonistic epistasis. We identify transcription factor (CRP) and RNA polymerase binding sites in the promotor region and their interactions. We conclude with a cautionary note that inferred properties of fitness landscapes may be severely influenced by biases in the sequence data. Funded in part by HFSP and James S. McDonnell Foundation.

Prediction of genetic values of quantitative traits with epistatic effects in plant breeding populations.

PubMed

Wang, D; Salah El-Basyoni, I; Stephen Baenziger, P; Crossa, J; Eskridge, K M; Dweikat, I

2012-11-01

Though epistasis has long been postulated to have a critical role in genetic regulation of important pathways as well as provide a major source of variation in the process of speciation, the importance of epistasis for genomic selection in the context of plant breeding is still being debated. In this paper, we report the results on the prediction of genetic values with epistatic effects for 280 accessions in the Nebraska Wheat Breeding Program using adaptive mixed least absolute shrinkage and selection operator (LASSO). The development of adaptive mixed LASSO, originally designed for association mapping, for the context of genomic selection is reported. The results show that adaptive mixed LASSO can be successfully applied to the prediction of genetic values while incorporating both marker main effects and epistatic effects. Especially, the prediction accuracy is substantially improved by the inclusion of two-locus epistatic effects (more than onefold in some cases as measured by cross-validation correlation coefficient), which is observed for multiple traits and planting locations. This points to significant potential in using non-additive genetic effects for genomic selection in crop breeding practices.

Leveraging population admixture to explain missing heritability of complex traits

PubMed Central

Zaitlen, Noah; Pasaniuc, Bogdan; Sankararaman, Sriram; Bhatia, Gaurav; Zhang, Jianqi; Gusev, Alexander; Young, Taylor; Tandon, Arti; Pollack, Samuela; Vilhjálmsson, Bjarni J.; Assimes, Themistocles L.; Berndt, Sonja I.; Blot, William J.; Chanock, Stephen; Franceschini, Nora; Goodman, Phyllis G.; He, Jing; Hennis, Anselm JM; Hsing, Ann; Ingles, Sue A.; Isaacs, William; Kittles, Rick A.; Klein, Eric A.; Lange, Leslie A.; Nemesure, Barbara; Patterson, Nick; Reich, David; Rybicki, Benjamin A.; Stanford, Janet L.; Stevens, Victoria L; Strom, Sara S.; Whitsel, Eric A; Witte, John S.; Xu, Jianfeng; Haiman, Christopher; Wilson, James G.; Kooperberg, Charles; Stram, Daniel; Reiner, Alex P.; Tang, Hua; Price, Alkes L.

2014-01-01

Despite recent progress on estimating the heritability explained by genotyped SNPs (hg2), a large gap between hg2 and estimates of total narrow-sense heritability (h2) remains. Explanations for this gap include rare variants, or upward bias in family-based estimates of h2 due to shared environment or epistasis. We estimate h2 from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (hγ2). We show that hγ2 = 2FSTCθ(1−θ)h2, where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We examined 21,497 African Americans from three cohorts, analyzing 13 phenotypes. For height and BMI, we obtained h2 estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of hg2 in these and other data, but smaller than family-based estimates of h2. PMID:25383972

Selection history and epistatic interactions impact dynamics of adaptation to novel environmental stresses.

PubMed

Lagator, Mato; Colegrave, Nick; Neve, Paul

2014-11-07

In rapidly changing environments, selection history may impact the dynamics of adaptation. Mutations selected in one environment may result in pleiotropic fitness trade-offs in subsequent novel environments, slowing the rates of adaptation. Epistatic interactions between mutations selected in sequential stressful environments may slow or accelerate subsequent rates of adaptation, depending on the nature of that interaction. We explored the dynamics of adaptation during sequential exposure to herbicides with different modes of action in Chlamydomonas reinhardtii. Evolution of resistance to two of the herbicides was largely independent of selection history. For carbetamide, previous adaptation to other herbicide modes of action positively impacted the likelihood of adaptation to this herbicide. Furthermore, while adaptation to all individual herbicides was associated with pleiotropic fitness costs in stress-free environments, we observed that accumulation of resistance mechanisms was accompanied by a reduction in overall fitness costs. We suggest that antagonistic epistasis may be a driving mechanism that enables populations to more readily adapt in novel environments. These findings highlight the potential for sequences of xenobiotics to facilitate the rapid evolution of multiple-drug and -pesticide resistance, as well as the potential for epistatic interactions between adaptive mutations to facilitate evolutionary rescue in rapidly changing environments. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

The origin of human complex diversity: Stochastic epistatic modules and the intrinsic compatibility between distributional robustness and phenotypic changeability.

PubMed

Ijichi, Shinji; Ijichi, Naomi; Ijichi, Yukina; Imamura, Chikako; Sameshima, Hisami; Kawaike, Yoichi; Morioka, Hirofumi

2018-01-01

The continuing prevalence of a highly heritable and hypo-reproductive extreme tail of a human neurobehavioral quantitative diversity suggests the possibility that the reproductive majority retains the genetic mechanism for the extremes. From the perspective of stochastic epistasis, the effect of an epistatic modifier variant can randomly vary in both phenotypic value and effect direction among the careers depending on the genetic individuality, and the modifier careers are ubiquitous in the population distribution. The neutrality of the mean genetic effect in the careers warrants the survival of the variant under selection pressures. Functionally or metabolically related modifier variants make an epistatic network module and dozens of modules may be involved in the phenotype. To assess the significance of stochastic epistasis, a simplified module-based model was employed. The individual repertoire of the modifier variants in a module also participates in the genetic individuality which determines the genetic contribution of each modifier in the career. Because the entire contribution of a module to the phenotypic outcome is consequently unpredictable in the model, the module effect represents the total contribution of the related modifiers as a stochastic unit in the simulations. As a result, the intrinsic compatibility between distributional robustness and quantitative changeability could mathematically be simulated using the model. The artificial normal distribution shape in large-sized simulations was preserved in each generation even if the lowest fitness tail was un-reproductive. The robustness of normality beyond generations is analogous to the real situations of human complex diversity including neurodevelopmental conditions. The repeated regeneration of the un-reproductive extreme tail may be inevitable for the reproductive majority's competence to survive and change, suggesting implications of the extremes for others. Further model-simulations to illustrate how the fitness of extreme individuals can be low through generations may be warranted to increase the credibility of this stochastic epistasis model.

Functional genomics annotation of a statistical epistasis network associated with bladder cancer susceptibility.

PubMed

Hu, Ting; Pan, Qinxin; Andrew, Angeline S; Langer, Jillian M; Cole, Michael D; Tomlinson, Craig R; Karagas, Margaret R; Moore, Jason H

2014-04-11

Several different genetic and environmental factors have been identified as independent risk factors for bladder cancer in population-based studies. Recent studies have turned to understanding the role of gene-gene and gene-environment interactions in determining risk. We previously developed the bioinformatics framework of statistical epistasis networks (SEN) to characterize the global structure of interacting genetic factors associated with a particular disease or clinical outcome. By applying SEN to a population-based study of bladder cancer among Caucasians in New Hampshire, we were able to identify a set of connected genetic factors with strong and significant interaction effects on bladder cancer susceptibility. To support our statistical findings using networks, in the present study, we performed pathway enrichment analyses on the set of genes identified using SEN, and found that they are associated with the carcinogen benzo[a]pyrene, a component of tobacco smoke. We further carried out an mRNA expression microarray experiment to validate statistical genetic interactions, and to determine if the set of genes identified in the SEN were differentially expressed in a normal bladder cell line and a bladder cancer cell line in the presence or absence of benzo[a]pyrene. Significant nonrandom sets of genes from the SEN were found to be differentially expressed in response to benzo[a]pyrene in both the normal bladder cells and the bladder cancer cells. In addition, the patterns of gene expression were significantly different between these two cell types. The enrichment analyses and the gene expression microarray results support the idea that SEN analysis of bladder in population-based studies is able to identify biologically meaningful statistical patterns. These results bring us a step closer to a systems genetic approach to understanding cancer susceptibility that integrates population and laboratory-based studies.

Discovering epistasis in large scale genetic association studies by exploiting graphics cards.

PubMed

Chen, Gary K; Guo, Yunfei

2013-12-03

Despite the enormous investments made in collecting DNA samples and generating germline variation data across thousands of individuals in modern genome-wide association studies (GWAS), progress has been frustratingly slow in explaining much of the heritability in common disease. Today's paradigm of testing independent hypotheses on each single nucleotide polymorphism (SNP) marker is unlikely to adequately reflect the complex biological processes in disease risk. Alternatively, modeling risk as an ensemble of SNPs that act in concert in a pathway, and/or interact non-additively on log risk for example, may be a more sensible way to approach gene mapping in modern studies. Implementing such analyzes genome-wide can quickly become intractable due to the fact that even modest size SNP panels on modern genotype arrays (500k markers) pose a combinatorial nightmare, require tens of billions of models to be tested for evidence of interaction. In this article, we provide an in-depth analysis of programs that have been developed to explicitly overcome these enormous computational barriers through the use of processors on graphics cards known as Graphics Processing Units (GPU). We include tutorials on GPU technology, which will convey why they are growing in appeal with today's numerical scientists. One obvious advantage is the impressive density of microprocessor cores that are available on only a single GPU. Whereas high end servers feature up to 24 Intel or AMD CPU cores, the latest GPU offerings from nVidia feature over 2600 cores. Each compute node may be outfitted with up to 4 GPU devices. Success on GPUs varies across problems. However, epistasis screens fare well due to the high degree of parallelism exposed in these problems. Papers that we review routinely report GPU speedups of over two orders of magnitude (>100x) over standard CPU implementations.

Discovering epistasis in large scale genetic association studies by exploiting graphics cards

PubMed Central

Chen, Gary K.; Guo, Yunfei

2013-01-01

Despite the enormous investments made in collecting DNA samples and generating germline variation data across thousands of individuals in modern genome-wide association studies (GWAS), progress has been frustratingly slow in explaining much of the heritability in common disease. Today's paradigm of testing independent hypotheses on each single nucleotide polymorphism (SNP) marker is unlikely to adequately reflect the complex biological processes in disease risk. Alternatively, modeling risk as an ensemble of SNPs that act in concert in a pathway, and/or interact non-additively on log risk for example, may be a more sensible way to approach gene mapping in modern studies. Implementing such analyzes genome-wide can quickly become intractable due to the fact that even modest size SNP panels on modern genotype arrays (500k markers) pose a combinatorial nightmare, require tens of billions of models to be tested for evidence of interaction. In this article, we provide an in-depth analysis of programs that have been developed to explicitly overcome these enormous computational barriers through the use of processors on graphics cards known as Graphics Processing Units (GPU). We include tutorials on GPU technology, which will convey why they are growing in appeal with today's numerical scientists. One obvious advantage is the impressive density of microprocessor cores that are available on only a single GPU. Whereas high end servers feature up to 24 Intel or AMD CPU cores, the latest GPU offerings from nVidia feature over 2600 cores. Each compute node may be outfitted with up to 4 GPU devices. Success on GPUs varies across problems. However, epistasis screens fare well due to the high degree of parallelism exposed in these problems. Papers that we review routinely report GPU speedups of over two orders of magnitude (>100x) over standard CPU implementations. PMID:24348518

Sparse models for correlative and integrative analysis of imaging and genetic data

PubMed Central

Lin, Dongdong; Cao, Hongbao; Calhoun, Vince D.

2014-01-01

The development of advanced medical imaging technologies and high-throughput genomic measurements has enhanced our ability to understand their interplay as well as their relationship with human behavior by integrating these two types of datasets. However, the high dimensionality and heterogeneity of these datasets presents a challenge to conventional statistical methods; there is a high demand for the development of both correlative and integrative analysis approaches. Here, we review our recent work on developing sparse representation based approaches to address this challenge. We show how sparse models are applied to the correlation and integration of imaging and genetic data for biomarker identification. We present examples on how these approaches are used for the detection of risk genes and classification of complex diseases such as schizophrenia. Finally, we discuss future directions on the integration of multiple imaging and genomic datasets including their interactions such as epistasis. PMID:25218561

Human MHC architecture and evolution: implications for disease association studies

PubMed Central

Traherne, J A

2008-01-01

Major histocompatibility complex (MHC) variation is a key determinant of susceptibility and resistance to a large number of infectious, autoimmune and other diseases. Identification of the MHC variants conferring susceptibility to disease is problematic, due to high levels of variation and linkage disequilibrium. Recent cataloguing and analysis of variation over the complete MHC has facilitated localization of susceptibility loci for autoimmune diseases, and provided insight into the MHC's evolution. This review considers how the unusual genetic characteristics of the MHC impact on strategies to identify variants causing, or contributing to, disease phenotypes. It also considers the MHC in relation to novel mechanisms influencing gene function and regulation, such as epistasis, epigenetics and microRNAs. These developments, along with recent technological advances, shed light on genetic association in complex disease. PMID:18397301

Gene Tree Discordance Does Not Explain Away the Temporal Decline of Convergence in Mammalian Protein Sequence Evolution.

PubMed

Zou, Zhengting; Zhang, Jianzhi

2017-07-01

Several authors reported lower frequencies of protein sequence convergence between more distantly related evolutionary lineages and attributed this trend to epistasis, which renders the acceptable amino acids at a site more different and convergence less likely in more divergent lineages. A recent primate study, however, suggested that this trend is at least partially and potentially entirely an artifact of gene tree discordance (GTD). Here, we demonstrate in a genome-wide data set from 17 mammals that the temporal trend remains (1) upon the control of the GTD level, (2) in genes whose genealogies are concordant with the species tree, and (3) for convergent changes, which are extremely unlikely to be caused by GTD. Similar results are observed in a comparable data set of 12 fruit flies in some but not all of these tests. We conclude that, at least in some cases, the temporal decline of convergence is genuine, reflecting an impact of epistasis on protein evolution. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

THE PEAKS AND GEOMETRY OF FITNESS LANDSCAPES

PubMed Central

CRONA, KRISTINA; GREENE, DEVIN; BARLOW, MIRIAM

2012-01-01

Fitness landscapes are central in the theory of adaptation. Recent work compares global and local properties of fitness landscapes. It has been shown that multi-peaked fitness landscapes have a local property called reciprocal sign epistasis interactions. The converse is not true. We show that no condition phrased in terms of reciprocal sign epistasis interactions only, implies multiple peaks. We give a sufficient condition for multiple peaks phrased in terms of two-way interactions. This result is surprising since it has been claimed that no sufficient local condition for multiple peaks exist. We show that our result cannot be generalized to sufficient conditions for three or more peaks. Our proof depends on fitness graphs, where nodes represent genotypes and where arrows point toward more fit genotypes. We also use fitness graphs in order to give a new brief proof of the equivalent characterizations of fitness landscapes lacking genetic constraints on accessible mutational trajectories. We compare a recent geometric classification of fitness landscape based on triangulations of polytopes with qualitative aspects of gene interactions. One observation is that fitness graphs provide information not contained in the geometric classification. We argue that a qualitative perspective may help relating theory of fitness landscapes and empirical observations. PMID:23036916

CMDR based differential evolution identifies the epistatic interaction in genome-wide association studies.

PubMed

Yang, Cheng-Hong; Chuang, Li-Yeh; Lin, Yu-Da

2017-08-01

Detecting epistatic interactions in genome-wide association studies (GWAS) is a computational challenge. Such huge numbers of single-nucleotide polymorphism (SNP) combinations limit the some of the powerful algorithms to be applied to detect the potential epistasis in large-scale SNP datasets. We propose a new algorithm which combines the differential evolution (DE) algorithm with a classification based multifactor-dimensionality reduction (CMDR), termed DECMDR. DECMDR uses the CMDR as a fitness measure to evaluate values of solutions in DE process for scanning the potential statistical epistasis in GWAS. The results indicated that DECMDR outperforms the existing algorithms in terms of detection success rate by the large simulation and real data obtained from the Wellcome Trust Case Control Consortium. For running time comparison, DECMDR can efficient to apply the CMDR to detect the significant association between cases and controls amongst all possible SNP combinations in GWAS. DECMDR is freely available at https://goo.gl/p9sLuJ . chuang@isu.edu.tw or e0955767257@yahoo.com.tw. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Inferring Microbial Fitness Landscapes

DTIC Science & Technology

2016-02-25

infer from data the determinants of microbial evolution with sufficient resolution that we can quantify 1. REPORT DATE (DD-MM-YYYY) 4. TITLE AND...Distribution Unlimited UU UU UU UU 25-02-2016 1-Oct-2012 30-Sep-2015 Final Report: Inferring Microbial Fitness Landscapes The views, opinions and/or findings...Triangle Park, NC 27709-2211 evolution, fitness landscapes, epistasis, microbial populations REPORT DOCUMENTATION PAGE 11. SPONSOR/MONITOR’S REPORT

An omnibus permutation test on ensembles of two-locus analyses can detect pure epistasis and genetic heterogeneity in genome-wide association studies.

PubMed

Setsirichok, Damrongrit; Tienboon, Phuwadej; Jaroonruang, Nattapong; Kittichaijaroen, Somkit; Wongseree, Waranyu; Piroonratana, Theera; Usavanarong, Touchpong; Limwongse, Chanin; Aporntewan, Chatchawit; Phadoongsidhi, Marong; Chaiyaratana, Nachol

2013-01-01

This article presents the ability of an omnibus permutation test on ensembles of two-locus analyses (2LOmb) to detect pure epistasis in the presence of genetic heterogeneity. The performance of 2LOmb is evaluated in various simulation scenarios covering two independent causes of complex disease where each cause is governed by a purely epistatic interaction. Different scenarios are set up by varying the number of available single nucleotide polymorphisms (SNPs) in data, number of causative SNPs and ratio of case samples from two affected groups. The simulation results indicate that 2LOmb outperforms multifactor dimensionality reduction (MDR) and random forest (RF) techniques in terms of a low number of output SNPs and a high number of correctly-identified causative SNPs. Moreover, 2LOmb is capable of identifying the number of independent interactions in tractable computational time and can be used in genome-wide association studies. 2LOmb is subsequently applied to a type 1 diabetes mellitus (T1D) data set, which is collected from a UK population by the Wellcome Trust Case Control Consortium (WTCCC). After screening for SNPs that locate within or near genes and exhibit no marginal single-locus effects, the T1D data set is reduced to 95,991 SNPs from 12,146 genes. The 2LOmb search in the reduced T1D data set reveals that 12 SNPs, which can be divided into two independent sets, are associated with the disease. The first SNP set consists of three SNPs from MUC21 (mucin 21, cell surface associated), three SNPs from MUC22 (mucin 22), two SNPs from PSORS1C1 (psoriasis susceptibility 1 candidate 1) and one SNP from TCF19 (transcription factor 19). A four-locus interaction between these four genes is also detected. The second SNP set consists of three SNPs from ATAD1 (ATPase family, AAA domain containing 1). Overall, the findings indicate the detection of pure epistasis in the presence of genetic heterogeneity and provide an alternative explanation for the aetiology of T1D in the UK population.

EFFECTS OF DIFFERENT LEVELS OF INBREEDING ON PROGENY FITNESS IN PLANTAGO CORONOPUS.

PubMed

Koelewijn, Hans Peter

1998-06-01

Inbreeding depression (δ) is a major selective force favoring outcrossing in flowering plants. Many phenotypic and genetic models of the evolution of selfing conclude that complete outcrossing should evolve whenever inbreeding depression is greater than one-half, otherwise selfing should evolve. Recent theoretical work, however, has challenged this view and emphasized (1) the importance of variation in inbreeding depression among individuals within a population; and (2) the nature of gene action between deleterious mutations at different loci (epistasis) as important determinants for the evolution of plant mating systems. The focus of this study was to examine the maintenance of inbreeding depression and the relationship between inbreeding level and inbreeding depression at both the population and the individual level in one population of the partially self-fertilizing plant Plantago coronopus (L.). Maternal plants, randomly selected from an area of about 50 m 2 in a natural population, were used to establish lines with expected inbreeding coefficients (f) of 0, 0.25, 0.50, 0.75, and 0.875. Inbreeding depression was estimated both in the greenhouse and at the site of origin of the maternal plants by comparing growth, survival, flowering, and seed production of the progeny with different inbreeding coefficients. No significant inbreeding depression for these fitness traits was detected in the greenhouse after 16 weeks. This was in strong contrast to the field, where the traits all displayed significant inbreeding depression and declined with increased inbreeding. The results were consistent with the view that mutation to mildly deleterious alleles is the primary cause of inbreeding depression. At the family level, significantly different maternal line responses (maternal parent × inbreeding level interaction) provide a mechanism for the invasion of a selfing variant into the population through any maternal line exhibiting purging of its genetic load. At the population level, evidence for synergistic epistasis was detected for the probability of flowering, but not for total seed production. At the family level, however, a significant interaction between inbreeding level and maternal families for both traits was observed, indicating that epistasis could play a role in the expression of inbreeding depression among maternal lines. © 1998 The Society for the Study of Evolution.

PTGER4 Expression-Modulating Polymorphisms in the 5p13.1 Region Predispose to Crohn's Disease and Affect NF-κB and XBP1 Binding Sites

PubMed Central

Czamara, Darina; Pasciuto, Giulia; Diegelmann, Julia; Wetzke, Martin; Olszak, Torsten; Wolf, Christiane; Müller-Myhsok, Bertram; Balschun, Tobias; Achkar, Jean-Paul; Kamboh, M. Ilyas; Franke, Andre; Duerr, Richard H.; Brand, Stephan

2012-01-01

Background Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. Methodology/Principal Findings A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10−5; 0.76 [0.67–0.87]) and of rs7720838 (p = 6.91×10−4; 0.81 [0.71–0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10−7 for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. Conclusions/Significance We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility. PMID:23300802

PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites.

PubMed

Glas, Jürgen; Seiderer, Julia; Czamara, Darina; Pasciuto, Giulia; Diegelmann, Julia; Wetzke, Martin; Olszak, Torsten; Wolf, Christiane; Müller-Myhsok, Bertram; Balschun, Tobias; Achkar, Jean-Paul; Kamboh, M Ilyas; Franke, Andre; Duerr, Richard H; Brand, Stephan

2012-01-01

Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if changes in PTGER4 expression modulate CD susceptibility.

Quantitative analysis of RNA-protein interactions on a massively parallel array for mapping biophysical and evolutionary landscapes

PubMed Central

Buenrostro, Jason D.; Chircus, Lauren M.; Araya, Carlos L.; Layton, Curtis J.; Chang, Howard Y.; Snyder, Michael P.; Greenleaf, William J.

2015-01-01

RNA-protein interactions drive fundamental biological processes and are targets for molecular engineering, yet quantitative and comprehensive understanding of the sequence determinants of affinity remains limited. Here we repurpose a high-throughput sequencing instrument to quantitatively measure binding and dissociation of MS2 coat protein to >107 RNA targets generated on a flow-cell surface by in situ transcription and inter-molecular tethering of RNA to DNA. We decompose the binding energy contributions from primary and secondary RNA structure, finding that differences in affinity are often driven by sequence-specific changes in association rates. By analyzing the biophysical constraints and modeling mutational paths describing the molecular evolution of MS2 from low- to high-affinity hairpins, we quantify widespread molecular epistasis, and a long-hypothesized structure-dependent preference for G:U base pairs over C:A intermediates in evolutionary trajectories. Our results suggest that quantitative analysis of RNA on a massively parallel array (RNAMaP) relationships across molecular variants. PMID:24727714

Quantitative genetic analysis of injury liability in infants and toddlers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phillips, K.; Matheny, A.P. Jr.

1995-02-27

A threshold model of latent liability was applied to infant and toddler twin data on total count of injuries sustained during the interval from birth to 36 months of age. A quantitative genetic analysis of estimated twin correlations in injury liability indicated strong genetic dominance effects, but no additive genetic variance was detected. Because interpretations involving overdominance have little research support, the results may be due to low order epistasis or other interaction effects. Boys had more injuries than girls, but this effect was found only for groups whose parents were prompted and questioned in detail about their children`s injuries.more » Activity and impulsivity are two behavioral predictors of childhood injury, and the results are discussed in relation to animal research on infant and adult activity levels, and impulsivity in adult humans. Genetic epidemiological approaches to childhood injury should aid in targeting higher risk children for preventive intervention. 30 refs., 4 figs., 3 tabs.« less

The genetics of pre-eclampsia and other hypertensive disorders of pregnancy

PubMed Central

Williams, Paula J.; Broughton Pipkin, Fiona

2011-01-01

Hypertension is the most frequent medical complication occurring during pregnancy. In this chapter, we aim to address the genetic contribution to these disorders, with specific focus on pre-eclampsia. The pathogenic mechanisms underlying pre-eclampsia remain to be elucidated; however, immune maladaptation, inadequate placental development and trophoblast invasion, placental ischaemia, oxidative stress and thrombosis are all thought to represent key factors in the development of disease. Furthermore, all of these components have genetic factors that may be involved in the pathogenic changes occurring. The familial nature of pre-eclampsia has been known for many years and, as such, extensive genetic research has been carried out in this area using strategies that include candidate gene studies and linkage analysis. Interactions between fetal and maternal genotypes, the effect of environmental factors, and epistasis will also be considered. PMID:21429808

Analysis of a mutant exhibiting conditional sorting to dense core secretory granules in Tetrahymena thermophila.

PubMed

Bowman, G R; Turkewitz, A P

2001-12-01

The formation of dense core granules (DCGs) requires both the sorting of granule contents from other secretory proteins and a postsorting maturation process. The Tetrahymena thermophila strain SB281 fails to synthesize DCGs, and previous analysis suggested that the defect lay at or near the sorting step. Because this strain represents one of the very few mutants in this pathway, we have undertaken a more complete study of the phenotype. Genetic epistasis analysis places the defect upstream of those in two other characterized Tetrahymena mutants. Using immunofluorescent detection of granule content proteins, as well as GFP tagging, we describe a novel cytoplasmic compartment to which granule contents can be sorted in growing SB281 cells. Cell fusion experiments indicate that this compartment is not a biosynthetic intermediate in DCG synthesis. Sorting in SB281 is strongly conditional with respect to growth. When cells are starved, the storage compartment is degraded and de novo synthesized granule proteins are rapidly secreted. The mutation in SB281 therefore appears to affect DCG synthesis at the level of both sorting and maturation.

Analysis of a mutant exhibiting conditional sorting to dense core secretory granules in Tetrahymena thermophila.

PubMed Central

Bowman, G R; Turkewitz, A P

2001-01-01

The formation of dense core granules (DCGs) requires both the sorting of granule contents from other secretory proteins and a postsorting maturation process. The Tetrahymena thermophila strain SB281 fails to synthesize DCGs, and previous analysis suggested that the defect lay at or near the sorting step. Because this strain represents one of the very few mutants in this pathway, we have undertaken a more complete study of the phenotype. Genetic epistasis analysis places the defect upstream of those in two other characterized Tetrahymena mutants. Using immunofluorescent detection of granule content proteins, as well as GFP tagging, we describe a novel cytoplasmic compartment to which granule contents can be sorted in growing SB281 cells. Cell fusion experiments indicate that this compartment is not a biosynthetic intermediate in DCG synthesis. Sorting in SB281 is strongly conditional with respect to growth. When cells are starved, the storage compartment is degraded and de novo synthesized granule proteins are rapidly secreted. The mutation in SB281 therefore appears to affect DCG synthesis at the level of both sorting and maturation. PMID:11779800

Predicting the evolution of sex on complex fitness landscapes.

PubMed

Misevic, Dusan; Kouyos, Roger D; Bonhoeffer, Sebastian

2009-09-01

Most population genetic theories on the evolution of sex or recombination are based on fairly restrictive assumptions about the nature of the underlying fitness landscapes. Here we use computer simulations to study the evolution of sex on fitness landscapes with different degrees of complexity and epistasis. We evaluate predictors of the evolution of sex, which are derived from the conditions established in the population genetic literature for the evolution of sex on simpler fitness landscapes. These predictors are based on quantities such as the variance of Hamming distance, mean fitness, additive genetic variance, and epistasis. We show that for complex fitness landscapes all the predictors generally perform poorly. Interestingly, while the simplest predictor, Delta Var(HD), also suffers from a lack of accuracy, it turns out to be the most robust across different types of fitness landscapes. Delta Var(HD) is based on the change in Hamming distance variance induced by recombination and thus does not require individual fitness measurements. The presence of loci that are not under selection can, however, severely diminish predictor accuracy. Our study thus highlights the difficulty of establishing reliable criteria for the evolution of sex on complex fitness landscapes and illustrates the challenge for both theoretical and experimental research on the origin and maintenance of sexual reproduction.

Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks.

PubMed

Bertolino, Alessandro; Di Giorgio, Annabella; Blasi, Giuseppe; Sambataro, Fabio; Caforio, Grazia; Sinibaldi, Lorenzo; Latorre, Valeria; Rampino, Antonio; Taurisano, Paolo; Fazio, Leonardo; Romano, Raffaella; Douzgou, Sofia; Popolizio, Teresa; Kolachana, Bhaskar; Nardini, Marcello; Weinberger, Daniel R; Dallapiccola, Bruno

2008-08-01

Dopamine modulation of neuronal activity in prefrontal cortex maps to an inverted U-curve. Dopamine is also an important factor in regulation of hippocampal mediated memory processing. Here, we investigated the effect of genetic variation of dopamine inactivation via catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) on hippocampal activity in healthy humans during different memory conditions. Using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in 82 subjects matched for a series of demographic and genetic variables, we studied the effect of the COMT valine (Val)(158)methionine (Met) and the DAT 3' variable number tandem repeat (VNTR) polymorphisms on function of the hippocampus during encoding of recognition memory and during working memory. Our results consistently demonstrated a double dissociation so that DAT 9-repeat carrier alleles modulated activity in the hippocampus in the exact opposite direction of DAT 10/10-repeat alleles based on COMT Val(158)Met genotype during different memory conditions. Similar results were evident in ventrolateral and dorsolateral prefrontal cortex. These findings suggest that genetically determined dopamine signaling during memory processing maps to a nonlinear relationship also in the hippocampus. Our data also demonstrate in human brain epistasis of two genes implicated in dopamine signaling on brain activity during different memory conditions.

Predicting the Evolution of Sex on Complex Fitness Landscapes

PubMed Central

Misevic, Dusan; Kouyos, Roger D.; Bonhoeffer, Sebastian

2009-01-01

Most population genetic theories on the evolution of sex or recombination are based on fairly restrictive assumptions about the nature of the underlying fitness landscapes. Here we use computer simulations to study the evolution of sex on fitness landscapes with different degrees of complexity and epistasis. We evaluate predictors of the evolution of sex, which are derived from the conditions established in the population genetic literature for the evolution of sex on simpler fitness landscapes. These predictors are based on quantities such as the variance of Hamming distance, mean fitness, additive genetic variance, and epistasis. We show that for complex fitness landscapes all the predictors generally perform poorly. Interestingly, while the simplest predictor, ΔVarHD, also suffers from a lack of accuracy, it turns out to be the most robust across different types of fitness landscapes. ΔVarHD is based on the change in Hamming distance variance induced by recombination and thus does not require individual fitness measurements. The presence of loci that are not under selection can, however, severely diminish predictor accuracy. Our study thus highlights the difficulty of establishing reliable criteria for the evolution of sex on complex fitness landscapes and illustrates the challenge for both theoretical and experimental research on the origin and maintenance of sexual reproduction. PMID:19763171

An Evolutionary Perspective on Epistasis and the Missing Heritability

PubMed Central

Hemani, Gibran; Knott, Sara; Haley, Chris

2013-01-01

The relative importance between additive and non-additive genetic variance has been widely argued in quantitative genetics. By approaching this question from an evolutionary perspective we show that, while additive variance can be maintained under selection at a low level for some patterns of epistasis, the majority of the genetic variance that will persist is actually non-additive. We propose that one reason that the problem of the “missing heritability” arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time. In addition, it can be shown that even a small reduction in linkage disequilibrium between causal variants and observed SNPs rapidly erodes estimates of epistatic variance, leading to an inflation in the perceived importance of additive effects. We demonstrate that the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards and that the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone. Given dense SNP panels the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly. PMID:23509438

RATES OF FITNESS DECLINE AND REBOUND SUGGEST PERVASIVE EPISTASIS

PubMed Central

Perfeito, L; Sousa, A; Bataillon, T; Gordo, I

2014-01-01

Unraveling the factors that determine the rate of adaptation is a major question in evolutionary biology. One key parameter is the effect of a new mutation on fitness, which invariably depends on the environment and genetic background. The fate of a mutation also depends on population size, which determines the amount of drift it will experience. Here, we manipulate both population size and genotype composition and follow adaptation of 23 distinct Escherichia coli genotypes. These have previously accumulated mutations under intense genetic drift and encompass a substantial fitness variation. A simple rule is uncovered: the net fitness change is negatively correlated with the fitness of the genotype in which new mutations appear—a signature of epistasis. We find that Fisher's geometrical model can account for the observed patterns of fitness change and infer the parameters of this model that best fit the data, using Approximate Bayesian Computation. We estimate a genomic mutation rate of 0.01 per generation for fitness altering mutations, albeit with a large confidence interval, a mean fitness effect of mutations of −0.01, and an effective number of traits nine in mutS− E. coli. This framework can be extended to confront a broader range of models with data and test different classes of fitness landscape models. PMID:24372601

iLOCi: a SNP interaction prioritization technique for detecting epistasis in genome-wide association studies

PubMed Central

2012-01-01

Background Genome-wide association studies (GWAS) do not provide a full account of the heritability of genetic diseases since gene-gene interactions, also known as epistasis are not considered in single locus GWAS. To address this problem, a considerable number of methods have been developed for identifying disease-associated gene-gene interactions. However, these methods typically fail to identify interacting markers explaining more of the disease heritability over single locus GWAS, since many of the interactions significant for disease are obscured by uninformative marker interactions e.g., linkage disequilibrium (LD). Results In this study, we present a novel SNP interaction prioritization algorithm, named iLOCi (Interacting Loci). This algorithm accounts for marker dependencies separately in case and control groups. Disease-associated interactions are then prioritized according to a novel ranking score calculated from the difference in marker dependencies for every possible pair between case and control groups. The analysis of a typical GWAS dataset can be completed in less than a day on a standard workstation with parallel processing capability. The proposed framework was validated using simulated data and applied to real GWAS datasets using the Wellcome Trust Case Control Consortium (WTCCC) data. The results from simulated data showed the ability of iLOCi to identify various types of gene-gene interactions, especially for high-order interaction. From the WTCCC data, we found that among the top ranked interacting SNP pairs, several mapped to genes previously known to be associated with disease, and interestingly, other previously unreported genes with biologically related roles. Conclusion iLOCi is a powerful tool for uncovering true disease interacting markers and thus can provide a more complete understanding of the genetic basis underlying complex disease. The program is available for download at http://www4a.biotec.or.th/GI/tools/iloci. PMID:23281813

A novel epistatic interaction at two loci causing hybrid male sterility in an inter-subspecific cross of rice (Oryza sativa L.).

PubMed

Kubo, Takahiko; Yamagata, Yoshiyuki; Eguchi, Maki; Yoshimura, Atsushi

2008-12-01

Postzygotic reproductive isolation (RI) often arises in inter-subspecific crosses as well as inter-specific crosses of rice (Oryza sativa L.). To further understand the genetic architecture of the postzygotic RI, we analyzed genes causing hybrid sterility and hybrid breakdown in a rice inter-subspecific cross. Here we report hybrid male sterility caused by epistatic interaction between two novel genes, S24 and S35, which were identified on rice chromosomes 5 and 1, respectively. Genetic analysis using near-isogenic lines (NILs) carrying IR24 (ssp. indica) segments with Asominori (ssp. japonica) genetic background revealed a complicated aspect of the epistasis. Allelic interaction at the S24 locus in the heterozygous plants caused abortion of male gametes carrying the Asominori allele (S24-as) independent of the S35 genotype. On the other hand, male gametes carrying the Asominori allele at the S35 locus (S35-as) showed abortion only when the IR24 allele at the S24 locus (S24-ir) was concurrently introgressed into the S35 heterozygous plants, indicating that the sterility phenotype due to S35 was dependent on the S24 genotype through negative epistasis between S24-ir and S35-as alleles. Due to the interaction between S24 and S35, self-pollination of the double heterozygous plants produced pollen-sterile progeny carrying the S24-ir/S24-ir S35-as/S35-ir genotype in addition to the S24 heterozygous plants. This result suggests that the S35 gene might function as a modifier of S24. This study presents strong evidence for the importance of epistatic interaction as a part of the genetic architecture of hybrid sterility in rice. In addition, it suggests that diverse systems have been developed as postzygotic RI mechanisms within the rice.

Comparative functional pan-genome analyses to build connections between genomic dynamics and phenotypic evolution in polycyclic aromatic hydrocarbon metabolism in the genus Mycobacterium.

PubMed

Kweon, Ohgew; Kim, Seong-Jae; Blom, Jochen; Kim, Sung-Kwan; Kim, Bong-Soo; Baek, Dong-Heon; Park, Su Inn; Sutherland, John B; Cerniglia, Carl E

2015-02-14

The bacterial genus Mycobacterium is of great interest in the medical and biotechnological fields. Despite a flood of genome sequencing and functional genomics data, significant gaps in knowledge between genome and phenome seriously hinder efforts toward the treatment of mycobacterial diseases and practical biotechnological applications. In this study, we propose the use of systematic, comparative functional pan-genomic analysis to build connections between genomic dynamics and phenotypic evolution in polycyclic aromatic hydrocarbon (PAH) metabolism in the genus Mycobacterium. Phylogenetic, phenotypic, and genomic information for 27 completely genome-sequenced mycobacteria was systematically integrated to reconstruct a mycobacterial phenotype network (MPN) with a pan-genomic concept at a network level. In the MPN, mycobacterial phenotypes show typical scale-free relationships. PAH degradation is an isolated phenotype with the lowest connection degree, consistent with phylogenetic and environmental isolation of PAH degraders. A series of functional pan-genomic analyses provide conserved and unique types of genomic evidence for strong epistatic and pleiotropic impacts on evolutionary trajectories of the PAH-degrading phenotype. Under strong natural selection, the detailed gene gain/loss patterns from horizontal gene transfer (HGT)/deletion events hypothesize a plausible evolutionary path, an epistasis-based birth and pleiotropy-dependent death, for PAH metabolism in the genus Mycobacterium. This study generated a practical mycobacterial compendium of phenotypic and genomic changes, focusing on the PAH-degrading phenotype, with a pan-genomic perspective of the evolutionary events and the environmental challenges. Our findings suggest that when selection acts on PAH metabolism, only a small fraction of possible trajectories is likely to be observed, owing mainly to a combination of the ambiguous phenotypic effects of PAHs and the corresponding pleiotropy- and epistasis-dependent evolutionary adaptation. Evolutionary constraints on the selection of trajectories, like those seen in PAH-degrading phenotypes, are likely to apply to the evolution of other phenotypes in the genus Mycobacterium.

Including non-additive genetic effects in Bayesian methods for the prediction of genetic values based on genome-wide markers

PubMed Central

2011-01-01

Background Molecular marker information is a common source to draw inferences about the relationship between genetic and phenotypic variation. Genetic effects are often modelled as additively acting marker allele effects. The true mode of biological action can, of course, be different from this plain assumption. One possibility to better understand the genetic architecture of complex traits is to include intra-locus (dominance) and inter-locus (epistasis) interaction of alleles as well as the additive genetic effects when fitting a model to a trait. Several Bayesian MCMC approaches exist for the genome-wide estimation of genetic effects with high accuracy of genetic value prediction. Including pairwise interaction for thousands of loci would probably go beyond the scope of such a sampling algorithm because then millions of effects are to be estimated simultaneously leading to months of computation time. Alternative solving strategies are required when epistasis is studied. Methods We extended a fast Bayesian method (fBayesB), which was previously proposed for a purely additive model, to include non-additive effects. The fBayesB approach was used to estimate genetic effects on the basis of simulated datasets. Different scenarios were simulated to study the loss of accuracy of prediction, if epistatic effects were not simulated but modelled and vice versa. Results If 23 QTL were simulated to cause additive and dominance effects, both fBayesB and a conventional MCMC sampler BayesB yielded similar results in terms of accuracy of genetic value prediction and bias of variance component estimation based on a model including additive and dominance effects. Applying fBayesB to data with epistasis, accuracy could be improved by 5% when all pairwise interactions were modelled as well. The accuracy decreased more than 20% if genetic variation was spread over 230 QTL. In this scenario, accuracy based on modelling only additive and dominance effects was generally superior to that of the complex model including epistatic effects. Conclusions This simulation study showed that the fBayesB approach is convenient for genetic value prediction. Jointly estimating additive and non-additive effects (especially dominance) has reasonable impact on the accuracy of prediction and the proportion of genetic variation assigned to the additive genetic source. PMID:21867519

Epistasis between polymorphisms in PCSK1 and DBH is associated with premature ovarian failure.

PubMed

Pyun, Jung-A; Kim, Sunshin; Cha, Dong Hyun; Kwack, KyuBum

2014-11-01

This study examined whether epistasis between single nucleotide polymorphisms (SNPs) within proprotein convertase subtilisin/kexin type 1 (PCSK1) and dopamine β-hydroxylase (DBH) genes is associated with premature ovarian failure (POF). One hundred twenty women with POF and 222 female controls were recruited for this study. To genotype SNPs within PCSK1 and DBH, we used a GoldenGate assay with VeraCode technology, which uses an allele-specific primer extension method. Two SNPs (rs155979 and rs3762986) within PCSK1 and one SNP (rs1611114) within DBH, which were located in the 5' flanking region, were involved in synergistic interactions. The C allele in the rs155979 SNP showed an increased risk of POF in a dominant model when AA genotype in the rs1611114 SNP was present (odds ratio, 3.60; 95% CI, 1.82-7.14; P = 0.00024), whereas the G allele in the rs1611114 SNP showed a reduced risk of POF in a dominant model when at least one C allele at the rs155979 SNP was present (odds ratio, 0.24; 95% CI, 0.11-0.51; P = 0.00018) or one G allele at the rs3762986 SNP was present (odds ratio, 0.33; 95% CI, 0.19-0.60; P = 0.00023). Epistases between SNPs within PCSK1 and DBH genes are significantly associated with susceptibility or resistance to POF.

Epistasis between 5-HTTLPR and ADRA2B polymorphisms influences attentional bias for emotional information in healthy volunteers.

PubMed

Naudts, Kris H; Azevedo, Ruben T; David, Anthony S; van Heeringen, Kees; Gibbs, Ayana A

2012-09-01

Individual differences in emotional processing are likely to contribute to vulnerability and resilience to emotional disorders such as depression and anxiety. Genetic variation is known to contribute to these differences but they remain incompletely understood. The serotonin transporter (5-HTTLPR) and α2B-adrenergic autoreceptor (ADRA2B) insertion/deletion polymorphisms impact on two separate but interacting monaminergic signalling mechanisms that have been implicated in both emotional processing and emotional disorders. Recent studies suggest that the 5-HTTLPR s allele is associated with a negative attentional bias and an increased risk of emotional disorders. However, such complex behavioural traits are likely to exhibit polygenicity, including epistasis. This study examined the contribution of the 5-HTTLPR and ADRA2B insertion/deletion polymorphisms to attentional biases for aversive information in 94 healthy male volunteers and found evidence of a significant epistatic effect (p<0.001). Specifically, in the presence of the 5-HTTLPR s allele, the attentional bias for aversive information was attenuated by possession of the ADRA2B deletion variant whereas in the absence of the s allele, the bias was enhanced. These data identify a cognitive mechanism linking genotype-dependent serotonergic and noradrenergic signalling that is likely to have implications for the development of cognitive markers for depression/anxiety as well as therapeutic drug effects and personalized approaches to treatment.

Symmetric Epistasis Estimation (SEE) and its application to dissecting interaction map of Plasmodium falciparum.

PubMed

Huang, Yang; Siwo, Geoffrey; Wuchty, Stefan; Ferdig, Michael T; Przytycka, Teresa M

2012-04-01

It is being increasingly recognized that many important phenotypic traits, including various diseases, are governed by a combination of weak genetic effects and their interactions. While the detection of epistatic interactions that involve a non-additive effect of two loci on a quantitative trait is particularly challenging, this interaction type is fundamental for the understanding of genome organization and gene regulation. However, current methods that detect epistatic interactions typically rely on the existence of a strong primary effect, considerably limiting the sensitivity of the search. To fill this gap, we developed a new method, SEE (Symmetric Epistasis Estimation), allowing the genome-wide detection of epistatic interactions without the need for a strong primary effect. We applied our approach to progeny crosses of the human malaria parasite P. falciparum and S. cerevisiae. We found an abundance of epistatic interactions in the parasite and a much smaller number of such interactions in yeast. The genome of P. falciparum also harboured several epistatic interaction hotspots that putatively play a role in drug resistance mechanisms. The abundance of observed epistatic interactions might suggest a mechanism of compensation for the extremely limited repertoire of transcription factors. Interestingly, epistatic interaction hotspots were associated with elevated levels of linkage disequilibrium, an observation that suggests selection pressure acting on P. falciparum, potentially reflecting host-pathogen interactions or drug-induced selection.

Clustering of Genetically Defined Allele Classes in the Caenorhabditis elegans DAF-2 Insulin/IGF-1 Receptor

PubMed Central

Patel, Dhaval S.; Garza-Garcia, Acely; Nanji, Manoj; McElwee, Joshua J.; Ackerman, Daniel; Driscoll, Paul C.; Gems, David

2008-01-01

The DAF-2 insulin/IGF-1 receptor regulates development, metabolism, and aging in the nematode Caenorhabditis elegans. However, complex differences among daf-2 alleles complicate analysis of this gene. We have employed epistasis analysis, transcript profile analysis, mutant sequence analysis, and homology modeling of mutant receptors to understand this complexity. We define an allelic series of nonconditional daf-2 mutants, including nonsense and deletion alleles, and a putative null allele, m65. The most severe daf-2 alleles show incomplete suppression by daf-18(0) and daf-16(0) and have a range of effects on early development. Among weaker daf-2 alleles there exist distinct mutant classes that differ in epistatic interactions with mutations in other genes. Mutant sequence analysis (including 11 newly sequenced alleles) reveals that class 1 mutant lesions lie only in certain extracellular regions of the receptor, while class 2 (pleiotropic) and nonconditional missense mutants have lesions only in the ligand-binding pocket of the receptor ectodomain or the tyrosine kinase domain. Effects of equivalent mutations on the human insulin receptor suggest an altered balance of intracellular signaling in class 2 alleles. These studies consolidate and extend our understanding of the complex genetics of daf-2 and its underlying molecular biology. PMID:18245374

A linkage and family-based association analysis of a potential neurocognitive endophenotype of bipolar disorder.

PubMed

Savitz, Jonathan; van der Merwe, Lize; Solms, Mark; Ramesar, Rajkumar

2007-01-01

The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance characterized by genetic and phenotypic heterogeneity, genetic epistasis, and gene-environment interactions. In this paper two strategies were used to ameliorate these confounding factors. A unique South African sample including 190 individuals of the relatively, reproductively isolated Afrikaner population was assessed with a battery of neuropsychological tests in an attempt to identify a BPD-associated quantitative trait or endophenotype. BPD individuals performed significantly worse than their unaffected relatives on visual and verbal memory tasks, a finding congruent with the literature. Afocused linkage and family-based association study was carried out using this memory-related endophenotype. In the largest 77-strong Afrikaner pedigree significant evidence for linkage was detected on chromosome 22q11, a region previously implicated in BPD. The quantitative transmission disequilibrium tests-based association analysis suggested that functional variants of the DRD4 and MAO-A genes modulate memory-related cognition. We speculate that polymorphisms at these loci may predispose to a subtype of BPD characterized by memory-related deficits.

Application of logistic regression to case-control association studies involving two causative loci.

PubMed

North, Bernard V; Curtis, David; Sham, Pak C

2005-01-01

Models in which two susceptibility loci jointly influence the risk of developing disease can be explored using logistic regression analysis. Comparison of likelihoods of models incorporating different sets of disease model parameters allows inferences to be drawn regarding the nature of the joint effect of the loci. We have simulated case-control samples generated assuming different two-locus models and then analysed them using logistic regression. We show that this method is practicable and that, for the models we have used, it can be expected to allow useful inferences to be drawn from sample sizes consisting of hundreds of subjects. Interactions between loci can be explored, but interactive effects do not exactly correspond with classical definitions of epistasis. We have particularly examined the issue of the extent to which it is helpful to utilise information from a previously identified locus when investigating a second, unknown locus. We show that for some models conditional analysis can have substantially greater power while for others unconditional analysis can be more powerful. Hence we conclude that in general both conditional and unconditional analyses should be performed when searching for additional loci.

The Genetic Architecture of Interspecific Variation in Mimulus

PubMed Central

Macnair, M. R.; Cumbes, Q. J.

1989-01-01

The genetic architecture of various floral and morphological differences between Mimulus cupriphilus and Mimulus guttatus is investigated. M. cupriphilus is believed to have speciated from M. guttatus in the recent past. The two parent species, the F(1) and F(2), and two backcrosses were grown and scored for 23 different characters. The analysis of means revealed significant epistasis for a number of the floral characters, particularly those involving the length of parts. Dominance was generally toward M. guttatus, except for the characters related to flowering time. Analysis of the genetic correlations between characters revealed that there were at least four different polygenic genetic systems, governing flowering time, size of flower, number of spots on the corolla, and general size. An analysis of minimum gene number suggested that there were at least 3-7 genes controlling floral size, and a different three controlling floral spot number. Two other characters, corolla lobe shape and stem color, were produced by independent major gene differences. Annuality was also shown to be heritable. The two species appear to utilize the same gene for copper tolerance. The results are discussed in the light of current theories of speciation. PMID:17246497

Age- and gender-specific epistasis between ADA and TNF-α influences human life-expectancy.

PubMed

Napolioni, Valerio; Carpi, Francesco M; Giannì, Paola; Sacco, Roberto; Di Blasio, Luca; Mignini, Fiorenzo; Lucarini, Nazzareno; Persico, Antonio M

2011-11-01

Aging is a complex phenotype with multiple determinants but a strong genetic component significantly impacts on survival to extreme ages. The dysregulation of immune responses occurring with increasing age is believed to contribute to human morbidity and mortality. Conversely, some genetic determinants of successful aging might reside in those polymorphisms for the immune system genes regulating immune responses. Here we examined the main effects of single loci and multi-locus interactions to test the hypothesis that the adenosine deaminase (ADA) and tumor necrosis factor alpha (TNF-α) genes may influence human life-expectancy. ADA (22G>A, rs73598374) and TNF-α (-308G>A, rs1800629; -238G>A, rs361525) functional SNPs have been determined for 1071 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes: for men (women), the first class consists of individuals<66 years old (<73 years old), the second class of individuals 66-88 years old (73-91 years old), and the third class of individuals>88 years old (>91 years old). Single-locus analysis showed that only ADA 22G>A is significantly associated with human life-expectancy in males (comparison 1 (age class 2 vs. age class 1), O.R. 1.943, P=0.036; comparison 2 (age class 3 vs. age class 2), O.R. 0.320, P=0.0056). Age- and gender-specific patterns of epistasis between ADA and TNF-α were found using Generalized Multifactor Dimensionality Reduction (GMDR). In comparison 1, a significant two-loci interaction occurs in females between ADA 22G>A and TNF-α -238G>A (Sign Test P=0.011). In comparison 2, both two-loci and three-loci interaction are significant associated with increased life-expectancy over 88 years in males. In conclusion, we report that a combination of functional SNPs within ADA and TNF-α genes can influence life-expectancy in a gender-specific manner and that males and females follow different pathways to attain longevity. Copyright © 2011 Elsevier Ltd. All rights reserved.

Epistasis between QTLs for bone density variation in Copenhagen × dark agouti F2 rats

PubMed Central

Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J.; Foroud, Tatiana; Turner, Charles H.

2010-01-01

The variation in several of the risk factors for osteoporotic fracture, including bone mineral density (BMD), has been shown to be strongly influenced by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 828 F2 progeny of Copenhagen and dark agouti rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted bone density (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine genome-wide significance thresholds for the full model and epistasis (interaction) LOD scores corresponding to an alpha level of 0.01. A novel locus on chromosome 15 and a previously reported chromosome 14 QTL demonstrated a strong epistatic effect on BMD at the femur by DXA (LOD = 5.4). Two novel QTLs on chromosomes 2 and 12 were found to interact to affect total BMD at the femur midshaft by pQCT (LOD = 5.0). These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation. PMID:19153792

Epistasis between QTLs for bone density variation in Copenhagen x dark agouti F2 rats.

PubMed

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2009-03-01

The variation in several of the risk factors for osteoporotic fracture, including bone mineral density (BMD), has been shown to be strongly influenced by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 828 F2 progeny of Copenhagen and dark agouti rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted bone density (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine genome-wide significance thresholds for the full model and epistasis (interaction) LOD scores corresponding to an alpha level of 0.01. A novel locus on chromosome 15 and a previously reported chromosome 14 QTL demonstrated a strong epistatic effect on BMD at the femur by DXA (LOD = 5.4). Two novel QTLs on chromosomes 2 and 12 were found to interact to affect total BMD at the femur midshaft by pQCT (LOD = 5.0). These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation.

Alleles versus genotypes: Genetic interactions and the dynamics of selection in sexual populations

NASA Astrophysics Data System (ADS)

Neher, Richard

2010-03-01

Physical interactions between amino-acids are essential for protein structure and activity, while protein-protein interactions and regulatory interactions are central to cellular function. As a consequence of these interactions, the combined effect of two mutations can differ from the sum of the individual effects of the mutations. This phenomenon of genetic interaction is known as epistasis. However, the importance of epistasis and its effects on evolutionary dynamics are poorly understood, especially in sexual populations where recombination breaks up existing combinations of alleles to produce new ones. Here, we present a computational model of selection dynamics involving many epistatic loci in a recombining population. We demonstrate that a large number of polymorphic interacting loci can, despite frequent recombination, exhibit cooperative behavior that locks alleles into favorable genotypes leading to a population consisting of a set of competing clones. As the recombination rate exceeds a certain critical value this ``genotype selection'' phase disappears in an abrupt transition giving way to ``allele selection'' - the phase where different loci are only weakly correlated as expected in sexually reproducing populations. Clustering of interacting sets of genes on a chromosome leads to the emergence of an intermediate regime, where localized blocks of cooperating alleles lock into genetic modules. Large populations attain highest fitness at a recombination rate just below critical, suggesting that natural selection might tune recombination rates to balance the beneficial aspect of exploration of genotype space with the breaking up of synergistic allele combinations.

A Model of Substitution Trajectories in Sequence Space and Long-Term Protein Evolution

PubMed Central

Usmanova, Dinara R.; Ferretti, Luca; Povolotskaya, Inna S.; Vlasov, Peter K.; Kondrashov, Fyodor A.

2015-01-01

The nature of factors governing the tempo and mode of protein evolution is a fundamental issue in evolutionary biology. Specifically, whether or not interactions between different sites, or epistasis, are important in directing the course of evolution became one of the central questions. Several recent reports have scrutinized patterns of long-term protein evolution claiming them to be compatible only with an epistatic fitness landscape. However, these claims have not yet been substantiated with a formal model of protein evolution. Here, we formulate a simple covarion-like model of protein evolution focusing on the rate at which the fitness impact of amino acids at a site changes with time. We then apply the model to the data on convergent and divergent protein evolution to test whether or not the incorporation of epistatic interactions is necessary to explain the data. We find that convergent evolution cannot be explained without the incorporation of epistasis and the rate at which an amino acid state switches from being acceptable at a site to being deleterious is faster than the rate of amino acid substitution. Specifically, for proteins that have persisted in modern prokaryotic organisms since the last universal common ancestor for one amino acid substitution approximately ten amino acid states switch from being accessible to being deleterious, or vice versa. Thus, molecular evolution can only be perceived in the context of rapid turnover of which amino acids are available for evolution. PMID:25415964

GENOME-WIDE GENETIC INTERACTION ANALYSIS OF GLAUCOMA USING EXPERT KNOWLEDGE DERIVED FROM HUMAN PHENOTYPE NETWORKS

PubMed Central

HU, TING; DARABOS, CHRISTIAN; CRICCO, MARIA E.; KONG, EMILY; MOORE, JASON H.

2014-01-01

The large volume of GWAS data poses great computational challenges for analyzing genetic interactions associated with common human diseases. We propose a computational framework for characterizing epistatic interactions among large sets of genetic attributes in GWAS data. We build the human phenotype network (HPN) and focus around a disease of interest. In this study, we use the GLAUGEN glaucoma GWAS dataset and apply the HPN as a biological knowledge-based filter to prioritize genetic variants. Then, we use the statistical epistasis network (SEN) to identify a significant connected network of pairwise epistatic interactions among the prioritized SNPs. These clearly highlight the complex genetic basis of glaucoma. Furthermore, we identify key SNPs by quantifying structural network characteristics. Through functional annotation of these key SNPs using Biofilter, a software accessing multiple publicly available human genetic data sources, we find supporting biomedical evidences linking glaucoma to an array of genetic diseases, proving our concept. We conclude by suggesting hypotheses for a better understanding of the disease. PMID:25592582

Genetic Architecture of Nest Building in Mice LG/J × SM/J

PubMed Central

Sauce, Bruno; de Brito, Reinaldo Alves; Peripato, Andrea Cristina

2012-01-01

Maternal care is critical to offspring growth and survival, which is greatly improved by building an effective nest. Some suggest that genetic variation and underlying genetic effects differ between fitness-related traits and other phenotypes. We investigated the genetic architecture of a fitness-related trait, nest building, in F2 female mice intercrossed from inbred strains SM/J and LG/J using a QTL analysis for six related nest phenotypes (Presence and Structure pre- and postpartum, prepartum Material Used and postpartum Temperature). We found 15 direct-effect QTLs explaining from 4 to 13% of the phenotypic variation in nest building, mostly with non-additive effect. Epistatic analyses revealed 71 significant epistatic interactions which together explain from 28.4 to 75.5% of the variation, indicating an important role for epistasis in the adaptive process of nest building behavior in mice. Our results suggest a genetic architecture with small direct effects and a larger number of epistatic interactions as expected for fitness-related phenotypes. PMID:22654894

Maternal dazap2 Regulates Germ Granules by Counteracting Dynein in Zebrafish Primordial Germ Cells.

PubMed

Forbes, Meredyth M; Rothhämel, Sophie; Jenny, Andreas; Marlow, Florence L

2015-07-07

Primordial germ cells (PGCs) are the stem cells of the germline. Generally, germline induction occurs via zygotic factors or the inheritance of maternal determinants called germ plasm (GP). GP is packaged into ribonucleoprotein complexes within oocytes and later promotes the germline fate in embryos. Once PGCs are specified by either mechanism, GP components localize to perinuclear granular-like structures. Although components of zebrafish PGC germ granules have been studied, the maternal factors regulating their assembly and contribution to germ cell development are unknown. Here, we show that the scaffold protein Dazap2 binds to Bucky ball, an essential regulator of oocyte polarity and GP assembly, and colocalizes with the GP in oocytes and in PGCs. Mutational analysis revealed a requirement for maternal Dazap2 (MDazap2) in germ-granule maintenance. Through molecular epistasis analyses, we show that MDazap2 is epistatic to Tdrd7 and maintains germ granules in the embryonic germline by counteracting Dynein activity. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Frontiers of Knowledge: An Interview with 2017 Edward Novitski Prize Recipient Jonathan Hodgkin.

PubMed

Hodgkin, Jonathan

2017-12-01

The Genetics Society of America's Edward Novitski Prize recognizes a single experimental accomplishment or a body of work in which an exceptional level of creativity and intellectual ingenuity has been used to design and execute scientific experiments to solve a difficult problem in genetics. The 2017 winner, Jonathan Hodgkin, used elegant genetic studies to unravel the sex determination pathway in Caenorhabditis elegans He inferred the order of genes in the pathway and their modes of regulation using epistasis analyses-a powerful tool that was quickly adopted by other researchers. He expanded the number and use of informational suppressor mutants in C. elegans that are able to act on many genes. He also introduced the use of collections of wild C. elegans to study naturally occurring genetic variation, paving the way for SNP mapping and QTL analysis, as well as studies of hybrid incompatibilities between worm species. His current work focuses on nematode-bacterial interactions and innate immunity. Copyright © 2017 by the Genetics Society of America.

Parallelism and Epistasis in Skeletal Evolution Identified through Use of Phylogenomic Mapping Strategies

PubMed Central

Daane, Jacob M.; Rohner, Nicolas; Konstantinidis, Peter; Djuranovic, Sergej; Harris, Matthew P.

2016-01-01

The identification of genetic mechanisms underlying evolutionary change is critical to our understanding of natural diversity, but is presently limited by the lack of genetic and genomic resources for most species. Here, we present a new comparative genomic approach that can be applied to a broad taxonomic sampling of nonmodel species to investigate the genetic basis of evolutionary change. Using our analysis pipeline, we show that duplication and divergence of fgfr1a is correlated with the reduction of scales within fishes of the genus Phoxinellus. As a parallel genetic mechanism is observed in scale-reduction within independent lineages of cypriniforms, our finding exposes significant developmental constraint guiding morphological evolution. In addition, we identified fixed variation in fgf20a within Phoxinellus and demonstrated that combinatorial loss-of-function of fgfr1a and fgf20a within zebrafish phenocopies the evolved scalation pattern. Together, these findings reveal epistatic interactions between fgfr1a and fgf20a as a developmental mechanism regulating skeletal variation among fishes. PMID:26452532

Genome-Wide Requirements for Resistance to Functionally Distinct DNA-Damaging Agents

PubMed Central

Proctor, Michael; Flaherty, Patrick; Jordan, Michael I; Arkin, Adam P; Davis, Ronald W; Nislow, Corey; Giaever, Guri

2005-01-01

The mechanistic and therapeutic differences in the cellular response to DNA-damaging compounds are not completely understood, despite intense study. To expand our knowledge of DNA damage, we assayed the effects of 12 closely related DNA-damaging agents on the complete pool of ~4,700 barcoded homozygous deletion strains of Saccharomyces cerevisiae. In our protocol, deletion strains are pooled together and grown competitively in the presence of compound. Relative strain sensitivity is determined by hybridization of PCR-amplified barcodes to an oligonucleotide array carrying the barcode complements. These screens identified genes in well-characterized DNA-damage-response pathways as well as genes whose role in the DNA-damage response had not been previously established. High-throughput individual growth analysis was used to independently confirm microarray results. Each compound produced a unique genome-wide profile. Analysis of these data allowed us to determine the relative importance of DNA-repair modules for resistance to each of the 12 profiled compounds. Clustering the data for 12 distinct compounds uncovered both known and novel functional interactions that comprise the DNA-damage response and allowed us to define the genetic determinants required for repair of interstrand cross-links. Further genetic analysis allowed determination of epistasis for one of these functional groups. PMID:16121259

Dominant Epistasis Between Two Quantitative Trait Loci Governing Sporulation Efficiency in Yeast Saccharomyces cerevisiae

PubMed Central

Bergman, Juraj; Mitrikeski, Petar T.

2015-01-01

Summary Sporulation efficiency in the yeast Saccharomyces cerevisiae is a well-established model for studying quantitative traits. A variety of genes and nucleotides causing different sporulation efficiencies in laboratory, as well as in wild strains, has already been extensively characterised (mainly by reciprocal hemizygosity analysis and nucleotide exchange methods). We applied a different strategy in order to analyze the variation in sporulation efficiency of laboratory yeast strains. Coupling classical quantitative genetic analysis with simulations of phenotypic distributions (a method we call phenotype modelling) enabled us to obtain a detailed picture of the quantitative trait loci (QTLs) relationships underlying the phenotypic variation of this trait. Using this approach, we were able to uncover a dominant epistatic inheritance of loci governing the phenotype. Moreover, a molecular analysis of known causative quantitative trait genes and nucleotides allowed for the detection of novel alleles, potentially responsible for the observed phenotypic variation. Based on the molecular data, we hypothesise that the observed dominant epistatic relationship could be caused by the interaction of multiple quantitative trait nucleotides distributed across a 60--kb QTL region located on chromosome XIV and the RME1 locus on chromosome VII. Furthermore, we propose a model of molecular pathways which possibly underlie the phenotypic variation of this trait. PMID:27904371

The genetic regulatory network centered on Pto-Wuschela and its targets involved in wood formation revealed by association studies.

PubMed

Yang, Xiaohui; Wei, Zunzheng; Du, Qingzhang; Chen, Jinhui; Wang, Qingshi; Quan, Mingyang; Song, Yuepeng; Xie, Jianbo; Zhang, Deqiang

2015-11-09

Transcription factors (TFs) regulate gene expression and can strongly affect phenotypes. However, few studies have examined TF variants and TF interactions with their targets in plants. Here, we used genetic association in 435 unrelated individuals of Populus tomentosa to explore the variants in Pto-Wuschela and its targets to decipher the genetic regulatory network of Pto-Wuschela. Our bioinformatics and co-expression analysis identified 53 genes with the motif TCACGTGA as putative targets of Pto-Wuschela. Single-marker association analysis showed that Pto-Wuschela was associated with wood properties, which is in agreement with the observation that it has higher expression in stem vascular tissues in Populus. Also, SNPs in the 53 targets were associated with growth or wood properties under additive or dominance effects, suggesting these genes and Pto-Wuschela may act in the same genetic pathways that affect variation in these quantitative traits. Epistasis analysis indicated that 75.5% of these genes directly or indirectly interacted Pto-Wuschela, revealing the coordinated genetic regulatory network formed by Pto-Wuschela and its targets. Thus, our study provides an alternative method for dissection of the interactions between a TF and its targets, which will strength our understanding of the regulatory roles of TFs in complex traits in plants.

The genetic basis of the fitness costs of antimicrobial resistance: a meta-analysis approach.

PubMed

Vogwill, Tom; MacLean, R Craig

2015-03-01

The evolution of antibiotic resistance carries a fitness cost, expressed in terms of reduced competitive ability in the absence of antibiotics. This cost plays a key role in the dynamics of resistance by generating selection against resistance when bacteria encounter an antibiotic-free environment. Previous work has shown that the cost of resistance is highly variable, but the underlying causes remain poorly understood. Here, we use a meta-analysis of the published resistance literature to determine how the genetic basis of resistance influences its cost. We find that on average chromosomal resistance mutations carry a larger cost than acquiring resistance via a plasmid. This may explain why resistance often evolves by plasmid acquisition. Second, we find that the cost of plasmid acquisition increases with the breadth of its resistance range. This suggests a potentially important limit on the evolution of extensive multidrug resistance via plasmids. We also find that epistasis can significantly alter the cost of mutational resistance. Overall, our study shows that the cost of antimicrobial resistance can be partially explained by its genetic basis. It also highlights both the danger associated with plasmidborne resistance and the need to understand why resistance plasmids carry a relatively low cost.

Quantification of the transferability of a designed protein specificity switch reveals extensive epistasis in molecular recognition

DOE PAGES

Melero, Cristina; Ollikainen, Noah; Harwood, Ian; ...

2014-10-13

Re-engineering protein–protein recognition is an important route to dissecting and controlling complex interaction networks. Experimental approaches have used the strategy of “second-site suppressors,” where a functional interaction is inferred between two proteins if a mutation in one protein can be compensated by a mutation in the second. Mimicking this strategy, computational design has been applied successfully to change protein recognition specificity by predicting such sets of compensatory mutations in protein–protein interfaces. To extend this approach, it would be advantageous to be able to “transplant” existing engineered and experimentally validated specificity changes to other homologous protein–protein complexes. Here, we test thismore » strategy by designing a pair of mutations that modulates peptide recognition specificity in the Syntrophin PDZ domain, confirming the designed interaction biochemically and structurally, and then transplanting the mutations into the context of five related PDZ domain–peptide complexes. We find a wide range of energetic effects of identical mutations in structurally similar positions, revealing a dramatic context dependence (epistasis) of designed mutations in homologous protein–protein interactions. To better understand the structural basis of this context dependence, we apply a structure-based computational model that recapitulates these energetic effects and we use this model to make and validate forward predictions. The context dependence of these mutations is captured by computational predictions, our results both highlight the considerable difficulties in designing protein–protein interactions and provide challenging benchmark cases for the development of improved protein modeling and design methods that accurately account for the context.« less

Mechanistic Explanations for Restricted Evolutionary Paths That Emerge from Gene Regulatory Networks

PubMed Central

Cotterell, James; Sharpe, James

2013-01-01

The extent and the nature of the constraints to evolutionary trajectories are central issues in biology. Constraints can be the result of systems dynamics causing a non-linear mapping between genotype and phenotype. How prevalent are these developmental constraints and what is their mechanistic basis? Although this has been extensively explored at the level of epistatic interactions between nucleotides within a gene, or amino acids within a protein, selection acts at the level of the whole organism, and therefore epistasis between disparate genes in the genome is expected due to their functional interactions within gene regulatory networks (GRNs) which are responsible for many aspects of organismal phenotype. Here we explore epistasis within GRNs capable of performing a common developmental function – converting a continuous morphogen input into discrete spatial domains. By exploring the full complement of GRN wiring designs that are able to perform this function, we analyzed all possible mutational routes between functional GRNs. Through this study we demonstrate that mechanistic constraints are common for GRNs that perform even a simple function. We demonstrate a common mechanistic cause for such a constraint involving complementation between counter-balanced gene-gene interactions. Furthermore we show how such constraints can be bypassed by means of “permissive” mutations that buffer changes in a direct route between two GRN topologies that would normally be unviable. We show that such bypasses are common and thus we suggest that unlike what was observed in protein sequence-function relationships, the “tape of life” is less reproducible when one considers higher levels of biological organization. PMID:23613807

Cost-effective GPU-grid for genome-wide epistasis calculations.

PubMed

Pütz, B; Kam-Thong, T; Karbalai, N; Altmann, A; Müller-Myhsok, B

2013-01-01

Until recently, genotype studies were limited to the investigation of single SNP effects due to the computational burden incurred when studying pairwise interactions of SNPs. However, some genetic effects as simple as coloring (in plants and animals) cannot be ascribed to a single locus but only understood when epistasis is taken into account [1]. It is expected that such effects are also found in complex diseases where many genes contribute to the clinical outcome of affected individuals. Only recently have such problems become feasible computationally. The inherently parallel structure of the problem makes it a perfect candidate for massive parallelization on either grid or cloud architectures. Since we are also dealing with confidential patient data, we were not able to consider a cloud-based solution but had to find a way to process the data in-house and aimed to build a local GPU-based grid structure. Sequential epistatsis calculations were ported to GPU using CUDA at various levels. Parallelization on the CPU was compared to corresponding GPU counterparts with regards to performance and cost. A cost-effective solution was created by combining custom-built nodes equipped with relatively inexpensive consumer-level graphics cards with highly parallel GPUs in a local grid. The GPU method outperforms current cluster-based systems on a price/performance criterion, as a single GPU shows speed performance comparable up to 200 CPU cores. The outlined approach will work for problems that easily lend themselves to massive parallelization. Code for various tasks has been made available and ongoing development of tools will further ease the transition from sequential to parallel algorithms.

An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development.

PubMed

Pedros, Christophe; Gaud, Guillaume; Bernard, Isabelle; Kassem, Sahar; Chabod, Marianne; Lagrange, Dominique; Andréoletti, Olivier; Dejean, Anne S; Lesourne, Renaud; Fournié, Gilbert J; Saoudi, Abdelhadi

2015-08-15

The development of inflammatory diseases depends on complex interactions between several genes and various environmental factors. Discovering new genetic risk factors and understanding the mechanisms whereby they influence disease development is of paramount importance. We previously reported that deficiency in Themis1, a new actor of TCR signaling, impairs regulatory T cell (Treg) function and predisposes Brown-Norway (BN) rats to spontaneous inflammatory bowel disease (IBD). In this study, we reveal that the epistasis between Themis1 and Vav1 controls the occurrence of these phenotypes. Indeed, by contrast with BN rats, Themis1 deficiency in Lewis rats neither impairs Treg suppressive functions nor induces pathological manifestations. By using congenic lines on the BN genomic background, we show that the impact of Themis1 deficiency on Treg suppressive functions depends on a 117-kb interval coding for a R63W polymorphism that impacts Vav1 expression and functions. Indeed, the introduction of a 117-kb interval containing the Lewis Vav1-R63 variant restores Treg function and protects Themis1-deficient BN rats from spontaneous IBD development. We further show that Themis1 binds more efficiently to the BN Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT and to fully promote the activation of Erk kinases. Together, these results highlight the importance of the signaling pathway involving epistasis between Themis1 and Vav1 in the control of Treg suppressive function and susceptibility to IBD development. Copyright © 2015 by The American Association of Immunologists, Inc.

Quantification of the transferability of a designed protein specificity switch reveals extensive epistasis in molecular recognition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melero, Cristina; Ollikainen, Noah; Harwood, Ian

Re-engineering protein–protein recognition is an important route to dissecting and controlling complex interaction networks. Experimental approaches have used the strategy of “second-site suppressors,” where a functional interaction is inferred between two proteins if a mutation in one protein can be compensated by a mutation in the second. Mimicking this strategy, computational design has been applied successfully to change protein recognition specificity by predicting such sets of compensatory mutations in protein–protein interfaces. To extend this approach, it would be advantageous to be able to “transplant” existing engineered and experimentally validated specificity changes to other homologous protein–protein complexes. Here, we test thismore » strategy by designing a pair of mutations that modulates peptide recognition specificity in the Syntrophin PDZ domain, confirming the designed interaction biochemically and structurally, and then transplanting the mutations into the context of five related PDZ domain–peptide complexes. We find a wide range of energetic effects of identical mutations in structurally similar positions, revealing a dramatic context dependence (epistasis) of designed mutations in homologous protein–protein interactions. To better understand the structural basis of this context dependence, we apply a structure-based computational model that recapitulates these energetic effects and we use this model to make and validate forward predictions. The context dependence of these mutations is captured by computational predictions, our results both highlight the considerable difficulties in designing protein–protein interactions and provide challenging benchmark cases for the development of improved protein modeling and design methods that accurately account for the context.« less

Accelerometer Data Analysis and Presentation Techniques

NASA Technical Reports Server (NTRS)

Rogers, Melissa J. B.; Hrovat, Kenneth; McPherson, Kevin; Moskowitz, Milton E.; Reckart, Timothy

1997-01-01

The NASA Lewis Research Center's Principal Investigator Microgravity Services project analyzes Orbital Acceleration Research Experiment and Space Acceleration Measurement System data for principal investigators of microgravity experiments. Principal investigators need a thorough understanding of data analysis techniques so that they can request appropriate analyses to best interpret accelerometer data. Accelerometer data sampling and filtering is introduced along with the related topics of resolution and aliasing. Specific information about the Orbital Acceleration Research Experiment and Space Acceleration Measurement System data sampling and filtering is given. Time domain data analysis techniques are discussed and example environment interpretations are made using plots of acceleration versus time, interval average acceleration versus time, interval root-mean-square acceleration versus time, trimmean acceleration versus time, quasi-steady three dimensional histograms, and prediction of quasi-steady levels at different locations. An introduction to Fourier transform theory and windowing is provided along with specific analysis techniques and data interpretations. The frequency domain analyses discussed are power spectral density versus frequency, cumulative root-mean-square acceleration versus frequency, root-mean-square acceleration versus frequency, one-third octave band root-mean-square acceleration versus frequency, and power spectral density versus frequency versus time (spectrogram). Instructions for accessing NASA Lewis Research Center accelerometer data and related information using the internet are provided.

A knowledge-driven interaction analysis reveals potential neurodegenerative mechanism of multiple sclerosis susceptibility.

PubMed

Bush, W S; McCauley, J L; DeJager, P L; Dudek, S M; Hafler, D A; Gibson, R A; Matthews, P M; Kappos, L; Naegelin, Y; Polman, C H; Hauser, S L; Oksenberg, J; Haines, J L; Ritchie, M D

2011-07-01

Gene-gene interactions are proposed as an important component of the genetic architecture of complex diseases, and are just beginning to be evaluated in the context of genome-wide association studies (GWAS). In addition to detecting epistasis, a benefit to interaction analysis is that it also increases power to detect weak main effects. We conducted a knowledge-driven interaction analysis of a GWAS of 931 multiple sclerosis (MS) trios to discover gene-gene interactions within established biological contexts. We identify heterogeneous signals, including a gene-gene interaction between CHRM3 (muscarinic cholinergic receptor 3) and MYLK (myosin light-chain kinase) (joint P=0.0002), an interaction between two phospholipase C-β isoforms, PLCβ1 and PLCβ4 (joint P=0.0098), and a modest interaction between ACTN1 (actinin alpha 1) and MYH9 (myosin heavy chain 9) (joint P=0.0326), all localized to calcium-signaled cytoskeletal regulation. Furthermore, we discover a main effect (joint P=5.2E-5) previously unidentified by single-locus analysis within another related gene, SCIN (scinderin), a calcium-binding cytoskeleton regulatory protein. This work illustrates that knowledge-driven interaction analysis of GWAS data is a feasible approach to identify new genetic effects. The results of this study are among the first gene-gene interactions and non-immune susceptibility loci for MS. Further, the implicated genes cluster within inter-related biological mechanisms that suggest a neurodegenerative component to MS.

Patterns of Reproductive Isolation in Eucalyptus-A Phylogenetic Perspective.

PubMed

Larcombe, Matthew J; Holland, Barbara; Steane, Dorothy A; Jones, Rebecca C; Nicolle, Dean; Vaillancourt, René E; Potts, Brad M

2015-07-01

We assess phylogenetic patterns of hybridization in the speciose, ecologically and economically important genus Eucalyptus, in order to better understand the evolution of reproductive isolation. Eucalyptus globulus pollen was applied to 99 eucalypt species, mainly from the large commercially important subgenus, Symphyomyrtus. In the 64 species that produce seeds, hybrid compatibility was assessed at two stages, hybrid-production (at approximately 1 month) and hybrid-survival (at 9 months), and compared with phylogenies based on 8,350 genome-wide DArT (diversity arrays technology) markers. Model fitting was used to assess the relationship between compatibility and genetic distance, and whether or not the strength of incompatibility "snowballs" with divergence. There was a decline in compatibility with increasing genetic distance between species. Hybridization was common within two closely related clades (one including E. globulus), but rare between E. globulus and species in two phylogenetically distant clades. Of three alternative models tested (linear, slowdown, and snowball), we found consistent support for a snowball model, indicating that the strength of incompatibility accelerates relative to genetic distance. Although we can only speculate about the genetic basis of this pattern, it is consistent with a Dobzhansky-Muller-model prediction that incompatibilities should snowball with divergence due to negative epistasis. Different rates of compatibility decline in the hybrid-production and hybrid-survival measures suggest that early-acting postmating barriers developed first and are stronger than later-acting barriers. We estimated that complete reproductive isolation can take up to 21-31 My in Eucalyptus. Practical implications for hybrid eucalypt breeding and genetic risk assessment in Australia are discussed. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The Role of Osteopontin (OPN/SPP1) Haplotypes in the Susceptibility to Crohn's Disease

PubMed Central

Bayrle, Corinna; Wetzke, Martin; Fries, Christoph; Tillack, Cornelia; Olszak, Torsten; Beigel, Florian; Steib, Christian; Friedrich, Matthias; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

2011-01-01

Background Osteopontin represents a multifunctional molecule playing a pivotal role in chronic inflammatory and autoimmune diseases. Its expression is increased in inflammatory bowel disease (IBD). The aim of our study was to analyze the association of osteopontin (OPN/SPP1) gene variants in a large cohort of IBD patients. Methodology/Principal Findings Genomic DNA from 2819 Caucasian individuals (n = 841 patients with Crohn's disease (CD), n = 473 patients with ulcerative colitis (UC), and n = 1505 healthy unrelated controls) was analyzed for nine OPN SNPs (rs2728127, rs2853744, rs11730582, rs11739060, rs28357094, rs4754 = p.Asp80Asp, rs1126616 = p.Ala236Ala, rs1126772 and rs9138). Considering the important role of osteopontin in Th17-mediated diseases, we performed analysis for epistasis with IBD-associated IL23R variants and analyzed serum levels of the Th17 cytokine IL-22. For four OPN SNPs (rs4754, rs1126616, rs1126772 and rs9138), we observed significantly different distributions between male and female CD patients. rs4754 was protective in male CD patients (p = 0.0004, OR = 0.69). None of the other investigated OPN SNPs was associated with CD or UC susceptibility. However, several OPN haplotypes showed significant associations with CD susceptibility. The strongest association was found for a haplotype consisting of the 8 OPN SNPs rs2728127-rs2853744-rs11730582-rs11439060-rs28357094-rs112661-rs1126772-rs9138 (omnibus p-value = 2.07×10−8). Overall, the mean IL-22 secretion in the combined group of OPN minor allele carriers with CD was significantly lower than that of CD patients with OPN wildtype alleles (p = 3.66×10−5). There was evidence for weak epistasis between the OPN SNP rs28357094 with the IL23R SNP rs10489629 (p = 4.18×10−2) and between OPN SNP rs1126616 and IL23R SNP rs2201841 (p = 4.18×10−2) but none of these associations remained significant after Bonferroni correction. Conclusions/Significance Our study identified OPN haplotypes as modifiers of CD susceptibility, while the combined effects of certain OPN variants may modulate IL-22 secretion. PMID:22242114

Accelerated Testing and Analysis | Photovoltaic Research | NREL

Science.gov Websites

& Engineering pages: Real-Time PV & Solar Resource Testing Systems Engineering Systems PV standards. Each year, NCPV researchers, along with solar companies and other national lab Accelerated Testing and Analysis Accelerated Testing and Analysis PV Research Other Reliability

Genetic architecture for susceptibility to gout in the KARE cohort study.

PubMed

Shin, Jimin; Kim, Younyoung; Kong, Minyoung; Lee, Chaeyoung

2012-06-01

This study aimed to identify functional associations of cis-regulatory regions with gout susceptibility using data resulted from a genome-wide association study (GWAS), and to show a genetic architecture for gout with interaction effects among genes within each of the identified functions. The GWAS was conducted with 8314 control subjects and 520 patients with gout in the Korea Association REsource cohort. However, genetic associations with any individual nucleotide variants were not discovered by Bonferroni multiple testing in the GWAS (P>1.42 × 10(-7)). Genomic regions enrichment analysis was employed to identify functional associations of cis-regulatory regions. This analysis revealed several biological processes associated with gout susceptibility, and they were quite different from those with serum uric acid level. Epistasis for susceptibility to gout was estimated using entropy decomposition with selected genes within each biological process identified by the genomic regions enrichment analysis. Some epistases among nucleotide sequence variants for gout susceptibility were found to be larger than their individual effects. This study provided the first evidence that genetic factors for gout susceptibility greatly differed from those for serum uric acid level, which may suggest that research endeavors for identifying genetic factors for gout susceptibility should not be heavily dependent on pathogenesis of uric acid. Interaction effects between genes should be examined to explain a large portion of phenotypic variability for gout susceptibility.

Retracing Evolution of Red Fluorescence in GFP-Like Proteins from Faviina Corals

PubMed Central

Field, Steven F.; Matz, Mikhail V.

2010-01-01

Proteins of the green fluorescent protein family represent a convenient experimental model to study evolution of novelty at the molecular level. Here, we focus on the origin of Kaede-like red fluorescent proteins characteristic of the corals of the Faviina suborder. We demonstrate, using an original approach involving resurrection and analysis of the library of possible evolutionary intermediates, that it takes on the order of 12 mutations, some of which strongly interact epistatically, to fully recapitulate the evolution of a red fluorescent phenotype from the ancestral green. Five of the identified mutations would not have been found without the help of ancestral reconstruction, because the corresponding site states are shared between extant red and green proteins due to their recent descent from a dual-function common ancestor. Seven of the 12 mutations affect residues that are not in close contact with the chromophore and thus must exert their effect indirectly through adjustments of the overall protein fold; the relevance of these mutations could not have been anticipated from the purely theoretical analysis of the protein's structure. Our results introduce a powerful experimental approach for comparative analysis of functional specificity in protein families even in the cases of pronounced epistasis, provide foundation for the detailed studies of evolutionary trajectories leading to novelty and complexity, and will help rational modification of existing fluorescent labels. PMID:19793832

Prioritizing GWAS Results: A Review of Statistical Methods and Recommendations for Their Application

PubMed Central

Cantor, Rita M.; Lange, Kenneth; Sinsheimer, Janet S.

2010-01-01

Genome-wide association studies (GWAS) have rapidly become a standard method for disease gene discovery. A substantial number of recent GWAS indicate that for most disorders, only a few common variants are implicated and the associated SNPs explain only a small fraction of the genetic risk. This review is written from the viewpoint that findings from the GWAS provide preliminary genetic information that is available for additional analysis by statistical procedures that accumulate evidence, and that these secondary analyses are very likely to provide valuable information that will help prioritize the strongest constellations of results. We review and discuss three analytic methods to combine preliminary GWAS statistics to identify genes, alleles, and pathways for deeper investigations. Meta-analysis seeks to pool information from multiple GWAS to increase the chances of finding true positives among the false positives and provides a way to combine associations across GWAS, even when the original data are unavailable. Testing for epistasis within a single GWAS study can identify the stronger results that are revealed when genes interact. Pathway analysis of GWAS results is used to prioritize genes and pathways within a biological context. Following a GWAS, association results can be assigned to pathways and tested in aggregate with computational tools and pathway databases. Reviews of published methods with recommendations for their application are provided within the framework for each approach. PMID:20074509

Methods for identifying SNP interactions: a review on variations of Logic Regression, Random Forest and Bayesian logistic regression.

PubMed

Chen, Carla Chia-Ming; Schwender, Holger; Keith, Jonathan; Nunkesser, Robin; Mengersen, Kerrie; Macrossan, Paula

2011-01-01

Due to advancements in computational ability, enhanced technology and a reduction in the price of genotyping, more data are being generated for understanding genetic associations with diseases and disorders. However, with the availability of large data sets comes the inherent challenges of new methods of statistical analysis and modeling. Considering a complex phenotype may be the effect of a combination of multiple loci, various statistical methods have been developed for identifying genetic epistasis effects. Among these methods, logic regression (LR) is an intriguing approach incorporating tree-like structures. Various methods have built on the original LR to improve different aspects of the model. In this study, we review four variations of LR, namely Logic Feature Selection, Monte Carlo Logic Regression, Genetic Programming for Association Studies, and Modified Logic Regression-Gene Expression Programming, and investigate the performance of each method using simulated and real genotype data. We contrast these with another tree-like approach, namely Random Forests, and a Bayesian logistic regression with stochastic search variable selection.

Diversity of Functionally Permissive Sequences in the Receptor-Binding Site of Influenza Hemagglutinin.

PubMed

Wu, Nicholas C; Xie, Jia; Zheng, Tianqing; Nycholat, Corwin M; Grande, Geramie; Paulson, James C; Lerner, Richard A; Wilson, Ian A

2017-06-14

Influenza A virus hemagglutinin (HA) initiates viral entry by engaging host receptor sialylated glycans via its receptor-binding site (RBS). The amino acid sequence of the RBS naturally varies across avian and human influenza virus subtypes and is also evolvable. However, functional sequence diversity in the RBS has not been fully explored. Here, we performed a large-scale mutational analysis of the RBS of A/WSN/33 (H1N1) and A/Hong Kong/1/1968 (H3N2) HAs. Many replication-competent mutants not yet observed in nature were identified, including some that could escape from an RBS-targeted broadly neutralizing antibody. This functional sequence diversity is made possible by pervasive epistasis in the RBS 220-loop and can be buffered by avidity in viral receptor binding. Overall, our study reveals that the HA RBS can accommodate a much greater range of sequence diversity than previously thought, which has significant implications for the complex evolutionary interrelationships between receptor specificity and immune escape. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic architecture of hybrid male sterility in Drosophila: analysis of intraspecies variation for interspecies isolation.

PubMed

Reed, Laura K; LaFlamme, Brooke A; Markow, Therese A

2008-08-27

The genetic basis of postzygotic isolation is a central puzzle in evolutionary biology. Evolutionary forces causing hybrid sterility or inviability act on the responsible genes while they still are polymorphic, thus we have to study these traits as they arise, before isolation is complete. Isofemale strains of D. mojavensis vary significantly in their production of sterile F(1) sons when females are crossed to D. arizonae males. We took advantage of the intraspecific polymorphism, in a novel design, to perform quantitative trait locus (QTL) mapping analyses directly on F(1) hybrid male sterility itself. We found that the genetic architecture of the polymorphism for hybrid male sterility (HMS) in the F(1) is complex, involving multiple QTL, epistasis, and cytoplasmic effects. The role of extensive intraspecific polymorphism, multiple QTL, and epistatic interactions in HMS in this young species pair shows that HMS is arising as a complex trait in this system. Directional selection alone would be unlikely to maintain polymorphism at multiple loci, thus we hypothesize that directional selection is unlikely to be the only evolutionary force influencing postzygotic isolation.

An end to endless forms: epistasis, phenotype distribution bias, and nonuniform evolution.

PubMed

Borenstein, Elhanan; Krakauer, David C

2008-10-01

Studies of the evolution of development characterize the way in which gene regulatory dynamics during ontogeny constructs and channels phenotypic variation. These studies have identified a number of evolutionary regularities: (1) phenotypes occupy only a small subspace of possible phenotypes, (2) the influence of mutation is not uniform and is often canalized, and (3) a great deal of morphological variation evolved early in the history of multicellular life. An important implication of these studies is that diversity is largely the outcome of the evolution of gene regulation rather than the emergence of new, structural genes. Using a simple model that considers a generic property of developmental maps-the interaction between multiple genetic elements and the nonlinearity of gene interaction in shaping phenotypic traits-we are able to recover many of these empirical regularities. We show that visible phenotypes represent only a small fraction of possibilities. Epistasis ensures that phenotypes are highly clustered in morphospace and that the most frequent phenotypes are the most similar. We perform phylogenetic analyses on an evolving, developmental model and find that species become more alike through time, whereas higher-level grades have a tendency to diverge. Ancestral phenotypes, produced by early developmental programs with a low level of gene interaction, are found to span a significantly greater volume of the total phenotypic space than derived taxa. We suggest that early and late evolution have a different character that we classify into micro- and macroevolutionary configurations. These findings complement the view of development as a key component in the production of endless forms and highlight the crucial role of development in constraining biotic diversity and evolutionary trajectories.

The thermodynamics of protein aggregation reactions may underpin the enhanced metabolic efficiency associated with heterosis, some balancing selection, and the evolution of ploidy levels.

PubMed

Ginn, B R

2017-07-01

Identifying the physical basis of heterosis (or "hybrid vigor") has remained elusive despite over a hundred years of research on the subject. The three main theories of heterosis are dominance theory, overdominance theory, and epistasis theory. Kacser and Burns (1981) identified the molecular basis of dominance, which has greatly enhanced our understanding of its importance to heterosis. This paper aims to explain how overdominance, and some features of epistasis, can similarly emerge from the molecular dynamics of proteins. Possessing multiple alleles at a gene locus results in the synthesis of different allozymes at reduced concentrations. This in turn reduces the rate at which each allozyme forms soluble oligomers, which are toxic and must be degraded, because allozymes co-aggregate at low efficiencies. The model developed in this paper can explain how heterozygosity impacts the metabolic efficiency of an organism. It can also explain why the viabilities of some inbred lines seem to decline rapidly at high inbreeding coefficients (F > 0.5), which may provide a physical basis for truncation selection for heterozygosity. Finally, the model has implications for the ploidy level of organisms. It can explain why polyploids are frequently found in environments where severe physical stresses promote the formation of soluble oligomers. The model can also explain why complex organisms, which need to synthesize aggregation-prone proteins that contain intrinsically unstructured regions (IURs) and multiple domains because they facilitate complex protein interaction networks (PINs), tend to be diploid while haploidy tends to be restricted to relatively simple organisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: Evidence for epistasis between 1p and IBD1

PubMed Central

Cho, Judy H.; Nicolae, Dan L.; Gold, Leslee H.; Fields, Carter T.; LaBuda, Michele C.; Rohal, Patrick M.; Pickles, Michael R.; Qin, Li; Fu, Yifan; Mann, Jasdeep S.; Kirschner, Barbara S.; Jabs, Ethylin Wang; Weber, James; Hanauer, Stephen B.; Bayless, Theodore M.; Brant, Steven R.

1998-01-01

The idiopathic inflammatory bowel diseases, Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic differences in familial risks have established that CD and UC are complex, non-Mendelian, related genetic disorders. We performed a genome-wide screen using 377 autosomal markers, on 297 CD, UC, or mixed relative pairs from 174 families, 37% Ashkenazim. We observed evidence for linkage at 3q for all families (multipoint logarithm of the odds score (MLod) = 2.29, P = 5.7 × 10−4), with greatest significance for non-Ashkenazim Caucasians (MLod = 3.39, P = 3.92 × 10−5), and at chromosome 1p (MLod = 2.65, P = 2.4 × 10−4) for all families. In a limited subset of mixed families (containing one member with CD and another with UC), evidence for linkage was observed on chromosome 4q (MLod = 2.76, P = 1.9 × 10−4), especially among Ashkenazim. There was confirmatory evidence for a CD locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (MLod = 1.69, P = 2.6 × 10−3), particularly among Ashkenazim (MLod = 1.51, P = 7.8 × 10−3); however, positive MLod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.016) evidence for linkage. This screen provides strong evidence that there are several major susceptibility loci contributing to the genetic risk for CD and UC. PMID:9636179

A framework for evolutionary systems biology

PubMed Central

Loewe, Laurence

2009-01-01

Background Many difficult problems in evolutionary genomics are related to mutations that have weak effects on fitness, as the consequences of mutations with large effects are often simple to predict. Current systems biology has accumulated much data on mutations with large effects and can predict the properties of knockout mutants in some systems. However experimental methods are too insensitive to observe small effects. Results Here I propose a novel framework that brings together evolutionary theory and current systems biology approaches in order to quantify small effects of mutations and their epistatic interactions in silico. Central to this approach is the definition of fitness correlates that can be computed in some current systems biology models employing the rigorous algorithms that are at the core of much work in computational systems biology. The framework exploits synergies between the realism of such models and the need to understand real systems in evolutionary theory. This framework can address many longstanding topics in evolutionary biology by defining various 'levels' of the adaptive landscape. Addressed topics include the distribution of mutational effects on fitness, as well as the nature of advantageous mutations, epistasis and robustness. Combining corresponding parameter estimates with population genetics models raises the possibility of testing evolutionary hypotheses at a new level of realism. Conclusion EvoSysBio is expected to lead to a more detailed understanding of the fundamental principles of life by combining knowledge about well-known biological systems from several disciplines. This will benefit both evolutionary theory and current systems biology. Understanding robustness by analysing distributions of mutational effects and epistasis is pivotal for drug design, cancer research, responsible genetic engineering in synthetic biology and many other practical applications. PMID:19239699

Pleiotropic Models of Polygenic Variation, Stabilizing Selection, and Epistasis

PubMed Central

Gavrilets, S.; de-Jong, G.

1993-01-01

We show that in polymorphic populations many polygenic traits pleiotropically related to fitness are expected to be under apparent ``stabilizing selection'' independently of the real selection acting on the population. This occurs, for example, if the genetic system is at a stable polymorphic equilibrium determined by selection and the nonadditive contributions of the loci to the trait value either are absent, or are random and independent of those to fitness. Stabilizing selection is also observed if the polygenic system is at an equilibrium determined by a balance between selection and mutation (or migration) when both additive and nonadditive contributions of the loci to the trait value are random and independent of those to fitness. We also compare different viability models that can maintain genetic variability at many loci with respect to their ability to account for the strong stabilizing selection on an additive trait. Let V(m) be the genetic variance supplied by mutation (or migration) each generation, V(g) be the genotypic variance maintained in the population, and n be the number of the loci influencing fitness. We demonstrate that in mutation (migration)-selection balance models the strength of apparent stabilizing selection is order V(m)/V(g). In the overdominant model and in the symmetric viability model the strength of apparent stabilizing selection is approximately 1/(2n) that of total selection on the whole phenotype. We show that a selection system that involves pairwise additive by additive epistasis in maintaining variability can lead to a lower genetic load and genetic variance in fitness (approximately 1/(2n) times) than an equivalent selection system that involves overdominance. We show that, in the epistatic model, the apparent stabilizing selection on an additive trait can be as strong as the total selection on the whole phenotype. PMID:8325491

Activin receptor inhibition by Smad2 regulates Drosophila wing disc patterning through BMP-response elements

PubMed Central

Peterson, Aidan J.; O'Connor, Michael B.

2013-01-01

Imaginal disc development in Drosophila requires coordinated cellular proliferation and tissue patterning. In our studies of TGFβ superfamily signaling components, we found that a protein null mutation of Smad2, the only Activin subfamily R-Smad in the fruit fly, produces overgrown wing discs that resemble gain of function for BMP subfamily signaling. The wing discs are expanded specifically along the anterior-posterior axis, with increased proliferation in lateral regions. The morphological defect is not observed in mutants for the TGFβ receptor baboon, and epistasis tests showed that baboon is epistatic to Smad2 for disc overgrowth. Rescue experiments indicate that Baboon binding, but not canonical transcription factor activity, of Smad2 is required for normal disc growth. Smad2 mutant discs generate a P-Mad stripe that is narrower and sharper than the normal gradient, and activation targets are correspondingly expressed in narrowed domains. Repression targets of P-Mad are profoundly mis-regulated, with brinker and pentagone reporter expression eliminated in Smad2 mutants. Loss of expression requires a silencer element previously shown to be controlled by BMP signaling. Epistasis experiments show that Baboon, Mad and Schnurri are required to mediate the ectopic silencer output in the absence of Smad2. Taken together, our results show that loss of Smad2 permits promiscuous Baboon activity, which represses genes subject to control by Mad-dependent silencer elements. The absence of Brinker and Pentagone in Smad2 mutants explains the compound wing disc phenotype. Our results highlight the physiological relevance of substrate inhibition of a kinase, and reveal a novel interplay between the Activin and BMP pathways. PMID:23293296

Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP.

PubMed

Bai, Hua; Post, Stephanie; Kang, Ping; Tatar, Marc

2015-01-01

Mutations of the insulin/IGF signaling (IIS) pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging. One candidate is target of rapamycin complex 1 (TORC1). Reduced TORC1 activity is reported to slow aging, whereas reduced IIS is reported to repress TORC1 activity. The eukaryotic translation initiation factor 4E binding protein (4E-BP) is repressed by TORC1, and activated 4E-BP is reported to increase Drosophila lifespan. Here we use genetic epistasis analyses to test whether longevity assurance mutants of chico, the Drosophila insulin receptor substrate homolog, require Drosophila d4eBP to slow aging. In chico heterozygotes, which are robustly long-lived, d4eBP is required but not sufficient to slow aging. Remarkably, d4eBP is not required or sufficient for chico homozygotes to extend longevity. Likewise, chico heterozygote females partially require d4eBP to preserve age-dependent locomotion, and both chico genotypes require d4eBP to improve stress-resistance. Reproduction and most measures of growth affected by either chico genotype are always independent of d4eBP. In females, chico heterozygotes paradoxically produce more rather than less phosphorylated 4E-BP (p4E-BP). Altered IRS function within the IIS pathway of Drosophila appears to have partial, conditional capacity to regulate aging through an unconventional interaction with 4E-BP.

Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation

PubMed Central

Dykes, Iain M.; Tempest, Lynne; Lee, Su-In; Turner, Eric E.

2011-01-01

The combinatorial expression of transcription factors frequently marks cellular identity in the nervous system, yet how these factors interact to determine specific neuronal phenotypes is not well understood. Sensory neurons of the trigeminal (TG) and dorsal root ganglia (DRG) co-express the homeodomain transcription factors Brn3a and Islet1, and past work has revealed partially overlapping programs of gene expression downstream of these factors. Here we examine sensory development in Brn3a/Islet1 double knockout mice (DKO mice). Sensory neurogenesis and the formation of the TG and DRG occur in DKO embryos, but the DRG are dorsally displaced, and the peripheral projections of the ganglia are markedly disturbed. Sensory neurons in DKO embryos show a profound loss of all early markers of sensory subtypes, including the Ntrk neurotrophin receptors, and the runt-family transcription factors Runx1 and Runx3. Examination of global gene expression in the E12.5 DRG of single and double mutant embryos shows that Brn3a and Islet1 are together required for nearly all aspects of sensory-specific gene expression, including several newly identified sensory markers. On a majority of targets Brn3a and Islet1 exhibit negative epistasis, in which the effects of the individual knockout alleles are less than additive in the DKO. Smaller subsets of targets exhibit positive epistasis, or are regulated exclusively by one factor. Brn3a/Islet1 double mutants also fail to developmentally repress neurogenic bHLH genes, and in vivo chromatin immunoprecipitation shows that Islet1 binds to a known Brn3a -regulated enhancer in the neurod4 gene, suggesting a mechanism of interaction between these genes. PMID:21734270

An Analysis Pipeline with Statistical and Visualization-Guided Knowledge Discovery for Michigan-Style Learning Classifier Systems

PubMed Central

Urbanowicz, Ryan J.; Granizo-Mackenzie, Ambrose; Moore, Jason H.

2014-01-01

Michigan-style learning classifier systems (M-LCSs) represent an adaptive and powerful class of evolutionary algorithms which distribute the learned solution over a sizable population of rules. However their application to complex real world data mining problems, such as genetic association studies, has been limited. Traditional knowledge discovery strategies for M-LCS rule populations involve sorting and manual rule inspection. While this approach may be sufficient for simpler problems, the confounding influence of noise and the need to discriminate between predictive and non-predictive attributes calls for additional strategies. Additionally, tests of significance must be adapted to M-LCS analyses in order to make them a viable option within fields that require such analyses to assess confidence. In this work we introduce an M-LCS analysis pipeline that combines uniquely applied visualizations with objective statistical evaluation for the identification of predictive attributes, and reliable rule generalizations in noisy single-step data mining problems. This work considers an alternative paradigm for knowledge discovery in M-LCSs, shifting the focus from individual rules to a global, population-wide perspective. We demonstrate the efficacy of this pipeline applied to the identification of epistasis (i.e., attribute interaction) and heterogeneity in noisy simulated genetic association data. PMID:25431544

Genetic Mapping of Quantitative Trait Loci Controlling Growth and Wood Quality Traits in Eucalyptus Grandis Using a Maternal Half-Sib Family and Rapd Markers

PubMed Central

Grattapaglia, D.; Bertolucci, FLG.; Penchel, R.; Sederoff, R. R.

1996-01-01

Quantitative trait loci (QTL) mapping of forest productivity traits was performed using an open pollinated half-sib family of Eucalyptus grandis. For volume growth, a sequential QTL mapping approach was applied using bulk segregant analysis (BSA), selective genotyping (SG) and cosegregation analysis (CSA). Despite the low heritability of this trait and the heterogeneous genetic background employed for mapping. BSA detected one putative QTL and SG two out of the three later found by CSA. The three putative QTL for volume growth were found to control 13.7% of the phenotypic variation, corresponding to an estimated 43.7% of the genetic variation. For wood specific gravity five QTL were identified controlling 24.7% of the phenotypic variation corresponding to 49% of the genetic variation. Overlapping QTL for CBH, WSG and percentage dry weight of bark were observed. A significant case of digenic epistasis was found, involving unlinked QTL for volume. Our results demonstrate the applicability of the within half-sib design for QTL mapping in forest trees and indicate the existence of major genes involved in the expression of economically important traits related to forest productivity in Eucalyptus grandis. These findings have important implications for marker-assisted tree breeding. PMID:8913761

Epistasis analysis for quantitative traits by functional regression model.

PubMed

Zhang, Futao; Boerwinkle, Eric; Xiong, Momiao

2014-06-01

The critical barrier in interaction analysis for rare variants is that most traditional statistical methods for testing interactions were originally designed for testing the interaction between common variants and are difficult to apply to rare variants because of their prohibitive computational time and poor ability. The great challenges for successful detection of interactions with next-generation sequencing (NGS) data are (1) lack of methods for interaction analysis with rare variants, (2) severe multiple testing, and (3) time-consuming computations. To meet these challenges, we shift the paradigm of interaction analysis between two loci to interaction analysis between two sets of loci or genomic regions and collectively test interactions between all possible pairs of SNPs within two genomic regions. In other words, we take a genome region as a basic unit of interaction analysis and use high-dimensional data reduction and functional data analysis techniques to develop a novel functional regression model to collectively test interactions between all possible pairs of single nucleotide polymorphisms (SNPs) within two genome regions. By intensive simulations, we demonstrate that the functional regression models for interaction analysis of the quantitative trait have the correct type 1 error rates and a much better ability to detect interactions than the current pairwise interaction analysis. The proposed method was applied to exome sequence data from the NHLBI's Exome Sequencing Project (ESP) and CHARGE-S study. We discovered 27 pairs of genes showing significant interactions after applying the Bonferroni correction (P-values < 4.58 × 10(-10)) in the ESP, and 11 were replicated in the CHARGE-S study. © 2014 Zhang et al.; Published by Cold Spring Harbor Laboratory Press.

Solar wind conditions leading to efficient radiation belt electron acceleration: A superposed epoch analysis

DOE PAGES

Li, W.; Thorne, R. M.; Bortnik, J.; ...

2015-09-07

In this study by determining preferential solar wind conditions leading to efficient radiation belt electron acceleration is crucial for predicting radiation belt electron dynamics. Using Van Allen Probes electron observations (>1 MeV) from 2012 to 2015, we identify a number of efficient and inefficient acceleration events separately to perform a superposed epoch analysis of the corresponding solar wind parameters and geomagnetic indices. By directly comparing efficient and inefficient acceleration events, we clearly show that prolonged southward Bz, high solar wind speed, and low dynamic pressure are critical for electron acceleration to >1 MeV energies in the heart of the outermore » radiation belt. We also evaluate chorus wave evolution using the superposed epoch analysis for the identified efficient and inefficient acceleration events and find that chorus wave intensity is much stronger and lasts longer during efficient electron acceleration events, supporting the scenario that chorus waves play a key role in MeV electron acceleration.« less

Dynamic analysis of four bar planar mechanism extended to six-bar planar mechanism with variable topology

NASA Astrophysics Data System (ADS)

Belleri, Basayya K.; Kerur, Shravankumar B.

2018-04-01

A computer-oriented procedure for solving the dynamic force analysis problem for general planar mechanisms is presented. This paper provides position analysis, velocity analysis, acceleration analysis and force analysis of six bar mechanism with variable topology approach. Six bar mechanism is constructed by joining two simple four bar mechanisms. Initially the position, velocity and acceleration analysis of first four bar mechanism are determined by using the input parameters. The outputs (angular displacement, velocity and acceleration of rocker)of first four bar mechanism are used as input parameter for the second four bar mechanism and the position, velocity, acceleration and forces are analyzed. With out-put parameters of second four-bar mechanism the force analysis of first four-bar mechanism is carried out.

Vibration measurement by temporal Fourier analyses of a digital hologram sequence.

PubMed

Fu, Yu; Pedrini, Giancarlo; Osten, Wolfgang

2007-08-10

A method for whole-field noncontact measurement of displacement, velocity, and acceleration of a vibrating object based on image-plane digital holography is presented. A series of digital holograms of a vibrating object are captured by use of a high-speed CCD camera. The result of the reconstruction is a three-dimensional complex-valued matrix with noise. We apply Fourier analysis and windowed Fourier analysis in both the spatial and the temporal domains to extract the displacement, the velocity, and the acceleration. The instantaneous displacement is obtained by temporal unwrapping of the filtered phase map, whereas the velocity and acceleration are evaluated by Fourier analysis and by windowed Fourier analysis along the time axis. The combination of digital holography and temporal Fourier analyses allows for evaluation of the vibration, without a phase ambiguity problem, and smooth spatial distribution of instantaneous displacement, velocity, and acceleration of each instant are obtained. The comparison of Fourier analysis and windowed Fourier analysis in velocity and acceleration measurements is also presented.

Accelerated life assessment of coating on the radar structure components in coastal environment.

PubMed

Liu, Zhe; Ming, ZhiMao

2016-07-04

This paper aimed to build an accelerated life test scheme and carry out quantitative analysis between accelerated life test in the laboratory and actual service for the coating composed of epoxy primer and polyurethane paint on structure components of some kind of radar served in the coastal environment of South China Sea. The accelerated life test scheme was built based on the service environment and failure analysis of the coating. The quantitative analysis between accelerated life test and actual service was conducted by comparing the gloss loss, discoloration, chalking, blistering, cracking and electrochemical impedance spectroscopy of the coating. The main factors leading to the coating failure were ultraviolet radiation, temperature, moisture, salt fog and loads, the accelerated life test included ultraviolet radiation, damp heat, thermal shock, fatigue and salt spray. The quantitative relationship was that one cycle of the accelerated life test was equal to actual service for one year. It was established that one cycle of the accelerated life test was equal to actual service for one year. It provided a precise way to predict actual service life of newly developed coatings for the manufacturer.

Exploratory Visual Analysis of Statistical Results from Microarray Experiments Comparing High and Low Grade Glioma

PubMed Central

Reif, David M.; Israel, Mark A.; Moore, Jason H.

2007-01-01

The biological interpretation of gene expression microarray results is a daunting challenge. For complex diseases such as cancer, wherein the body of published research is extensive, the incorporation of expert knowledge provides a useful analytical framework. We have previously developed the Exploratory Visual Analysis (EVA) software for exploring data analysis results in the context of annotation information about each gene, as well as biologically relevant groups of genes. We present EVA as a flexible combination of statistics and biological annotation that provides a straightforward visual interface for the interpretation of microarray analyses of gene expression in the most commonly occuring class of brain tumors, glioma. We demonstrate the utility of EVA for the biological interpretation of statistical results by analyzing publicly available gene expression profiles of two important glial tumors. The results of a statistical comparison between 21 malignant, high-grade glioblastoma multiforme (GBM) tumors and 19 indolent, low-grade pilocytic astrocytomas were analyzed using EVA. By using EVA to examine the results of a relatively simple statistical analysis, we were able to identify tumor class-specific gene expression patterns having both statistical and biological significance. Our interactive analysis highlighted the potential importance of genes involved in cell cycle progression, proliferation, signaling, adhesion, migration, motility, and structure, as well as candidate gene loci on a region of Chromosome 7 that has been implicated in glioma. Because EVA does not require statistical or computational expertise and has the flexibility to accommodate any type of statistical analysis, we anticipate EVA will prove a useful addition to the repertoire of computational methods used for microarray data analysis. EVA is available at no charge to academic users and can be found at http://www.epistasis.org. PMID:19390666

Analysis of ballistic transport in nanoscale devices by using an accelerated finite element contact block reduction approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, H.; Li, G., E-mail: gli@clemson.edu

2014-08-28

An accelerated Finite Element Contact Block Reduction (FECBR) approach is presented for computational analysis of ballistic transport in nanoscale electronic devices with arbitrary geometry and unstructured mesh. Finite element formulation is developed for the theoretical CBR/Poisson model. The FECBR approach is accelerated through eigen-pair reduction, lead mode space projection, and component mode synthesis techniques. The accelerated FECBR is applied to perform quantum mechanical ballistic transport analysis of a DG-MOSFET with taper-shaped extensions and a DG-MOSFET with Si/SiO{sub 2} interface roughness. The computed electrical transport properties of the devices obtained from the accelerated FECBR approach and associated computational cost as amore » function of system degrees of freedom are compared with those obtained from the original CBR and direct inversion methods. The performance of the accelerated FECBR in both its accuracy and efficiency is demonstrated.« less

International Space Station Increment-6/8 Microgravity Environment Summary Report November 2002 to April 2004

NASA Technical Reports Server (NTRS)

Jules, Kenol; Hrovat, Kenneth; Kelly, Eric; Reckart, Timothy

2006-01-01

This summary report presents the analysis results of some of the processed acceleration data measured aboard the International Space Station during the period of November 2002 to April 2004. Two accelerometer systems were used to measure the acceleration levels for the activities that took place during Increment-6/8. However, not all of the activities during that period were analyzed in order to keep the size of the report manageable. The National Aeronautics and Space Administration sponsors the Microgravity Acceleration Measurement System and the Space Acceleration Measurement System to support microgravity science experiments that require microgravity acceleration measurements. On April 19, 2001, both the Microgravity Acceleration Measurement System and the Space Acceleration Measurement System units were launched on STS-100 from the Kennedy Space Center for installation on the International Space Station. The Microgravity Acceleration Measurement System unit was flown to the station in support of science experiments requiring quasi-steady acceleration measurements, while the Space Acceleration Measurement System unit was flown to support experiments requiring vibratory acceleration measurement. Both acceleration systems are also used in support of the vehicle microgravity requirements verification as well as in support of the International Space Station support cadre. The International Space Station Increment-6/8 reduced gravity environment analysis presented in this report uses acceleration data collected by both sets of accelerometer systems: 1. The Microgravity Acceleration Measurement System, which consists of two sensors: the Orbital Acceleration Research Experiment Sensor Subsystem, a low frequency range sensor (up to 1 Hz), is used to characterize the quasi-steady environment for payloads and vehicle, and the High Resolution Accelerometer Package, which is used to characterize the vibratory environment up to 100 Hz. 2. The Space Acceleration Measurement System measures vibratory acceleration data in the range of 0.01 to 400 Hz. This summary report presents analysis of some selected quasi-steady and vibratory activities measured by these accelerometers during Increment-6/8 from November 2002 to April 2004.

The Caenorhabditis elegans EGL-15 Signaling Pathway Implicates a DOS-Like Multisubstrate Adaptor Protein in Fibroblast Growth Factor Signal Transduction

PubMed Central

Schutzman, Jennifer L.; Borland, Christina Z.; Newman, John C.; Robinson, Matthew K.; Kokel, Michelle; Stern, Michael J.

2001-01-01

EGL-15 is a fibroblast growth factor receptor in the nematode Caenorhabditis elegans. Components that mediate EGL-15 signaling have been identified via mutations that confer a Clear (Clr) phenotype, indicative of hyperactivity of this pathway, or a suppressor-of-Clr (Soc) phenotype, indicative of reduced pathway activity. We have isolated a gain-of-function allele of let-60 ras that confers a Clr phenotype and implicated both let-60 ras and components of a mitogen-activated protein kinase cascade in EGL-15 signaling by their Soc phenotype. Epistasis analysis indicates that the gene soc-1 functions in EGL-15 signaling by acting either upstream of or independently of LET-60 RAS. soc-1 encodes a multisubstrate adaptor protein with an amino-terminal pleckstrin homology domain that is structurally similar to the DOS protein in Drosophila and mammalian GAB1. DOS is known to act with the cytoplasmic tyrosine phosphatase Corkscrew (CSW) in signaling pathways in Drosophila. Similarly, the C. elegans CSW ortholog PTP-2 was found to be involved in EGL-15 signaling. Structure-function analysis of SOC-1 and phenotypic analysis of single and double mutants are consistent with a model in which SOC-1 and PTP-2 act together in a pathway downstream of EGL-15 and the Src homology domain 2 (SH2)/SH3-adaptor protein SEM-5/GRB2 contributes to SOC-1-independent activities of EGL-15. PMID:11689700

Summary Report of Mission Acceleration Measurements for STS-78. Launched June 20, 1996

NASA Technical Reports Server (NTRS)

Hakimzadeh, Roshanak; Hrovat, Kenneth; McPherson, Kevin M.; Moskowitz, Milton E.; Rogers, Melissa J. B.

1997-01-01

The microgravity environment of the Space Shuttle Columbia was measured during the STS-78 mission using accelerometers from three different instruments: the Orbital Acceleration Research Experiment, the Space Acceleration Measurement System and the Microgravity Measurement Assembly. The quasi-steady environment was also calculated in near real-time during the mission by the Microgravity Analysis Workstation. The Orbital Acceleration Research Experiment provided investigators with real-time quasi-steady acceleration measurements. The Space Acceleration Measurement System recorded higher frequency data on-board for post-mission analysis. The Microgravity Measurement Assembly provided investigators with real-time quasi-steady and higher frequency acceleration measurements. The Microgravity Analysis Workstation provided calculation of the quasi-steady environment. This calculation was presented to the science teams in real-time during the mission. The microgravity environment related to several different Orbiter, crew and experiment operations is presented and interpreted in this report. A radiator deploy, the Flight Control System checkout, and a vernier reaction control system reboost demonstration had minimal effects on the acceleration environment, with excitation of frequencies in the 0.01 to 10 Hz range. Flash Evaporator System venting had no noticeable effect on the environment while supply and waste water dumps caused excursions of 2 x lO(exp -6) to 4 x 10(exp -6) g in the Y(sub b) and Z(sub b) directions. Crew sleep and ergometer exercise periods can be clearly seen in the acceleration data, as expected. Accelerations related to the two Life Science Laboratory Equipment Refrigerator/Freezers were apparent in the data as are accelerations caused by the Johnson Space Center Projects Centrifuge. As on previous microgravity missions, several signals are present in the acceleration data for which a source has not been identified. The causes of these accelerations are under investigation.

Analysis of accelerated motion in the theory of relativity

NASA Technical Reports Server (NTRS)

Jones, R. T.

1976-01-01

Conventional treatments of accelerated motion in the theory of relativity have led to certain difficulties of interpretation. Certain reversals in the apparent gravitational field of an accelerated body may be avoided by simpler analysis based on the use of restricted conformal transformations. In the conformal theory the velocity of light remains constant even for experimenters in accelerated motion. The problem considered is that of rectilinear motion with a variable velocity. The motion takes place along the x or x' axis of two coordinate systems.

Punctuated equilibrium and shock waves in molecular models of biological evolution.

PubMed

Saakian, David B; Ghazaryan, Makar H; Hu, Chin-Kun

2014-08-01

We consider the dynamics in infinite population evolution models with a general symmetric fitness landscape. We find shock waves, i.e., discontinuous transitions in the mean fitness, in evolution dynamics even with smooth fitness landscapes, which means that the search for the optimal evolution trajectory is more complicated. These shock waves appear in the case of positive epistasis and can be used to represent punctuated equilibria in biological evolution during long geological time scales. We find exact analytical solutions for discontinuous dynamics at the large-genome-length limit and derive optimal mutation rates for a fixed fitness landscape to send the population from the initial configuration to some final configuration in the fastest way.

Systematic profiling of Caenorhabditis elegans locomotive behaviors reveals additional components in G-protein Gαq signaling.

PubMed

Yu, Hui; Aleman-Meza, Boanerges; Gharib, Shahla; Labocha, Marta K; Cronin, Christopher J; Sternberg, Paul W; Zhong, Weiwei

2013-07-16

Genetic screens have been widely applied to uncover genetic mechanisms of movement disorders. However, most screens rely on human observations of qualitative differences. Here we demonstrate the application of an automatic imaging system to conduct a quantitative screen for genes regulating the locomotive behavior in Caenorhabditis elegans. Two hundred twenty-seven neuronal signaling genes with viable homozygous mutants were selected for this study. We tracked and recorded each animal for 4 min and analyzed over 4,400 animals of 239 genotypes to obtain a quantitative, 10-parameter behavioral profile for each genotype. We discovered 87 genes whose inactivation causes movement defects, including 50 genes that had never been associated with locomotive defects. Computational analysis of the high-content behavioral profiles predicted 370 genetic interactions among these genes. Network partition revealed several functional modules regulating locomotive behaviors, including sensory genes that detect environmental conditions, genes that function in multiple types of excitable cells, and genes in the signaling pathway of the G protein Gαq, a protein that is essential for animal life and behavior. We developed quantitative epistasis analysis methods to analyze the locomotive profiles and validated the prediction of the γ isoform of phospholipase C as a component in the Gαq pathway. These results provided a system-level understanding of how neuronal signaling genes coordinate locomotive behaviors. This study also demonstrated the power of quantitative approaches in genetic studies.

Power of data mining methods to detect genetic associations and interactions.

PubMed

Molinaro, Annette M; Carriero, Nicholas; Bjornson, Robert; Hartge, Patricia; Rothman, Nathaniel; Chatterjee, Nilanjan

2011-01-01

Genetic association studies, thus far, have focused on the analysis of individual main effects of SNP markers. Nonetheless, there is a clear need for modeling epistasis or gene-gene interactions to better understand the biologic basis of existing associations. Tree-based methods have been widely studied as tools for building prediction models based on complex variable interactions. An understanding of the power of such methods for the discovery of genetic associations in the presence of complex interactions is of great importance. Here, we systematically evaluate the power of three leading algorithms: random forests (RF), Monte Carlo logic regression (MCLR), and multifactor dimensionality reduction (MDR). We use the algorithm-specific variable importance measures (VIMs) as statistics and employ permutation-based resampling to generate the null distribution and associated p values. The power of the three is assessed via simulation studies. Additionally, in a data analysis, we evaluate the associations between individual SNPs in pro-inflammatory and immunoregulatory genes and the risk of non-Hodgkin lymphoma. The power of RF is highest in all simulation models, that of MCLR is similar to RF in half, and that of MDR is consistently the lowest. Our study indicates that the power of RF VIMs is most reliable. However, in addition to tuning parameters, the power of RF is notably influenced by the type of variable (continuous vs. categorical) and the chosen VIM. Copyright © 2011 S. Karger AG, Basel.

A robust multifactor dimensionality reduction method for detecting gene-gene interactions with application to the genetic analysis of bladder cancer susceptibility

PubMed Central

Gui, Jiang; Andrew, Angeline S.; Andrews, Peter; Nelson, Heather M.; Kelsey, Karl T.; Karagas, Margaret R.; Moore, Jason H.

2010-01-01

A central goal of human genetics is to identify and characterize susceptibility genes for common complex human diseases. An important challenge in this endeavor is the modeling of gene-gene interaction or epistasis that can result in non-additivity of genetic effects. The multifactor dimensionality reduction (MDR) method was developed as machine learning alternative to parametric logistic regression for detecting interactions in absence of significant marginal effects. The goal of MDR is to reduce the dimensionality inherent in modeling combinations of polymorphisms using a computational approach called constructive induction. Here, we propose a Robust Multifactor Dimensionality Reduction (RMDR) method that performs constructive induction using a Fisher’s Exact Test rather than a predetermined threshold. The advantage of this approach is that only those genotype combinations that are determined to be statistically significant are considered in the MDR analysis. We use two simulation studies to demonstrate that this approach will increase the success rate of MDR when there are only a few genotype combinations that are significantly associated with case-control status. We show that there is no loss of success rate when this is not the case. We then apply the RMDR method to the detection of gene-gene interactions in genotype data from a population-based study of bladder cancer in New Hampshire. PMID:21091664

Heuristic Identification of Biological Architectures for Simulating Complex Hierarchical Genetic Interactions

PubMed Central

Moore, Jason H; Amos, Ryan; Kiralis, Jeff; Andrews, Peter C

2015-01-01

Simulation plays an essential role in the development of new computational and statistical methods for the genetic analysis of complex traits. Most simulations start with a statistical model using methods such as linear or logistic regression that specify the relationship between genotype and phenotype. This is appealing due to its simplicity and because these statistical methods are commonly used in genetic analysis. It is our working hypothesis that simulations need to move beyond simple statistical models to more realistically represent the biological complexity of genetic architecture. The goal of the present study was to develop a prototype genotype–phenotype simulation method and software that are capable of simulating complex genetic effects within the context of a hierarchical biology-based framework. Specifically, our goal is to simulate multilocus epistasis or gene–gene interaction where the genetic variants are organized within the framework of one or more genes, their regulatory regions and other regulatory loci. We introduce here the Heuristic Identification of Biological Architectures for simulating Complex Hierarchical Interactions (HIBACHI) method and prototype software for simulating data in this manner. This approach combines a biological hierarchy, a flexible mathematical framework, a liability threshold model for defining disease endpoints, and a heuristic search strategy for identifying high-order epistatic models of disease susceptibility. We provide several simulation examples using genetic models exhibiting independent main effects and three-way epistatic effects. PMID:25395175

Phosphorylation of a WRKY transcription factor by MAPKs is required for pollen development and function in Arabidopsis.

PubMed

Guan, Yuefeng; Meng, Xiangzong; Khanna, Reshma; LaMontagne, Erica; Liu, Yidong; Zhang, Shuqun

2014-01-01

Plant male gametogenesis involves complex and dynamic changes in gene expression. At present, little is known about the transcription factors involved in this process and how their activities are regulated. Here, we show that a pollen-specific transcription factor, WRKY34, and its close homolog, WRKY2, are required for male gametogenesis in Arabidopsis thaliana. When overexpressed using LAT52, a strong pollen-specific promoter, epitope-tagged WRKY34 is temporally phosphorylated by MPK3 and MPK6, two mitogen-activated protein kinases (MAPKs, or MPKs), at early stages in pollen development. During pollen maturation, WRKY34 is dephosphorylated and degraded. Native promoter-driven WRKY34-YFP fusion also follows the same expression pattern at the protein level. WRKY34 functions redundantly with WRKY2 in pollen development, germination, and pollen tube growth. Loss of MPK3/MPK6 phosphorylation sites in WRKY34 compromises the function of WRKY34 in vivo. Epistasis interaction analysis confirmed that MPK6 belongs to the same genetic pathway of WRKY34 and WRKY2. Our study demonstrates the importance of temporal post-translational regulation of WRKY transcription factors in the control of developmental phase transitions in plants.

EBIC: an evolutionary-based parallel biclustering algorithm for pattern discovery.

PubMed

Orzechowski, Patryk; Sipper, Moshe; Huang, Xiuzhen; Moore, Jason H

2018-05-22

Biclustering algorithms are commonly used for gene expression data analysis. However, accurate identification of meaningful structures is very challenging and state-of-the-art methods are incapable of discovering with high accuracy different patterns of high biological relevance. In this paper a novel biclustering algorithm based on evolutionary computation, a subfield of artificial intelligence (AI), is introduced. The method called EBIC aims to detect order-preserving patterns in complex data. EBIC is capable of discovering multiple complex patterns with unprecedented accuracy in real gene expression datasets. It is also one of the very few biclustering methods designed for parallel environments with multiple graphics processing units (GPUs). We demonstrate that EBIC greatly outperforms state-of-the-art biclustering methods, in terms of recovery and relevance, on both synthetic and genetic datasets. EBIC also yields results over 12 times faster than the most accurate reference algorithms. EBIC source code is available on GitHub at https://github.com/EpistasisLab/ebic. Correspondence and requests for materials should be addressed to P.O. (email: patryk.orzechowski@gmail.com) and J.H.M. (email: jhmoore@upenn.edu). Supplementary Data with results of analyses and additional information on the method is available at Bioinformatics online.

Genetic Architecture of Hybrid Male Sterility in Drosophila: Analysis of Intraspecies Variation for Interspecies Isolation

PubMed Central

Reed, Laura K.; LaFlamme, Brooke A.; Markow, Therese A.

2008-01-01

Background The genetic basis of postzygotic isolation is a central puzzle in evolutionary biology. Evolutionary forces causing hybrid sterility or inviability act on the responsible genes while they still are polymorphic, thus we have to study these traits as they arise, before isolation is complete. Methodology/Principal Findings Isofemale strains of D. mojavensis vary significantly in their production of sterile F1 sons when females are crossed to D. arizonae males. We took advantage of the intraspecific polymorphism, in a novel design, to perform quantitative trait locus (QTL) mapping analyses directly on F1 hybrid male sterility itself. We found that the genetic architecture of the polymorphism for hybrid male sterility (HMS) in the F1 is complex, involving multiple QTL, epistasis, and cytoplasmic effects. Conclusions/Significance The role of extensive intraspecific polymorphism, multiple QTL, and epistatic interactions in HMS in this young species pair shows that HMS is arising as a complex trait in this system. Directional selection alone would be unlikely to maintain polymorphism at multiple loci, thus we hypothesize that directional selection is unlikely to be the only evolutionary force influencing postzygotic isolation. PMID:18728782

Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. II. Mapping hybrid male sterility loci on the third chromosome.

PubMed

Tao, Yun; Zeng, Zhao-Bang; Li, Jian; Hartl, Daniel L; Laurie, Cathy C

2003-08-01

Hybrid male sterility (HMS) is a rapidly evolving mechanism of reproductive isolation in Drosophila. Here we report a genetic analysis of HMS in third-chromosome segments of Drosophila mauritiana that were introgressed into a D. simulans background. Qualitative genetic mapping was used to localize 10 loci on 3R and a quantitative trait locus (QTL) procedure (multiple-interval mapping) was used to identify 19 loci on the entire chromosome. These genetic incompatibilities often show dominance and complex patterns of epistasis. Most of the HMS loci have relatively small effects and generally at least two or three of them are required to produce complete sterility. Only one small region of the third chromosome of D. mauritiana by itself causes a high level of infertility when introgressed into D. simulans. By comparison with previous studies of the X chromosome, we infer that HMS loci are only approximately 40% as dense on this autosome as they are on the X chromosome. These results are consistent with the gradual evolution of hybrid incompatibilities as a by-product of genetic divergence in allopatric populations.

Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. II. Mapping hybrid male sterility loci on the third chromosome.

PubMed Central

Tao, Yun; Zeng, Zhao-Bang; Li, Jian; Hartl, Daniel L; Laurie, Cathy C

2003-01-01

Hybrid male sterility (HMS) is a rapidly evolving mechanism of reproductive isolation in Drosophila. Here we report a genetic analysis of HMS in third-chromosome segments of Drosophila mauritiana that were introgressed into a D. simulans background. Qualitative genetic mapping was used to localize 10 loci on 3R and a quantitative trait locus (QTL) procedure (multiple-interval mapping) was used to identify 19 loci on the entire chromosome. These genetic incompatibilities often show dominance and complex patterns of epistasis. Most of the HMS loci have relatively small effects and generally at least two or three of them are required to produce complete sterility. Only one small region of the third chromosome of D. mauritiana by itself causes a high level of infertility when introgressed into D. simulans. By comparison with previous studies of the X chromosome, we infer that HMS loci are only approximately 40% as dense on this autosome as they are on the X chromosome. These results are consistent with the gradual evolution of hybrid incompatibilities as a by-product of genetic divergence in allopatric populations. PMID:12930748

The inheritance of fingerprint patterns.

PubMed

Slatis, H M; Katznelson, M B; Bonné-Tamir, B

1976-05-01

Analysis of the fingerprints of 571 members of the Habbanite isolate suggest inherited patterns and pattern sequences. A genetic theory has been developed; it assumes that the basic fingerprint pattern sequence is all ulnar loops and that a variety of genes cause deviations from this pattern sequence. Genes that have been proposed include: (1) a semidominant gene for whorls on the thumbs (one homozygote has whorls on both thumbs, the other has ulnar loops on both thumbs and the heterozygote usually has two ulnar loops or one ulnar loop and one whorl); (2) a semidominant gene for whorls on the ring fingers which acts like the gene for whorls on the thumbs; (3) a dominant gene for arches on the thumbs and often on other fingers; (4) one or more dominant genes for arches on the fingers; (5) a dominant gene for whorls on all fingers except for an ulnar loop on the middle finger; (6) a dominant gene for radial loops on the index fingers, frequently associated with an arch on the middle fingers; and (7) a recessive gene for radial loops on the ring and little fingers. These genes may act independently or may show epistasis.

The inheritance of fingerprint patterns.

PubMed Central

Slatis, H M; Katznelson, M B; Bonné-Tamir, B

1976-01-01

Analysis of the fingerprints of 571 members of the Habbanite isolate suggest inherited patterns and pattern sequences. A genetic theory has been developed; it assumes that the basic fingerprint pattern sequence is all ulnar loops and that a variety of genes cause deviations from this pattern sequence. Genes that have been proposed include: (1) a semidominant gene for whorls on the thumbs (one homozygote has whorls on both thumbs, the other has ulnar loops on both thumbs and the heterozygote usually has two ulnar loops or one ulnar loop and one whorl); (2) a semidominant gene for whorls on the ring fingers which acts like the gene for whorls on the thumbs; (3) a dominant gene for arches on the thumbs and often on other fingers; (4) one or more dominant genes for arches on the fingers; (5) a dominant gene for whorls on all fingers except for an ulnar loop on the middle finger; (6) a dominant gene for radial loops on the index fingers, frequently associated with an arch on the middle fingers; and (7) a recessive gene for radial loops on the ring and little fingers. These genes may act independently or may show epistasis. PMID:1266855

The heparan sulfate-modifying enzyme glucuronyl C5-epimerase HSE-5 controls Caenorhabditis elegans Q neuroblast polarization during migration.

PubMed

Wang, Xiangming; Liu, Jianhong; Zhu, Zhiwen; Ou, Guangshuo

2015-03-15

Directional cell migration is fundamental for neural development, and extracellular factors are pivotal for this process. Heparan sulfate proteoglycans (HSPGs) that carry long chains of differentially modified sugar residues contribute to extracellular matrix; however, the functions of HSPG in guiding cell migration remain elusive. Here, we used the Caenorhabditis elegans mutant pool from the Million Mutation Project and isolated a mutant allele of the heparan sulfate-modifying enzyme glucuronyl C5-epimerase HSE-5. Loss-of-function of this enzyme resulted in defective Q neuroblast migration. We showed that hse-5 controlled Q cell migration in a cell non-autonomous manner. By performing live cell imaging in hse-5 mutant animals, we found that hse-5 controlled initial polarization during Q neuroblast migration. Furthermore, our genetic epistasis analysis demonstrated that lon-2 might act downstream of hse-5. Finally, rescue of the hse-5 mutant phenotype by expression of human and mouse hse-5 homologs suggested a conserved function for this gene in neural development. Taken together, our results indicated that proper HSPG modification in the extracellular matrix by HSE-5 is essential for neuroblast polarity during migration. Copyright © 2015 Elsevier Inc. All rights reserved.

Parallelism and Epistasis in Skeletal Evolution Identified through Use of Phylogenomic Mapping Strategies.

PubMed

Daane, Jacob M; Rohner, Nicolas; Konstantinidis, Peter; Djuranovic, Sergej; Harris, Matthew P

2016-01-01

The identification of genetic mechanisms underlying evolutionary change is critical to our understanding of natural diversity, but is presently limited by the lack of genetic and genomic resources for most species. Here, we present a new comparative genomic approach that can be applied to a broad taxonomic sampling of nonmodel species to investigate the genetic basis of evolutionary change. Using our analysis pipeline, we show that duplication and divergence of fgfr1a is correlated with the reduction of scales within fishes of the genus Phoxinellus. As a parallel genetic mechanism is observed in scale-reduction within independent lineages of cypriniforms, our finding exposes significant developmental constraint guiding morphological evolution. In addition, we identified fixed variation in fgf20a within Phoxinellus and demonstrated that combinatorial loss-of-function of fgfr1a and fgf20a within zebrafish phenocopies the evolved scalation pattern. Together, these findings reveal epistatic interactions between fgfr1a and fgf20a as a developmental mechanism regulating skeletal variation among fishes. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Gene-Gene-Environment Interactions of Serotonin Transporter, Monoamine Oxidase A and Childhood Maltreatment Predict Aggressive Behavior in Chinese Adolescents

PubMed Central

Zhang, Yun; Ming, Qing-sen; Yi, Jin-yao; Wang, Xiang; Chai, Qiao-lian; Yao, Shu-qiao

2017-01-01

Gene-environment interactions that moderate aggressive behavior have been identified independently in the serotonin transporter (5-HTT) gene and monoamine oxidase A gene (MAOA). The aim of the present study was to investigate epistasis interactions between MAOA-variable number tandem repeat (VNTR), 5-HTTlinked polymorphism (LPR) and child abuse and the effects of these on aggressive tendencies in a group of otherwise healthy adolescents. A group of 546 Chinese male adolescents completed the Child Trauma Questionnaire and Youth self-report of the Child Behavior Checklist. Buccal cells were collected for DNA analysis. The effects of childhood abuse, MAOA-VNTR, 5-HTTLPR genotypes and their interactive gene-gene-environmental effects on aggressive behavior were analyzed using a linear regression model. The effect of child maltreatment was significant, and a three-way interaction among MAOA-VNTR, 5-HTTLPR and sexual abuse (SA) relating to aggressive behaviors was identified. Chinese male adolescents with high expression of the MAOA-VNTR allele and 5-HTTLPR “SS” genotype exhibited the highest aggression tendencies with an increase in SA during childhood. The findings reported support aggression being a complex behavior involving the synergistic effects of gene-gene-environment interactions. PMID:28203149

NWSC nickel cadmium spacecraft cell accelerated life test program data analysis

NASA Technical Reports Server (NTRS)

Lander, J.

1980-01-01

An analysis of the data leading to a proposed accelerated life test scheme to test a nickel cadmium cell under spacecraft usage conditions is described. The amount and concentration of electrolyte and the amount of precharge in the cell are discussed in relation to the design of the cell and the accelerated test design. A failure analysis of the cell is summarized. The analysis included such environmental test variables as the depth of discharge, the temperature, the amount of recharge and the charge and discharge rate.

Accelerated test design

NASA Technical Reports Server (NTRS)

Mcdermott, P. P.

1980-01-01

The design of an accelerated life test program for electric batteries is discussed. A number of observations and suggestions on the procedures and objectives for conducting an accelerated life test program are presented. Equations based on nonlinear regression analysis for predicting the accelerated life test parameters are discussed.

MAPA: Implementation of the Standard Interchange Format and use for analyzing lattices

NASA Astrophysics Data System (ADS)

Shasharina, Svetlana G.; Cary, John R.

1997-05-01

MAPA (Modular Accelerator Physics Analysis) is an object oriented application for accelerator design and analysis with a Motif based graphical user interface. MAPA has been ported to AIX, Linux, HPUX, Solaris, and IRIX. MAPA provides an intuitive environment for accelerator study and design. The user can bring up windows for fully nonlinear analysis of accelerator lattices in any number of dimensions. The current graphical analysis methods of Lifetime plots and Surfaces of Section have been used to analyze the improved lattice designs of Wan, Cary, and Shasharina (this conference). MAPA can now read and write Standard Interchange Format (MAD) accelerator description files and it has a general graphical user interface for adding, changing, and deleting elements. MAPA's consistency checks prevent deletion of used elements and prevent creation of recursive beam lines. Plans include development of a richer set of modeling tools and the ability to invoke existing modeling codes through the MAPA interface. MAPA will be demonstrated on a Pentium 150 laptop running Linux.

Choosing order of operations to accelerate strip structure analysis in parameter range

NASA Astrophysics Data System (ADS)

Kuksenko, S. P.; Akhunov, R. R.; Gazizov, T. R.

2018-05-01

The paper considers the issue of using iteration methods in solving the sequence of linear algebraic systems obtained in quasistatic analysis of strip structures with the method of moments. Using the analysis of 4 strip structures, the authors have proved that additional acceleration (up to 2.21 times) of the iterative process can be obtained during the process of solving linear systems repeatedly by means of choosing a proper order of operations and a preconditioner. The obtained results can be used to accelerate the process of computer-aided design of various strip structures. The choice of the order of operations to accelerate the process is quite simple, universal and could be used not only for strip structure analysis but also for a wide range of computational problems.

Analysis of walking variability through simultaneous evaluation of the head, lumbar, and lower-extremity acceleration in healthy youth

PubMed Central

Toda, Haruki; Nagano, Akinori; Luo, Zhiwei

2016-01-01

[Purpose] The purpose of this study was to clarify whether walking speed affects acceleration variability of the head, lumbar, and lower extremity by simultaneously evaluating of acceleration. [Subjects and Methods] Twenty young individuals recruited from among the staff at Kurashiki Heisei Hospital participated in this study. Eight accelerometers were used to measure the head, lumbar and lower extremity accelerations. The participants were instructed to walk at five walking speeds prescribed by a metronome. Acceleration variability was assessed by a cross-correlation analysis normalized using z-transform in order to evaluate stride-to-stride variability. [Results] Vertical acceleration variability was the smallest in all body parts, and walking speed effect had laterality. Antero-posterior acceleration variability was significantly associated with walking speed at sites other than the head. Medio-lateral acceleration variability of the bilateral hip alone was smaller than the antero-posterior variability. [Conclusion] The findings of this study suggest that the effect of walking speed changes on the stride-to-stride acceleration variability was individual for each body parts, and differs among directions. PMID:27390419

On accelerated flow of MHD powell-eyring fluid via homotopy analysis method

NASA Astrophysics Data System (ADS)

Salah, Faisal; Viswanathan, K. K.; Aziz, Zainal Abdul

2017-09-01

The aim of this article is to obtain the approximate analytical solution for incompressible magnetohydrodynamic (MHD) flow for Powell-Eyring fluid induced by an accelerated plate. Both constant and variable accelerated cases are investigated. Approximate analytical solution in each case is obtained by using the Homotopy Analysis Method (HAM). The resulting nonlinear analysis is carried out to generate the series solution. Finally, Graphical outcomes of different values of the material constants parameters on the velocity flow field are discussed and analyzed.

Genomic networks of hybrid sterility.

PubMed

Turner, Leslie M; White, Michael A; Tautz, Diethard; Payseur, Bret A

2014-02-01

Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci ("Dobzhansky-Muller incompatibilities"). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is difficult. With subspecies in the early stages of speciation, an array of genetic tools, and detailed knowledge of reproductive biology, house mice (Mus musculus) provide a model system for dissecting hybrid incompatibilities. Male hybrids between M. musculus subspecies often show reduced fertility. Previous studies identified loci and several X chromosome-autosome interactions that contribute to sterility. To characterize the genetic basis of hybrid sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven 'hotspots,' seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL-but not cis eQTL-were substantially lower when mapping was restricted to a 'fertile' subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. The integrated mapping approach we employed is applicable in a broad range of organisms and we advocate for widespread adoption of a network-centered approach in speciation genetics.

Predictable Phenotypes of Antibiotic Resistance Mutations.

PubMed

Knopp, M; Andersson, D I

2018-05-15

Antibiotic-resistant bacteria represent a major threat to our ability to treat bacterial infections. Two factors that determine the evolutionary success of antibiotic resistance mutations are their impact on resistance level and the fitness cost. Recent studies suggest that resistance mutations commonly show epistatic interactions, which would complicate predictions of their stability in bacterial populations. We analyzed 13 different chromosomal resistance mutations and 10 host strains of Salmonella enterica and Escherichia coli to address two main questions. (i) Are there epistatic interactions between different chromosomal resistance mutations? (ii) How does the strain background and genetic distance influence the effect of chromosomal resistance mutations on resistance and fitness? Our results show that the effects of combined resistance mutations on resistance and fitness are largely predictable and that epistasis remains rare even when up to four mutations were combined. Furthermore, a majority of the mutations, especially target alteration mutations, demonstrate strain-independent phenotypes across different species. This study extends our understanding of epistasis among resistance mutations and shows that interactions between different resistance mutations are often predictable from the characteristics of the individual mutations. IMPORTANCE The spread of antibiotic-resistant bacteria imposes an urgent threat to public health. The ability to forecast the evolutionary success of resistant mutants would help to combat dissemination of antibiotic resistance. Previous studies have shown that the phenotypic effects (fitness and resistance level) of resistance mutations can vary substantially depending on the genetic context in which they occur. We conducted a broad screen using many different resistance mutations and host strains to identify potential epistatic interactions between various types of resistance mutations and to determine the effect of strain background on resistance phenotypes. Combinations of several different mutations showed a large amount of phenotypic predictability, and the majority of the mutations displayed strain-independent phenotypes. However, we also identified a few outliers from these patterns, illustrating that the choice of host organism can be critically important when studying antibiotic resistance mutations. Copyright © 2018 Knopp and Andersson.

Genomic Networks of Hybrid Sterility

PubMed Central

Turner, Leslie M.; White, Michael A.; Tautz, Diethard; Payseur, Bret A.

2014-01-01

Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci (“Dobzhansky-Muller incompatibilities”). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is difficult. With subspecies in the early stages of speciation, an array of genetic tools, and detailed knowledge of reproductive biology, house mice (Mus musculus) provide a model system for dissecting hybrid incompatibilities. Male hybrids between M. musculus subspecies often show reduced fertility. Previous studies identified loci and several X chromosome-autosome interactions that contribute to sterility. To characterize the genetic basis of hybrid sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven ‘hotspots,’ seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL—but not cis eQTL—were substantially lower when mapping was restricted to a ‘fertile’ subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. The integrated mapping approach we employed is applicable in a broad range of organisms and we advocate for widespread adoption of a network-centered approach in speciation genetics. PMID:24586194

Genetic architecture of differences between populations of cowpea weevil (Callosobruchus maculatus) evolved in the same environment.

PubMed

Bieri, Jonas; Kawecki, Tadeusz J

2003-02-01

We investigated the genetic architecture underlying differentiation in fitness-related traits between two pairs of populations of the seed beetle Callosobruchus maculatus (Coleoptera: Bruchidae). These populations had geographically distant (> 2000 km) origins but evolved in a uniform laboratory environment for 120 generations. For each pair of populations (Nigeria x Yemen and Cameroon x Uganda) we estimated the means of five fitness-related characters and a measure of fitness (net reproductive rate R0) in each of the parental populations and 12 types of hybrids (two F1 and two F2 lines and eight backcrosses). Models containing up to nine composite genetic parameters were fitted to the means of the 14 lines. The patterns of line means for all traits in the Nigeria x Yemen cross and for four traits (larval survival, developmental rate, female body weight, and fecundity) in the Cameroon x Uganda cross were best explained by models including additive, dominance, and maternal effects, but excluding epistasis. We did not find any evidence for outbreeding depression for any trait. An epistatic component of divergence was detected for egg hatching success and R0 in the Cameroon x Uganda cross, but its sign was opposite to that expected under outbreeding depression, that is, additive x additive epistasis had a positive effect on the performance of F2 hybrids. All traits except fecundity showed a pattern of heterosis. A large difference of egg-hatching success between the two reciprocal F1 lines in that cross was best explained as fertilization incompatibility between Cameroon females and sperm carrying Uganda genes. The results suggest that these populations have not converged to the same life-history phenotype and genetic architecture, despite 120 generations of uniform natural selection. However, the absence of outbreeding depression implies that they did not evolve toward different adaptive peaks.

The common occurrence of epistasis in the determination of human pigmentation and its impact on DNA-based pigmentation phenotype prediction.

PubMed

Pośpiech, Ewelina; Wojas-Pelc, Anna; Walsh, Susan; Liu, Fan; Maeda, Hitoshi; Ishikawa, Takaki; Skowron, Małgorzata; Kayser, Manfred; Branicki, Wojciech

2014-07-01

The role of epistatic effects in the determination of complex traits is often underlined but its significance in the prediction of pigmentation phenotypes has not been evaluated so far. The prediction of pigmentation from genetic data can be useful in forensic science to describe the physical appearance of an unknown offender, victim, or missing person who cannot be identified via conventional DNA profiling. Available forensic DNA prediction systems enable the reliable prediction of several eye and hair colour categories. However, there is still space for improvement. Here we verified the association of 38 candidate DNA polymorphisms from 13 genes and explored the extent to which interactions between them may be involved in human pigmentation and their impact on forensic DNA prediction in particular. The model-building set included 718 Polish samples and the model-verification set included 307 independent Polish samples and additional 72 samples from Japan. In total, 29 significant SNP-SNP interactions were found with 5 of them showing an effect on phenotype prediction. For predicting green eye colour, interactions between HERC2 rs12913832 and OCA2 rs1800407 as well as TYRP1 rs1408799 raised the prediction accuracy expressed by AUC from 0.667 to 0.697 and increased the prediction sensitivity by >3%. Interaction between MC1R 'R' variants and VDR rs731236 increased the sensitivity for light skin by >1% and by almost 3% for dark skin colour prediction. Interactions between VDR rs1544410 and TYR rs1042602 as well as between MC1R 'R' variants and HERC2 rs12913832 provided an increase in red/non-red hair prediction accuracy from an AUC of 0.902-0.930. Our results thus underline epistasis as a common phenomenon in human pigmentation genetics and demonstrate that considering SNP-SNP interactions in forensic DNA phenotyping has little impact on eye, hair and skin colour prediction. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Improving power output of inertial energy harvesters by employing principal component analysis of input acceleration

NASA Astrophysics Data System (ADS)

Smilek, Jan; Hadas, Zdenek

2017-02-01

In this paper we propose the use of principal component analysis to process the measured acceleration data in order to determine the direction of acceleration with the highest variance on given frequency of interest. This method can be used for improving the power generated by inertial energy harvesters. Their power output is highly dependent on the excitation acceleration magnitude and frequency, but the axes of acceleration measurements might not always be perfectly aligned with the directions of movement, and therefore the generated power output might be severely underestimated in simulations, possibly leading to false conclusions about the feasibility of using the inertial energy harvester for the examined application.

Ion Beam Facilities at the National Centre for Accelerator based Research using a 3 MV Pelletron Accelerator

NASA Astrophysics Data System (ADS)

Trivedi, T.; Patel, Shiv P.; Chandra, P.; Bajpai, P. K.

A 3.0 MV (Pelletron 9 SDH 4, NEC, USA) low energy ion accelerator has been recently installed as the National Centre for Accelerator based Research (NCAR) at the Department of Pure & Applied Physics, Guru Ghasidas Vishwavidyalaya, Bilaspur, India. The facility is aimed to carried out interdisciplinary researches using ion beams with high current TORVIS (for H, He ions) and SNICS (for heavy ions) ion sources. The facility includes two dedicated beam lines, one for ion beam analysis (IBA) and other for ion implantation/ irradiation corresponding to switching magnet at +20 and -10 degree, respectively. Ions with 60 kV energy are injected into the accelerator tank where after stripping positively charged ions are accelerated up to 29 MeV for Au. The installed ion beam analysis techniques include RBS, PIXE, ERDA and channelling.

Bridging the gap between high and low acceleration for planetary escape

NASA Astrophysics Data System (ADS)

Indrikis, Janis; Preble, Jeffrey C.

With the exception of the often time consuming analysis by numerical optimization, no single orbit transfer analysis technique exists that can be applied over a wide range of accelerations. Using the simple planetary escape (parabolic trajectory) mission some of the more common techniques are considered as the limiting bastions at the high and the extremely low acceleration regimes. The brachistochrone, the minimum time of flight path, is proposed as the technique to bridge the gap between the high and low acceleration regions, providing a smooth bridge over the entire acceleration spectrum. A smooth and continuous velocity requirement is established for the planetary escape mission. By using these results, it becomes possible to determine the effect of finite accelerations on mission performance and target propulsion and power system designs which are consistent with a desired mission objective.

Generation of low-emittance electron beams in electrostatic accelerators for FEL applications

NASA Astrophysics Data System (ADS)

Chen, Teng; Elias, Luis R.

1995-02-01

This paper reports results of transverse emittance studies and beam propagation in electrostatic accelerators for free electron laser applications. In particular, we discuss emittance growth analysis of a low current electron beam system consisting of a miniature thermoionic electron gun and a National Electrostatics Accelerator (NEC) tube. The emittance growth phenomenon is discussed in terms of thermal effects in the electron gun cathode and aberrations produced by field gradient changes occurring inside the electron gun and throughout the accelerator tube. A method of reducing aberrations using a magnetic solenoidal field is described. Analysis of electron beam emittance was done with the EGUN code. Beam propagation along the accelerator tube was studied using a cylindrically symmetric beam envelope equation that included beam self-fields and the external accelerator fields which were derived from POISSON simulations.

Residual acceleration data on IML-1: Development of a data reduction and dissemination plan

NASA Technical Reports Server (NTRS)

Rogers, Melissa J. B.; Alexander, J. Iwan D.; Wolf, Randy

1992-01-01

The main thrust of our work in the third year of contract NAG8-759 was the development and analysis of various data processing techniques that may be applicable to residual acceleration data. Our goal is the development of a data processing guide that low gravity principal investigators can use to assess their need for accelerometer data and then formulate an acceleration data analysis strategy. The work focused on the flight of the first International Microgravity Laboratory (IML-1) mission. We are also developing a data base management system to handle large quantities of residual acceleration data. This type of system should be an integral tool in the detailed analysis of accelerometer data. The system will manage a large graphics data base in the support of supervised and unsupervised pattern recognition. The goal of the pattern recognition phase is to identify specific classes of accelerations so that these classes can be easily recognized in any data base. The data base management system is being tested on the Spacelab 3 (SL3) residual acceleration data.

Analysis techniques for residual acceleration data

NASA Technical Reports Server (NTRS)

Rogers, Melissa J. B.; Alexander, J. Iwan D.; Snyder, Robert S.

1990-01-01

Various aspects of residual acceleration data are of interest to low-gravity experimenters. Maximum and mean values and various other statistics can be obtained from data as collected in the time domain. Additional information may be obtained through manipulation of the data. Fourier analysis is discussed as a means of obtaining information about dominant frequency components of a given data window. Transformation of data into different coordinate axes is useful in the analysis of experiments with different orientations and can be achieved by the use of a transformation matrix. Application of such analysis techniques to residual acceleration data provides additional information than what is provided in a time history and increases the effectiveness of post-flight analysis of low-gravity experiments.

Revealing evolutionary pathways by fitness landscape reconstruction.

PubMed

Kogenaru, Manjunatha; de Vos, Marjon G J; Tans, Sander J

2009-01-01

The concept of epistasis has since long been used to denote non-additive fitness effects of genetic changes and has played a central role in understanding the evolution of biological systems. Owing to an array of novel experimental methodologies, it has become possible to experimentally determine epistatic interactions as well as more elaborate genotype-fitness maps. These data have opened up the investigation of a host of long-standing questions in evolutionary biology, such as the ruggedness of fitness landscapes and the accessibility of mutational trajectories, the evolution of sex, and the origin of robustness and modularity. Here we review this recent and timely marriage between systems biology and evolutionary biology, which holds the promise to understand evolutionary dynamics in a more mechanistic and predictive manner.

Kernel machine SNP set analysis provides new insight into the association between obesity and polymorphisms located on the chromosomal 16q.12.2 region: Tehran Lipid and Glucose Study.

PubMed

Javanrouh, Niloufar; Daneshpour, Maryam S; Soltanian, Ali Reza; Tapak, Leili

2018-06-05

Obesity is a serious health problem that leads to low quality of life and early mortality. To the purpose of prevention and gene therapy for such a worldwide disease, genome wide association study is a powerful tool for finding SNPs associated with increased risk of obesity. To conduct an association analysis, kernel machine regression is a generalized regression method, has an advantage of considering the epistasis effects as well as the correlation between individuals due to unknown factors. In this study, information of the people who participated in Tehran cardio-metabolic genetic study was used. They were genotyped for the chromosomal region, evaluation 986 variations located at 16q12.2; build 38hg. Kernel machine regression and single SNP analysis were used to assess the association between obesity and SNPs genotyped data. We found that associated SNP sets with obesity, were almost in the FTO (P = 0.01), AIKTIP (P = 0.02) and MMP2 (P = 0.02) genes. Moreover, two SNPs, i.e., rs10521296 and rs11647470, showed significant association with obesity using kernel regression (P = 0.02). In conclusion, significant sets were randomly distributed throughout the region with more density around the FTO, AIKTIP and MMP2 genes. Furthermore, two intergenic SNPs showed significant association after using kernel machine regression. Therefore, more studies have to be conducted to assess their functionality or precise mechanism. Copyright © 2018 Elsevier B.V. All rights reserved.

The Interactions between the Long Non-coding RNA NERDL and Its Target Gene Affect Wood Formation in Populus tomentosa

PubMed Central

Shi, Wan; Quan, Mingyang; Du, Qingzhang; Zhang, Deqiang

2017-01-01

Long non-coding RNAs (lncRNAs) are important regulatory factors for plant growth and development, but little is known about the allelic interactions of lncRNAs with mRNA in perennial plants. Here, we analyzed the interaction of the NERD (Needed for RDR2-independent DNA methylation) Populus tomentosa gene PtoNERD with its putative regulator, the lncRNA NERDL (NERD-related lncRNA), which partially overlaps with the promoter region of this gene. Expression analysis in eight tissues showed a positive correlation between NERDL and PtoNERD (r = 0.62), suggesting that the interaction of NERDL with its putative target might be involved in wood formation. We conducted association mapping in a natural population of P. tomentosa (435 unrelated individuals) to evaluate genetic variation and the interaction of the lncRNA NERDL with PtoNERD. Using additive and dominant models, we identified 30 SNPs (P < 0.01) associated with five tree growth and wood property traits. Each SNP explained 3.90–8.57% of phenotypic variance, suggesting that NERDL and its putative target play a common role in wood formation. Epistasis analysis uncovered nine SNP-SNP association pairs between NERDL and PtoNERD, with an information gain of -7.55 to 2.16%, reflecting the strong interactions between NERDL and its putative target. This analysis provides a powerful method for deciphering the genetic interactions of lncRNAs with mRNA and dissecting the complex genetic network of quantitative traits in trees. PMID:28674544

Multi-location wheat stripe rust QTL analysis: genetic background and epistatic interactions.

PubMed

Vazquez, M Dolores; Zemetra, Robert; Peterson, C James; Chen, Xianming M; Heesacker, Adam; Mundt, Christopher C

2015-07-01

Epistasis and genetic background were important influences on expression of stripe rust resistance in two wheat RIL populations, one with resistance conditioned by two major genes and the other conditioned by several minor QTL. Stripe rust is a foliar disease of wheat (Triticum aestivum L.) caused by the air-borne fungus Puccinia striiformis f. sp. tritici and is present in most regions around the world where commercial wheat is grown. Breeding for durable resistance to stripe rust continues to be a priority, but also is a challenge due to the complexity of interactions among resistance genes and to the wide diversity and continuous evolution of the pathogen races. The goal of this study was to detect chromosomal regions for resistance to stripe rust in two winter wheat populations, 'Tubbs'/'NSA-98-0995' (T/N) and 'Einstein'/'Tubbs' (E/T), evaluated across seven environments and mapped with diversity array technology and simple sequence repeat markers covering polymorphic regions of ≈1480 and 1117 cM, respectively. Analysis of variance for phenotypic data revealed significant (P < 0.01) genotypic differentiation for stripe rust among the recombinant inbred lines. Results for quantitative trait loci/locus (QTL) analysis in the E/T population indicated that two major QTL located in chromosomes 2AS and 6AL, with epistatic interaction between them, were responsible for the main phenotypic response. For the T/N population, eight QTL were identified, with those in chromosomes 2AL and 2BL accounting for the largest percentage of the phenotypic variance.

QALMA: A computational toolkit for the analysis of quality protocols for medical linear accelerators in radiation therapy

NASA Astrophysics Data System (ADS)

Rahman, Md Mushfiqur; Lei, Yu; Kalantzis, Georgios

2018-01-01

Quality Assurance (QA) for medical linear accelerator (linac) is one of the primary concerns in external beam radiation Therapy. Continued advancements in clinical accelerators and computer control technology make the QA procedures more complex and time consuming which often, adequate software accompanied with specific phantoms is required. To ameliorate that matter, we introduce QALMA (Quality Assurance for Linac with MATLAB), a MALAB toolkit which aims to simplify the quantitative analysis of QA for linac which includes Star-Shot analysis, Picket Fence test, Winston-Lutz test, Multileaf Collimator (MLC) log file analysis and verification of light & radiation field coincidence test.

A new perspective on global mean sea level (GMSL) acceleration

NASA Astrophysics Data System (ADS)

Watson, Phil J.

2016-06-01

The vast body of contemporary climate change science is largely underpinned by the premise of a measured acceleration from anthropogenic forcings evident in key climate change proxies -- greenhouse gas emissions, temperature, and mean sea level. By virtue, over recent years, the issue of whether or not there is a measurable acceleration in global mean sea level has resulted in fierce, widespread professional, social, and political debate. Attempts to measure acceleration in global mean sea level (GMSL) have often used comparatively crude analysis techniques providing little temporal instruction on these key questions. This work proposes improved techniques to measure real-time velocity and acceleration based on five GMSL reconstructions spanning the time frame from 1807 to 2014 with substantially improved temporal resolution. While this analysis highlights key differences between the respective reconstructions, there is now more robust, convincing evidence of recent acceleration in the trend of GMSL.

CEACAM6 Gene Variants in Inflammatory Bowel Disease

PubMed Central

Fries, Christoph; Tillack, Cornelia; Pfennig, Simone; Weidinger, Maria; Beigel, Florian; Olszak, Torsten; Lass, Ulrich; Göke, Burkhard; Ochsenkühn, Thomas; Wolf, Christiane; Lohse, Peter; Müller-Myhsok, Bertram; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

2011-01-01

Background The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn's disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD). Methodology In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC), and 1,350 healthy, unrelated controls) was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839). In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. Conclusions This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment. PMID:21559399

Association genetics and transcriptome analysis reveal a gibberellin-responsive pathway involved in regulating photosynthesis.

PubMed

Xie, Jianbo; Tian, Jiaxing; Du, Qingzhang; Chen, Jinhui; Li, Ying; Yang, Xiaohui; Li, Bailian; Zhang, Deqiang

2016-05-01

Gibberellins (GAs) regulate a wide range of important processes in plant growth and development, including photosynthesis. However, the mechanism by which GAs regulate photosynthesis remains to be understood. Here, we used multi-gene association to investigate the effect of genes in the GA-responsive pathway, as constructed by RNA sequencing, on photosynthesis, growth, and wood property traits, in a population of 435 Populus tomentosa By analyzing changes in the transcriptome following GA treatment, we identified many key photosynthetic genes, in agreement with the observed increase in measurements of photosynthesis. Regulatory motif enrichment analysis revealed that 37 differentially expressed genes related to photosynthesis shared two essential GA-related cis-regulatory elements, the GA response element and the pyrimidine box. Thus, we constructed a GA-responsive pathway consisting of 47 genes involved in regulating photosynthesis, including GID1, RGA, GID2, MYBGa, and 37 photosynthetic differentially expressed genes. Single nucleotide polymorphism (SNP)-based association analysis showed that 142 SNPs, representing 40 candidate genes in this pathway, were significantly associated with photosynthesis, growth, and wood property traits. Epistasis analysis uncovered interactions between 310 SNP-SNP pairs from 37 genes in this pathway, revealing possible genetic interactions. Moreover, a structural gene-gene matrix based on a time-course of transcript abundances provided a better understanding of the multi-gene pathway affecting photosynthesis. The results imply a functional role for these genes in mediating photosynthesis, growth, and wood properties, demonstrating the potential of combining transcriptome-based regulatory pathway construction and genetic association approaches to detect the complex genetic networks underlying quantitative traits. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Identification of stable QTLs causing chalk in rice grains in nine environments.

PubMed

Zhao, Xiangqian; Daygon, Venea D; McNally, Kenneth L; Hamilton, Ruaraidh Sackville; Xie, Fangming; Reinke, Russell F; Fitzgerald, Melissa A

2016-01-01

A novel QTL cluster for chalkiness on Chr04 was identified using single environment analysis and joint mapping across 9 environments in Asia and South American. QTL NILs showed that each had a significant effect on chalk. Chalk in rice grains leads to a significant loss in the proportion of marketable grains in a harvested crop, leading to a significant financial loss to rice farmers and traders. To identify the genetic basis of chalkiness, two sets of recombinant inbred lines (RILs) derived from reciprocal crosses between Lemont and Teqing were used to find stable QTLs for chalkiness. The RILs were grown in seven locations in Asia and Latin American and in two controlled environments in phytotrons. A total of 32 (21) and 46 (22) QTLs for DEC and PGWC, most of them explaining more than 10% of phenotypic variation, were detected based on single environment analysis in T/L (L/T) population, respectively. Seven (2) and 7 (3) QTLs for DEC and PGWC were identified in the T/L (L/T) population using joined analysis across all environments, respectively. Six major QTLs clusters were found on five chromosomes: 1, 2, 4, 5 and 11. The biggest cluster at id4007289-RM252 on Chr04 was a novelty, including 16 and 4 QTLs detected by single environment analysis and joint mapping across all environments, respectively. The detected digenic epistatic QTLs explained up to 13% of phenotypic variation, suggesting that epistasis play an important role in the genetic control of chalkiness in rice. QTL NILs showed that each QTL cluster had a significant effect on chalk. These chromosomal regions could be targets for MAS, fine mapping and map-based cloning for low chalkiness breeding.

Vibration environment - Acceleration mapping strategy and microgravity requirements for Spacelab and Space Station

NASA Technical Reports Server (NTRS)

Martin, Gary L.; Baugher, Charles R.; Delombard, Richard

1990-01-01

In order to define the acceleration requirements for future Shuttle and Space Station Freedom payloads, methods and hardware characterizing accelerations on microgravity experiment carriers are discussed. The different aspects of the acceleration environment and the acceptable disturbance levels are identified. The space acceleration measurement system features an adjustable bandwidth, wide dynamic range, data storage, and ability to be easily reconfigured and is expected to fly on the Spacelab Life Sciences-1. The acceleration characterization and analysis project describes the Shuttle acceleration environment and disturbance mechanisms, and facilitates the implementation of the microgravity research program.

WarpIV: In situ visualization and analysis of ion accelerator simulations

DOE PAGES

Rubel, Oliver; Loring, Burlen; Vay, Jean -Luc; ...

2016-05-09

The generation of short pulses of ion beams through the interaction of an intense laser with a plasma sheath offers the possibility of compact and cheaper ion sources for many applications--from fast ignition and radiography of dense targets to hadron therapy and injection into conventional accelerators. To enable the efficient analysis of large-scale, high-fidelity particle accelerator simulations using the Warp simulation suite, the authors introduce the Warp In situ Visualization Toolkit (WarpIV). WarpIV integrates state-of-the-art in situ visualization and analysis using VisIt with Warp, supports management and control of complex in situ visualization and analysis workflows, and implements integrated analyticsmore » to facilitate query- and feature-based data analytics and efficient large-scale data analysis. WarpIV enables for the first time distributed parallel, in situ visualization of the full simulation data using high-performance compute resources as the data is being generated by Warp. The authors describe the application of WarpIV to study and compare large 2D and 3D ion accelerator simulations, demonstrating significant differences in the acceleration process in 2D and 3D simulations. WarpIV is available to the public via https://bitbucket.org/berkeleylab/warpiv. The Warp In situ Visualization Toolkit (WarpIV) supports large-scale, parallel, in situ visualization and analysis and facilitates query- and feature-based analytics, enabling for the first time high-performance analysis of large-scale, high-fidelity particle accelerator simulations while the data is being generated by the Warp simulation suite. Furthermore, this supplemental material https://extras.computer.org/extra/mcg2016030022s1.pdf provides more details regarding the memory profiling and optimization and the Yee grid recentering optimization results discussed in the main article.« less

Inertial Mass Viewed as Reaction of the Vacuum to Accelerated Motion

NASA Technical Reports Server (NTRS)

Rueda, Alfonso; Haisch, Bernhard

1999-01-01

Preliminary analysis of the momentum flux (or of the Poynting vector) of the classical electromagnetic version of the quantum vacuum consisting of zero-point radiation impinging on accelerated objects as viewed by an inertial observer suggests that the resistance to acceleration attributed to inertia may be a force of opposition originating in the vacuum. This analysis avoids the ad hoc modeling of particle-field interaction dynamics used previously by Haisck Rueda and Puthoff (1994) to derive a similar result. This present approach is not dependent upon what happens at the particle point but on how an external observer assesses the kinematical characteristics of the zero-point radiation impinging on the accelerated object. A relativistic form of the equation of motion results from the present analysis.

Accelerated test plan for nickel cadmium spacecraft batteries

NASA Technical Reports Server (NTRS)

Hennigan, T. J.

1973-01-01

An accelerated test matrix is outlined that includes acceptance, baseline and post-cycling tests, chemical and physical analyses, and the data analysis procedures to be used in determining the feasibility of an accelerated test for sealed, nickel cadmium cells.

Exceedance statistics of accelerations resulting from thruster firings on the Apollo-Soyuz mission

NASA Technical Reports Server (NTRS)

Fichtl, G. H.; Holland, R. L.

1981-01-01

Spacecraft acceleration resulting from firings of vernier control system thrusters is an important consideration in the design, planning, execution and post-flight analysis of laboratory experiments in space. In particular, scientists and technologists involved with the development of experiments to be performed in space in many instances required statistical information on the magnitude and rate of occurrence of spacecraft accelerations. Typically, these accelerations are stochastic in nature, so that it is useful to characterize these accelerations in statistical terms. Statistics of spacecraft accelerations are summarized.

International Space Station Increment-2 Microgravity Environment Summary Report

NASA Technical Reports Server (NTRS)

Jules, Kenol; Hrovat, Kenneth; Kelly, Eric; McPherson, Kevin; Reckart, Timothy

2002-01-01

This summary report presents the results of some of the processed acceleration data, collected aboard the International Space Station during the period of May to August 2001, the Increment-2 phase of the station. Two accelerometer systems were used to measure the acceleration levels during activities that took place during the Increment-2 segment. However, not all of the activities were analyzed for this report due to time constraints, lack of precise information regarding some payload operations and other station activities. The National Aeronautics and Space Administration sponsors the Microgravity Acceleration Measurement System and the Space Acceleration Microgravity System to support microgravity science experiments, which require microgravity acceleration measurements. On April 19, 2001, both the Microgravity Acceleration Measurement System and the Space Acceleration Measurement System units were launched on STS-100 from the Kennedy Space Center for installation on the International Space Station. The Microgravity Acceleration Measurement System unit was flown to the station in support of science experiments requiring quasi-steady acceleration measurements, while the Space Acceleration Measurement System unit was flown to support experiments requiring vibratory acceleration measurement. Both acceleration systems are also used in support of vehicle microgravity requirements verification. The International Space Station Increment-2 reduced gravity environment analysis presented in this report uses acceleration data collected by both sets of accelerometer systems: 1) The Microgravity Acceleration Measurement System, which consists of two sensors: the Orbital Acceleration Research Experiment Sensor Subsystem, a low frequency range sensor (up to 1 Hz), is used to characterize the quasi-steady environment for payloads and the vehicle, and the High Resolution Accelerometer Package, which is used to characterize the vibratory environment up to 100 Hz. 2) The Space Acceleration Measurement System, which is a high frequency sensor, measures vibratory acceleration data in the range of 0.01 to 300 Hz. This summary report presents analysis of some selected quasisteady and vibratory activities measured by these accelerometers during Increment-2 from May to August 20, 2001.

International Space Station Increment-3 Microgravity Environment Summary Report

NASA Technical Reports Server (NTRS)

Jules, Kenol; Hrovat, Kenneth; Kelly, Eric; McPherson, Kevin; Reckart, Timothy; Grodsinksy, Carlos

2002-01-01

This summary report presents the results of some of the processed acceleration data measured aboard the International Space Station during the period of August to December 2001. Two accelerometer systems were used to measure the acceleration levels for the activities that took place during Increment-3. However, not all of the activities were analyzed for this report due to time constraint and lack of precise timeline information regarding some payload operations and station activities. The National Aeronautics and Space Administration sponsors the Microgravity Acceleration Measurement System and the Space Acceleration Microgravity System to support microgravity science experiments which require microgravity acceleration measurements. On April 19, 2001, both the Microgravity Acceleration Measurement System and the Space Acceleration Measurement System units were launched on STS-100 from the Kennedy Space Center for installation on the International Space Station. The Microgravity Acceleration Measurement System unit was flown to the station in support of science experiments requiring quasi-steady acceleration measurements, while the Space Acceleration Measurement System unit was flown to support experiments requiring vibratory acceleration measurement. Both acceleration systems are also used in support of the vehicle microgravity requirements verification. The International Space Station Increment-3 reduced gravity environment analysis presented in this report uses acceleration data collected by both sets of accelerometer systems: (1) The Microgravity Acceleration Measurement System, which consists of two sensors: the Orbital Acceleration Research Experiment Sensor Subsystem, a low frequency range sensor (up to 1 Hz), is used to characterize the quasi-steady environment for payloads and vehicle, and the High Resolution Accelerometer Package, which is used to characterize the vibratory environment up to 100 Hz. (2) The Space Acceleration Measurement System, which is a high frequency sensor, measures vibratory acceleration data in the range of 0.01 to 400 Hz. This summary report presents analysis of some selected quasi-steady and vibratory activities measured by these accelerometers during Increment-3 from August to December, 2001.

Measurement Model and Precision Analysis of Accelerometers for Maglev Vibration Isolation Platforms.

PubMed

Wu, Qianqian; Yue, Honghao; Liu, Rongqiang; Zhang, Xiaoyou; Ding, Liang; Liang, Tian; Deng, Zongquan

2015-08-14

High precision measurement of acceleration levels is required to allow active control for vibration isolation platforms. It is necessary to propose an accelerometer configuration measurement model that yields such a high measuring precision. In this paper, an accelerometer configuration to improve measurement accuracy is proposed. The corresponding calculation formulas of the angular acceleration were derived through theoretical analysis. A method is presented to minimize angular acceleration noise based on analysis of the root mean square noise of the angular acceleration. Moreover, the influence of installation position errors and accelerometer orientation errors on the calculation precision of the angular acceleration is studied. Comparisons of the output differences between the proposed configuration and the previous planar triangle configuration under the same installation errors are conducted by simulation. The simulation results show that installation errors have a relatively small impact on the calculation accuracy of the proposed configuration. To further verify the high calculation precision of the proposed configuration, experiments are carried out for both the proposed configuration and the planar triangle configuration. On the basis of the results of simulations and experiments, it can be concluded that the proposed configuration has higher angular acceleration calculation precision and can be applied to different platforms.

Measurement Model and Precision Analysis of Accelerometers for Maglev Vibration Isolation Platforms

PubMed Central

Wu, Qianqian; Yue, Honghao; Liu, Rongqiang; Zhang, Xiaoyou; Ding, Liang; Liang, Tian; Deng, Zongquan

2015-01-01

High precision measurement of acceleration levels is required to allow active control for vibration isolation platforms. It is necessary to propose an accelerometer configuration measurement model that yields such a high measuring precision. In this paper, an accelerometer configuration to improve measurement accuracy is proposed. The corresponding calculation formulas of the angular acceleration were derived through theoretical analysis. A method is presented to minimize angular acceleration noise based on analysis of the root mean square noise of the angular acceleration. Moreover, the influence of installation position errors and accelerometer orientation errors on the calculation precision of the angular acceleration is studied. Comparisons of the output differences between the proposed configuration and the previous planar triangle configuration under the same installation errors are conducted by simulation. The simulation results show that installation errors have a relatively small impact on the calculation accuracy of the proposed configuration. To further verify the high calculation precision of the proposed configuration, experiments are carried out for both the proposed configuration and the planar triangle configuration. On the basis of the results of simulations and experiments, it can be concluded that the proposed configuration has higher angular acceleration calculation precision and can be applied to different platforms. PMID:26287203

Combining ability for yield and fruit quality in the pepper Capsicum annuum.

PubMed

do Nascimento, N F F; do Rêgo, E R; Nascimento, M F; Bruckner, C H; Finger, F L; do Rêgo, M M

2014-04-29

The objective of this study was to determine the effects of the general and specific combining abilities (GCA and SCA, respectively) of 15 characteristics and to evaluate the most promising crosses and the reciprocal effect between the hybrids of six parents of the Capsicum annuum species. Six parents, belonging to the Horticultural Germplasm Bank of Centro de Ciências Agrárias of Universidade Federal da Paraíba, were crossed in complete diallel manner. The 30 hybrids generated and the parents were then analyzed in a completely randomized design with three replicates. The data were submitted to analysis of variance at 1% probability, and the means were grouped by the Scott-Knott test at 1% probability. The diallel analysis was performed according to the Griffing method, model I and fixed model. Both additive and non-additive effects influenced the hybrids' performance, as indicated by the GCA/SCA ratio. The non-additive effects, epistasis and/or dominance, played a more important role than the additive effects in pedicel length, pericarp thickness, fresh matter, dry matter content, seed yield per fruit, fruit yield per plant, days to fructification, and total soluble solids. The GCA effects were more important than the SCA effects in the fruit weight, fruit length and diameter, placenta length, yield, vitamin C, and titratable acidity characteristics. The results found here clearly show that ornamental pepper varieties can be developed through hybridization in breeding programs with C. annuum.

Identification of additive, dominant, and epistatic variation conferred by key genes in cellulose biosynthesis pathway in Populus tomentosa†

PubMed Central

Du, Qingzhang; Tian, Jiaxing; Yang, Xiaohui; Pan, Wei; Xu, Baohua; Li, Bailian; Ingvarsson, Pär K.; Zhang, Deqiang

2015-01-01

Economically important traits in many species generally show polygenic, quantitative inheritance. The components of genetic variation (additive, dominant and epistatic effects) of these traits conferred by multiple genes in shared biological pathways remain to be defined. Here, we investigated 11 full-length genes in cellulose biosynthesis, on 10 growth and wood-property traits, within a population of 460 unrelated Populus tomentosa individuals, via multi-gene association. To validate positive associations, we conducted single-marker analysis in a linkage population of 1,200 individuals. We identified 118, 121, and 43 associations (P< 0.01) corresponding to additive, dominant, and epistatic effects, respectively, with low to moderate proportions of phenotypic variance (R2). Epistatic interaction models uncovered a combination of three non-synonymous sites from three unique genes, representing a significant epistasis for diameter at breast height and stem volume. Single-marker analysis validated 61 associations (false discovery rate, Q ≤ 0.10), representing 38 SNPs from nine genes, and its average effect (R2 = 3.8%) nearly 2-fold higher than that identified with multi-gene association, suggesting that multi-gene association can capture smaller individual variants. Moreover, a structural gene–gene network based on tissue-specific transcript abundances provides a better understanding of the multi-gene pathway affecting tree growth and lignocellulose biosynthesis. Our study highlights the importance of pathway-based multiple gene associations to uncover the nature of genetic variance for quantitative traits and may drive novel progress in molecular breeding. PMID:25428896

The Genetics of Resistance to Morinda Fruit Toxin During the Postembryonic Stages in Drosophila sechellia

PubMed Central

Huang, Yan; Erezyilmaz, Deniz

2015-01-01

Although a great deal has been learned regarding the genetic changes that give rise to adaptation in bacteria and yeast, an understanding of how new complex traits arise in multicellular organisms is far less complete. Many phytophagous insect species are ecological specialists that have adapted to utilize a single host plant. Drosophila sechellia is a specialist that utilizes the ripe fruit of Morinda citrifolia, which is toxic to its sibling species, D. simulans. Here we apply multiplexed shotgun genotyping and QTL analysis to examine the genetic basis of resistance to M. citrifolia fruit toxin in interspecific hybrids. We identify a locus of large effect on the third chromosome (QTL-IIIsima) in the D. simulans backcross that was not detected in previous analyses. We also identify a highly significant QTL of large effect on the X chromosome, QTL-Xsim. Additional smaller-effect loci were also identified in the D. simulans and D. sechellia backcrosses. We did not detect significant epistasis between loci. Instead, our analysis reveals large and smaller-effect loci that contribute to M. citrifolia resistance additively. The additive effect of each locus suggests that partial resistance to lower levels of M. citrifolia toxin could be passed through introgression from D. sechellia to D. simulans in nature. The identification of the major effect loci, QTL-IIIsima and QTL-Xsim, is an important step toward identifying the molecular basis of adaptation in a multicellular organism. PMID:26224784

Identification and allelic dissection uncover roles of lncRNAs in secondary growth of Populus tomentosa.

PubMed

Zhou, Daling; Du, Qingzhang; Chen, Jinhui; Wang, Qingshi; Zhang, Deqiang

2017-10-01

Long non-coding RNAs (lncRNAs) function in various biological processes. However, their roles in secondary growth of plants remain poorly understood. Here, 15,691 lncRNAs were identified from vascular cambium, developing xylem, and mature xylem of Populus tomentosa with high and low biomass using RNA-seq, including 1,994 lncRNAs that were differentially expressed (DE) among the six libraries. 3,569 cis-regulated and 3,297 trans-regulated protein-coding genes were predicted as potential target genes (PTGs) of the DE lncRNAs to participate in biological regulation. Then, 476 and 28 lncRNAs were identified as putative targets and endogenous target mimics (eTMs) of Populus known microRNAs (miRNAs), respectively. Genome re-sequencing of 435 individuals from a natural population of P. tomentosa found 34,015 single nucleotide polymorphisms (SNPs) within 178 lncRNA loci and 522 PTGs. Single-SNP associations analysis detected 2,993 associations with 10 growth and wood-property traits under additive and dominance model. Epistasis analysis identified 17,656 epistatic SNP pairs, providing evidence for potential regulatory interactions between lncRNAs and their PTGs. Furthermore, a reconstructed epistatic network, representing interactions of 8 lncRNAs and 15 PTGs, might enrich regulation roles of genes in the phenylpropanoid pathway. These findings may enhance our understanding of non-coding genes in plants. © The Author 2017. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

A missense allele of KARRIKIN-INSENSITIVE2 impairs ligand-binding and downstream signaling in Arabidopsis thaliana.

PubMed

Lee, Inhye; Kim, Kuglae; Lee, Sumin; Lee, Seungjun; Hwang, Eunjin; Shin, Kihye; Kim, Dayoung; Choi, Jungki; Choi, Hyunmo; Cha, Jeong Seok; Kim, Hoyoung; Lee, Rin-A; Jeong, Suyeong; Kim, Jeongsik; Kim, Yumi; Nam, Hong Gil; Park, Soon-Ki; Cho, Hyun-Soo; Soh, Moon-Soo

2018-06-27

A smoke-derived compound, karrikin (KAR), and an endogenous but as yet unidentified KARRIKIN INSENSITIVE2 (KAI2) ligand (KL) have been identified as chemical cues in higher plants that impact on multiple aspects of growth and development. Genetic screening of light-signaling mutants in Arabidopsis thaliana has identified a mutant designated as ply2 (pleiotropic long hypocotyl2) that has pleiotropic light-response defects. In this study, we used positional cloning to identify the molecular lesion of ply2 as a missense mutation of KAI2/HYPOSENSITIVE TO LIGHT, which causes a single amino acid substitution, Ala219Val. Physiological analysis and genetic epistasis analysis with the KL-signaling components MORE AXILLARY GROWTH2 (MAX2) and SUPPRESSOR OF MAX2 1 suggested that the pleiotropic phenotypes of the ply2 mutant can be ascribed to a defect in KL-signaling. Molecular and biochemical analyses revealed that the mutant KAI2ply2 protein is impaired in its ligand-binding activity. In support of this conclusion, X-ray crystallography studies suggested that the KAI2ply2 mutation not only results in a narrowed entrance gate for the ligand but also alters the structural flexibility of the helical lid domains. We discuss the structural implications of the Ala219 residue with regard to ligand-specific binding and signaling of KAI2, together with potential functions of KL-signaling in the context of the light-regulatory network in Arabidopsis thaliana.

Can superhorizon cosmological perturbations explain the acceleration of the universe?

NASA Astrophysics Data System (ADS)

Hirata, Christopher M.; Seljak, Uroš

2005-10-01

We investigate the recent suggestions by Barausse et al. and Kolb et al. that the acceleration of the universe could be explained by large superhorizon fluctuations generated by inflation. We show that no acceleration can be produced by this mechanism. We begin by showing how the application of Raychaudhuri equation to inhomogeneous cosmologies results in several “no go” theorems for accelerated expansion. Next we derive an exact solution for a specific case of initial perturbations, for which application of the Kolb et al. expressions leads to an acceleration, while the exact solution reveals that no acceleration is present. We show that the discrepancy can be traced to higher-order terms that were dropped in the Kolb et al. analysis. We proceed with the analysis of initial value formulation of general relativity to argue that causality severely limits what observable effects can be derived from superhorizon perturbations. By constructing a Riemann normal coordinate system on initial slice we show that no infrared divergence terms arise in this coordinate system. Thus any divergences found previously can be eliminated by a local rescaling of coordinates and are unobservable. We perform an explicit analysis of the variance of the deceleration parameter for the case of single-field inflation using usual coordinates and show that the infrared-divergent terms found by Barausse et al. and Kolb et al. cancel against several additional terms not considered in their analysis. Finally, we argue that introducing isocurvature perturbations does not alter our conclusion that the accelerating expansion of the universe cannot be explained by superhorizon modes.

Combining Acceleration and Displacement Dependent Modal Frequency Responses Using an MSC/NASTRAN DMAP Alter

NASA Technical Reports Server (NTRS)

Barnett, Alan R.; Widrick, Timothy W.; Ludwiczak, Damian R.

1996-01-01

Solving for dynamic responses of free-free launch vehicle/spacecraft systems acted upon by buffeting winds is commonly performed throughout the aerospace industry. Due to the unpredictable nature of this wind loading event, these problems are typically solved using frequency response random analysis techniques. To generate dynamic responses for spacecraft with statically-indeterminate interfaces, spacecraft contractors prefer to develop models which have response transformation matrices developed for mode acceleration data recovery. This method transforms spacecraft boundary accelerations and displacements into internal responses. Unfortunately, standard MSC/NASTRAN modal frequency response solution sequences cannot be used to combine acceleration- and displacement-dependent responses required for spacecraft mode acceleration data recovery. External user-written computer codes can be used with MSC/NASTRAN output to perform such combinations, but these methods can be labor and computer resource intensive. Taking advantage of the analytical and computer resource efficiencies inherent within MS C/NASTRAN, a DMAP Alter has been developed to combine acceleration- and displacement-dependent modal frequency responses for performing spacecraft mode acceleration data recovery. The Alter has been used successfully to efficiently solve a common aerospace buffeting wind analysis.

Pics d'accélération du mouvement sismique observés lors du séisme de Chichi à Taiwan : application à l'estimation de l'aléa sismiqueAnalysis of peak ground accelerations during the Chichi earthquake, Taiwan: application to seismic hazard evaluation

NASA Astrophysics Data System (ADS)

Chang, Tsui-Yu; Cotton, Fabrice; Angelier, Jacques; Shin, Tzay-Chyn

2001-07-01

Attenuation laws are widely used in order to estimate the peak ground acceleration that may occur at a given locality during an earthquake, for hazard evaluation purposes. However, these simplified laws should be regarded acceptable only in the first approximation, because numerous significant parameters at the local and regional scales are often ignored. We examined the relationship between distance and peak acceleration based on examples from the dense accelerometric network of Taiwan, specifically for the Chichi destructive earthquake. We thus observed significant discrepancies between the predicted and observed accelerations, resulting from (1) near-field saturation, (2) amplification in sedimentary basins, and (3) hanging wall effect. We mapped the residual accelerations (difference between observed and predicted peak ground accelerations). This highlights the role of the regional structure, independently revealed by the geological analysis, as a significant factor that controls the transmission of the seismic accelerations.

Detecting chaos in particle accelerators through the frequency map analysis method.

PubMed

Papaphilippou, Yannis

2014-06-01

The motion of beams in particle accelerators is dominated by a plethora of non-linear effects, which can enhance chaotic motion and limit their performance. The application of advanced non-linear dynamics methods for detecting and correcting these effects and thereby increasing the region of beam stability plays an essential role during the accelerator design phase but also their operation. After describing the nature of non-linear effects and their impact on performance parameters of different particle accelerator categories, the theory of non-linear particle motion is outlined. The recent developments on the methods employed for the analysis of chaotic beam motion are detailed. In particular, the ability of the frequency map analysis method to detect chaotic motion and guide the correction of non-linear effects is demonstrated in particle tracking simulations but also experimental data.

Development of dual-beam system using an electrostatic accelerator for in-situ observation of swift heavy ion irradiation effects on materials

NASA Astrophysics Data System (ADS)

Matsuda, M.; Asozu, T.; Sataka, M.; Iwase, A.

2013-11-01

We have developed the dual beam system which accelerates two kinds of ion beams simultaneously especially for real-time ion beam analysis. We have also developed the alternating beam system which can efficiently change beam species in a short time in order to realize efficient ion beam analysis in a limited beam time. The acceleration of the dual beam is performed by the 20 UR Pelletron™ tandem accelerator in which an ECR ion source is mounted at the high voltage terminal [1,2]. The multi-charged ions of two or more elements can be simultaneously generated from the ECR ion source, so dual-beam irradiation is achieved by accelerating ions with the same charge to mass ratio (for example, 132Xe11+ and 12C+). It enables us to make a real-time beam analysis such as Rutherford Back Scattering (RBS) method, while a target is irradiated with swift heavy ions. For the quick change of the accelerating ion beam, the program of automatic setting of the optical parameter of the accelerator has been developed. The switchover time for changing the ion beam is about 5 min. These developments have been applied to the study on the ion beam mixing caused by high-density electronic excitation induced by swift heavy ions.

Development of the Accelerator Mass Spectrometry technology at the Comenius University in Bratislava

NASA Astrophysics Data System (ADS)

Povinec, Pavel P.; Masarik, Jozef; Ješkovský, Miroslav; Kaizer, Jakub; Šivo, Alexander; Breier, Robert; Pánik, Ján; Staníček, Jaroslav; Richtáriková, Marta; Zahoran, Miroslav; Zeman, Jakub

2015-10-01

An Accelerator Mass Spectrometry (AMS) laboratory has been established at the Centre for Nuclear and Accelerator Technologies (CENTA) at the Comenius University in Bratislava comprising of a MC-SNICS ion source, 3 MV Pelletron tandem accelerator, and an analyzer of accelerated ions. The preparation of targets for 14C and 129I AMS measurements is described in detail. The development of AMS techniques for potassium, uranium and thorium analysis in radiopure materials required for ultra-low background underground experiments is briefly mentioned.

Theory of unfolded cyclotron accelerator

NASA Astrophysics Data System (ADS)

Rax, J.-M.; Robiche, J.

2010-10-01

An acceleration process based on the interaction between an ion, a tapered periodic magnetic structure, and a circularly polarized oscillating electric field is identified and analyzed, and its potential is evaluated. A Hamiltonian analysis is developed in order to describe the interplay between the cyclotron motion, the electric acceleration, and the magnetic modulation. The parameters of this universal class of magnetic modulation leading to continuous acceleration without Larmor radius increase are expressed analytically. Thus, this study provides the basic scaling of what appears as a compact unfolded cyclotron accelerator.

An Integrative Genetic Study of Rice Metabolism, Growth and Stochastic Variation Reveals Potential C/N Partitioning Loci

NASA Astrophysics Data System (ADS)

Li, Baohua; Zhang, Yuanyuan; Mohammadi, Seyed Abolghasem; Huai, Dongxin; Zhou, Yongming; Kliebenstein, Daniel J.

2016-07-01

Studying the genetic basis of variation in plant metabolism has been greatly facilitated by genomic and metabolic profiling advances. In this study, we use metabolomics and growth measurements to map QTL in rice, a major staple crop. Previous rice metabolism studies have largely focused on identifying genes controlling major effect loci. To complement these studies, we conducted a replicated metabolomics analysis on a japonica (Lemont) by indica (Teqing) rice recombinant inbred line population and focused on the genetic variation for primary metabolism. Using independent replicated studies, we show that in contrast to other rice studies, the heritability of primary metabolism is similar to Arabidopsis. The vast majority of metabolic QTLs had small to moderate effects with significant polygenic epistasis. Two metabolomics QTL hotspots had opposing effects on carbon and nitrogen rich metabolites suggesting that they may influence carbon and nitrogen partitioning, with one locus co-localizing with SUSIBA2 (WRKY78). Comparing QTLs for metabolomic and a variety of growth related traits identified few overlaps. Interestingly, the rice population displayed fewer loci controlling stochastic variation for metabolism than was found in Arabidopsis. Thus, it is possible that domestication has differentially impacted stochastic metabolite variation more than average metabolite variation.

Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis

PubMed Central

Sales, Katiuchia Uzzun; Friis, Stine; Konkel, Joanne E.; Godiksen, Sine; Hatakeyama, Marcia; Hansen, Karina K.; Rogatto, Silvia Regina; Szabo, Roman; Vogel, Lotte K.; Chen, Wanjun; Gutkind, J. Silvio; Bugge, Thomas H.

2014-01-01

The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of NFκB through Gαi. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia, and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NFκB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis. PMID:24469043

Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis.

PubMed

Sales, K U; Friis, S; Konkel, J E; Godiksen, S; Hatakeyama, M; Hansen, K K; Rogatto, S R; Szabo, R; Vogel, L K; Chen, W; Gutkind, J S; Bugge, T H

2015-01-15

The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of nuclear factor (NF)κB through Gαi. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NFκB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis.

Hierarchical nuclear and cytoplasmic genetic architectures for plant growth and defense within Arabidopsis.

PubMed

Joseph, Bindu; Corwin, Jason A; Züst, Tobias; Li, Baohua; Iravani, Majid; Schaepman-Strub, Gabriela; Turnbull, Lindsay A; Kliebenstein, Daniel J

2013-06-01

To understand how genetic architecture translates between phenotypic levels, we mapped the genetic architecture of growth and defense within the Arabidopsis thaliana Kas × Tsu recombinant inbred line population. We measured plant growth using traditional size measurements and size-corrected growth rates. This population contains genetic variation in both the nuclear and cytoplasmic genomes, allowing us to separate their contributions. The cytoplasmic genome regulated a significant variance in growth but not defense, which was due to cytonuclear epistasis. Furthermore, growth adhered to an infinitesimal model of genetic architecture, while defense metabolism was more of a moderate-effect model. We found a lack of concordance between quantitative trait loci (QTL) regulating defense and those regulating growth. Given the published evidence proving the link between glucosinolates and growth, this is likely a false negative result caused by the limited population size. This size limitation creates an inability to test the entire potential genetic landscape possible between these two parents. We uncovered a significant effect of glucosinolates on growth once we accounted for allelic differences in growth QTLs. Therefore, other growth QTLs can mask the effects of defense upon growth. Investigating direct links across phenotypic hierarchies is fraught with difficulty; we identify issues complicating this analysis.

Hierarchical Nuclear and Cytoplasmic Genetic Architectures for Plant Growth and Defense within Arabidopsis[C][W

PubMed Central

Joseph, Bindu; Corwin, Jason A.; Züst, Tobias; Li, Baohua; Iravani, Majid; Schaepman-Strub, Gabriela; Turnbull, Lindsay A.; Kliebenstein, Daniel J.

2013-01-01

To understand how genetic architecture translates between phenotypic levels, we mapped the genetic architecture of growth and defense within the Arabidopsis thaliana Kas × Tsu recombinant inbred line population. We measured plant growth using traditional size measurements and size-corrected growth rates. This population contains genetic variation in both the nuclear and cytoplasmic genomes, allowing us to separate their contributions. The cytoplasmic genome regulated a significant variance in growth but not defense, which was due to cytonuclear epistasis. Furthermore, growth adhered to an infinitesimal model of genetic architecture, while defense metabolism was more of a moderate-effect model. We found a lack of concordance between quantitative trait loci (QTL) regulating defense and those regulating growth. Given the published evidence proving the link between glucosinolates and growth, this is likely a false negative result caused by the limited population size. This size limitation creates an inability to test the entire potential genetic landscape possible between these two parents. We uncovered a significant effect of glucosinolates on growth once we accounted for allelic differences in growth QTLs. Therefore, other growth QTLs can mask the effects of defense upon growth. Investigating direct links across phenotypic hierarchies is fraught with difficulty; we identify issues complicating this analysis. PMID:23749847

Nucleotide variation at the dopa decarboxylase (Ddc) gene in natural populations of Drosophila melanogaster.

PubMed

Tatarenkov, Andrey; Ayala, Francisco J

2007-08-01

We studied nucleotide sequence variation at the gene coding for dopa decarboxylase (Ddc) in seven populations of Drosophila melanogaster. Strength and pattern of linkage disequilibrium are somewhat distinct in the extensively sampled Spanish and Raleigh populations. In the Spanish population, a few sites are in strong positive association, whereas a large number of sites in the Raleigh population are associated nonrandomly but the association is not strong. Linkage disequilibrium analysis shows presence of two groups of haplotypes in the populations, each of which is fairly diverged, suggesting epistasis or inversion polymorphism. There is evidence of two forms of natural selection acting on Ddc. The McDonald-Kreitman test indicates a deficit of fixed amino acid differences between D. melanogaster and D. simulans, which may be due to negative selection. An excess of derived alleles at high frequency, significant according to the H-test, is consistent with the effect of hitchhiking. The hitchhiking may have been caused by directional selection downstream of the locus studied, as suggested by a gradual decrease of the polymorphism-to-divergence ratio. Altogether, the Ddc locus exhibits a complicated pattern of variation apparently due to several evolutionary forces. Such a complex pattern may be a result of an unusually high density of functionally important genes.

Diverse Roles of Axonemal Dyneins in Drosophila Auditory Neuron Function and Mechanical Amplification in Hearing.

PubMed

Karak, Somdatta; Jacobs, Julie S; Kittelmann, Maike; Spalthoff, Christian; Katana, Radoslaw; Sivan-Loukianova, Elena; Schon, Michael A; Kernan, Maurice J; Eberl, Daniel F; Göpfert, Martin C

2015-11-26

Much like vertebrate hair cells, the chordotonal sensory neurons that mediate hearing in Drosophila are motile and amplify the mechanical input of the ear. Because the neurons bear mechanosensory primary cilia whose microtubule axonemes display dynein arms, we hypothesized that their motility is powered by dyneins. Here, we describe two axonemal dynein proteins that are required for Drosophila auditory neuron function, localize to their primary cilia, and differently contribute to mechanical amplification in hearing. Promoter fusions revealed that the two axonemal dynein genes Dmdnah3 (=CG17150) and Dmdnai2 (=CG6053) are expressed in chordotonal neurons, including the auditory ones in the fly's ear. Null alleles of both dyneins equally abolished electrical auditory neuron responses, yet whereas mutations in Dmdnah3 facilitated mechanical amplification, amplification was abolished by mutations in Dmdnai2. Epistasis analysis revealed that Dmdnah3 acts downstream of Nan-Iav channels in controlling the amplificatory gain. Dmdnai2, in addition to being required for amplification, was essential for outer dynein arms in auditory neuron cilia. This establishes diverse roles of axonemal dyneins in Drosophila auditory neuron function and links auditory neuron motility to primary cilia and axonemal dyneins. Mutant defects in sperm competition suggest that both dyneins also function in sperm motility.

Critical analysis of industrial electron accelerators

NASA Astrophysics Data System (ADS)

Korenev, S.

2004-09-01

The critical analysis of electron linacs for industrial applications (degradation of PTFE, curing of composites, modification of materials, sterlization and others) is considered in this report. Main physical requirements for industrial electron accelerators consist in the variations of beam parameters, such as kinetic energy and beam power. Questions for regulation of these beam parameters are considered. The level of absorbed dose in the irradiated product and throughput determines the main parameters of electron accelerator. The type of ideal electron linac for industrial applications is discussed.

On the modulation of the Jovian decametric radiation by Io. I - Acceleration of charged particles

NASA Technical Reports Server (NTRS)

Smith, R. A.; Goertz, C. K.

1978-01-01

A steady-state analysis of the current circuit between Io and the Jovian ionosphere is performed, assuming that the current is carried by electrons accelerated through potential double layers in the Io flux tube. The circuit analysis indicates that electrons may be accelerated up to energies of several hundred keV. Several problems associated with the formation of double layers are also discussed. The parallel potential drops decouple the flux tube from the satellite's orbital motion.

MASS SPECTROMETRY

DOEpatents

Nier, A.O.C.

1959-08-25

A voltage switching apparatus is described for use with a mass spectrometer in the concentratron analysis of several components of a gas mixture. The system automatically varies the voltage on the accelerating electrode of the mass spectrometer through a program of voltages which corresponds to the particular gas components under analysis. Automatic operation may be discontinued at any time to permit the operator to manually select any desired predetermined accelerating voltage. Further, the system may be manually adjusted to vary the accelerating voltage over a wide range.

The Particle Adventure | What is fundamental? | Fundamental

Science.gov Websites

Quiz - What particles are made of The four interactions How does matter interact? The unseen effect structure Rutherford's result Rutherford's analysis How physicists experiment Deflected probe Detecting the Energy-mass conversion Accelerators How to obtain particles to accelerate Accelerating particles

An overview of the facilities, activities, and developments at the University of North Texas Ion Beam Modification and Analysis Laboratory (IBMAL)

NASA Astrophysics Data System (ADS)

Rout, Bibhudutta; Dhoubhadel, Mangal S.; Poudel, Prakash R.; Kummari, Venkata C.; Pandey, Bimal; Deoli, Naresh T.; Lakshantha, Wickramaarachchige J.; Mulware, Stephen J.; Baxley, Jacob; Manuel, Jack E.; Pacheco, Jose L.; Szilasi, Szabolcs; Weathers, Duncan L.; Reinert, Tilo; Glass, Gary A.; Duggan, Jerry L.; McDaniel, Floyd D.

2013-07-01

The Ion Beam Modification and Analysis Laboratory (IBMAL) at the University of North Texas includes several accelerator facilities with capabilities of producing a variety of ion beams from tens of keV to several MeV in energy. The four accelerators are used for research, graduate and undergraduate education, and industrial applications. The NEC 3MV Pelletron tandem accelerator has three ion sources for negative ions: He Alphatross and two different SNICS-type sputter ion sources. Presently, the tandem accelerator has four high-energy beam transport lines and one low-energy beam transport line directly taken from the negative ion sources for different research experiments. For the low-energy beam line, the ion energy can be varied from ˜20 to 80 keV for ion implantation/modification of materials. The four post-acceleration beam lines include a heavy-ion nuclear microprobe; multi-purpose PIXE, RBS, ERD, NRA, and broad-beam single-event upset; high-energy ion implantation line; and trace-element accelerator mass spectrometry. The NEC 3MV single-ended Pelletron accelerator has an RF ion source mainly for hydrogen, helium and heavier inert gases. We recently installed a capacitive liner to the terminal potential stabilization system for high terminal voltage stability and high-resolution microprobe analysis. The accelerator serves a beam line for standard RBS and RBS/C. Another beamline for high energy focused ion beam application using a magnetic quadrupole lens system is currently under construction. This beam line will also serve for developmental work on an electrostatic lens system. The third accelerator is a 200 kV Cockcroft-Walton accelerator with an RF ion source. The fourth accelerator is a 2.5 MV Van de Graaff accelerator, which was in operation for last several decades is currently planned to be used mainly for educational purpose. Research projects that will be briefly discussed include materials synthesis/modification for photonic, electronic, and magnetic applications, surface sputtering and micro-fabrication of materials, development of high-energy ion microprobe systems, and educational and outreach activities.

An overview of the facilities, activities, and developments at the University of North Texas Ion Beam Modification and Analysis Laboratory (IBMAL)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rout, Bibhudutta; Dhoubhadel, Mangal S.; Poudel, Prakash R.

2013-07-03

The Ion Beam Modification and Analysis Laboratory (IBMAL) at the University of North Texas includes several accelerator facilities with capabilities of producing a variety of ion beams from tens of keV to several MeV in energy. The four accelerators are used for research, graduate and undergraduate education, and industrial applications. The NEC 3MV Pelletron tandem accelerator has three ion sources for negative ions: He Alphatross and two different SNICS-type sputter ion sources. Presently, the tandem accelerator has four high-energy beam transport lines and one low-energy beam transport line directly taken from the negative ion sources for different research experiments. Formore » the low-energy beam line, the ion energy can be varied from {approx}20 to 80 keV for ion implantation/modification of materials. The four post-acceleration beam lines include a heavy-ion nuclear microprobe; multi-purpose PIXE, RBS, ERD, NRA, and broad-beam single-event upset; high-energy ion implantation line; and trace-element accelerator mass spectrometry. The NEC 3MV single-ended Pelletron accelerator has an RF ion source mainly for hydrogen, helium and heavier inert gases. We recently installed a capacitive liner to the terminal potential stabilization system for high terminal voltage stability and high-resolution microprobe analysis. The accelerator serves a beam line for standard RBS and RBS/C. Another beamline for high energy focused ion beam application using a magnetic quadrupole lens system is currently under construction. This beam line will also serve for developmental work on an electrostatic lens system. The third accelerator is a 200 kV Cockcroft-Walton accelerator with an RF ion source. The fourth accelerator is a 2.5 MV Van de Graaff accelerator, which was in operation for last several decades is currently planned to be used mainly for educational purpose. Research projects that will be briefly discussed include materials synthesis/modification for photonic, electronic, and magnetic applications, surface sputtering and micro-fabrication of materials, development of high-energy ion microprobe systems, and educational and outreach activities.« less

Study on Online Analysis of Transfer Function of Variable-Speed Rolling Mill Motor with Shaft Torsional Vibration Systems

NASA Astrophysics Data System (ADS)

Tamaoki, Toshifumi; Takanezawa, Makoto; Kimoto, Masanori; Morita, Noboru; Hoshino, Takeo; Hashizume, Kenji

The torsional vibration between metal rolling rolls and a rolling mill motor, may occur in recent days, as a result of higher speed response adjustment for variable speed rolling mill motor drive system. Issues in this paper are focused on excess acceleration value, in tangential direction of the mill motor rotor, which is caused by the motor shaft torsional resonance at the white noise signal superposition to the speed reference signal of the motor drive system for the online transfer function analysis. As a result of the acceleration analysis, the acceleration values in “G” (Relative acceleration value on the basis of Gravity) can be plotted on “Bode-Diagram”, which is namely frequency response for the speed signal amplitude transmission ratio. In addition, relation between the white noise amplitude reduction and the transfer function analysis accuracy deterioration is also examined, in this paper. As the amplitude of the white noise decreases, the analysis error increases because of the reduction in the resolution when the amplitude of the white noise signal is small.

Exceedance statistics of accelerations resulting from thruster firings on the Apollo-Soyuz mission

NASA Technical Reports Server (NTRS)

Fichtl, G. H.; Holland, R. L.

1983-01-01

Spacecraft acceleration resulting from firings of vernier control system thrusters is an important consideration in the design, planning, execution and post-flight analysis of laboratory experiments in space. In particular, scientists and technologists involved with the development of experiments to be performed in space in many instances required statistical information on the magnitude and rate of occurrence of spacecraft accelerations. Typically, these accelerations are stochastic in nature, so that it is useful to characterize these accelerations in statistical terms. Statistics of spacecraft accelerations are summarized. Previously announced in STAR as N82-12127

Time-dependent diffusive acceleration of test particles at shocks

NASA Astrophysics Data System (ADS)

Drury, L. O'C.

1991-07-01

A theoretical description is developed for the acceleration of test particles at a steady plane nonrelativistic shock. The mean and the variance of the acceleration-time distribution are expressed analytically for the condition under which the diffusion coefficient is arbitrarily dependent on position and momentum. The formula for an acceleration rate with arbitrary spatial variation in the diffusion coefficient developed by Drury (1987) is supplemented by a general theory of time dependence. An approximation scheme is developed by means of the analysis which permits the description of the spectral cutoff resulting from the finite shock age. The formulas developed in the analysis are also of interest for analyzing the observations of heliospheric shocks made from spacecraft.

Interface for the rapid analysis of liquid samples by accelerator mass spectrometry

DOEpatents

Turteltaub, Kenneth; Ognibene, Ted; Thomas, Avi; Daley, Paul F; Salazar Quintero, Gary A; Bench, Graham

2014-02-04

An interface for the analysis of liquid sample having carbon content by an accelerator mass spectrometer including a wire, defects on the wire, a system for moving the wire, a droplet maker for producing droplets of the liquid sample and placing the droplets of the liquid sample on the wire in the defects, a system that converts the carbon content of the droplets of the liquid sample to carbon dioxide gas in a helium stream, and a gas-accepting ion source connected to the accelerator mass spectrometer that receives the carbon dioxide gas of the sample in a helium stream and introduces the carbon dioxide gas of the sample into the accelerator mass spectrometer.

Design and Analysis of Megawatt Class Free Electron Laser Weapons

DTIC Science & Technology

2015-12-01

accelerating structure. The SRF linear accelerator stores RF fields within its niobium cavities. Superconductors require less average RF power than...is needed to cool the superconductor for the SRF linear accelerator. A current outstanding research topic is the RF frequency to use for the SRF

Signature energetic analysis of accelerate electron beam after first acceleration station by accelerating stand of Joint Institute for Nuclear Research

NASA Astrophysics Data System (ADS)

Sledneva, A. S.; Kobets, V. V.

2017-06-01

The linear electron accelerator based on the LINAC - 800 accelerator imported from the Netherland is created at Joint Institute for Nuclear Research in the framework of the project on creation of the Testbed with an electron beam of a linear accelerator with an energy up to 250 MV. Currently two accelerator stations with a 60 MV energy of a beam are put in operation and the work is to put the beam through accelerating section of the third accelerator station. The electron beam with an energy of 23 MeV is used for testing the crystals (BaF2, CsI (native), and LYSO) in order to explore the opportunity to use them in particle detectors in experiments: Muon g-2, Mu2e, Comet, whose preparation requires a detailed study of the detectors properties such as their irradiation by the accelerator beams.

Development of a residual acceleration data reduction and dissemination plan

NASA Technical Reports Server (NTRS)

Rogers, Melissa J. B.

1992-01-01

A major obstacle in evaluating the residual acceleration environment in an orbiting space laboratory is the amount of data collected during a given mission: gigabytes of data will be available as SAMS units begin to fly regularly. Investigators taking advantage of the reduced gravity conditions of space should not be overwhelmed by the accelerometer data which describe these conditions. We are therefore developing a data reduction and analysis plan that will allow principal investigators of low-g experiments to create experiment-specific residual acceleration data bases for post-flight analysis. The basic aspects of the plan can also be used to characterize the acceleration environment of earth orbiting laboratories. Our development of the reduction plan is based on the following program of research: the identification of experiment sensitivities by order of magnitude estimates and numerical modelling; evaluation of various signal processing techniques appropriate for the reduction, supplementation, and dissemination of residual acceleration data; and testing and implementation of the plan on existing acceleration data bases. The orientation of the residual acceleration vector with respect to some set of coordinate axes is important for experiments with known directional sensitivity. Orientation information can be obtained from the evaluation of direction cosines. Fourier analysis is commonly used to transform time history data into the frequency domain. Common spectral representations are the amplitude spectrum which gives the average of the components of the time series at each frequency and the power spectral density which indicates the power or energy present in the series per unit frequency interval. The data reduction and analysis scheme developed involves a two tiered structure to: (1) identify experiment characteristics and mission events that can be used to limit the amount of accelerator data an investigator should be interested in; and (2) process the data in a way that will be meaningful to the experiment objectives. A general outline of the plan is given.

International Space Station Increment-4/5 Microgravity Environment Summary Report

NASA Technical Reports Server (NTRS)

Jules, Kenol; Hrovat, Kenneth; Kelly, Eric; McPherson, Kevin; Reckart, Timothy

2003-01-01

This summary report presents the results of some of the processed acceleration data measured aboard the International Space Station during the period of December 2001 to December 2002. Unlike the past two ISS Increment reports, which were increment specific, this summary report covers two increments: Increments 4 and 5, hereafter referred to as Increment-4/5. Two accelerometer systems were used to measure the acceleration levels for the activities that took place during Increment-4/5. Due to time constraint and lack of precise timeline information regarding some payload operations and station activities, not a11 of the activities were analyzed for this report. The National Aeronautics and Space Administration sponsors the Microgravity Acceleration Measurement System and the Space Acceleration Microgravity System to support microgravity science experiments which require microgravity acceleration measurements. On April 19, 2001, both the Microgravity Acceleration Measurement System and the Space Acceleration Measurement System units were launched on STS-100 from the Kennedy Space Center for installation on the International Space Station. The Microgravity Acceleration Measurement System supports science experiments requiring quasi-steady acceleration measurements, while the Space Acceleration Measurement System unit supports experiments requiring vibratory acceleration measurement. The International Space Station Increment-4/5 reduced gravity environment analysis presented in this report uses acceleration data collected by both sets of accelerometer systems: The Microgravity Acceleration Measurement System, which consists of two sensors: the low-frequency Orbital Acceleration Research Experiment Sensor Subsystem and the higher frequency High Resolution Accelerometer Package. The low frequency sensor measures up to 1 Hz, but is routinely trimmean filtered to yield much lower frequency acceleration data up to 0.01 Hz. This filtered data can be mapped to arbitrary locations for characterizing the quasi-steady environment for payloads and the vehicle. The high frequency sensor is used to characterize the vibratory environment up to 100 Hz at a single measurement location. The Space Acceleration Measurement System, which deploys high frequency sensors, measures vibratory acceleration data in the range of 0.01 to 400 Hz at multiple measurement locations. This summary report presents analysis of some selected quasi-steady and vibratory activities measured by these accelerometers during Increment- 4/5 from December 2001 to December 2002.

Study of strength kinetics of sand concrete system of accelerated hardening

NASA Astrophysics Data System (ADS)

Sharanova, A. V.; Lenkova, D. A.; Panfilova, A. D.

2018-04-01

Methods of calorimetric analysis are used to study the dynamics of the hydration processes of concretes with different accelerator contents. The efficiency of the isothermal calorimetry method is shown for study of strength kinetics of concrete mixtures of accelerated hardening, promising for additive technologies in civil engineering.

Inviscid linear stability analysis of two vertical columns of different densities in a gravitational acceleration field

DOE PAGES

Prathama, Aditya Heru; Pantano, Carlos

2017-08-09

Here, we study the inviscid linear stability of a vertical interface separating two fluids of different densities and subject to a gravitational acceleration field parallel to the interface. In this arrangement, the two free streams are constantly accelerated, which means that the linear stability analysis is not amenable to Fourier or Laplace solution in time. Instead, we derive the equations analytically by the initial-value problem method and express the solution in terms of the well-known parabolic cylinder function. The results, which can be classified as an accelerating Kelvin–Helmholtz configuration, show that even in the presence of surface tension, the interfacemore » is unconditionally unstable at all wavemodes. This is a consequence of the ever increasing momentum of the free streams, as gravity accelerates them indefinitely. The instability can be shown to grow as the exponential of a quadratic function of time.« less

Detailed analysis of Honeywell In-Space Accelerometer data - STS-32. [crystal microstructure response to different types of residual acceleration

NASA Technical Reports Server (NTRS)

Rogers, Melissa J. B.; Alexander, J. I. D.; Schoess, Jeff

1993-01-01

The Honeywell In-Space Accelerometer (HISA) system collected data in the mid-deck area of the Shuttle Columbia during the flight of STS-32, January 1990. The resulting data were to be used to investigate the response of crystal microstructure to different types of residual acceleration. The HISA is designed to detect and record transient and oscillatory accelerations. The sampling and electronics package stored averaged accelerations over two sampling periods; two sampling rates were available: 1 Hz and 50 Hz. Analysis of the HISA data followed the CMMR Acceleration Data Processing Guide, considering in-house computer modelling of a float-zone indium crystal growth experiment. Characteristic examples of HISA data showing the response to the primary reaction control system, Orbiter Maneuvering System operations, and crew treadmill activity are presented. Various orbiter structural modes are excited by these and other activities.

Nitridation of silicon by nitrogen neutral beam

NASA Astrophysics Data System (ADS)

Hara, Yasuhiro; Shimizu, Tomohiro; Shingubara, Shoso

2016-02-01

Silicon nitridation was investigated at room temperature using a nitrogen neutral beam (NB) extracted at acceleration voltages of less than 100 V. X-ray photoelectron spectroscopy (XPS) analysis confirmed the formation of a Si3N4 layer on a Si (1 0 0) substrate when the acceleration voltage was higher than 20 V. The XPS depth profile indicated that nitrogen diffused to a depth of 36 nm for acceleration voltages of 60 V and higher. The thickness of the silicon nitrided layer increased with the acceleration voltages from 20 V to 60 V. Cross-sectional transmission electron microscopy (TEM) analysis indicated a Si3N4 layer thickness of 3.1 nm was obtained at an acceleration voltage of 100 V. Moreover, it was proved that the nitrided silicon layer formed by the nitrogen NB at room temperature was effective as the passivation film in the wet etching process.

Design and Analysis of a New Hair Sensor for Multi-Physical Signal Measurement

PubMed Central

Yang, Bo; Hu, Di; Wu, Lei

2016-01-01

A new hair sensor for multi-physical signal measurements, including acceleration, angular velocity and air flow, is presented in this paper. The entire structure consists of a hair post, a torsional frame and a resonant signal transducer. The hair post is utilized to sense and deliver the physical signals of the acceleration and the air flow rate. The physical signals are converted into frequency signals by the resonant transducer. The structure is optimized through finite element analysis. The simulation results demonstrate that the hair sensor has a frequency of 240 Hz in the first mode for the acceleration or the air flow sense, 3115 Hz in the third and fourth modes for the resonant conversion, and 3467 Hz in the fifth and sixth modes for the angular velocity transformation, respectively. All the above frequencies present in a reasonable modal distribution and are separated from interference modes. The input-output analysis of the new hair sensor demonstrates that the scale factor of the acceleration is 12.35 Hz/g, the scale factor of the angular velocity is 0.404 nm/deg/s and the sensitivity of the air flow is 1.075 Hz/(m/s)2, which verifies the multifunction sensitive characteristics of the hair sensor. Besides, the structural optimization of the hair post is used to improve the sensitivity of the air flow rate and the acceleration. The analysis results illustrate that the hollow circular hair post can increase the sensitivity of the air flow and the II-shape hair post can increase the sensitivity of the acceleration. Moreover, the thermal analysis confirms the scheme of the frequency difference for the resonant transducer can prominently eliminate the temperature influences on the measurement accuracy. The air flow analysis indicates that the surface area increase of hair post is significantly beneficial for the efficiency improvement of the signal transmission. In summary, the structure of the new hair sensor is proved to be feasible by comprehensive simulation and analysis. PMID:27399716

Muscle contributions to knee extension in the early stance phase in patients with knee osteoarthritis.

PubMed

Ogaya, Shinya; Kubota, Ryo; Chujo, Yuta; Hirooka, Eiko; Kwang-Ho, Kim; Hase, Kimitaka

2017-10-01

The aim of this study was to analyze individual muscle contributions to knee angular acceleration using a musculoskeletal simulation analysis and evaluate knee extension mechanics in the early stance phase in patients with knee osteoarthritis (OA). The subjects comprised 15 patients with medial knee OA and 14 healthy elderly individuals. All participants underwent gait performance test using 8 infrared cameras and two force plates to measure the kinetic and kinematic data. The simulation was driven by 92 Hill-type muscle-tendon units of the lower extremities and a trunk with 23° of freedom. We analyzed each muscle contribution to knee angular acceleration in the 5%-15% and 15%-25% periods of the stance phase (% SP) using an induced acceleration analysis. We compared accelerations by individual muscles between the two groups using an analysis of covariance for controlling gait speed. Patients with knee OA had a significantly lesser knee extension acceleration by the vasti muscles and higher knee acceleration by hip adductors than those in controls in 5-15% SP. In addition, knee OA resulted in significantly lesser knee extension acceleration by the vasti muscles in 15-25% SP. These results indicate that patients with knee OA have decreased dependency on the vasti muscles to control knee movements during early stance phase. Hip adductor muscles, which mainly control mediolateral motion, partly compensate for the weak knee extension by the vasti muscles in patients with knee OA. Copyright © 2017 Elsevier B.V. All rights reserved.

The Impact of Back-Sputtered Carbon on the Accelerator Grid Wear Rates of the NEXT and NSTAR Ion Thrusters

NASA Technical Reports Server (NTRS)

Soulas, George C.

2013-01-01

A study was conducted to quantify the impact of back-sputtered carbon on the downstream accelerator grid erosion rates of the NEXT (NASA's Evolutionary Xenon Thruster) Long Duration Test (LDT1). A similar analysis that was conducted for the NSTAR (NASA's Solar Electric Propulsion Technology Applications Readiness Program) Life Demonstration Test (LDT2) was used as a foundation for the analysis developed herein. A new carbon surface coverage model was developed that accounted for multiple carbon adlayers before complete surface coverage is achieved. The resulting model requires knowledge of more model inputs, so they were conservatively estimated using the results of past thin film sputtering studies and particle reflection predictions. In addition, accelerator current densities across the grid were rigorously determined using an ion optics code to determine accelerator current distributions and an algorithm to determine beam current densities along a grid using downstream measurements. The improved analysis was applied to the NSTAR test results for evaluation. The improved analysis demonstrated that the impact of back-sputtered carbon on pit and groove wear rate for the NSTAR LDT2 was negligible throughout most of eroded grid radius. The improved analysis also predicted the accelerator current density for transition from net erosion to net deposition considerably more accurately than the original analysis. The improved analysis was used to estimate the impact of back-sputtered carbon on the accelerator grid pit and groove wear rate of the NEXT Long Duration Test (LDT1). Unlike the NSTAR analysis, the NEXT analysis was more challenging because the thruster was operated for extended durations at various operating conditions and was unavailable for measurements because the test is ongoing. As a result, the NEXT LDT1 estimates presented herein are considered preliminary until the results of future posttest analyses are incorporated. The worst-case impact of carbon back-sputtering was determined to be the full power operating condition, but the maximum impact of back-sputtered carbon was only a four percent reduction in wear rate. As a result, back-sputtered carbon is estimated to have an insignificant impact on the first failure mode of the NEXT LDT at all operating conditions.

An Analysis of the Airspeeds and Normal Accelerations of sikorsky S-42A Airplanes in Commercial Transport Operation

DTIC Science & Technology

1948-10-01

OPERATION By Walter G. Walker SUMMARY Acceleration and airspeed data taken on four Sikorsky S-42A air- planes operated on Caribbean routes and...INTRODUCTION Previous analyses (references 1 to 3) present the results obtained from acceleration and airspeed data taken during commercial transport...N.ADA TN No. 1733 This" paper gl.ves the results of’ an. analysis of’. V-G data taken on f’our Sikorsky S-42A f’ly:l.ng boats operated on Caribbean

Analysis of lead-acid battery accelerated testing data

NASA Astrophysics Data System (ADS)

Clifford, J. E.; Thomas, R. E.

1983-06-01

Battelle conducted an independent review and analysis of the accelerated test procedures and test data obtained by Exide in the 3 year Phase 1 program to develop advanced lead acid batteries for utility load leveling. Of special importance is the extensive data obtained in deep discharge cycling tests on 60 cells at elevated temperatures over a 2-1/2 year period. The principal uncertainty in estimating cell life relates to projecting cycle life data at elevated temperature to the lower operating temperatures. The accelerated positive grid corrosion test involving continuous overcharge at 500C provided some indication of the degree of grid corrosion that might be tolerable before failure. The accelerated positive material shedding test was not examined in any detail. Recommendations are made for additional studies.

Analysis of secondary particle behavior in multiaperture, multigrid accelerator for the ITER neutral beam injector.

PubMed

Mizuno, T; Taniguchi, M; Kashiwagi, M; Umeda, N; Tobari, H; Watanabe, K; Dairaku, M; Sakamoto, K; Inoue, T

2010-02-01

Heat load on acceleration grids by secondary particles such as electrons, neutrals, and positive ions, is a key issue for long pulse acceleration of negative ion beams. Complicated behaviors of the secondary particles in multiaperture, multigrid (MAMuG) accelerator have been analyzed using electrostatic accelerator Monte Carlo code. The analytical result is compared to experimental one obtained in a long pulse operation of a MeV accelerator, of which second acceleration grid (A2G) was removed for simplification of structure. The analytical results show that relatively high heat load on the third acceleration grid (A3G) since stripped electrons were deposited mainly on A3G. This heat load on the A3G can be suppressed by installing the A2G. Thus, capability of MAMuG accelerator is demonstrated for suppression of heat load due to secondary particles by the intermediate grids.

Novel genetic risk markers for ulcerative colitis in the IL2/IL21 region are in epistasis with IL23R and suggest a common genetic background for ulcerative colitis and celiac disease.

PubMed

Glas, Jürgen; Stallhofer, Johannes; Ripke, Stephan; Wetzke, Martin; Pfennig, Simone; Klein, Wolfram; Epplen, Jörg T; Griga, Thomas; Schiemann, Uwe; Lacher, Martin; Koletzko, Sibylle; Folwaczny, Matthias; Lohse, Peter; Göke, Burkhard; Ochsenkühn, Thomas; Müller-Myhsok, Bertram; Brand, Stephan

2009-07-01

Recently, a genome-wide association study showed that single-nucleotide polymorphisms (SNPs) in the chromosome 4q27 region containing IL2 and IL21 are associated with celiac disease. Given the increased prevalence of inflammatory bowel disease (IBD) among celiac disease patients, we investigated the possible involvement of these SNPs in IBD. Five SNPs strongly associated with celiac disease within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block on chromosome 4q27 and one coding SNP within the IL21 gene were analyzed in a large German IBD cohort. The study population comprised a total of 2,948 Caucasian individuals, including 1,461 IBD patients (ulcerative colitis (UC): n=514, Crohn's disease (CD): n=947) and 1,487 healthy unrelated controls. Three of the five celiac disease risk markers had a protective effect on UC susceptibility, and this effect remained significant after correcting for multiple testing: rs6840978: P=0.0082, P(corr)=0.049, odds ratio (OR) 0.77, 95% confidence interval (CI) 0.63-0.93; rs6822844: P=0.0028, P(corr)=0.017, OR 0.73, 95% CI 0.59-0.90; rs13119723: P=0.0058, P(corr)=0.035, OR 0.75, 95% CI 0.61-0.92. A haplotype consisting of the six SNPs tested was markedly associated with UC susceptibility (P=0.0025, P(corr)=0.015, OR 0.72, 95% CI 0.58-0.89). Moreover, in UC, epistasis was observed between the IL23R SNP rs1004819 and three SNPs in the KIAA1109/TENR/IL2/IL21 block (rs13151961, rs13119723, and rs6822844). Similar to other autoimmune diseases such as celiac disease, rheumatoid arthritis, type 1 diabetes, Graves' disease, and psoriatic arthritis, genetic variation in the chromosome 4q27 region predisposes to UC, suggesting a common genetic background for these diseases.

Multigenerational effects of inbreeding in Cucurbita pepo ssp. texana (Cucurbitaceae).

PubMed

Hayes, C Nelson; Winsor, James A; Stephenson, Andrew G

2005-02-01

The shape of the fitness function relating the decline in fitness with coefficient of inbreeding (f) can provide evidence concerning the genetic basis of inbreeding depression, but few studies have examined inbreeding depression across a range of f using noncultivated species. Futhermore, studies have rarely examined the effects of inbreeding depression in the maternal parent on offspring fitness. To estimate the shape of the fitness function, we examined the relationship between f and fitness across a range off from 0.000 to 0.875 for components of both male and female fitness in Cucurbita pepo ssp. texana. Each measure of female fitness declined with f, including pistillate flower number, fruit number, seed number per fruit, seed mass per fruit, and percentage seed germination. Several aspects of male fitness also declined with f, including staminate flower number, pollen number per flower, and the number of days of flowering, although cumulative inbreeding depression was less severe for male (0.34) than for female function (0.39). Fitness tended to decline linearly with f between f = 0.00 and f = 0.75 for most traits and across cumulative lifetime fitness (mean = 0.66), suggesting that individual genes causing inbreeding depression are additive and the result of many alleles of small effect. However, most traits also showed a small reduction in inbreeding depression between f = 0.75 and f = 0.875, and evidence of purging or diminishing epistasis was found for in vitro pollen-tube growth rate. To examine inbreeding depression as a maternal effect, we performed outcross pollinations on f = 0.0 and f = 0.5 mothers and found that depression due to maternal inbreeding was 0.07, compared to 0.10 for offspring produced through one generation of selfing. In at least some families, maternal inbreeding reduced fruit number, seed number and mass, staminate flower number, pollen diameter, and pollen-tube growth rate. Collectively these results suggest that, while the fitness function appears to be largely linear for most traits, maternal effects may compound the effects of inbreeding depression in multigenerational studies, though this may be partially offset by purging or diminishing epistasis.

Imaging oxytocin × dopamine interactions: an epistasis effect of CD38 and COMT gene variants influences the impact of oxytocin on amygdala activation to social stimuli

PubMed Central

Sauer, Carina; Montag, Christian; Reuter, Martin; Kirsch, Peter

2013-01-01

Although oxytocin (OT) has become a major target for the investigation of positive social processes, it can be assumed that it exerts its effects in concert with other neurotransmitters. One candidate for such an interaction is dopamine (DA). For both systems, genetic variants have been identified that influence the availability of the particular substance. A variant of the gene coding for the transmembrane protein CD38 (rs3796863), which is engaged in OT secretion, has been associated with OT plasma level. The common catechol-O-methyltransferase (COMT) val158met polymorphism is known to influence COMT activity and therefore the degradation of DA. The present study aimed to investigate OT × DA interactions in the context of an OT challenge study. Hence, we tested the influence of the above mentioned genetic variants and their interaction on the activation of different brain regions (amygdala, VTA, ventral striatum and fusiform gyrus) during the presentation of social stimuli. In a pharmacological cross-over design 55 participants were investigated under OT and placebo (PLA) by means of fMRI. Brain imaging results revealed no significant effects for VTA or ventral striatum. Regarding the fusiform gyrus, we could not find any effects apart from those already described in Sauer et al. (2012). Analyses of amygdala activation resulted in no gene main effect, no gene × substance interaction but a significant gene × gene × substance interaction. While under PLA the effect of CD38 on bilateral amygdala activation to social stimuli was modulated by the COMT genotype, no such epistasis effect was found under OT. Our results provide evidence for an OT × DA interaction during responses to social stimuli. We postulate that the effect of central OT secretion on amygdala response is modulated by the availability of DA. Therefore, for an understanding of the effect of social hormones on social behavior, interactions of OT with other transmitter systems have to be taken into account. PMID:23554586

DOE Office of Scientific and Technical Information (OSTI.GOV)

Won, Jong-Pil, E-mail: jpwon@konkuk.ac.kr; Hwang, Un-Jong; Lee, Su-Jin

This study evaluated the performance of shotcrete using high strength C{sub 12}A{sub 7} mineral-based accelerator that has been developed to improve the durability and long-term strength. Rebound, compressive strength and flexural strength were tested in the field. Test result showed that existing C{sub 12}A{sub 7} mineral-based accelerator exhibits better early strength than the high-strength C{sub 12}A{sub 7} mineral-based accelerator until the early age, but high-strength C{sub 12}A{sub 7} mineral-based accelerator shows about 29% higher at the long-term age of 28 days. Microstructural analysis such as scanning electron microscope (SEM), X-ray diffraction (XRD) and nitrogen adsorption method was evaluated to analyzemore » long-term strength development mechanism of high strength C{sub 12}A{sub 7} mineral-based accelerator. As analysis result, it had more dense structure due to the reaction product by adding material that used to enhanced strength. It had better resistance performance in chloride ion penetration, freezing–thawing and carbonation than shotcrete that used existing C{sub 12}A{sub 7} mineral-based accelerator.« less

Physicochemical stability and biological activity of Withania somnifera extract under real-time and accelerated storage conditions.

PubMed

Patil, Dada; Gautam, Manish; Jadhav, Umesh; Mishra, Sanjay; Karupothula, Suresh; Gairola, Sunil; Jadhav, Suresh; Patwardhan, Bhushan

2010-03-01

Stability testing at preformulation stages is a crucial part of drug development. We studied physicochemical stability and biological activity of Withania somnifera (ashwagandha) dried root aqueous extract during six months real-time and under accelerated storage conditions. The characteristic constituents of ashwagandha roots include withanolides such as withaferin A and withanolide A. We modified and validated the HPLC-DAD method for quantitative measurement of withanolides and fingerprint analysis. The results suggest a significant decline in withaferin A and withanolide A content under real and accelerated conditions. The HPLC fingerprint analysis showed significant changes in some peaks during real and accelerated storage (> 20 %). We also observed incidences of clump formation and moisture sensitivity (> 10 %) under real-time and accelerated storage conditions. These changes were concurrent with a significant decline in immunomodulatory activity (p < 0.01) during the third month of the accelerated storage. Thus, adequate control of temperature and humidity is important for WSE containing formulations. This study may help in proposing suitable guidance for storage conditions and shelf life of ashwagandha formulations. (c) Georg Thieme Verlag KG Stuttgart . New York.

Automatic Beam Path Analysis of Laser Wakefield Particle Acceleration Data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rubel, Oliver; Geddes, Cameron G.R.; Cormier-Michel, Estelle

2009-10-19

Numerical simulations of laser wakefield particle accelerators play a key role in the understanding of the complex acceleration process and in the design of expensive experimental facilities. As the size and complexity of simulation output grows, an increasingly acute challenge is the practical need for computational techniques that aid in scientific knowledge discovery. To that end, we present a set of data-understanding algorithms that work in concert in a pipeline fashion to automatically locate and analyze high energy particle bunches undergoing acceleration in very large simulation datasets. These techniques work cooperatively by first identifying features of interest in individual timesteps,more » then integrating features across timesteps, and based on the information derived perform analysis of temporally dynamic features. This combination of techniques supports accurate detection of particle beams enabling a deeper level of scientific understanding of physical phenomena than hasbeen possible before. By combining efficient data analysis algorithms and state-of-the-art data management we enable high-performance analysis of extremely large particle datasets in 3D. We demonstrate the usefulness of our methods for a variety of 2D and 3D datasets and discuss the performance of our analysis pipeline.« less

Microgravity acceleration measurement and environment characterization science (17-IML-1)

NASA Technical Reports Server (NTRS)

1992-01-01

The Space Acceleration Measurement System (SAMS) is a general purpose instrumentation system designed to measure the accelerations onboard the Shuttle Orbiter and Shuttle/Spacelab vehicles. These measurements are used to support microgravity experiments and investigation into the microgravity environment of the vehicle. Acceleration measurements can be made at locations remote from the SAMS main instrumentation unit by the use of up to three remote triaxial sensor heads. The prime objective for SAMS on the International Microgravity Lab (IML-1) mission will be to measure the accelerations experienced by the Fluid Experiment System (FES). The SAMS acceleration measurements for FES will be complemented by low level, low frequency acceleration measurements made by the Orbital Acceleration Research Experiment (OARE) installed on the shuttle. Secondary objectives for SAMS will be to measure accelerations at several specific locations to enable the acceleration transfer function of the Spacelab module to be analyzed. This analysis effort will be in conjunction with similar measurements analyses on other Spacelab missions.

Assessment of Homomorphic Analysis for Human Activity Recognition from Acceleration Signals.

PubMed

Vanrell, Sebastian Rodrigo; Milone, Diego Humberto; Rufiner, Hugo Leonardo

2017-07-03

Unobtrusive activity monitoring can provide valuable information for medical and sports applications. In recent years, human activity recognition has moved to wearable sensors to deal with unconstrained scenarios. Accelerometers are the preferred sensors due to their simplicity and availability. Previous studies have examined several \\azul{classic} techniques for extracting features from acceleration signals, including time-domain, time-frequency, frequency-domain, and other heuristic features. Spectral and temporal features are the preferred ones and they are generally computed from acceleration components, leaving the acceleration magnitude potential unexplored. In this study, based on homomorphic analysis, a new type of feature extraction stage is proposed in order to exploit discriminative activity information present in acceleration signals. Homomorphic analysis can isolate the information about whole body dynamics and translate it into a compact representation, called cepstral coefficients. Experiments have explored several configurations of the proposed features, including size of representation, signals to be used, and fusion with other features. Cepstral features computed from acceleration magnitude obtained one of the highest recognition rates. In addition, a beneficial contribution was found when time-domain and moving pace information was included in the feature vector. Overall, the proposed system achieved a recognition rate of 91.21% on the publicly available SCUT-NAA dataset. To the best of our knowledge, this is the highest recognition rate on this dataset.

A System-Level Pathway-Phenotype Association Analysis Using Synthetic Feature Random Forest

PubMed Central

Pan, Qinxin; Hu, Ting; Malley, James D.; Andrew, Angeline S.; Karagas, Margaret R.; Moore, Jason H.

2015-01-01

As the cost of genome-wide genotyping decreases, the number of genome-wide association studies (GWAS) has increased considerably. However, the transition from GWAS findings to the underlying biology of various phenotypes remains challenging. As a result, due to its system-level interpretability, pathway analysis has become a popular tool for gaining insights on the underlying biology from high-throughput genetic association data. In pathway analyses, gene sets representing particular biological processes are tested for significant associations with a given phenotype. Most existing pathway analysis approaches rely on single-marker statistics and assume that pathways are independent of each other. As biological systems are driven by complex biomolecular interactions, embracing the complex relationships between single-nucleotide polymorphisms (SNPs) and pathways needs to be addressed. To incorporate the complexity of gene-gene interactions and pathway-pathway relationships, we propose a system-level pathway analysis approach, synthetic feature random forest (SF-RF), which is designed to detect pathway-phenotype associations without making assumptions about the relationships among SNPs or pathways. In our approach, the genotypes of SNPs in a particular pathway are aggregated into a synthetic feature representing that pathway via Random Forest (RF). Multiple synthetic features are analyzed using RF simultaneously and the significance of a synthetic feature indicates the significance of the corresponding pathway. We further complement SF-RF with pathway-based Statistical Epistasis Network (SEN) analysis that evaluates interactions among pathways. By investigating the pathway SEN, we hope to gain additional insights into the genetic mechanisms contributing to the pathway-phenotype association. We apply SF-RF to a population-based genetic study of bladder cancer and further investigate the mechanisms that help explain the pathway-phenotype associations using SEN. The bladder cancer associated pathways we found are both consistent with existing biological knowledge and reveal novel and plausible hypotheses for future biological validations. PMID:24535726

Traumatic stress and accelerated DNA methylation age: A meta-analysis.

PubMed

Wolf, Erika J; Maniates, Hannah; Nugent, Nicole; Maihofer, Adam X; Armstrong, Don; Ratanatharathorn, Andrew; Ashley-Koch, Allison E; Garrett, Melanie; Kimbrel, Nathan A; Lori, Adriana; Va Mid-Atlantic Mirecc Workgroup; Aiello, Allison E; Baker, Dewleen G; Beckham, Jean C; Boks, Marco P; Galea, Sandro; Geuze, Elbert; Hauser, Michael A; Kessler, Ronald C; Koenen, Karestan C; Miller, Mark W; Ressler, Kerry J; Risbrough, Victoria; Rutten, Bart P F; Stein, Murray B; Ursano, Robert J; Vermetten, Eric; Vinkers, Christiaan H; Uddin, Monica; Smith, Alicia K; Nievergelt, Caroline M; Logue, Mark W

2018-06-01

Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results. We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables. Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors. Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD. Published by Elsevier Ltd.

Magnetogasdynamic compression of a coaxial plasma accelerator flow for micrometeoroid simulation

NASA Technical Reports Server (NTRS)

Igenbergs, E. B.; Shriver, E. L.

1974-01-01

A new configuration of a coaxial plasma accelerator with self-energized magnetic compressor coil attached is described. It is shown that the circuit may be treated theoretically by analyzing an equivalent circuit mesh. The results obtained from the theoretical analysis compare favorably with the results measured experimentally. Using this accelerator configuration, glass beads of 125 micron diameter were accelerated to velocities as high as 11 kilometers per second, while 700 micron diameter glass beads were accelerated to velocities as high as 5 kilometers per second. The velocities are within the hypervelocity regime of meteoroids.

Quantitative Approach to Failure Mode and Effect Analysis for Linear Accelerator Quality Assurance

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Daniel, Jennifer C., E-mail: jennifer.odaniel@duke.edu; Yin, Fang-Fang

Purpose: To determine clinic-specific linear accelerator quality assurance (QA) TG-142 test frequencies, to maximize physicist time efficiency and patient treatment quality. Methods and Materials: A novel quantitative approach to failure mode and effect analysis is proposed. Nine linear accelerator-years of QA records provided data on failure occurrence rates. The severity of test failure was modeled by introducing corresponding errors into head and neck intensity modulated radiation therapy treatment plans. The relative risk of daily linear accelerator QA was calculated as a function of frequency of test performance. Results: Although the failure severity was greatest for daily imaging QA (imaging vsmore » treatment isocenter and imaging positioning/repositioning), the failure occurrence rate was greatest for output and laser testing. The composite ranking results suggest that performing output and lasers tests daily, imaging versus treatment isocenter and imaging positioning/repositioning tests weekly, and optical distance indicator and jaws versus light field tests biweekly would be acceptable for non-stereotactic radiosurgery/stereotactic body radiation therapy linear accelerators. Conclusions: Failure mode and effect analysis is a useful tool to determine the relative importance of QA tests from TG-142. Because there are practical time limitations on how many QA tests can be performed, this analysis highlights which tests are the most important and suggests the frequency of testing based on each test's risk priority number.« less

Modern Computational Techniques for the HMMER Sequence Analysis

PubMed Central

2013-01-01

This paper focuses on the latest research and critical reviews on modern computing architectures, software and hardware accelerated algorithms for bioinformatics data analysis with an emphasis on one of the most important sequence analysis applications—hidden Markov models (HMM). We show the detailed performance comparison of sequence analysis tools on various computing platforms recently developed in the bioinformatics society. The characteristics of the sequence analysis, such as data and compute-intensive natures, make it very attractive to optimize and parallelize by using both traditional software approach and innovated hardware acceleration technologies. PMID:25937944

Independent Confirmation of the Pioneer 10 Anomalous Acceleration

NASA Technical Reports Server (NTRS)

Markwardt, Craig B.

2002-01-01

I perform an independent analysis of radio Doppler tracking data from the Pioneer 10 spacecraft for the time period 1987-1994. All of the tracking data were taken from public archive sources, and the analysis tools were developed independently by myself. I confirm that an apparent anomalous acceleration is acting on the Pioneer 10 spacecraft, which is not accounted for by present physical models of spacecraft navigation. My best fit value for the acceleration, including corrections for systematic biases and uncertainties, is (8.60 plus or minus 1.34) x 10(exp -8) centimeters per second, directed towards the Sun. This value compares favorably to previous results. I examine the robustness of my result to various perturbations of the analysis method, and find agreement to within plus or minus 5%. The anomalous acceleration is reasonably constant with time, with a characteristic variation time scale of greater than 70 yr. Such a variation timescale is still too short to rule out on-board thermal radiation effects, based on this particular Pioneer 10 data set.

Angular velocities, angular accelerations, and coriolis accelerations

NASA Technical Reports Server (NTRS)

Graybiel, A.

1975-01-01

Weightlessness, rotating environment, and mathematical analysis of Coriolis acceleration is described for man's biological effective force environments. Effects on the vestibular system are summarized, including the end organs, functional neurology, and input-output relations. Ground-based studies in preparation for space missions are examined, including functional tests, provocative tests, adaptive capacity tests, simulation studies, and antimotion sickness.

Accelerated roadbuilding on the north umpqua—an economic analysis.

Treesearch

Brian R. Payne

1972-01-01

This study evaluates the economic desirability of accelerated roadbuilding for access to old-growth timber on a unit of the Umpqua National Forest in Oregon. As of 1966, four accelerated roadbuilding alternatives were found economically inferior to the then current rate of construction. Only in the case of substantial, continuing inflation were projected rates of...

Modeling Acceleration of a System of Two Objects Using the Concept of Limits

ERIC Educational Resources Information Center

Sokolowski, Andrzej

2018-01-01

Traditional school laboratory exercises on a system of moving objects connected by strings involve deriving expressions for the system acceleration, a = (?F)/m, and sketching a graph of acceleration vs. force. While being in the form of rational functions, these expressions present great opportunities for broadening the scope of the analysis by…

Using Hand Grip Force as a Correlate of Longitudinal Acceleration Comfort for Rapid Transit Trains

PubMed Central

Guo, Beiyuan; Gan, Weide; Fang, Weining

2015-01-01

Longitudinal acceleration comfort is one of the essential metrics used to evaluate the ride comfort of train. The aim of this study was to investigate the effectiveness of using hand grip force as a correlate of longitudinal acceleration comfort of rapid transit trains. In the paper, a motion simulation system was set up and a two-stage experiment was designed to investigate the role of the grip force on the longitudinal comfort of rapid transit trains. The results of the experiment show that the incremental grip force was linearly correlated with the longitudinal acceleration value, while the incremental grip force had no correlation with the direction of the longitudinal acceleration vector. The results also show that the effects of incremental grip force and acceleration duration on the longitudinal comfort of rapid transit trains were significant. Based on multiple regression analysis, a step function model was established to predict the longitudinal comfort of rapid transit trains using the incremental grip force and the acceleration duration. The feasibility and practicably of the model was verified by a field test. Furthermore, a comparative analysis shows that the motion simulation system and the grip force based model were valid to support the laboratory studies on the longitudinal comfort of rapid transit trains. PMID:26147730

Wavefront-sensor-based electron density measurements for laser-plasma accelerators.

PubMed

Plateau, G R; Matlis, N H; Geddes, C G R; Gonsalves, A J; Shiraishi, S; Lin, C; van Mourik, R A; Leemans, W P

2010-03-01

Characterization of the electron density in laser produced plasmas is presented using direct wavefront analysis of a probe laser beam. The performance of a laser-driven plasma-wakefield accelerator depends on the plasma wavelength and hence on the electron density. Density measurements using a conventional folded-wave interferometer and using a commercial wavefront sensor are compared for different regimes of the laser-plasma accelerator. It is shown that direct wavefront measurements agree with interferometric measurements and, because of the robustness of the compact commercial device, offer greater phase sensitivity and straightforward analysis, improving shot-to-shot plasma density diagnostics.

Wavefront-sensor-based electron density measurements for laser-plasma accelerators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plateau, Guillaume; Matlis, Nicholas; Geddes, Cameron

2010-02-20

Characterization of the electron density in laser produced plasmas is presented using direct wavefront analysis of a probe laser beam. The performance of a laser-driven plasma-wakefield accelerator depends on the plasma wavelength, hence on the electron density. Density measurements using a conventional folded-wave interferometer and using a commercial wavefront sensor are compared for different regimes of the laser-plasma accelerator. It is shown that direct wavefront measurements agree with interferometric measurements and, because of the robustness of the compact commercial device, have greater phase sensitivity, straightforward analysis, improving shot-to-shot plasma-density diagnostics.

Genetic analysis of post-mating reproductive barriers in hybridizing European Populus species

PubMed Central

Macaya-Sanz, D; Suter, L; Joseph, J; Barbará, T; Alba, N; González-Martínez, S C; Widmer, A; Lexer, C

2011-01-01

Molecular genetic analyses of experimental crosses provide important information on the strength and nature of post-mating barriers to gene exchange between divergent populations, which are topics of great interest to evolutionary geneticists and breeders. Although not a trivial task in long-lived organisms such as trees, experimental interspecific recombinants can sometimes be created through controlled crosses involving natural F1's. Here, we used this approach to understand the genetics of post-mating isolation and barriers to introgression in Populus alba and Populus tremula, two ecologically divergent, hybridizing forest trees. We studied 86 interspecific backcross (BC1) progeny and >350 individuals from natural populations of these species for up to 98 nuclear genetic markers, including microsatellites, indels and single nucleotide polymorphisms, and inferred the origin of the cytoplasm of the cross with plastid DNA. Genetic analysis of the BC1 revealed extensive segregation distortions on six chromosomes, and >90% of these (12 out of 13) favored P. tremula donor alleles in the heterospecific genomic background. Since selection was documented during early diploid stages of the progeny, this surprising result was attributed to epistasis, cyto-nuclear coadaptation, heterozygote advantage at nuclear loci experiencing introgression or a combination of these. Our results indicate that gene flow across ‘porous' species barriers affects these poplars and aspens beyond neutral, Mendelian expectations and suggests the mechanisms responsible. Contrary to expectations, the Populus sex determination region is not protected from introgression. Understanding the population dynamics of the Populus sex determination region will require tests based on natural interspecific hybrid zones. PMID:21587301

Genetic analysis of post-mating reproductive barriers in hybridizing European Populus species.

PubMed

Macaya-Sanz, D; Suter, L; Joseph, J; Barbará, T; Alba, N; González-Martínez, S C; Widmer, A; Lexer, C

2011-10-01

Molecular genetic analyses of experimental crosses provide important information on the strength and nature of post-mating barriers to gene exchange between divergent populations, which are topics of great interest to evolutionary geneticists and breeders. Although not a trivial task in long-lived organisms such as trees, experimental interspecific recombinants can sometimes be created through controlled crosses involving natural F(1)'s. Here, we used this approach to understand the genetics of post-mating isolation and barriers to introgression in Populus alba and Populus tremula, two ecologically divergent, hybridizing forest trees. We studied 86 interspecific backcross (BC(1)) progeny and >350 individuals from natural populations of these species for up to 98 nuclear genetic markers, including microsatellites, indels and single nucleotide polymorphisms, and inferred the origin of the cytoplasm of the cross with plastid DNA. Genetic analysis of the BC(1) revealed extensive segregation distortions on six chromosomes, and >90% of these (12 out of 13) favored P. tremula donor alleles in the heterospecific genomic background. Since selection was documented during early diploid stages of the progeny, this surprising result was attributed to epistasis, cyto-nuclear coadaptation, heterozygote advantage at nuclear loci experiencing introgression or a combination of these. Our results indicate that gene flow across 'porous' species barriers affects these poplars and aspens beyond neutral, Mendelian expectations and suggests the mechanisms responsible. Contrary to expectations, the Populus sex determination region is not protected from introgression. Understanding the population dynamics of the Populus sex determination region will require tests based on natural interspecific hybrid zones.

RAB-7 Antagonizes LET-23 EGFR Signaling during Vulva Development in Caenorhabditis elegans

PubMed Central

Skorobogata, Olga; Rocheleau, Christian E.

2012-01-01

The Rab7 GTPase regulates late endosome trafficking of the Epidermal Growth Factor Receptor (EGFR) to the lysosome for degradation. However, less is known about how Rab7 activity, functioning late in the endocytic pathway, affects EGFR signaling. Here we used Caenorhabditis elegans vulva cell fate induction, a paradigm for genetic analysis of EGFR/Receptor Tyrosine Kinase (RTK) signaling, to assess the genetic requirements for rab-7. Using a rab-7 deletion mutant, we demonstrate that rab-7 antagonizes LET-23 EGFR signaling to a similar extent, but in a distinct manner, as previously described negative regulators such as sli-1 c-Cbl. Epistasis analysis places rab-7 upstream of or in parallel to lin-3 EGF and let-23 EGFR. However, expression of gfp::rab-7 in the Vulva Presursor Cells (VPCs) is sufficient to rescue the rab-7(−) VPC induction phenotypes indicating that RAB-7 functions in the signal receiving cell. We show that components of the Endosomal Sorting Complex Required for Transport (ESCRT)-0, and -I, complexes, hgrs-1 Hrs, and vps-28, also antagonize signaling, suggesting that LET-23 EGFR likely transits through Multivesicular Bodies (MVBs) en route to the lysosome. Consistent with RAB-7 regulating LET-23 EGFR trafficking, rab-7 mutants have increased number of LET-23::GFP-positive endosomes. Our data imply that Rab7, by mediating EGFR trafficking and degradation, plays an important role in downregulation of EGFR signaling. Failure to downregulate EGFR signaling contributes to oncogenesis, and thus Rab7 could possess tumor suppressor activity in humans. PMID:22558469

A Computational Approach to Estimating Nondisjunction Frequency in Saccharomyces cerevisiae

PubMed Central

Chu, Daniel B.; Burgess, Sean M.

2016-01-01

Errors segregating homologous chromosomes during meiosis result in aneuploid gametes and are the largest contributing factor to birth defects and spontaneous abortions in humans. Saccharomyces cerevisiae has long served as a model organism for studying the gene network supporting normal chromosome segregation. Measuring homolog nondisjunction frequencies is laborious, and involves dissecting thousands of tetrads to detect missegregation of individually marked chromosomes. Here we describe a computational method (TetFit) to estimate the relative contributions of meiosis I nondisjunction and random-spore death to spore inviability in wild type and mutant strains. These values are based on finding the best-fit distribution of 4, 3, 2, 1, and 0 viable-spore tetrads to an observed distribution. Using TetFit, we found that meiosis I nondisjunction is an intrinsic component of spore inviability in wild-type strains. We show proof-of-principle that the calculated average meiosis I nondisjunction frequency determined by TetFit closely matches empirically determined values in mutant strains. Using these published data sets, TetFit uncovered two classes of mutants: Class A mutants skew toward increased nondisjunction death, and include those with known defects in establishing pairing, recombination, and/or synapsis of homologous chromosomes. Class B mutants skew toward random spore death, and include those with defects in sister-chromatid cohesion and centromere function. Epistasis analysis using TetFit is facilitated by the low numbers of tetrads (as few as 200) required to compare the contributions to spore death in different mutant backgrounds. TetFit analysis does not require any special strain construction, and can be applied to previously observed tetrad distributions. PMID:26747203

Functional characterization of two SOS-regulated genes involved in mitomycin C resistance in Caulobacter crescentus.

PubMed

Lopes-Kulishev, Carina O; Alves, Ingrid R; Valencia, Estela Y; Pidhirnyj, María I; Fernández-Silva, Frank S; Rodrigues, Ticiane R; Guzzo, Cristiane R; Galhardo, Rodrigo S

2015-09-01

The SOS response is a universal bacterial regulon involved in the cellular response to DNA damage and other forms of stress. In Caulobacter crescentus, previous work has identified a plethora of genes that are part of the SOS regulon, but the biological roles of several of them remain to be determined. In this study, we report that two genes, hereafter named mmcA and mmcB, are involved in the defense against DNA damage caused by mitomycin C (MMC), but not against lesions induced by other common DNA damaging agents, such as UVC light, methyl methanesulfonate (MMS) and hydrogen peroxide. mmcA is a conserved gene that encodes a member of the glyoxalases/dioxygenases protein family, and acts independently of known DNA repair pathways. On the other hand, epistasis analysis showed that mmcB acts in the same pathway as imuC (dnaE2), and is required specifically for MMC-induced mutagenesis, but not for that induced by UV light, suggesting a role for MmcB in translesion synthesis-dependent repair of MMC damage. We show that the lack of MMC-induced mutability in the mmcB strain is not caused by lack of proper SOS induction of the imuABC operon, involved in translesion synthesis (TLS) in C. crescentus. Based on this data and on structural analysis of a close homolog, we propose that MmcB is an endonuclease which creates substrates for ImuABC-mediated TLS patches. Copyright © 2015 Elsevier B.V. All rights reserved.

RAB-7 antagonizes LET-23 EGFR signaling during vulva development in Caenorhabditis elegans.

PubMed

Skorobogata, Olga; Rocheleau, Christian E

2012-01-01

The Rab7 GTPase regulates late endosome trafficking of the Epidermal Growth Factor Receptor (EGFR) to the lysosome for degradation. However, less is known about how Rab7 activity, functioning late in the endocytic pathway, affects EGFR signaling. Here we used Caenorhabditis elegans vulva cell fate induction, a paradigm for genetic analysis of EGFR/Receptor Tyrosine Kinase (RTK) signaling, to assess the genetic requirements for rab-7. Using a rab-7 deletion mutant, we demonstrate that rab-7 antagonizes LET-23 EGFR signaling to a similar extent, but in a distinct manner, as previously described negative regulators such as sli-1 c-Cbl. Epistasis analysis places rab-7 upstream of or in parallel to lin-3 EGF and let-23 EGFR. However, expression of gfp::rab-7 in the Vulva Presursor Cells (VPCs) is sufficient to rescue the rab-7(-) VPC induction phenotypes indicating that RAB-7 functions in the signal receiving cell. We show that components of the Endosomal Sorting Complex Required for Transport (ESCRT)-0, and -I, complexes, hgrs-1 Hrs, and vps-28, also antagonize signaling, suggesting that LET-23 EGFR likely transits through Multivesicular Bodies (MVBs) en route to the lysosome. Consistent with RAB-7 regulating LET-23 EGFR trafficking, rab-7 mutants have increased number of LET-23::GFP-positive endosomes. Our data imply that Rab7, by mediating EGFR trafficking and degradation, plays an important role in downregulation of EGFR signaling. Failure to downregulate EGFR signaling contributes to oncogenesis, and thus Rab7 could possess tumor suppressor activity in humans.

Genome wide analysis of flowering time trait in multiple environments via high-throughput genotyping technique in Brassica napus L.

PubMed

Li, Lun; Long, Yan; Zhang, Libin; Dalton-Morgan, Jessica; Batley, Jacqueline; Yu, Longjiang; Meng, Jinling; Li, Maoteng

2015-01-01

The prediction of the flowering time (FT) trait in Brassica napus based on genome-wide markers and the detection of underlying genetic factors is important not only for oilseed producers around the world but also for the other crop industry in the rotation system in China. In previous studies the low density and mixture of biomarkers used obstructed genomic selection in B. napus and comprehensive mapping of FT related loci. In this study, a high-density genome-wide SNP set was genotyped from a double-haploid population of B. napus. We first performed genomic prediction of FT traits in B. napus using SNPs across the genome under ten environments of three geographic regions via eight existing genomic predictive models. The results showed that all the models achieved comparably high accuracies, verifying the feasibility of genomic prediction in B. napus. Next, we performed a large-scale mapping of FT related loci among three regions, and found 437 associated SNPs, some of which represented known FT genes, such as AP1 and PHYE. The genes tagged by the associated SNPs were enriched in biological processes involved in the formation of flowers. Epistasis analysis showed that significant interactions were found between detected loci, even among some known FT related genes. All the results showed that our large scale and high-density genotype data are of great practical and scientific values for B. napus. To our best knowledge, this is the first evaluation of genomic selection models in B. napus based on a high-density SNP dataset and large-scale mapping of FT loci.

A detailed view on Model-Based Multifactor Dimensionality Reduction for detecting gene-gene interactions in case-control data in the absence and presence of noise

PubMed Central

CATTAERT, TOM; CALLE, M. LUZ; DUDEK, SCOTT M.; MAHACHIE JOHN, JESTINAH M.; VAN LISHOUT, FRANÇOIS; URREA, VICTOR; RITCHIE, MARYLYN D.; VAN STEEN, KRISTEL

2010-01-01

SUMMARY Analyzing the combined effects of genes and/or environmental factors on the development of complex diseases is a great challenge from both the statistical and computational perspective, even using a relatively small number of genetic and non-genetic exposures. Several data mining methods have been proposed for interaction analysis, among them, the Multifactor Dimensionality Reduction Method (MDR), which has proven its utility in a variety of theoretical and practical settings. Model-Based Multifactor Dimensionality Reduction (MB-MDR), a relatively new MDR-based technique that is able to unify the best of both non-parametric and parametric worlds, was developed to address some of the remaining concerns that go along with an MDR-analysis. These include the restriction to univariate, dichotomous traits, the absence of flexible ways to adjust for lower-order effects and important confounders, and the difficulty to highlight epistasis effects when too many multi-locus genotype cells are pooled into two new genotype groups. Whereas the true value of MB-MDR can only reveal itself by extensive applications of the method in a variety of real-life scenarios, here we investigate the empirical power of MB-MDR to detect gene-gene interactions in the absence of any noise and in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. For the considered simulation settings, we show that the power is generally higher for MB-MDR than for MDR, in particular in the presence of genetic heterogeneity, phenocopy, or low minor allele frequencies. PMID:21158747

Layers of epistasis: genome-wide regulatory networks and network approaches to genome-wide association studies.

PubMed

Cowper-Sal lari, Richard; Cole, Michael D; Karagas, Margaret R; Lupien, Mathieu; Moore, Jason H

2011-01-01

The conceptual foundation of the genome-wide association study (GWAS) has advanced unchecked since its conception. A revision might seem premature as the potential of GWAS has not been fully realized. Multiple technical and practical limitations need to be overcome before GWAS can be fairly criticized. But with the completion of hundreds of studies and a deeper understanding of the genetic architecture of disease, warnings are being raised. The results compiled to date indicate that risk-associated variants lie predominantly in noncoding regions of the genome. Additionally, alternative methodologies are uncovering large and heterogeneous sets of rare variants underlying disease. The fear is that, even in its fulfillment, the current GWAS paradigm might be incapable of dissecting all kinds of phenotypes. In the following text, we review several initiatives that aim to overcome these limitations. The overarching theme of these studies is the inclusion of biological knowledge to both the analysis and interpretation of genotyping data. GWAS is uninformed of biology by design and although there is some virtue in its simplicity, it is also its most conspicuous deficiency. We propose a framework in which to integrate these novel approaches, both empirical and theoretical, in the form of a genome-wide regulatory network (GWRN). By processing experimental data into networks, emerging data types based on chromatin immunoprecipitation are made computationally tractable. This will give GWAS re-analysis efforts the most current and relevant substrates, and root them firmly on our knowledge of human disease. Copyright © 2010 John Wiley & Sons, Inc.

Modelling of proton acceleration in application to a ground level enhancement

NASA Astrophysics Data System (ADS)

Afanasiev, A.; Vainio, R.; Rouillard, A. P.; Battarbee, M.; Aran, A.; Zucca, P.

2018-06-01

Context. The source of high-energy protons (above 500 MeV) responsible for ground level enhancements (GLEs) remains an open question in solar physics. One of the candidates is a shock wave driven by a coronal mass ejection, which is thought to accelerate particles via diffusive-shock acceleration. Aims: We perform physics-based simulations of proton acceleration using information on the shock and ambient plasma parameters derived from the observation of a real GLE event. We analyse the simulation results to find out which of the parameters are significant in controlling the acceleration efficiency and to get a better understanding of the conditions under which the shock can produce relativistic protons. Methods: We use the results of the recently developed technique to determine the shock and ambient plasma parameters, applied to the 17 May 2012 GLE event, and carry out proton acceleration simulations with the Coronal Shock Acceleration (CSA) model. Results: We performed proton acceleration simulations for nine individual magnetic field lines characterised by various plasma conditions. Analysis of the simulation results shows that the acceleration efficiency of the shock, i.e. its ability to accelerate particles to high energies, tends to be higher for those shock portions that are characterised by higher values of the scattering-centre compression ratio rc and/or the fast-mode Mach number MFM. At the same time, the acceleration efficiency can be strengthened by enhanced plasma density in the corresponding flux tube. The simulations show that protons can be accelerated to GLE energies in the shock portions characterised by the highest values of rc. Analysis of the delays between the flare onset and the production times of protons of 1 GV rigidity for different field lines in our simulations, and a subsequent comparison of those with the observed values indicate a possibility that quasi-perpendicular portions of the shock play the main role in producing relativistic protons.

Response of long, flexible cantilever beams applied root motions. [spacecraft structures

NASA Technical Reports Server (NTRS)

Fralich, R. W.

1976-01-01

Results are presented for an analysis of the response of long, flexible cantilever beams to applied root rotational accelerations. Maximum values of deformation, slope, bending moment, and shear are found as a function of magnitude and duration of acceleration input. Effects of tip mass and its eccentricity and rotatory inertia on the response are also investigated. It is shown that flexible beams can withstand large root accelerations provided the period of applied acceleration can be kept small relative to the beam fundamental period.

Detection of linear ego-acceleration from optic flow.

PubMed

Festl, Freya; Recktenwald, Fabian; Yuan, Chunrong; Mallot, Hanspeter A

2012-07-20

Human observers are able to estimate various ego-motion parameters from optic flow, including rotation, translational heading, time-to-collision (TTC), time-to-passage (TTP), etc. The perception of linear ego-acceleration or deceleration, i.e., changes of translational velocity, is less well understood. While time-to-passage experiments indicate that ego-acceleration is neglected, subjects are able to keep their (perceived) speed constant under changing conditions, indicating that some sense of ego-acceleration or velocity change must be present. In this paper, we analyze the relation of ego-acceleration estimates and geometrical parameters of the environment using simulated flights through cylindrical and conic (narrowing or widening) corridors. Theoretical analysis shows that a logarithmic ego-acceleration parameter, called the acceleration rate ρ, can be calculated from retinal acceleration measurements. This parameter is independent of the geometrical layout of the scene; if veridical ego-motion is known at some instant in time, acceleration rate allows updating of ego-motion without further depth-velocity calibration. Results indicate, however, that subjects systematically confuse ego-acceleration with corridor narrowing and ego-deceleration with corridor widening, while veridically judging ego-acceleration in straight corridors. We conclude that judgments of ego-acceleration are based on first-order retinal flow and do not make use of acceleration rate or retinal acceleration.

CD44 functions in Wnt signaling by regulating LRP6 localization and activation

PubMed Central

Schmitt, M; Metzger, M; Gradl, D; Davidson, G; Orian-Rousseau, V

2015-01-01

Wnt reception at the membrane is complex and not fully understood. CD44 is a major Wnt target gene in the intestine and is essential for Wnt-induced tumor progression in colorectal cancer. Here we show that CD44 acts as a positive regulator of the Wnt receptor complex. Downregulation of CD44 expression decreases, whereas CD44 overexpression increases Wnt activity in a concentration-dependent manner. Epistasis experiments place CD44 function at the level of the Wnt receptor LRP6. Mechanistically, CD44 physically associates with LRP6 upon Wnt treatment and modulates LRP6 membrane localization. Moreover, CD44 regulates Wnt signaling in the developing brain of Xenopus laevis embryos as shown by a decreased expression of Wnt targets tcf-4 and en-2 in CD44 morphants. PMID:25301071

STS-107 Microgravity Environment Summary Report

NASA Technical Reports Server (NTRS)

Jules, Kenol; Hrovat, Kenneth; Kelly, Eric; Reckhart, Timothy

2005-01-01

This summary report presents the results of the processed acceleration data measured aboard the Columbia orbiter during the STS-107 microgravity mission from January 16 to February 1, 2003. Two accelerometer systems were used to measure the acceleration levels due to vehicle and science operations activities that took place during the 16-day mission. Due to lack of precise timeline information regarding some payload's operations, not all of the activities were analyzed for this report. However, a general characterization of the microgravity environment of the Columbia Space Shuttle during the 16-day mission is presented followed by a more specific characterization of the environment for some designated payloads during their operations. Some specific quasi-steady and vibratory microgravity environment characterization analyses were performed for the following payloads: Structure of Flame Balls at Low Lewis-number-2, Laminar Soot Processes-2, Mechanics of Granular Materials-3 and Water Mist Fire-Suppression Experiment. The Physical Science Division of the National Aeronautics and Space Administration sponsors the Orbital Acceleration Research Experiment and the Space Acceleration Measurement System for Free Flyer to support microgravity science experiments, which require microgravity acceleration measurements. On January 16, 2003, both the Orbital Acceleration Research Experiment and the Space Acceleration Measurement System for Free Flyer accelerometer systems were launched on the Columbia Space Transportation System-107 from the Kennedy Space Center. The Orbital Acceleration Research Experiment supported science experiments requiring quasi-steady acceleration measurements, while the Space Acceleration Measurement System for Free Flyer unit supported experiments requiring vibratory acceleration measurement. The Columbia reduced gravity environment analysis presented in this report uses acceleration data collected by these two sets of accelerometer systems: The Orbital Acceleration Research Experiment is a low frequency sensor, which measures acceleration up to 1 Hz, but the 1 Hz acceleration data is trimmean filtered to yield much lower frequency acceleration data up to 0.01 Hz. This filtered data can be mapped to other locations for characterizing the quasi-steady environment for payloads and the vehicle. The Space Acceleration Measurement System for Free Flyer measures vibratory acceleration in the range of 0.01 to 200 Hz at multiple measurement locations. The vibratory acceleration data measured by this system is used to assess the local vibratory environment for payloads as well as to measure the disturbance causes by the vehicle systems, crew exercise devices and payloads operation disturbances. This summary report presents analysis of selected quasi-steady and vibratory activities measured by these two accelerometers during the Columbia 16-day microgravity mission from January 16 to February 1, 2003.

Analysis of flame acceleration in open or vented obstructed pipes

NASA Astrophysics Data System (ADS)

Bychkov, Vitaly; Sadek, Jad; Akkerman, V'yacheslav

2017-01-01

While flame propagation through obstacles is often associated with turbulence and/or shocks, Bychkov et al. [V. Bychkov et al., Phys. Rev. Lett. 101, 164501 (2008), 10.1103/PhysRevLett.101.164501] have revealed a shockless, conceptually laminar mechanism of extremely fast flame acceleration in semiopen obstructed pipes (one end of a pipe is closed; a flame is ignited at the closed end and propagates towards the open one). The acceleration is devoted to a powerful jet flow produced by delayed combustion in the spaces between the obstacles, with turbulence playing only a supplementary role in this process. In the present work, this formulation is extended to pipes with both ends open in order to describe the recent experiments and modeling by Yanez et al. [J. Yanez et al., arXiv:1208.6453] as well as the simulations by Middha and Hansen [P. Middha and O. R. Hansen, Process Safety Prog. 27, 192 (2008) 10.1002/prs.10242]. It is demonstrated that flames accelerate strongly in open or vented obstructed pipes and the acceleration mechanism is similar to that in semiopen ones (shockless and laminar), although acceleration is weaker in open pipes. Starting with an inviscid approximation, we subsequently incorporate hydraulic resistance (viscous forces) into the analysis for the sake of comparing its role to that of a jet flow driving acceleration. It is shown that hydraulic resistance is actually not required to drive flame acceleration. In contrast, this is a supplementary effect, which moderates acceleration. On the other hand, viscous forces are nevertheless an important effect because they are responsible for the initial delay occurring before the flame acceleration onset, which is observed in the experiments and simulations. Accounting for this effect provides good agreement between the experiments, modeling, and the present theory.

Muscle contributions to the acceleration of the whole body centre of mass during recovery from forward loss of balance by stepping in young and older adults.

PubMed

Graham, David F; Carty, Christopher P; Lloyd, David G; Barrett, Rod S

2017-01-01

The purpose of this study was to determine the muscular contributions to the acceleration of the whole body centre of mass (COM) of older compared to younger adults that were able to recover from forward loss of balance with a single step. Forward loss of balance was achieved by releasing participants (14 older adults and 6 younger adults) from a static whole-body forward lean angle of approximately 18 degrees. 10 older adults and 6 younger adults were able to recover with a single step and included in subsequent analysis. A scalable anatomical model consisting of 36 degrees-of-freedom was used to compute kinematics and joint moments from motion capture and force plate data. Forces for 92 muscle actuators were computed using Static Optimisation and Induced Acceleration Analysis was used to compute individual muscle contributions to the three-dimensional acceleration of the whole body COM. There were no significant differences between older and younger adults in step length, step time, 3D COM accelerations or muscle contributions to 3D COM accelerations. The stance and stepping leg Gastrocnemius and Soleus muscles were primarily responsible for the vertical acceleration experienced by the COM. The Gastrocnemius and Soleus from the stance side leg together with bilateral Hamstrings accelerated the COM forwards throughout balance recovery while the Vasti and Soleus of the stepping side leg provided the majority of braking accelerations following foot contact. The Hip Abductor muscles provided the greatest contribution to medial-lateral accelerations of the COM. Deficits in the neuromuscular control of the Gastrocnemius, Soleus, Vasti and Hip Abductors in particular could adversely influence balance recovery and may be important targets in interventions to improve balance recovery performance.

Muscle contributions to the acceleration of the whole body centre of mass during recovery from forward loss of balance by stepping in young and older adults

PubMed Central

Graham, David F.; Carty, Christopher P.; Lloyd, David G.

2017-01-01

The purpose of this study was to determine the muscular contributions to the acceleration of the whole body centre of mass (COM) of older compared to younger adults that were able to recover from forward loss of balance with a single step. Forward loss of balance was achieved by releasing participants (14 older adults and 6 younger adults) from a static whole-body forward lean angle of approximately 18 degrees. 10 older adults and 6 younger adults were able to recover with a single step and included in subsequent analysis. A scalable anatomical model consisting of 36 degrees-of-freedom was used to compute kinematics and joint moments from motion capture and force plate data. Forces for 92 muscle actuators were computed using Static Optimisation and Induced Acceleration Analysis was used to compute individual muscle contributions to the three-dimensional acceleration of the whole body COM. There were no significant differences between older and younger adults in step length, step time, 3D COM accelerations or muscle contributions to 3D COM accelerations. The stance and stepping leg Gastrocnemius and Soleus muscles were primarily responsible for the vertical acceleration experienced by the COM. The Gastrocnemius and Soleus from the stance side leg together with bilateral Hamstrings accelerated the COM forwards throughout balance recovery while the Vasti and Soleus of the stepping side leg provided the majority of braking accelerations following foot contact. The Hip Abductor muscles provided the greatest contribution to medial-lateral accelerations of the COM. Deficits in the neuromuscular control of the Gastrocnemius, Soleus, Vasti and Hip Abductors in particular could adversely influence balance recovery and may be important targets in interventions to improve balance recovery performance. PMID:29069097

Accelerated test program

NASA Technical Reports Server (NTRS)

Ford, F. E.; Harkness, J. M.

1977-01-01

A brief discussion on the accelerated testing of batteries is given. The statistical analysis and the various aspects of the modeling that was done and the results attained from the model are also briefly discussed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rubel, Oliver; Loring, Burlen; Vay, Jean -Luc

The generation of short pulses of ion beams through the interaction of an intense laser with a plasma sheath offers the possibility of compact and cheaper ion sources for many applications--from fast ignition and radiography of dense targets to hadron therapy and injection into conventional accelerators. To enable the efficient analysis of large-scale, high-fidelity particle accelerator simulations using the Warp simulation suite, the authors introduce the Warp In situ Visualization Toolkit (WarpIV). WarpIV integrates state-of-the-art in situ visualization and analysis using VisIt with Warp, supports management and control of complex in situ visualization and analysis workflows, and implements integrated analyticsmore » to facilitate query- and feature-based data analytics and efficient large-scale data analysis. WarpIV enables for the first time distributed parallel, in situ visualization of the full simulation data using high-performance compute resources as the data is being generated by Warp. The authors describe the application of WarpIV to study and compare large 2D and 3D ion accelerator simulations, demonstrating significant differences in the acceleration process in 2D and 3D simulations. WarpIV is available to the public via https://bitbucket.org/berkeleylab/warpiv. The Warp In situ Visualization Toolkit (WarpIV) supports large-scale, parallel, in situ visualization and analysis and facilitates query- and feature-based analytics, enabling for the first time high-performance analysis of large-scale, high-fidelity particle accelerator simulations while the data is being generated by the Warp simulation suite. Furthermore, this supplemental material https://extras.computer.org/extra/mcg2016030022s1.pdf provides more details regarding the memory profiling and optimization and the Yee grid recentering optimization results discussed in the main article.« less

An extended car-following model considering the acceleration derivative in some typical traffic environments

NASA Astrophysics Data System (ADS)

Zhou, Tong; Chen, Dong; Liu, Weining

2018-03-01

Based on the full velocity difference and acceleration car-following model, an extended car-following model is proposed by considering the vehicle’s acceleration derivative. The stability condition is given by applying the control theory. Considering some typical traffic environments, the results of theoretical analysis and numerical simulation show the extended model has a more actual acceleration of string vehicles than that of the previous models in starting process, stopping process and sudden brake. Meanwhile, the traffic jams more easily occur when the coefficient of vehicle’s acceleration derivative increases, which is presented by space-time evolution. The results confirm that the vehicle’s acceleration derivative plays an important role in the traffic jamming transition and the evolution of traffic congestion.

The Impact of Back-Sputtered Carbon on the Accelerator Grid Wear Rates of the NEXT and NSTAR Ion Thrusters

NASA Technical Reports Server (NTRS)

Soulas, George C.

2013-01-01

A study was conducted to quantify the impact of back-sputtered carbon on the downstream accelerator grid erosion rates of the NASA's Evolutionary Xenon Thruster (NEXT) Long Duration Test (LDT1). A similar analysis that was conducted for the NASA's Solar Electric Propulsion Technology Applications Readiness Program (NSTAR) Life Demonstration Test (LDT2) was used as a foundation for the analysis developed herein. A new carbon surface coverage model was developed that accounted for multiple carbon adlayers before complete surface coverage is achieved. The resulting model requires knowledge of more model inputs, so they were conservatively estimated using the results of past thin film sputtering studies and particle reflection predictions. In addition, accelerator current densities across the grid were rigorously determined using an ion optics code to determine accelerator current distributions and an algorithm to determine beam current densities along a grid using downstream measurements. The improved analysis was applied to the NSTAR test results for evaluation. The improved analysis demonstrated that the impact of back-sputtered carbon on pit and groove wear rate for the NSTAR LDT2 was negligible throughout most of eroded grid radius. The improved analysis also predicted the accelerator current density for transition from net erosion to net deposition considerably more accurately than the original analysis. The improved analysis was used to estimate the impact of back-sputtered carbon on the accelerator grid pit and groove wear rate of the NEXT Long Duration Test (LDT1). Unlike the NSTAR analysis, the NEXT analysis was more challenging because the thruster was operated for extended durations at various operating conditions and was unavailable for measurements because the test is ongoing. As a result, the NEXT LDT1 estimates presented herein are considered preliminary until the results of future post-test analyses are incorporated. The worst-case impact of carbon back-sputtering was determined to be the full power operating condition, but the maximum impact of back-sputtered carbon was only a 4 percent reduction in wear rate. As a result, back-sputtered carbon is estimated to have an insignificant impact on the first failure mode of the NEXT LDT1 at all operating conditions.

Shelf-Stable Adhesive for Reduction of Composite Repair Hazardous Waste

DTIC Science & Technology

2008-09-01

1. Our microencapsulation approach is compatible with commonly used epoxy resins and catalyst accelerants 2. The microcapsules can be...thermally stable barrier to diffusion of accelerant and/or epoxy resin through the capsule’s walls [14]. 3.2 Microencapsulation Microcapsules ... microencapsulation of the catalyst accelerant. Thermal analysis of microcapsules made from carrageenan blends showed that they formed an effective

Sensitivity analysis of tall buildings in Semarang, Indonesia due to fault earthquakes with maximum 7 Mw

NASA Astrophysics Data System (ADS)

Partono, Windu; Pardoyo, Bambang; Atmanto, Indrastono Dwi; Azizah, Lisa; Chintami, Rouli Dian

2017-11-01

Fault is one of the dangerous earthquake sources that can cause building failure. A lot of buildings were collapsed caused by Yogyakarta (2006) and Pidie (2016) fault source earthquakes with maximum magnitude 6.4 Mw. Following the research conducted by Team for Revision of Seismic Hazard Maps of Indonesia 2010 and 2016, Lasem, Demak and Semarang faults are three closest earthquake sources surrounding Semarang. The ground motion from those three earthquake sources should be taken into account for structural design and evaluation. Most of tall buildings, with minimum 40 meter high, in Semarang were designed and constructed following the 2002 and 2012 Indonesian Seismic Code. This paper presents the result of sensitivity analysis research with emphasis on the prediction of deformation and inter-story drift of existing tall building within the city against fault earthquakes. The analysis was performed by conducting dynamic structural analysis of 8 (eight) tall buildings using modified acceleration time histories. The modified acceleration time histories were calculated for three fault earthquakes with magnitude from 6 Mw to 7 Mw. The modified acceleration time histories were implemented due to inadequate time histories data caused by those three fault earthquakes. Sensitivity analysis of building against earthquake can be predicted by evaluating surface response spectra calculated using seismic code and surface response spectra calculated from acceleration time histories from a specific earthquake event. If surface response spectra calculated using seismic code is greater than surface response spectra calculated from acceleration time histories the structure will stable enough to resist the earthquake force.

Accelerated Near-Threshold Fatigue Crack Growth Behavior of an Aluminum Powder Metallurgy Alloy

NASA Technical Reports Server (NTRS)

Piascik, Robert S.; Newman, John A.

2002-01-01

Fatigue crack growth (FCG) research conducted in the near threshold regime has identified a room temperature creep crack growth damage mechanism for a fine grain powder metallurgy (PM) aluminum alloy (8009). At very low DK, an abrupt acceleration in room temperature FCG rate occurs at high stress ratio (R = Kmin/Kmax). The near threshold accelerated FCG rates are exacerbated by increased levels of Kmax (Kmax less than 0.4 KIC). Detailed fractographic analysis correlates accelerated FCG with the formation of crack-tip process zone micro-void damage. Experimental results show that the near threshold and Kmax influenced accelerated crack growth is time and temperature dependent.

An enhancement of NASTRAN for the seismic analysis of structures. [nuclear power plants

NASA Technical Reports Server (NTRS)

Burroughs, J. W.

1980-01-01

New modules, bulk data cards and DMAP sequence were added to NASTRAN to aid in the seismic analysis of nuclear power plant structures. These allow input consisting of acceleration time histories and result in the generation of acceleration floor response spectra. The resulting system contains numerous user convenience features, as well as being reasonably efficient.

Derivation of improved load transformation matrices for launchers-spacecraft coupled analysis, and direct computation of margins of safety

NASA Technical Reports Server (NTRS)

Klein, M.; Reynolds, J.; Ricks, E.

1989-01-01

Load and stress recovery from transient dynamic studies are improved upon using an extended acceleration vector in the modal acceleration technique applied to structural analysis. Extension of the normal LTM (load transformation matrices) stress recovery to automatically compute margins of safety is presented with an application to the Hubble space telescope.

The ASTRO-1 preliminary design review coupled load analysis

NASA Technical Reports Server (NTRS)

Mcghee, D. S.

1984-01-01

Results of the ASTRO-1 preliminary design review coupled loads analysis are presented. The M6.0Y Generic Shuttle mathematical models were used. Internal accelerations, interface forces, relative displacements, and net e.g., accelerations were recovered for two ASTRO-1 payloads in a tandem configuration. Twenty-seven load cases were computed and summarized. Load exceedences were found and recommendations made.

TrackPlot Enhancements: Support for Multiple Animal Tracks and Gyros

DTIC Science & Technology

2015-09-30

visualization and kinematic analysis of marine animal movements derived from archival tag data. Tags are supported that have sensors for pressure, acceleration...1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. TrackPlot Enhancements: Support for Multiple Animal ...in combination with accelerometer and magnetometer data. 2) the extraction and frequency analysis of accelerations and rotation in animal

Estimation of Stresses in a Dry Sand Layer Tested on Shaking Table

NASA Astrophysics Data System (ADS)

Sawicki, Andrzej; Kulczykowski, Marek; Jankowski, Robert

2012-12-01

Theoretical analysis of shaking table experiments, simulating earthquake response of a dry sand layer, is presented. The aim of such experiments is to study seismic-induced compaction of soil and resulting settlements. In order to determine the soil compaction, the cyclic stresses and strains should be calculated first. These stresses are caused by the cyclic horizontal acceleration at the base of soil layer, so it is important to determine the stress field as function of the base acceleration. It is particularly important for a proper interpretation of shaking table tests, where the base acceleration is controlled but the stresses are hard to measure, and they can only be deduced. Preliminary experiments have shown that small accelerations do not lead to essential settlements, whilst large accelerations cause some phenomena typical for limit states, including a visible appearance of slip lines. All these problems should be well understood for rational planning of experiments. The analysis of these problems is presented in this paper. First, some heuristic considerations about the dynamics of experimental system are presented. Then, the analysis of boundary conditions, expressed as resultants of respective stresses is shown. A particular form of boundary conditions has been chosen, which satisfies the macroscopic boundary conditions and the equilibrium equations. Then, some considerations are presented in order to obtain statically admissible stress field, which does not exceed the Coulomb-Mohr yield conditions. Such an approach leads to determination of the limit base accelerations, which do not cause the plastic state in soil. It was shown that larger accelerations lead to increase of the lateral stresses, and the respective method, which may replace complex plasticity analyses, is proposed. It is shown that it is the lateral stress coefficient K0 that controls the statically admissible stress field during the shaking table experiments.

Analysis on the time and frequency domains of the acceleration in front crawl stroke.

PubMed

Gil, Joaquín Madera; Moreno, Luis-Millán González; Mahiques, Juan Benavent; Muñoz, Víctor Tella

2012-05-01

The swimming involves accelerations and decelerations in the swimmer's body. Thus, the main objective of this study is to make a temporal and frequency analysis of the acceleration in front crawl swimming, regarding the gender and the performance. The sample was composed by 31 male swimmers (15 of high-level and 16 of low-level) and 20 female swimmers (11 of high-level and 9 of low-level). The acceleration was registered from the third complete cycle during eight seconds in a 25 meters maximum velocity test. A position transducer (200Hz) was used to collect the data, and it was synchronized to an aquatic camera (25Hz). The acceleration in the temporal (root mean square, minimum and maximum of the acceleration) and frequency (power peak, power peak frequency and spectral area) domains was calculated with Fourier analysis, as well as the velocity and the spectrums distribution in function to present one or more main peaks (type 1 and type 2). A one-way ANOVA was used to establish differences between gender and performance. Results show differences between genders in all the temporal domain variables (p<0.05) and only the Spectral Area (SA) in the frequency domain (p<0.05). Between gender and performance, only the Root Mean Square (RMS) showed differences in the performance of the male swimmers (p<0.05) and in the higher level swimmers, the Maximum (Max) and the Power Peak (PP) of the acceleration showed differences between both genders (p<0.05). These results confirms the importance of knowing the RMS to determine the efficiency of the swimmers regarding gender and performance level.

Rapid analysis of scattering from periodic dielectric structures using accelerated Cartesian expansions.

PubMed

Baczewski, Andrew D; Miller, Nicholas C; Shanker, Balasubramaniam

2012-04-01

The analysis of fields in periodic dielectric structures arise in numerous applications of recent interest, ranging from photonic bandgap structures and plasmonically active nanostructures to metamaterials. To achieve an accurate representation of the fields in these structures using numerical methods, dense spatial discretization is required. This, in turn, affects the cost of analysis, particularly for integral-equation-based methods, for which traditional iterative methods require O(N2) operations, N being the number of spatial degrees of freedom. In this paper, we introduce a method for the rapid solution of volumetric electric field integral equations used in the analysis of doubly periodic dielectric structures. The crux of our method is the accelerated Cartesian expansion algorithm, which is used to evaluate the requisite potentials in O(N) cost. Results are provided that corroborate our claims of acceleration without compromising accuracy, as well as the application of our method to a number of compelling photonics applications.

Jerome Lewis Duggan: A Nuclear Physicist and a Well-Known, Six-Decade Accelerator Application Conference (CAARI) Organizer

NASA Astrophysics Data System (ADS)

Del McDaniel, Floyd; Doyle, Barney L.

Jerry Duggan was an experimental MeV-accelerator-based nuclear and atomic physicist who, over the past few decades, played a key role in the important transition of this field from basic to applied physics. His fascination for and application of particle accelerators spanned almost 60 years, and led to important discoveries in the following fields: accelerator-based analysis (accelerator mass spectrometry, ion beam techniques, nuclear-based analysis, nuclear microprobes, neutron techniques); accelerator facilities, stewardship, and technology development; accelerator applications (industrial, medical, security and defense, and teaching with accelerators); applied research with accelerators (advanced synthesis and modification, radiation effects, nanosciences and technology); physics research (atomic and molecular physics, and nuclear physics); and many other areas and applications. Here we describe Jerry’s physics education at the University of North Texas (B. S. and M. S.) and Louisiana State University (Ph.D.). We also discuss his research at UNT, LSU, and Oak Ridge National Laboratory, his involvement with the industrial aspects of accelerators, and his impact on many graduate students, colleagues at UNT and other universities, national laboratories, and industry and acquaintances around the world. Along the way, we found it hard not to also talk about his love of family, sports, fishing, and other recreational activities. While these were significant accomplishments in his life, Jerry will be most remembered for his insight in starting and his industry in maintaining and growing what became one of the most diverse accelerator conferences in the world — the International Conference on the Application of Accelerators in Research and Industry, or what we all know as CAARI. Through this conference, which he ran almost single-handed for decades, Jerry came to know, and became well known by, literally thousands of atomic and nuclear physicists, accelerator engineers and vendors, medical doctors, cultural heritage experts... the list goes on and on. While thousands of his acquaintances already miss Jerry, this is being felt most by his family and us (B.D. and F.D.M).

Jerome Lewis Duggan: A Nuclear Physicist and a Well-Known, Six-Decade Accelerator Application Conference (CAARI) Organizer

NASA Astrophysics Data System (ADS)

Del McDaniel, Floyd; Doyle, Barney L.

Jerry Duggan was an experimental MeV-accelerator-based nuclear and atomic physicist who, over the past few decades, played a key role in the important transition of this field from basic to applied physics. His fascination for and application of particle accelerators spanned almost 60 years, and led to important discoveries in the following fields: accelerator-based analysis (accelerator mass spectrometry, ion beam techniques, nuclear-based analysis, nuclear microprobes, neutron techniques); accelerator facilities, stewardship, and technology development; accelerator applications (industrial, medical, security and defense, and teaching with accelerators); applied research with accelerators (advanced synthesis and modification, radiation effects, nanosciences and technology); physics research (atomic and molecular physics, and nuclear physics); and many other areas and applications. Here we describe Jerry's physics education at the University of North Texas (B. S. and M. S.) and Louisiana State University (Ph.D.). We also discuss his research at UNT, LSU, and Oak Ridge National Laboratory, his involvement with the industrial aspects of accelerators, and his impact on many graduate students, colleagues at UNT and other universities, national laboratories, and industry and acquaintances around the world. Along the way, we found it hard not to also talk about his love of family, sports, fishing, and other recreational activities. While these were significant accomplishments in his life, Jerry will be most remembered for his insight in starting and his industry in maintaining and growing what became one of the most diverse accelerator conferences in the world — the International Conference on the Application of Accelerators in Research and Industry, or what we all know as CAARI. Through this conference, which he ran almost single-handed for decades, Jerry came to know, and became well known by, literally thousands of atomic and nuclear physicists, accelerator engineers and vendors, medical doctors, cultural heritage experts... the list goes on and on. While thousands of his acquaintances already miss Jerry, this is being felt most by his family and us (B.D. and F.D.M).

Short-Term, Intermittent Fasting Induces Long-Lasting Gut Health and TOR-Independent Lifespan Extension.

PubMed

Catterson, James H; Khericha, Mobina; Dyson, Miranda C; Vincent, Alec J; Callard, Rebecca; Haveron, Steven M; Rajasingam, Arjunan; Ahmad, Mumtaz; Partridge, Linda

2018-06-04

Intermittent fasting (IF) can improve function and health during aging in laboratory model organisms, but the mechanisms at work await elucidation. We subjected fruit flies (Drosophila melanogaster) to varying degrees of IF and found that just one month of a 2-day fed:5-day fasted IF regime at the beginning of adulthood was sufficient to extend lifespan. This long-lasting, beneficial effect of early IF was not due to reduced fecundity. Starvation resistance and resistance to oxidative and xenobiotic stress were increased after IF. Early-life IF also led to higher lipid content in 60-day-old flies, a potential explanation for increased longevity. Guts of flies 40 days post-IF showed a significant reduction in age-related pathologies and improved gut barrier function. Improved gut health was also associated with reduced relative bacterial abundance. Early IF thus induced profound long-term changes. Pharmacological and genetic epistasis analysis showed that IF acted independently of the TOR pathway because rapamycin and IF acted additively to extend lifespan, and global expression of a constitutively active S6K did not attenuate the IF-induced lifespan extension. We conclude that short-term IF during early life can induce long-lasting beneficial effects, with robust increase in lifespan in a TOR-independent manner, probably at least in part by preserving gut health. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Regulation of a hitchhiking behavior by neuronal insulin and TGF-β signaling in the nematode Caenorhabditis elegans.

PubMed

Lee, Daehan; Lee, Harksun; Kim, Nari; Lim, Daisy S; Lee, Junho

2017-03-04

Free-living nematode Caenorhabditis elegans exhibits various behaviors to adapt to the fluctuating environment. When early larvae of C. elegans experience the harsh environmental condition, they develop to an alternative developmental stage called dauer, which shows nictation, a stage-specific waving behavior. Nictation enables dauers to attach to more mobile animals, which helps them disperse to other habitats beyond physical barriers. However, underlying molecular mechanisms that regulate nictation behavior are largely unknown. In this study, we show that insulin signaling and transforming growth beta (TGF-β) signaling, the two major parallel signaling pathways that mediate dauer development, are involved in the regulation of dauer-specific nictation behavior. Genetic analysis revealed that downregulation of insulin signaling enhanced nictation behavior. Heat-shock induced rescue experiments showed that the action period of the insulin signaling is before dauer formation. Surprisingly, lowering of TGF-β signaling inhibited the normal performance of nictation, suggesting that TGF-β signaling acts in an opposite way from that for dauer formation. Cell-specific rescue experiments revealed that two signaling pathways act in the nervous system and an epistasis experiment showed that TGF-β signaling is epistatic to insulin signaling. Taken together, we propose that the neuroendocrinal insulin signaling and TGF-β signaling regulate nictation behavior during development in response to environmental conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

Dopamine negatively modulates the NCA ion channels in C. elegans

PubMed Central

Topalidou, Irini; Pereira, Laura

2017-01-01

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels. PMID:28968387

GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling.

PubMed

Khanna, Puja; Lee, Joan Shuying; Sereemaspun, Amornpun; Lee, Haeryun; Baeg, Gyeong Hun

2018-06-22

Dysregulated JAK/STAT signaling has been implicated in breast cancer metastasis, which is associated with high relapse risks. However, mechanisms underlying JAK/STAT signaling-mediated breast tumorigenesis are poorly understood. Here, we showed that GRAMD1B expression is upregulated on IL-6 but downregulated upon treatment with the JAK2 inhibitor AG490 in the breast cancer MDA-MB-231 cells. Notably, Gramd1b knockdown caused morphological changes of the cells, characterized by the formation of membrane ruffling and protrusions, implicating its role in cell migration. Consistently, GRAMD1B inhibition significantly enhanced cell migration, with an increase in the levels of the Rho family of GTPases. We also found that Gramd1b knockdown-mediated pro-migratory phenotype is associated with JAK2/STAT3 and Akt activation, and that JAK2 or Akt inhibition efficiently suppresses the phenotype. Interestingly, AG490 dose-dependently increased p-Akt levels, and our epistasis analysis suggested that the effect of JAK/STAT inhibition on p-Akt is via the regulation of GRAMD1B expression. Taken together, our results suggest that GRAMD1B is a key signaling molecule that functions to inhibit cell migration in breast cancer by negating both JAK/STAT and Akt signaling, providing the foundation for its development as a novel biomarker in breast cancer.

Dopamine negatively modulates the NCA ion channels in C. elegans.

PubMed

Topalidou, Irini; Cooper, Kirsten; Pereira, Laura; Ailion, Michael

2017-10-01

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.

Lrs14 transcriptional regulators influence biofilm formation and cell motility of Crenarchaea

PubMed Central

Orell, Alvaro; Peeters, Eveline; Vassen, Victoria; Jachlewski, Silke; Schalles, Sven; Siebers, Bettina; Albers, Sonja-Verena

2013-01-01

Like bacteria, archaea predominately exist as biofilms in nature. However, the environmental cues and the molecular mechanisms driving archaeal biofilm development are not characterized. Here we provide data suggesting that the transcriptional regulators belonging to the Lrs14-like protein family constitute a key regulatory factor during Sulfolobus biofilm development. Among the six lrs14-like genes encoded by Sulfolobus acidocaldarius, the deletion of three led to markedly altered biofilm phenotypes. Although Δsaci1223 and Δsaci1242 deletion mutants were impaired in biofilm formation, the Δsaci0446 deletion strain exhibited a highly increased extracellular polymeric substance (EPS) production, leading to a robust biofilm structure. Moreover, although the expression of the adhesive pili (aap) genes was upregulated, the genes of the motility structure, the archaellum (fla), were downregulated rendering the Δsaci0446 strain non-motile. Gel shift assays confirmed that Saci0446 bound to the promoter regions of fla and aap thus controlling the expression of both cell surface structures. In addition, genetic epistasis analysis using Δsaci0446 as background strain identified a gene cluster involved in the EPS biosynthetic pathway of S. acidocaldarius. These results provide insights into both the molecular mechanisms that govern biofilm formation in Crenarchaea and the functionality of the Lrs14-like proteins, an archaea-specific class of transcriptional regulators. PMID:23657363

Regulation of Hippo signalling by p38 signalling

PubMed Central

Huang, Dashun; Li, Xiaojiao; Sun, Li; Huang, Ping; Ying, Hao; Wang, Hui; Wu, Jiarui; Song, Haiyun

2016-01-01

The Hippo signalling pathway has a crucial role in growth control during development, and its dysregulation contributes to tumorigenesis. Recent studies uncover multiple upstream regulatory inputs into Hippo signalling, which affects phosphorylation of the transcriptional coactivator Yki/YAP/TAZ by Wts/Lats. Here we identify the p38 mitogen-activated protein kinase (MAPK) pathway as a new upstream branch of the Hippo pathway. In Drosophila, overexpression of MAPKK gene licorne (lic), or MAPKKK gene Mekk1, promotes Yki activity and induces Hippo target gene expression. Loss-of-function studies show that lic regulates Hippo signalling in ovary follicle cells and in the wing disc. Epistasis analysis indicates that Mekk1 and lic affect Hippo signalling via p38b and wts. We further demonstrate that the Mekk1-Lic-p38b cascade inhibits Hippo signalling by promoting F-actin accumulation and Jub phosphorylation. In addition, p38 signalling modulates actin filaments and Hippo signalling in parallel to small GTPases Ras, Rac1, and Rho1. Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton. Upregulation or downregulation of the p38 pathway regulates YAP-mediated transcription. Our work thus reveals a conserved crosstalk between the p38 MAPK pathway and the Hippo pathway in growth regulation. PMID:27402810

TDM1 Regulation Determines the Number of Meiotic Divisions

PubMed Central

Cifuentes, Marta; Jolivet, Sylvie; Cromer, Laurence; Harashima, Hirofumi; Bulankova, Petra; Renne, Charlotte; Crismani, Wayne; Nomura, Yuko; Nakagami, Hirofumi; Sugimoto, Keiko; Schnittger, Arp; Riha, Karel; Mercier, Raphael

2016-01-01

Cell cycle control must be modified at meiosis to allow two divisions to follow a single round of DNA replication, resulting in ploidy reduction. The mechanisms that ensure meiosis termination at the end of the second and not at the end of first division are poorly understood. We show here that Arabidopsis thaliana TDM1, which has been previously shown to be essential for meiotic termination, interacts directly with the Anaphase-Promoting Complex. Further, mutations in TDM1 in a conserved putative Cyclin-Dependant Kinase (CDK) phosphorylation site (T16-P17) dominantly provoked premature meiosis termination after the first division, and the production of diploid spores and gametes. The CDKA;1-CYCA1.2/TAM complex, which is required to prevent premature meiotic exit, phosphorylated TDM1 at T16 in vitro. Finally, while CYCA1;2/TAM was previously shown to be expressed only at meiosis I, TDM1 is present throughout meiosis. These data, together with epistasis analysis, lead us to propose that TDM1 is an APC/C component whose function is to ensure meiosis termination at the end of meiosis II, and whose activity is inhibited at meiosis I by CDKA;1-TAM-mediated phosphorylation to prevent premature meiotic exit. This provides a molecular mechanism for the differential decision of performing an additional round of division, or not, at the end of meiosis I and II, respectively. PMID:26871453

Dissection of genetic architecture of rice plant height and heading date by multiple-strategy-based association studies

PubMed Central

Zhou, Liyuan; Liu, Shouye; Wu, Weixun; Chen, Daibo; Zhan, Xiaodeng; Zhu, Aike; Zhang, Yingxin; Cheng, Shihua; Cao, Liyong; Lou, Xiangyang; Xu, Haiming

2016-01-01

Xieyou9308 is a certified super hybrid rice cultivar with a high grain yield. To investigate its underlying genetic basis of high yield potential, a recombinant inbred line (RIL) population derived from the cross between the maintainer line XieqingzaoB (XQZB) and the restorer line Zhonghui9308 (ZH9308) was constructed for identification of quantitative trait SNPs (QTSs) associated with two important agronomic traits, plant height (PH) and heading date (HD). By re-sequencing of 138 recombinant inbred lines (RILs), a total of ~0.7 million SNPs were identified for the association studies on the PH and HD. Three association mapping strategies (including hypothesis-free genome-wide association and its two complementary hypothesis-engaged ones, QTL-based association and gene-based association) were adopted for data analysis. Using a saturated mixed linear model including epistasis and environmental interaction, we identified a total of 31 QTSs associated with either the PH or the HD. The total estimated heritability across three analyses ranged from 37.22% to 45.63% and from 37.53% to 55.96% for the PH and HD, respectively. In this study we examined the feasibility of association studies in an experimental population (RIL) and identified several common loci through multiple strategies which could be preferred candidates for further research. PMID:27406081

CDC-42 Orients Cell Migration during Epithelial Intercalation in the Caenorhabditis elegans Epidermis.

PubMed

Walck-Shannon, Elise; Lucas, Bethany; Chin-Sang, Ian; Reiner, David; Kumfer, Kraig; Cochran, Hunter; Bothfeld, William; Hardin, Jeff

2016-11-01

Cell intercalation is a highly directed cell rearrangement that is essential for animal morphogenesis. As such, intercalation requires orchestration of cell polarity across the plane of the tissue. CDC-42 is a Rho family GTPase with key functions in cell polarity, yet its role during epithelial intercalation has not been established because its roles early in embryogenesis have historically made it difficult to study. To circumvent these early requirements, in this paper we use tissue-specific and conditional loss-of-function approaches to identify a role for CDC-42 during intercalation of the Caenorhabditis elegans dorsal embryonic epidermis. CDC-42 activity is enriched in the medial tips of intercalating cells, which extend as cells migrate past one another. Moreover, CDC-42 is involved in both the efficient formation and orientation of cell tips during cell rearrangement. Using conditional loss-of-function we also show that the PAR complex functions in tip formation and orientation. Additionally, we find that the sole C. elegans Eph receptor, VAB-1, functions during this process in an Ephrin-independent manner. Using epistasis analysis, we find that vab-1 lies in the same genetic pathway as cdc-42 and is responsible for polarizing CDC-42 activity to the medial tip. Together, these data establish a previously uncharacterized role for polarized CDC-42, in conjunction with PAR-6, PAR-3 and an Eph receptor, during epithelial intercalation.

CDC-42 Orients Cell Migration during Epithelial Intercalation in the Caenorhabditis elegans Epidermis

PubMed Central

Lucas, Bethany; Chin-Sang, Ian; Reiner, David; Kumfer, Kraig

2016-01-01

Cell intercalation is a highly directed cell rearrangement that is essential for animal morphogenesis. As such, intercalation requires orchestration of cell polarity across the plane of the tissue. CDC-42 is a Rho family GTPase with key functions in cell polarity, yet its role during epithelial intercalation has not been established because its roles early in embryogenesis have historically made it difficult to study. To circumvent these early requirements, in this paper we use tissue-specific and conditional loss-of-function approaches to identify a role for CDC-42 during intercalation of the Caenorhabditis elegans dorsal embryonic epidermis. CDC-42 activity is enriched in the medial tips of intercalating cells, which extend as cells migrate past one another. Moreover, CDC-42 is involved in both the efficient formation and orientation of cell tips during cell rearrangement. Using conditional loss-of-function we also show that the PAR complex functions in tip formation and orientation. Additionally, we find that the sole C. elegans Eph receptor, VAB-1, functions during this process in an Ephrin-independent manner. Using epistasis analysis, we find that vab-1 lies in the same genetic pathway as cdc-42 and is responsible for polarizing CDC-42 activity to the medial tip. Together, these data establish a previously uncharacterized role for polarized CDC-42, in conjunction with PAR-6, PAR-3 and an Eph receptor, during epithelial intercalation. PMID:27861585

Arabidopsis MLO2 is a negative regulator of sensitivity to extracellular reactive oxygen species.

PubMed

Cui, Fuqiang; Wu, Hongpo; Safronov, Omid; Zhang, Panpan; Kumar, Rajeev; Kollist, Hannes; Salojärvi, Jarkko; Panstruga, Ralph; Overmyer, Kirk

2018-04-01

The atmospheric pollutant ozone (O 3 ) is a strong oxidant that causes extracellular reactive oxygen species (ROS) formation, has significant ecological relevance, and is used here as a non-invasive ROS inducer to study plant signalling. Previous genetic screens identified several mutants exhibiting enhanced O 3 sensitivity, but few with enhanced tolerance. We found that loss-of-function mutants in Arabidopsis MLO2, a gene implicated in susceptibility to powdery mildew disease, exhibit enhanced dose-dependent tolerance to O 3 and extracellular ROS, but a normal response to intracellular ROS. This phenotype is increased in a mlo2 mlo6 mlo12 triple mutant, reminiscent of the genetic redundancy of MLO genes in powdery mildew resistance. Stomatal assays revealed that enhanced O 3 tolerance in mlo2 mutants is not caused by altered stomatal conductance. We explored modulation of the mlo2-associated O 3 tolerance, powdery mildew resistance, and early senescence phenotypes by genetic epistasis analysis, involving mutants with known effects on ROS sensitivity or antifungal defence. Mining of publicly accessible microarray data suggests that these MLO proteins regulate accumulation of abiotic stress response transcripts, and transcript accumulation of MLO2 itself is O 3 responsive. In summary, our data reveal MLO2 as a novel negative regulator in plant ROS responses, which links biotic and abiotic stress response pathways. © 2018 John Wiley & Sons Ltd.

Oxygen radical absorbance capacity (ORAC) and phenolic and anthocyanin concentrations in fruit and leaf tissues of highbush blueberry.

PubMed

Ehlenfeldt, M K; Prior, R L

2001-05-01

Antioxidant capacity, as measured by oxygen radical absorbance capacity (ORAC), and total phenolic and total anthocyanin contents were evaluated in fruit tissues of 87 highbush blueberry (Vacciniumcorymbosum L.) and species-introgressed highbush blueberry cultivars. ORAC and phenolic levels were evaluated in leaf tissues of the same materials. Average values for ORAC, phenolics, and anthocyanins in fruit were 15.9 ORAC units, 1.79 mg/g (gallic acid equivalents), and 0.95 mg/g (cyanidin-3-glucoside equivalents), respectively. Cv. Rubel had the highest ORAC per gram of fresh weight values, at 31.1 units, and cv. Elliott had the highest values on the basis of ORAC per square centimeter of surface area. In leaf tissue, values for both ORAC and phenolics were significantly higher than in fruit tissue, with mean values of 490 ORAC units and 44.80 mg/g (gallic acid equivalents), respectively. Leaf ORAC had a low, but significant, correlation with fruit phenolics and anthocyanins, but not with fruit ORAC. An analysis of ORAC values versus calculated midparent values in 11 plants from the 87-cultivar group in which all parents were tested suggested that, across cultivars, ORAC inheritance is additive. An investigation of ORAC values in a family of 44 cv. Rubel x Duke seedlings showed negative epistasis for ORAC values, suggesting Rubel may have gene combinations contributing to ORAC that are broken up during hybridization.

QTLs Analysis and Validation for Fiber Quality Traits Using Maternal Backcross Population in Upland Cotton.

PubMed

Ma, Lingling; Zhao, Yanpeng; Wang, Yumei; Shang, Lianguang; Hua, Jinping

2017-01-01

Cotton fiber is renewable natural fiber source for textile. Improving fiber quality is an essential goal for cotton breeding project. In present study, F 14 recombinant inbred line (RIL) population was backcrossed by the maternal parent to obtain a backcross (BC) population, derived from one Upland cotton hybrid. Three repetitive field trials were performed by randomized complete block design with two replicates in three locations in 2015, together with the BC population, common male parent and the RIL population. Totally, 26 QTLs in BC population explained 5.00-14.17% of phenotype variation (PV) and 37 quantitative trait loci (QTL) were detected in RIL population explaining 5.13-34.00% of PV. Seven common QTLs detected simultaneously in two populations explained PV from 7.69 to 23.05%. A total of 20 QTLs in present study verified the previous results across three environments in 2012. Particularly, qFL-Chr5-2 controlling fiber length on chromosome 5 explained 34.00% of PV, while qFL-Chr5-3 only within a 0.8 cM interval explained 13.93% of PV on average in multiple environments. These stable QTLs explaining great variation offered essential information for marker-assisted selection (MAS) to improve fiber quality traits. Lots of epistasis being detected in both populations acted as one of important genetic compositions of fiber quality traits.

Histone H3 and the histone acetyltransferase Hat1p contribute to DNA double-strand break repair.

PubMed

Qin, Song; Parthun, Mark R

2002-12-01

The modification of newly synthesized histones H3 and H4 by type B histone acetyltransferases has been proposed to play a role in the process of chromatin assembly. The type B histone acetyltransferase Hat1p and specific lysine residues in the histone H3 NH(2)-terminal tail (primarily lysine 14) are redundantly required for telomeric silencing. As many gene products, including other factors involved in chromatin assembly, have been found to participate in both telomeric silencing and DNA damage repair, we tested whether mutations in HAT1 and the histone H3 tail were also sensitive to DNA-damaging agents. Indeed, mutations both in specific lysine residues in the histone H3 tail and in HAT1 resulted in sensitivity to methyl methanesulfonate. The DNA damage sensitivity of the histone H3 and HAT1 mutants was specific for DNA double-strand breaks, as these mutants were sensitive to the induction of an exogenous restriction endonuclease, EcoRI, but not to UV irradiation. While histone H3 mutations had minor effects on nonhomologous end joining, the primary defect in the histone H3 and HAT1 mutants was in the recombinational repair of DNA double-strand breaks. Epistasis analysis indicates that the histone H3 and HAT1 mutants may influence DNA double-strand break repair through Asf1p-dependent chromatin assembly.

Caenorhabditis elegans OSR-1 regulates behavioral and physiological responses to hyperosmotic environments.

PubMed Central

Solomon, Aharon; Bandhakavi, Sricharan; Jabbar, Sean; Shah, Rena; Beitel, Greg J; Morimoto, Richard I

2004-01-01

The molecular mechanisms that enable multicellular organisms to sense and modulate their responses to hyperosmotic environments are poorly understood. Here, we employ Caenorhabditis elegans to characterize the response of a multicellular organism to osmotic stress and establish a genetic screen to isolate mutants that are osmotic stress resistant (OSR). In this study, we describe the cloning of a novel gene, osr-1, and demonstrate that it regulates osmosensation, adaptation, and survival in hyperosmotic environments. Whereas wild-type animals exposed to hyperosmotic conditions rapidly lose body volume, motility, and viability, osr-1(rm1) mutant animals maintain normal body volume, motility, and viability even upon chronic exposures to high osmolarity environments. In addition, osr-1(rm1) animals are specifically resistant to osmotic stress and are distinct from previously characterized osmotic avoidance defective (OSM) and general stress resistance age-1(hx546) mutants. OSR-1 is expressed in the hypodermis and intestine, and expression of OSR-1 in hypodermal cells rescues the osr-1(rm1) phenotypes. Genetic epistasis analysis indicates that OSR-1 regulates survival under osmotic stress via CaMKII and a conserved p38 MAP kinase signaling cascade and regulates osmotic avoidance and resistance to acute dehydration likely by distinct mechanisms. We suggest that OSR-1 plays a central role in integrating stress detection and adaptation responses by invoking multiple signaling pathways to promote survival under hyperosmotic environments. PMID:15166144

Automated image analysis of placental villi and syncytial knots in histological sections.

PubMed

Kidron, Debora; Vainer, Ifat; Fisher, Yael; Sharony, Reuven

2017-05-01

Delayed villous maturation and accelerated villous maturation diagnosed in histologic sections are morphologic manifestations of pathophysiological conditions. The inter-observer agreement among pathologists in assessing these conditions is moderate at best. We investigated whether automated image analysis of placental villi and syncytial knots could improve standardization in diagnosing these conditions. Placentas of antepartum fetal death at or near term were diagnosed as normal, delayed or accelerated villous maturation. Histologic sections of 5 cases per group were photographed at ×10 magnification. Automated image analysis of villi and syncytial knots was performed, using ImageJ public domain software. Analysis of hundreds of histologic images was carried out within minutes on a personal computer, using macro commands. Compared to normal placentas, villi from delayed maturation were larger and fewer, with fewer and smaller syncytial knots. Villi from accelerated maturation were smaller. The data were further analyzed according to horizontal placental zones and groups of villous size. Normal placentas can be discriminated from placentas of delayed or accelerated villous maturation using automated image analysis. Automated image analysis of villi and syncytial knots is not equivalent to interpretation by the human eye. Each method has advantages and disadvantages in assessing the 2-dimensional histologic sections representing the complex, 3-dimensional villous tree. Image analysis of placentas provides quantitative data that might help in standardizing and grading of placentas for diagnostic and research purposes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enabling More than Moore: Accelerated Reliability Testing and Risk Analysis for Advanced Electronics Packaging

NASA Technical Reports Server (NTRS)

Ghaffarian, Reza; Evans, John W.

2014-01-01

For five decades, the semiconductor industry has distinguished itself by the rapid pace of improvement in miniaturization of electronics products-Moore's Law. Now, scaling hits a brick wall, a paradigm shift. The industry roadmaps recognized the scaling limitation and project that packaging technologies will meet further miniaturization needs or ak.a "More than Moore". This paper presents packaging technology trends and accelerated reliability testing methods currently being practiced. Then, it presents industry status on key advanced electronic packages, factors affecting accelerated solder joint reliability of area array packages, and IPC/JEDEC/Mil specifications for characterizations of assemblies under accelerated thermal and mechanical loading. Finally, it presents an examples demonstrating how Accelerated Testing and Analysis have been effectively employed in the development of complex spacecraft thereby reducing risk. Quantitative assessments necessarily involve the mathematics of probability and statistics. In addition, accelerated tests need to be designed which consider the desired risk posture and schedule for particular project. Such assessments relieve risks without imposing additional costs. and constraints that are not value added for a particular mission. Furthermore, in the course of development of complex systems, variances and defects will inevitably present themselves and require a decision concerning their disposition, necessitating quantitative assessments. In summary, this paper presents a comprehensive view point, from technology to systems, including the benefits and impact of accelerated testing in offsetting risk.

Transport modes during crystal growth in a centrifuge

NASA Technical Reports Server (NTRS)

Arnold, William A.; Wilcox, William R.; Carlson, Frederick; Chait, Arnon; Regel', Liia L.

1992-01-01

Flow modes arising under average acceleration in centrifugal crystal growth, the gradient of acceleration, and the Coriolis force are investigated using a fully nonlinear three-dimensional numerical model for a centrifugal crystal growth experiment. The analysis focuses on an examination of the quasi-steady state flow modes. The importance of the gradient acceleration is determined by the value of a new nondimensional number, Ad.

Beam-driven acceleration in ultra-dense plasma media

DOE PAGES

Shin, Young-Min

2014-09-15

Accelerating parameters of beam-driven wakefield acceleration in an extremely dense plasma column has been analyzed with the dynamic framed particle-in-cell plasma simulator, and compared with analytic calculations. In the model, a witness beam undergoes a TeV/m scale alternating potential gradient excited by a micro-bunched drive beam in a 10 25 m -3 and 1.6 x 10 28 m -3 plasma column. The acceleration gradient, energy gain, and transformer ratio have been extensively studied in quasi-linear, linear-, and blowout-regimes. The simulation analysis indicated that in the beam-driven acceleration system a hollow plasma channel offers 20 % higher acceleration gradient by enlargingmore » the channel radius (r) from 0.2 Ap to 0.6 .Ap in a blowout regime. This paper suggests a feasibility of TeV/m scale acceleration with a hollow crystalline structure (e.g. nanotubes) of high electron plasma density.« less

Electron cyclotron harmonic wave acceleration

NASA Technical Reports Server (NTRS)

Karimabadi, H.; Menyuk, C. R.; Sprangle, P.; Vlahos, L.

1987-01-01

A nonlinear analysis of particle acceleration in a finite bandwidth, obliquely propagating electromagnetic cyclotron wave is presented. It has been suggested by Sprangle and Vlahos in 1983 that the narrow bandwidth cyclotron radiation emitted by the unstable electron distribution inside a flaring solar loop can accelerate electrons outside the loop by the interaction of a monochromatic wave propagating along the ambient magnetic field with the ambient electrons. It is shown here that electrons gyrating and streaming along a uniform, static magnetic field can be accelerated by interacting with the fundamental or second harmonic of a monochromatic, obliquely propagating cyclotron wave. It is also shown that the acceleration is virtually unchanged when a wave with finite bandwidth is considered. This acceleration mechanism can explain the observed high-energy electrons in type III bursts.

Determination of the cosmological rate of change of G and the tidal accelerations of earth and moon from ancient and modern astronomical data

NASA Technical Reports Server (NTRS)

Muller, P. M.

1976-01-01

The theory and numerical analysis of ancient astronomical observations (1374 to 1715) are combined with modern data in a simultaneous solution for: the tidal acceleration of the lunar longitude; the observed apparent acceleration of the earth's rotation; the true nontidal geophysical part of this acceleration; and the rate of change in the gravitational constant. Provided are three independent determinations of a rate of change of G consistent with the Hubble Constant and a near zero nontidal rotational acceleration of the earth. The tidal accelerations are shown to have remained constant during the historical period within uncertainties. Ancient and modern solar system data, and extragalactic observations provided a completely consistent astronomical and cosmological scheme.

Automated detection and analysis of particle beams in laser-plasma accelerator simulations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ushizima, Daniela Mayumi; Geddes, C.G.; Cormier-Michel, E.

Numerical simulations of laser-plasma wakefield (particle) accelerators model the acceleration of electrons trapped in plasma oscillations (wakes) left behind when an intense laser pulse propagates through the plasma. The goal of these simulations is to better understand the process involved in plasma wake generation and how electrons are trapped and accelerated by the wake. Understanding of such accelerators, and their development, offer high accelerating gradients, potentially reducing size and cost of new accelerators. One operating regime of interest is where a trapped subset of electrons loads the wake and forms an isolated group of accelerated particles with low spread inmore » momentum and position, desirable characteristics for many applications. The electrons trapped in the wake may be accelerated to high energies, the plasma gradient in the wake reaching up to a gigaelectronvolt per centimeter. High-energy electron accelerators power intense X-ray radiation to terahertz sources, and are used in many applications including medical radiotherapy and imaging. To extract information from the simulation about the quality of the beam, a typical approach is to examine plots of the entire dataset, visually determining the adequate parameters necessary to select a subset of particles, which is then further analyzed. This procedure requires laborious examination of massive data sets over many time steps using several plots, a routine that is unfeasible for large data collections. Demand for automated analysis is growing along with the volume and size of simulations. Current 2D LWFA simulation datasets are typically between 1GB and 100GB in size, but simulations in 3D are of the order of TBs. The increase in the number of datasets and dataset sizes leads to a need for automatic routines to recognize particle patterns as particle bunches (beam of electrons) for subsequent analysis. Because of the growth in dataset size, the application of machine learning techniques for scientific data mining is increasingly considered. In plasma simulations, Bagherjeiran et al. presented a comprehensive report on applying graph-based techniques for orbit classification. They used the KAM classifier to label points and components in single and multiple orbits. Love et al. conducted an image space analysis of coherent structures in plasma simulations. They used a number of segmentation and region-growing techniques to isolate regions of interest in orbit plots. Both approaches analyzed particle accelerator data, targeting the system dynamics in terms of particle orbits. However, they did not address particle dynamics as a function of time or inspected the behavior of bunches of particles. Ruebel et al. addressed the visual analysis of massive laser wakefield acceleration (LWFA) simulation data using interactive procedures to query the data. Sophisticated visualization tools were provided to inspect the data manually. Ruebel et al. have integrated these tools to the visualization and analysis system VisIt, in addition to utilizing efficient data management based on HDF5, H5Part, and the index/query tool FastBit. In Ruebel et al. proposed automatic beam path analysis using a suite of methods to classify particles in simulation data and to analyze their temporal evolution. To enable researchers to accurately define particle beams, the method computes a set of measures based on the path of particles relative to the distance of the particles to a beam. To achieve good performance, this framework uses an analysis pipeline designed to quickly reduce the amount of data that needs to be considered in the actual path distance computation. As part of this process, region-growing methods are utilized to detect particle bunches at single time steps. Efficient data reduction is essential to enable automated analysis of large data sets as described in the next section, where data reduction methods are steered to the particular requirements of our clustering analysis. Previously, we have described the application of a set of algorithms to automate the data analysis and classification of particle beams in the LWFA simulation data, identifying locations with high density of high energy particles. These algorithms detected high density locations (nodes) in each time step, i.e. maximum points on the particle distribution for only one spatial variable. Each node was correlated to a node in previous or later time steps by linking these nodes according to a pruned minimum spanning tree (PMST). We call the PMST representation 'a lifetime diagram', which is a graphical tool to show temporal information of high dense groups of particles in the longitudinal direction for the time series. Electron bunch compactness was described by another step of the processing, designed to partition each time step, using fuzzy clustering, into a fixed number of clusters.« less

Bioimaging of cells and tissues using accelerator-based sources.

PubMed

Petibois, Cyril; Cestelli Guidi, Mariangela

2008-07-01

A variety of techniques exist that provide chemical information in the form of a spatially resolved image: electron microprobe analysis, nuclear microprobe analysis, synchrotron radiation microprobe analysis, secondary ion mass spectrometry, and confocal fluorescence microscopy. Linear (LINAC) and circular (synchrotrons) particle accelerators have been constructed worldwide to provide to the scientific community unprecedented analytical performances. Now, these facilities match at least one of the three analytical features required for the biological field: (1) a sufficient spatial resolution for single cell (< 1 mum) or tissue (<1 mm) analyses, (2) a temporal resolution to follow molecular dynamics, and (3) a sensitivity in the micromolar to nanomolar range, thus allowing true investigations on biological dynamics. Third-generation synchrotrons now offer the opportunity of bioanalytical measurements at nanometer resolutions with incredible sensitivity. Linear accelerators are more specialized in their physical features but may exceed synchrotron performances. All these techniques have become irreplaceable tools for developing knowledge in biology. This review highlights the pros and cons of the most popular techniques that have been implemented on accelerator-based sources to address analytical issues on biological specimens.

Initial Flow Matching Results of MHD Energy Bypass on a Supersonic Turbojet Engine Using the Numerical Propulsion System Simulation (NPSS) Environment

NASA Technical Reports Server (NTRS)

Benyo, Theresa L.

2010-01-01

Preliminary flow matching has been demonstrated for a MHD energy bypass system on a supersonic turbojet engine. The Numerical Propulsion System Simulation (NPSS) environment was used to perform a thermodynamic cycle analysis to properly match the flows from an inlet to a MHD generator and from the exit of a supersonic turbojet to a MHD accelerator. Working with various operating conditions such as the enthalpy extraction ratio and isentropic efficiency of the MHD generator and MHD accelerator, interfacing studies were conducted between the pre-ionizers, the MHD generator, the turbojet engine, and the MHD accelerator. This paper briefly describes the NPSS environment used in this analysis and describes the NPSS analysis of a supersonic turbojet engine with a MHD generator/accelerator energy bypass system. Results from this study have shown that using MHD energy bypass in the flow path of a supersonic turbojet engine increases the useful Mach number operating range from 0 to 3.0 Mach (not using MHD) to an explored and desired range of 0 to 7.0 Mach.

Dynamic Multivariate Accelerated Corrosion Test Protocol

DTIC Science & Technology

2014-10-01

atmospheric, accelerated, AA2024-T3, AA6061-T6, AA7075-T3, 1010 steel, AgCl, rare earth conversion coat, magnesium rich primer, polyurethane , Eyring, Monte...morphology and elemental analysis by scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and electrochemical determinations of...in the FT-IR analysis; degradation of the components of the high performance polyurethane coatings exposed in the UV/ozone chamber were more

Using "Short" Interrupted Time-Series Analysis To Measure the Impacts of Whole-School Reforms: With Applications to a Study of Accelerated Schools.

ERIC Educational Resources Information Center

Bloom, Howard S.

2002-01-01

Introduces an new approach for measuring the impact of whole school reforms. The approach, based on "short" interrupted time-series analysis, is explained, its statistical procedures are outlined, and how it was used in the evaluation of a major whole-school reform, Accelerated Schools is described (H. Bloom and others, 2001). (SLD)

Logic Model Checking of Unintended Acceleration Claims in Toyota Vehicles

NASA Technical Reports Server (NTRS)

Gamble, Ed

2012-01-01

Part of the US Department of Transportation investigation of Toyota sudden unintended acceleration (SUA) involved analysis of the throttle control software, JPL Laboratory for Reliable Software applied several techniques including static analysis and logic model checking, to the software; A handful of logic models were build, Some weaknesses were identified; however, no cause for SUA was found; The full NASA report includes numerous other analyses

Forced vibration analysis of rotating cyclic structures in NASTRAN

NASA Technical Reports Server (NTRS)

Elchuri, V.; Gallo, A. M.; Skalski, S. C.

1981-01-01

A new capability was added to the general purpose finite element program NASTRAN Level 17.7 to conduct forced vibration analysis of tuned cyclic structures rotating about their axis of symmetry. The effects of Coriolis and centripetal accelerations together with those due to linear acceleration of the axis of rotation were included. The theoretical, user's, programmer's and demonstration manuals for this new capability are presented.

Hardware accelerated high performance neutron transport computation based on AGENT methodology

NASA Astrophysics Data System (ADS)

Xiao, Shanjie

The spatial heterogeneity of the next generation Gen-IV nuclear reactor core designs brings challenges to the neutron transport analysis. The Arbitrary Geometry Neutron Transport (AGENT) AGENT code is a three-dimensional neutron transport analysis code being developed at the Laboratory for Neutronics and Geometry Computation (NEGE) at Purdue University. It can accurately describe the spatial heterogeneity in a hierarchical structure through the R-function solid modeler. The previous version of AGENT coupled the 2D transport MOC solver and the 1D diffusion NEM solver to solve the three dimensional Boltzmann transport equation. In this research, the 2D/1D coupling methodology was expanded to couple two transport solvers, the radial 2D MOC solver and the axial 1D MOC solver, for better accuracy. The expansion was benchmarked with the widely applied C5G7 benchmark models and two fast breeder reactor models, and showed good agreement with the reference Monte Carlo results. In practice, the accurate neutron transport analysis for a full reactor core is still time-consuming and thus limits its application. Therefore, another content of my research is focused on designing a specific hardware based on the reconfigurable computing technique in order to accelerate AGENT computations. It is the first time that the application of this type is used to the reactor physics and neutron transport for reactor design. The most time consuming part of the AGENT algorithm was identified. Moreover, the architecture of the AGENT acceleration system was designed based on the analysis. Through the parallel computation on the specially designed, highly efficient architecture, the acceleration design on FPGA acquires high performance at the much lower working frequency than CPUs. The whole design simulations show that the acceleration design would be able to speedup large scale AGENT computations about 20 times. The high performance AGENT acceleration system will drastically shortening the computation time for 3D full-core neutron transport analysis, making the AGENT methodology unique and advantageous, and thus supplies the possibility to extend the application range of neutron transport analysis in either industry engineering or academic research.

Automated Fetal Heart Rate Analysis in Labor: Decelerations and Overshoots

NASA Astrophysics Data System (ADS)

Georgieva, A. E.; Payne, S. J.; Moulden, M.; Redman, C. W. G.

2010-10-01

Electronic fetal heart rate (FHR) recording is a standard way of monitoring fetal health in labor. Decelerations and accelerations usually indicate fetal distress and normality respectively. But one type of acceleration may differ, namely an overshoot that may atypically reflect fetal stress. Here we describe a new method for detecting decelerations, accelerations and overshoots as part of a novel system for computerized FHR analysis (OxSyS). There was poor agreement between clinicians when identifying these FHR features visually, which precluded setting a gold standard of interpretation. We therefore introduced `modified' Sensitivity (SE°) and `modified' Positive Predictive Value (PPV°) as appropriate performance measures with which the algorithm was optimized. The relation between overshoots and fetal compromise in labor was studied in 15 cases and 15 controls. Overshoots showed promise as an indicator of fetal compromise. Unlike ordinary accelerations, overshoots cannot be considered to be reassuring features of fetal health.

Longitudinal dynamics of twin electron bunches in the Linac Coherent Light Source

DOE PAGES

Zhang, Zhen; Ding, Yuantao; Marinelli, Agostino; ...

2015-03-02

The recent development of two-color x-ray free-electron lasers, as well as the successful demonstration of high-gradient witness bunch acceleration in a plasma, have generated strong interest in electron bunch trains, where two or more electron bunches are generated, accelerated and compressed in the same accelerating bucket. In this paper we give a detailed analysis of a twin-bunch technique in a high-energy linac. This method allows the generation of two electron bunches with high peak current and independent control of time delay and energy separation. We find that the wakefields in the accelerator structures play an important role in the twin-bunchmore » compression, and through analysis show that they can be used to extend the available time delay range. As a result, based on the theoretical model and simulations we propose several methods to achieve larger time delay.« less

Statistical properties of the radiation belt seed population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boyd, A. J.; Spence, H. E.; Huang, C. -L.

Here, we present a statistical analysis of phase space density data from the first 26 months of the Van Allen Probes mission. In particular, we investigate the relationship between the tens and hundreds of keV seed electrons and >1 MeV core radiation belt electron population. Using a cross-correlation analysis, we find that the seed and core populations are well correlated with a coefficient of ≈0.73 with a time lag of 10–15 h. We present evidence of a seed population threshold that is necessary for subsequent acceleration. The depth of penetration of the seed population determines the inner boundary of themore » acceleration process. However, we show that an enhanced seed population alone is not enough to produce acceleration in the higher energies, implying that the seed population of hundreds of keV electrons is only one of several conditions required for MeV electron radiation belt acceleration.« less

Statistical properties of the radiation belt seed population

DOE PAGES

Boyd, A. J.; Spence, H. E.; Huang, C. -L.; ...

2016-07-25

Here, we present a statistical analysis of phase space density data from the first 26 months of the Van Allen Probes mission. In particular, we investigate the relationship between the tens and hundreds of keV seed electrons and >1 MeV core radiation belt electron population. Using a cross-correlation analysis, we find that the seed and core populations are well correlated with a coefficient of ≈0.73 with a time lag of 10–15 h. We present evidence of a seed population threshold that is necessary for subsequent acceleration. The depth of penetration of the seed population determines the inner boundary of themore » acceleration process. However, we show that an enhanced seed population alone is not enough to produce acceleration in the higher energies, implying that the seed population of hundreds of keV electrons is only one of several conditions required for MeV electron radiation belt acceleration.« less

Accelerated Threshold Fatigue Crack Growth Effect-Powder Metallurgy Aluminum Alloy

NASA Technical Reports Server (NTRS)

Piascik, R. S.; Newman, J. A.

2002-01-01

Fatigue crack growth (FCG) research conducted in the near threshold regime has identified a room temperature creep crack growth damage mechanism for a fine grain powder metallurgy (PM) aluminum alloy (8009). At very low (Delta) K, an abrupt acceleration in room temperature FCG rate occurs at high stress ratio (R = K(sub min)/K(sub max)). The near threshold accelerated FCG rates are exacerbated by increased levels of K(sub max) (K(sub max) = 0.4 K(sub IC)). Detailed fractographic analysis correlates accelerated FCG with the formation of crack-tip process zone micro-void damage. Experimental results show that the near threshold and K(sub max) influenced accelerated crack growth is time and temperature dependent.

Acceleration and sensitivity analysis of lattice kinetic Monte Carlo simulations using parallel processing and rate constant rescaling

NASA Astrophysics Data System (ADS)

Núñez, M.; Robie, T.; Vlachos, D. G.

2017-10-01

Kinetic Monte Carlo (KMC) simulation provides insights into catalytic reactions unobtainable with either experiments or mean-field microkinetic models. Sensitivity analysis of KMC models assesses the robustness of the predictions to parametric perturbations and identifies rate determining steps in a chemical reaction network. Stiffness in the chemical reaction network, a ubiquitous feature, demands lengthy run times for KMC models and renders efficient sensitivity analysis based on the likelihood ratio method unusable. We address the challenge of efficiently conducting KMC simulations and performing accurate sensitivity analysis in systems with unknown time scales by employing two acceleration techniques: rate constant rescaling and parallel processing. We develop statistical criteria that ensure sufficient sampling of non-equilibrium steady state conditions. Our approach provides the twofold benefit of accelerating the simulation itself and enabling likelihood ratio sensitivity analysis, which provides further speedup relative to finite difference sensitivity analysis. As a result, the likelihood ratio method can be applied to real chemistry. We apply our methodology to the water-gas shift reaction on Pt(111).

Time-dependent inertia analysis of vehicle mechanisms

NASA Astrophysics Data System (ADS)

Salmon, James Lee

Two methods for performing transient inertia analysis of vehicle hardware systems are developed in this dissertation. The analysis techniques can be used to predict the response of vehicle mechanism systems to the accelerations associated with vehicle impacts. General analytical methods for evaluating translational or rotational system dynamics are generated and evaluated for various system characteristics. The utility of the derived techniques are demonstrated by applying the generalized methods to two vehicle systems. Time dependent acceleration measured during a vehicle to vehicle impact are used as input to perform a dynamic analysis of an automobile liftgate latch and outside door handle. Generalized Lagrange equations for a non-conservative system are used to formulate a second order nonlinear differential equation defining the response of the components to the transient input. The differential equation is solved by employing the fourth order Runge-Kutta method. The events are then analyzed using commercially available two dimensional rigid body dynamic analysis software. The results of the two analytical techniques are compared to experimental data generated by high speed film analysis of tests of the two components performed on a high G acceleration sled at Ford Motor Company.

GPU-accelerated automatic identification of robust beam setups for proton and carbon-ion radiotherapy

NASA Astrophysics Data System (ADS)

Ammazzalorso, F.; Bednarz, T.; Jelen, U.

2014-03-01

We demonstrate acceleration on graphic processing units (GPU) of automatic identification of robust particle therapy beam setups, minimizing negative dosimetric effects of Bragg peak displacement caused by treatment-time patient positioning errors. Our particle therapy research toolkit, RobuR, was extended with OpenCL support and used to implement calculation on GPU of the Port Homogeneity Index, a metric scoring irradiation port robustness through analysis of tissue density patterns prior to dose optimization and computation. Results were benchmarked against an independent native CPU implementation. Numerical results were in agreement between the GPU implementation and native CPU implementation. For 10 skull base cases, the GPU-accelerated implementation was employed to select beam setups for proton and carbon ion treatment plans, which proved to be dosimetrically robust, when recomputed in presence of various simulated positioning errors. From the point of view of performance, average running time on the GPU decreased by at least one order of magnitude compared to the CPU, rendering the GPU-accelerated analysis a feasible step in a clinical treatment planning interactive session. In conclusion, selection of robust particle therapy beam setups can be effectively accelerated on a GPU and become an unintrusive part of the particle therapy treatment planning workflow. Additionally, the speed gain opens new usage scenarios, like interactive analysis manipulation (e.g. constraining of some setup) and re-execution. Finally, through OpenCL portable parallelism, the new implementation is suitable also for CPU-only use, taking advantage of multiple cores, and can potentially exploit types of accelerators other than GPUs.

A 5MV Tandetron to Universidad Autonoma de Madrid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tengblad, Olof

1999-11-16

A 5MV Tandetron accelerator is being projected for the Center of Material Analysis of the Universidad Autonoma de Madrid. The accelerator will be dedicated to Material Science but it meant to be open to all fields of science and industry that can profit from this kind of installations. Estimated construction time and delivery of the accelerator implies that the first experiments can be performed in the spring 2001.

Sensitivity Analysis of the Off-Normal Conditions of the SPIDER Accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veltri, P.; Agostinetti, P.; Antoni, V.

2011-09-26

In the context of the development of the 1 MV neutral beam injector for the ITER tokamak, the study on beam formation and acceleration has considerable importance. This effort includes the ion source and accelerator SPIDER (Source for Production of Ions of Deuterium Extracted from an Rf plasma) ion source, planned to be built in Padova, and designed to extract and accelerate a 355 A/m{sup 2} current of H{sup -}(or 285 A/m{sup 2} D{sup -}) up to 100 kV. Exhaustive simulations were already carried out during the accelerator optimization leading to the present design. However, as it is expected thatmore » the accelerator shall operate also in case of pre-programmed or undesired off-normal conditions, the investigation of a large set of off-normal scenarios is necessary. These analyses will also be useful for the evaluation of the real performances of the machine, and should help in interpreting experimental results, or in identifying dangerous operating conditions.The present contribution offers an overview of the results obtained during the investigation of these off-normal conditions, by means of different modeling tools and codes. The results, showed a good flexibility of the device in different operating conditions. Where the consequences of the abnormalities appeared to be problematic further analysis were addressed.« less

Dynamically correlated mutations drive human Influenza A evolution.

PubMed

Tria, F; Pompei, S; Loreto, V

2013-01-01

Human Influenza A virus undergoes recurrent changes in the hemagglutinin (HA) surface protein, primarily involved in the human antibody recognition. Relevant antigenic changes, enabling the virus to evade host immune response, have been recognized to occur in parallel to multiple mutations at antigenic sites in HA. Yet, the role of correlated mutations (epistasis) in driving the molecular evolution of the virus still represents a challenging puzzle. Further, though circulation at a global geographic level is key for the survival of Influenza A, its role in shaping the viral phylodynamics remains largely unexplored. Here we show, through a sequence based epidemiological model, that epistatic effects between amino acids substitutions, coupled with a reservoir that mimics worldwide circulating viruses, are key determinants that drive human Influenza A evolution. Our approach explains all the up-to-date observations characterizing the evolution of H3N2 subtype, including phylogenetic properties, nucleotide fixation patterns, and composition of antigenic clusters.

Genomic investigations of evolutionary dynamics and epistasis in microbial evolution experiments.

PubMed

Jerison, Elizabeth R; Desai, Michael M

2015-12-01

Microbial evolution experiments enable us to watch adaptation in real time, and to quantify the repeatability and predictability of evolution by comparing identical replicate populations. Further, we can resurrect ancestral types to examine changes over evolutionary time. Until recently, experimental evolution has been limited to measuring phenotypic changes, or to tracking a few genetic markers over time. However, recent advances in sequencing technology now make it possible to extensively sequence clones or whole-population samples from microbial evolution experiments. Here, we review recent work exploiting these techniques to understand the genomic basis of evolutionary change in experimental systems. We first focus on studies that analyze the dynamics of genome evolution in microbial systems. We then survey work that uses observations of sequence evolution to infer aspects of the underlying fitness landscape, concentrating on the epistatic interactions between mutations and the constraints these interactions impose on adaptation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Inferring genetic interactions from comparative fitness data

PubMed Central

2017-01-01

Darwinian fitness is a central concept in evolutionary biology. In practice, however, it is hardly possible to measure fitness for all genotypes in a natural population. Here, we present quantitative tools to make inferences about epistatic gene interactions when the fitness landscape is only incompletely determined due to imprecise measurements or missing observations. We demonstrate that genetic interactions can often be inferred from fitness rank orders, where all genotypes are ordered according to fitness, and even from partial fitness orders. We provide a complete characterization of rank orders that imply higher order epistasis. Our theory applies to all common types of gene interactions and facilitates comprehensive investigations of diverse genetic interactions. We analyzed various genetic systems comprising HIV-1, the malaria-causing parasite Plasmodium vivax, the fungus Aspergillus niger, and the TEM-family of β-lactamase associated with antibiotic resistance. For all systems, our approach revealed higher order interactions among mutations. PMID:29260711

Inferring genetic interactions from comparative fitness data.

PubMed

Crona, Kristina; Gavryushkin, Alex; Greene, Devin; Beerenwinkel, Niko

2017-12-20

Darwinian fitness is a central concept in evolutionary biology. In practice, however, it is hardly possible to measure fitness for all genotypes in a natural population. Here, we present quantitative tools to make inferences about epistatic gene interactions when the fitness landscape is only incompletely determined due to imprecise measurements or missing observations. We demonstrate that genetic interactions can often be inferred from fitness rank orders, where all genotypes are ordered according to fitness, and even from partial fitness orders. We provide a complete characterization of rank orders that imply higher order epistasis. Our theory applies to all common types of gene interactions and facilitates comprehensive investigations of diverse genetic interactions. We analyzed various genetic systems comprising HIV-1, the malaria-causing parasite Plasmodium vivax , the fungus Aspergillus niger , and the TEM-family of β-lactamase associated with antibiotic resistance. For all systems, our approach revealed higher order interactions among mutations.

Mapping mutational effects along the evolutionary landscape of HIV envelope

PubMed Central

Hilton, Sarah K; Overbaugh, Julie

2018-01-01

The immediate evolutionary space accessible to HIV is largely determined by how single amino acid mutations affect fitness. These mutational effects can shift as the virus evolves. However, the prevalence of such shifts in mutational effects remains unclear. Here, we quantify the effects on viral growth of all amino acid mutations to two HIV envelope (Env) proteins that differ at >100 residues. Most mutations similarly affect both Envs, but the amino acid preferences of a minority of sites have clearly shifted. These shifted sites usually prefer a specific amino acid in one Env, but tolerate many amino acids in the other. Surprisingly, shifts are only slightly enriched at sites that have substituted between the Envs—and many occur at residues that do not even contact substitutions. Therefore, long-range epistasis can unpredictably shift Env’s mutational tolerance during HIV evolution, although the amino acid preferences of most sites are conserved between moderately diverged viral strains. PMID:29590010

Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling.

PubMed

Troll, Joshua V; Hamilton, M Kristina; Abel, Melissa L; Ganz, Julia; Bates, Jennifer M; Stephens, W Zac; Melancon, Ellie; van der Vaart, Michiel; Meijer, Annemarie H; Distel, Martin; Eisen, Judith S; Guillemin, Karen

2018-02-23

Resident microbes promote many aspects of host development, although the mechanisms by which microbiota influence host tissues remain unclear. We showed previously that the microbiota is required for allocation of appropriate numbers of secretory cells in the zebrafish intestinal epithelium. Because Notch signaling is crucial for secretory fate determination, we conducted epistasis experiments to establish whether the microbiota modulates host Notch signaling. We also investigated whether innate immune signaling transduces microbiota cues via the Myd88 adaptor protein. We provide the first evidence that microbiota-induced, Myd88-dependent signaling inhibits host Notch signaling in the intestinal epithelium, thereby promoting secretory cell fate determination. These results connect microbiota activity via innate immune signaling to the Notch pathway, which also plays crucial roles in intestinal homeostasis throughout life and when impaired can result in chronic inflammation and cancer. © 2018. Published by The Company of Biologists Ltd.

Tanning accelerators: prevalence, predictors of use, and adverse effects.

PubMed

Herrmann, Jennifer L; Cunningham, Rachel; Cantor, Alan; Elewski, Boni E; Elmets, Craig A

2015-01-01

Tanning accelerators are topical products used by indoor tanners to augment and hasten the tanning process. These products contain tyrosine, psoralens, and/or other chemicals. We sought to better define the population using accelerators, identify predictors of their use, and describe any related adverse effects. This cross-sectional study surveyed 200 indoor tanners about their tanning practices and accelerator use. Primary analysis compared accelerator users with nonusers with respect to questionnaire variables. Descriptive statistics and χ(2) contingency tables were applied to identify statistically significant variables. Of respondents, 53% used accelerators; 97% were female and 3% were male with a median age of 22 years (range: 19-67). Users were more likely to spray tan, tan frequently, and be addicted to tanning. Acne and rashes were more common in accelerator users. Adverse reactions to accelerators prevented their further use 31% of the time. A limited adult population was evaluated; exact accelerator ingredients were not examined. Tanning accelerator users are high-risk indoor tanners who tan more frequently and who are more likely addicted to tanning. Acne and rashes are more common with these products and act as only mild deterrents to continued use. Additional research should investigate accelerators' longer-term health effects. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Analysis of Monte Carlo accelerated iterative methods for sparse linear systems: Analysis of Monte Carlo accelerated iterative methods for sparse linear systems

DOE PAGES

Benzi, Michele; Evans, Thomas M.; Hamilton, Steven P.; ...

2017-03-05

Here, we consider hybrid deterministic-stochastic iterative algorithms for the solution of large, sparse linear systems. Starting from a convergent splitting of the coefficient matrix, we analyze various types of Monte Carlo acceleration schemes applied to the original preconditioned Richardson (stationary) iteration. We expect that these methods will have considerable potential for resiliency to faults when implemented on massively parallel machines. We also establish sufficient conditions for the convergence of the hybrid schemes, and we investigate different types of preconditioners including sparse approximate inverses. Numerical experiments on linear systems arising from the discretization of partial differential equations are presented.

Vibration analysis of the SA349/2 helicopter

NASA Technical Reports Server (NTRS)

Heffernan, Ruth; Precetti, Dominique; Johnson, Wayne

1991-01-01

Helicopter airframe vibration is examined using calculations and measurements for the SA349/2 research helicopter. The hub loads, which transmit excitations to the fuselage, are predicted using a comprehensive rotorcraft analysis and correlated with measuring hub loads. The predicted and measured hub loads are then coupled with finite element models representing the SA349/2 fuselage. The resulting vertical acceleration at the pilot seat is examined. Adjustments are made to the airframe structural models to examine the sensitivity of predicted vertical acceleration to the model. Changes of a few percent to the damping and frequency of specific models lead to large reductions in predicted vibration, and to major improvements in the correlations with measured pilot-seat vertical acceleration.

Correlation between X-ray flux and rotational acceleration in Vela X-1

NASA Technical Reports Server (NTRS)

Deeter, J. E.; Boynton, P. E.; Shibazaki, N.; Hayakawa, S.; Nagase, F.

1989-01-01

The results of a search for correlations between X-ray flux and angular acceleration for the accreting binary pulsar Vela X-1 are presented. Results are based on data obtained with the Hakucho satellite during the interval 1982 to 1984. In undertaking this correlation analysis, it was necessary to modify the usual statistical method to deal with conditions imposed by generally unavoidable satellite observing constraints, most notably a mismatch in sampling between the two variables. The results are suggestive of a correlation between flux and the absolute value of the angular acceleration, at a significance level of 96 percent. The implications of the methods and results for future observations and analysis are discussed.

Λ CDM is Consistent with SPARC Radial Acceleration Relation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keller, B. W.; Wadsley, J. W., E-mail: kellerbw@mcmaster.ca

2017-01-20

Recent analysis of the Spitzer Photometry and Accurate Rotation Curve (SPARC) galaxy sample found a surprisingly tight relation between the radial acceleration inferred from the rotation curves and the acceleration due to the baryonic components of the disk. It has been suggested that this relation may be evidence for new physics, beyond Λ CDM . In this Letter, we show that 32 galaxies from the MUGS2 match the SPARC acceleration relation. These cosmological simulations of star-forming, rotationally supported disks were simulated with a WMAP3 Λ CDM cosmology, and match the SPARC acceleration relation with less scatter than the observational data.more » These results show that this acceleration relation is a consequence of dissipative collapse of baryons, rather than being evidence for exotic dark-sector physics or new dynamical laws.« less

Method for Direct Measurement of Cosmic Acceleration by 21-cm Absorption Systems

NASA Astrophysics Data System (ADS)

Yu, Hao-Ran; Zhang, Tong-Jie; Pen, Ue-Li

2014-07-01

So far there is only indirect evidence that the Universe is undergoing an accelerated expansion. The evidence for cosmic acceleration is based on the observation of different objects at different distances and requires invoking the Copernican cosmological principle and Einstein's equations of motion. We examine the direct observability using recession velocity drifts (Sandage-Loeb effect) of 21-cm hydrogen absorption systems in upcoming radio surveys. This measures the change in velocity of the same objects separated by a time interval and is a model-independent measure of acceleration. We forecast that for a CHIME-like survey with a decade time span, we can detect the acceleration of a ΛCDM universe with 5σ confidence. This acceleration test requires modest data analysis and storage changes from the normal processing and cannot be recovered retroactively.

A quantitative analysis of coupled oscillations using mobile accelerometer sensors

NASA Astrophysics Data System (ADS)

Castro-Palacio, Juan Carlos; Velázquez-Abad, Luisberis; Giménez, Fernando; Monsoriu, Juan A.

2013-05-01

In this paper, smartphone acceleration sensors were used to perform a quantitative analysis of mechanical coupled oscillations. Symmetric and asymmetric normal modes were studied separately in the first two experiments. In the third, a coupled oscillation was studied as a combination of the normal modes. Results indicate that acceleration sensors of smartphones, which are very familiar to students, represent valuable measurement instruments for introductory and first-year physics courses.

Three Dimensional Gait Analysis Using Wearable Acceleration and Gyro Sensors Based on Quaternion Calculations

PubMed Central

Tadano, Shigeru; Takeda, Ryo; Miyagawa, Hiroaki

2013-01-01

This paper proposes a method for three dimensional gait analysis using wearable sensors and quaternion calculations. Seven sensor units consisting of a tri-axial acceleration and gyro sensors, were fixed to the lower limbs. The acceleration and angular velocity data of each sensor unit were measured during level walking. The initial orientations of the sensor units were estimated using acceleration data during upright standing position and the angular displacements were estimated afterwards using angular velocity data during gait. Here, an algorithm based on quaternion calculation was implemented for orientation estimation of the sensor units. The orientations of the sensor units were converted to the orientations of the body segments by a rotation matrix obtained from a calibration trial. Body segment orientations were then used for constructing a three dimensional wire frame animation of the volunteers during the gait. Gait analysis was conducted on five volunteers, and results were compared with those from a camera-based motion analysis system. Comparisons were made for the joint trajectory in the horizontal and sagittal plane. The average RMSE and correlation coefficient (CC) were 10.14 deg and 0.98, 7.88 deg and 0.97, 9.75 deg and 0.78 for the hip, knee and ankle flexion angles, respectively. PMID:23877128

Shortening tobacco life cycle accelerates functional gene identification in genomic research.

PubMed

Ning, G; Xiao, X; Lv, H; Li, X; Zuo, Y; Bao, M

2012-11-01

Definitive allocation of function requires the introduction of genetic mutations and analysis of their phenotypic consequences. Novel, rapid and convenient techniques or materials are very important and useful to accelerate gene identification in functional genomics research. Here, over-expression of PmFT (Prunus mume), a novel FT orthologue, and PtFT (Populus tremula) lead to shortening of the tobacco life cycle. A series of novel short life cycle stable tobacco lines (30-50 days) were developed through repeated self-crossing selection breeding. Based on the second transformation via a gusA reporter gene, the promoter from BpFULL1 in silver birch (Betula pendula) and the gene (CPC) from Arabidopsis thaliana were effectively tested using short life cycle tobacco lines. Comparative analysis among wild type, short life cycle tobacco and Arabidopsis transformation system verified that it is optional to accelerate functional gene studies by shortening host plant material life cycle, at least in these short life cycle tobacco lines. The results verified that the novel short life cycle transgenic tobacco lines not only combine the advantages of economic nursery requirements and a simple transformation system, but also provide a robust, effective and stable host system to accelerate gene analysis. Thus, shortening tobacco life cycle strategy is feasible to accelerate heterologous or homologous functional gene identification in genomic research. © 2012 German Botanical Society and The Royal Botanical Society of the Netherlands.

Maximum Acceleration Recording Circuit

NASA Technical Reports Server (NTRS)

Bozeman, Richard J., Jr.

1995-01-01

Coarsely digitized maximum levels recorded in blown fuses. Circuit feeds power to accelerometer and makes nonvolatile record of maximum level to which output of accelerometer rises during measurement interval. In comparison with inertia-type single-preset-trip-point mechanical maximum-acceleration-recording devices, circuit weighs less, occupies less space, and records accelerations within narrower bands of uncertainty. In comparison with prior electronic data-acquisition systems designed for same purpose, circuit simpler, less bulky, consumes less power, costs and analysis of data recorded in magnetic or electronic memory devices. Circuit used, for example, to record accelerations to which commodities subjected during transportation on trucks.

Timing of recent accelerations of Pine Island Glacier, Antarctica

USGS Publications Warehouse

Joughin, I.; Rignot, E.; Rosanova, C.E.; Lucchitta, B.K.; Bohlander, J.

2003-01-01

We have used Interferometric Synthetic Aperture Radar (InSAR) data and sequential Landsat imagery to identify and temporally constrain two acceleration events on Pine Island Glacier (PIG). These two events are separated by a period of at least seven years (1987 - 1994). The change in discharge between two flux gates indicates that the majority of the increase in discharge associated with the second acceleration originates well inland (>80 km) from the grounding line. An analysis indicates that changes in driving stress consistent with observed thinning rates are sufficient in magnitude to explain much of the acceleration.

The influence of acceleration loading curve characteristics on traumatic brain injury.

PubMed

Post, Andrew; Blaine Hoshizaki, T; Gilchrist, Michael D; Brien, Susan; Cusimano, Michael D; Marshall, Shawn

2014-03-21

To prevent brain trauma, understanding the mechanism of injury is essential. Once the mechanism of brain injury has been identified, prevention technologies could then be developed to aid in their prevention. The incidence of brain injury is linked to how the kinematics of a brain injury event affects the internal structures of the brain. As a result it is essential that an attempt be made to describe how the characteristics of the linear and rotational acceleration influence specific traumatic brain injury lesions. As a result, the purpose of this study was to examine the influence of the characteristics of linear and rotational acceleration pulses and how they account for the variance in predicting the outcome of TBI lesions, namely contusion, subdural hematoma (SDH), subarachnoid hemorrhage (SAH), and epidural hematoma (EDH) using a principal components analysis (PCA). Monorail impacts were conducted which simulated falls which caused the TBI lesions. From these reconstructions, the characteristics of the linear and rotational acceleration were determined and used for a PCA analysis. The results indicated that peak resultant acceleration variables did not account for any of the variance in predicting TBI lesions. The majority of the variance was accounted for by duration of the resultant and component linear and rotational acceleration. In addition, the components of linear and rotational acceleration characteristics on the x, y, and z axes accounted for the majority of the remainder of the variance after duration. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of the marginal fit of metal copings fabricated on three different marginal designs using conventional and accelerated casting techniques: an in vitro study.

PubMed

Vaidya, Sharad; Parkash, Hari; Bhargava, Akshay; Gupta, Sharad

2014-01-01

Abundant resources and techniques have been used for complete coverage crown fabrication. Conventional investing and casting procedures for phosphate-bonded investments require a 2- to 4-h procedure before completion. Accelerated casting techniques have been used, but may not result in castings with matching marginal accuracy. The study measured the marginal gap and determined the clinical acceptability of single cast copings invested in a phosphate-bonded investment with the use of conventional and accelerated methods. One hundred and twenty cast coping samples were fabricated using conventional and accelerated methods, with three finish lines: Chamfer, shoulder and shoulder with bevel. Sixty copings were prepared with each technique. Each coping was examined with a stereomicroscope at four predetermined sites and measurements of marginal gaps were documented for each. A master chart was prepared for all the data and was analyzed using Statistical Package for the Social Sciences version. Evidence of marginal gap was then evaluated by t-test. Analysis of variance and Post-hoc analysis were used to compare two groups as well as to make comparisons between three subgroups . Measurements recorded showed no statistically significant difference between conventional and accelerated groups. Among the three marginal designs studied, shoulder with bevel showed the best marginal fit with conventional as well as accelerated casting techniques. Accelerated casting technique could be a vital alternative to the time-consuming conventional casting technique. The marginal fit between the two casting techniques showed no statistical difference.

Design of a low-cost, compact SRF accelerator for flue gas and wastewater treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ciovati, Gianluigi

2016-04-01

Funding is being requested pursuant to a proposal that was submitted and reviewed through the Portfolio Analysis and Management System (PAMS). PAMS Proposal ID: 222439. The proposed project consists of the design of a novel superconducting continuous-wave accelerator capable of providing a beam current of ~1 A at an energy of 1-2 MeV for the treatment of flue gases and wastewater streams. The novel approach consists on studying the feasibility of using a single-cell Nb cavity coated with a thin Nb3Sn layer of the inner surface and conductively cooled by to 4.2 K by cryocoolers inside a compact cryomodule. Themore » proposed study will include beam transport simulations, thermal and mechanical engineering analysis of the cryomodule and a cost analysis for both the fabrications costs and the operational and maintenance costs of such accelerator. The outcome of the project will be a report summarizing the analysis and results from the design study.« less

Estimation of payload loads using rigid body interface accelerations. [in structural design of launch vehicle systems

NASA Technical Reports Server (NTRS)

Chen, J. C.; Garba, J. A.; Wada, B. K.

1978-01-01

In the design/analysis process of a payload structural system, the accelerations at the payload/launch vehicle interface obtained from a system analysis using a rigid payload are often used as the input forcing function to the elastic payload to obtain structural design loads. Such an analysis is at best an approximation since the elastic coupling effects are neglected. This paper develops a method wherein the launch vehicle/rigid payload interface accelerations are modified to account for the payload elasticity. The advantage of the proposed method, which is exact to the extent that the physical system can be described by a truncated set of generalized coordinates, is that the complete design/analysis process can be performed within the organization responsible for the payload design. The method requires the updating of the system normal modes to account for payload changes, but does not require a complete transient solution using the composite system model. An application to a real complex structure, the Viking Spacecraft System, is given.

Rapid analysis of scattering from periodic dielectric structures using accelerated Cartesian expansions

DOE PAGES

Baczewski, Andrew David; Miller, Nicholas C.; Shanker, Balasubramaniam

2012-03-22

Here, the analysis of fields in periodic dielectric structures arise in numerous applications of recent interest, ranging from photonic bandgap structures and plasmonically active nanostructures to metamaterials. To achieve an accurate representation of the fields in these structures using numerical methods, dense spatial discretization is required. This, in turn, affects the cost of analysis, particularly for integral-equation-based methods, for which traditional iterative methods require Ο(Ν 2) operations, Ν being the number of spatial degrees of freedom. In this paper, we introduce a method for the rapid solution of volumetric electric field integral equations used in the analysis of doubly periodicmore » dielectric structures. The crux of our method is the accelerated Cartesian expansion algorithm, which is used to evaluate the requisite potentials in Ο(Ν) cost. Results are provided that corroborate our claims of acceleration without compromising accuracy, as well as the application of our method to a number of compelling photonics applications.« less

Summary Report of Mission Acceleration Measurements for MSL-1: STS-83, Launched April 14, 1997; STS-94, Launched July 1, 1997

NASA Technical Reports Server (NTRS)

Moskowitz, Milton E.; Hrovat, Kenneth; Tschen, Peter; McPherson, Kevin; Nati, Maurizio; Reckart, Timothy A.

1998-01-01

The microgravity environment of the Space Shuttle Columbia was measured during the STS-83 and STS-94 flights of the Microgravity Science Laboratory (MSL-1) mission using four different accelerometer systems: the Orbital Acceleration Research Experiment (OARE), the Space Acceleration Measurement System (SAMS), the Microgravity Measurement Assembly (MMA), and the Quasi-Steady Acceleration Measurement (QSAM) system. All four accelerometer systems provided investigators with acceleration measurements downlinked in near-real-time. Data from each system was recorded for post-mission analysis. The OARE measured the Shuttle's acceleration with high resolution in the quasi-steady frequency regime below about 0.1 Hz. The SAMS provided investigators with higher frequency acceleration measurements up to 25 Hz. The QSAM and MMA systems provided investigators with quasi-steady and higher frequency (up to 100 Hz) acceleration measurements, respectively. The microgravity environment related to various Orbiter maneuvers, crew activities, and experiment operations as measured by the OARE and MMA is presented and interpreted in section 8 of this report.

Status of MAPA (Modular Accelerator Physics Analysis) and the Tech-X Object-Oriented Accelerator Library

NASA Astrophysics Data System (ADS)

Cary, J. R.; Shasharina, S.; Bruhwiler, D. L.

1998-04-01

The MAPA code is a fully interactive accelerator modeling and design tool consisting of a GUI and two object-oriented C++ libraries: a general library suitable for treatment of any dynamical system, and an accelerator library including many element types plus an accelerator class. The accelerator library inherits directly from the system library, which uses hash tables to store any relevant parameters or strings. The GUI can access these hash tables in a general way, allowing the user to invoke a window displaying all relevant parameters for a particular element type or for the accelerator class, with the option to change those parameters. The system library can advance an arbitrary number of dynamical variables through an arbitrary mapping. The accelerator class inherits this capability and overloads the relevant functions to advance the phase space variables of a charged particle through a string of elements. Among other things, the GUI makes phase space plots and finds fixed points of the map. We discuss the object hierarchy of the two libraries and use of the code.

The radiation field measurement and analysis outside the shielding of A 10 MeV electron irradiation accelerator

NASA Astrophysics Data System (ADS)

Shang, Jing; Li, Juexin; Xu, Bing; Li, Yuxiong

2011-10-01

Electron accelerators are employed widely for diverse purposes in the irradiation-processing industry, from sterilizing medical products to treating gemstones. Because accelerators offer high efficiency, high power, and require little preventative maintenance, they are becoming more and more popular than using the 60Co isotope approach. However, the electron accelerator exposes potential radiation hazards. To protect workers and the public from exposure to radiation, the radiation field around the electronic accelerator must be assessed, especially that outside the shielding. Thus, we measured the radiation dose at different positions outside the shielding of a 10-MeV electron accelerator using a new data-acquisition unit named Mini-DDL (Mini-Digital Data Logging). The measurements accurately reflect the accelerator's radiation status. In this paper, we present our findings, results and compare them with our theoretical calculations. We conclude that the measurements taken outside the irradiation hall are consistent with the findings from our calculations, except in the maze outside the door of the accelerator room. We discuss the reason for this discrepancy.

International Space Station Increment-2 Quick Look Report

NASA Technical Reports Server (NTRS)

Jules, Kenol; Hrovat, Kenneth; Kelly, Eric

2001-01-01

The objective of this quick look report is to disseminate the International Space Station (ISS) Increment-2 reduced gravity environment preliminary analysis in a timely manner to the microgravity scientific community. This report is a quick look at the processed acceleration data collected by the Microgravity Acceleration Measurement System (MAMS) during the period of May 3 to June 8, 2001. The report is by no means an exhaustive examination of all the relevant activities, which occurred during the time span mentioned above for two reasons. First, the time span being considered in this report is rather short since the MAMS was not active throughout the time span being considered to allow a detailed characterization. Second, as the name of the report implied, it is a quick look at the acceleration data. Consequently, a more comprehensive report, the ISS Increment-2 report, will be published following the conclusion of the Increment-2 tour of duty. NASA sponsors the MAMS and the Space Acceleration Microgravity System (SAMS) to support microgravity science experiments, which require microgravity acceleration measurements. On April 19, 2001, both the MAMS and the SAMS units were launched on STS-100 from the Kennedy Space Center for installation on the ISS. The MAMS unit was flown to the station in support of science experiments requiring quasisteady acceleration data measurements, while the SAMS unit was flown to support experiments requiring vibratory acceleration data measurement. Both acceleration systems are also used in support of the vehicle microgravity requirements verification. The ISS reduced gravity environment analysis presented in this report uses mostly the MAMS acceleration data measurements (the Increment-2 report will cover both systems). The MAMS has two sensors. The MAMS Orbital Acceleration Research Experiment Sensor Subsystem, which is a low frequency range sensor (up to 1 Hz), is used to characterize the quasi-steady environment for payloads and vehicle. The MAMS High Resolution Acceleration Package is used to characterize the ISS vibratory environment up to 100 Hz. This quick look report presents some selected quasi-steady and vibratory activities recorded by the MAMS during the ongoing ISS Increment-2 tour of duty.

Gauging the cosmic acceleration with recent type Ia supernovae data sets

NASA Astrophysics Data System (ADS)

Velten, Hermano; Gomes, Syrios; Busti, Vinicius C.

2018-04-01

We revisit a model-independent estimator for cosmic acceleration based on type Ia supernovae distance measurements. This approach does not rely on any specific theory for gravity, energy content, nor parametrization for the scale factor or deceleration parameter and is based on falsifying the null hypothesis that the Universe never expanded in an accelerated way. By generating mock catalogs of known cosmologies, we test the robustness of this estimator, establishing its limits of applicability. We detail the pros and cons of such an approach. For example, we find that there are specific counterexamples in which the estimator wrongly provides evidence against acceleration in accelerating cosmologies. The dependence of the estimator on the H0 value is also discussed. Finally, we update the evidence for acceleration using the recent UNION2.1 and Joint Light-Curve Analysis samples. Contrary to recent claims, available data strongly favor an accelerated expansion of the Universe in complete agreement with the standard Λ CDM model.

Regulators of pseudohyphal differentiation in Saccharomyces cerevisiae identified through multicopy suppressor analysis in ammonium permease mutant strains.

PubMed Central

Lorenz, M C; Heitman, J

1998-01-01

Nitrogen-starved diploid cells of the yeast Saccharomyces cerevisiae differentiate into a filamentous, pseudohyphal growth form. Recognition of nitrogen starvation is mediated, at least in part, by the ammonium permease Mep2p and the Galpha subunit Gpa2p. Genetic activation of the pheromone-responsive MAP kinase cascade, which is also required for filamentous growth, only weakly suppresses the filamentation defect of Deltamep2/Deltamep2 and Deltagpa2/Deltagpa2 strain. Surprisingly, deletion of Mep1p, an ammonium permease not previously thought to regulate differentiation, significantly enhances the potency of MAP kinase activation, such that the STE11-4 allele induces filamentation to near wild-type levels in Deltamep1/Deltamep1 Deltamep2/Deltamep2 and Deltamep1/Deltamep1 Deltagpa2/Deltagpa2 strains. To identify additional regulatory components, we isolated high-copy suppressors of the filamentation defect of the Deltamep1/Deltamep1 Deltamep2/Deltamep2 mutant. Multicopy expression of TEC1, PHD1, PHD2 (MSS10/MSN1/FUP4), MSN5, CDC6, MSS11, MGA1, SKN7, DOT6, HMS1, HMS2, or MEP2 each restored filamentation in a Deltamep1/Deltamep1 Deltamep2/Deltamep2 strain. Overexpression of SRK1 (SSD1), URE2, DAL80, MEP1, or MEP3 suppressed only the growth defect of the Deltamep1/Deltamep1 Deltamep2/Deltamep2 mutant strain. Characterization of these genes through deletion analysis and epistasis underscores the complexity of this developmental pathway and suggests that stress conditions other than nitrogen deprivation may also promote filamentous growth. PMID:9832522

Knowledge-Driven Analysis Identifies a Gene–Gene Interaction Affecting High-Density Lipoprotein Cholesterol Levels in Multi-Ethnic Populations

PubMed Central

Ma, Li; Brautbar, Ariel; Boerwinkle, Eric; Sing, Charles F.

2012-01-01

Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene–gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein–protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected P c = 0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene–gene interaction in the European American cohorts from the Framingham Heart Study (P c = 0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; P c = 0.006). The interaction between these two loci is also significant in the African American sample from ARIC (P c = 0.004) and in the Hispanic American sample from MESA (P c = 0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene–gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations. PMID:22654671

Spargel/dPGC-1 Is a New Downstream Effector in the Insulin–TOR Signaling Pathway in Drosophila

PubMed Central

Mukherjee, Subhas; Duttaroy, Atanu

2013-01-01

Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin–TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin–TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway. PMID:23934892

Genetic Analysis Reveals a Hierarchy of Interactions between Polycystin-Encoding Genes and Genes Controlling Cilia Function during Left-Right Determination

PubMed Central

Grimes, Daniel T.; Keynton, Jennifer L.; Buenavista, Maria T.; Jin, Xingjian; Patel, Saloni H.; Kyosuke, Shinohara; Williams, Debbie J.; Hamada, Hiroshi; Hussain, Rohanah; Nauli, Surya M.; Norris, Dominic P.

2016-01-01

During mammalian development, left-right (L-R) asymmetry is established by a cilia-driven leftward fluid flow within a midline embryonic cavity called the node. This ‘nodal flow’ is detected by peripherally-located crown cells that each assemble a primary cilium which contain the putative Ca2+ channel PKD2. The interaction of flow and crown cell cilia promotes left side-specific expression of Nodal in the lateral plate mesoderm (LPM). Whilst the PKD2-interacting protein PKD1L1 has also been implicated in L-R patterning, the underlying mechanism by which flow is detected and the genetic relationship between Polycystin function and asymmetric gene expression remains unknown. Here, we characterize a Pkd1l1 mutant line in which Nodal is activated bilaterally, suggesting that PKD1L1 is not required for LPM Nodal pathway activation per se, but rather to restrict Nodal to the left side downstream of nodal flow. Epistasis analysis shows that Pkd1l1 acts as an upstream genetic repressor of Pkd2. This study therefore provides a genetic pathway for the early stages of L-R determination. Moreover, using a system in which cultured cells are supplied artificial flow, we demonstrate that PKD1L1 is sufficient to mediate a Ca2+ signaling response after flow stimulation. Finally, we show that an extracellular PKD domain within PKD1L1 is crucial for PKD1L1 function; as such, destabilizing the domain causes L-R defects in the mouse. Our demonstration that PKD1L1 protein can mediate a response to flow coheres with a mechanosensation model of flow sensation in which the force of fluid flow drives asymmetric gene expression in the embryo. PMID:27272319

Loss of the ETR1 ethylene receptor reduces the inhibitory effect of far-red light and darkness on seed germination of Arabidopsis thaliana

PubMed Central

Wilson, Rebecca L.; Bakshi, Arkadipta; Binder, Brad M.

2014-01-01

When exposed to far-red light followed by darkness, wild-type Arabidopsis thaliana seeds fail to germinate or germinate very poorly. We have previously shown that the ethylene receptor ETR1 (ETHYLENE RESPONSE1) inhibits and ETR2 stimulates seed germination of Arabidopsis during salt stress. This function of ETR1 requires the full-length receptor. These roles are independent of ethylene levels and sensitivity and are mainly mediated by a change in abscisic acid (ABA) sensitivity. In the current study we find that etr1-6 and etr1-7 loss-of-function mutant seeds germinate better than wild-type seeds after illumination with far-red light or when germinated in the dark indicating an inhibitory role for ETR1. Surprisingly, this function of ETR1 does not require the receiver domain. No differences between these mutants and wild-type are seen when germination proceeds after treatment with white, blue, green, or red light. Loss of any of the other four ethylene receptor isoforms has no measurable effect on germination after far-red light treatment. An analysis of the transcript abundance for genes encoding ABA and gibberellic acid (GA) metabolic enzymes indicates that etr1-6 mutants may produce more GA and less ABA than wild-type seeds after illumination with far-red light which correlates with the better germination of the mutants. Epistasis analysis suggests that ETR1 may genetically interact with the phytochromes (phy), PHYA and PHYB to control germination and growth. This study shows that of the five ethylene receptor isoforms in Arabidopsis, ETR1 has a unique role in modulating the effects of red and far-red light on plant growth and development. PMID:25221561

Effects of TEA·HCl hardening accelerator on the workability of cement-based materials

NASA Astrophysics Data System (ADS)

Pan, Wenhao; Ding, Zhaoyang; Chen, Yanwen

2017-03-01

The aim of the test is to research the influence rules of TEA·HCl on the workability of cement paste and concrete. Based on the features of the new hardening accelerator, an experimental analysis system were established through different dosages of hardening accelerator, and the feasibility of such accelerator to satisfy the need of practical engineering was verified. The results show that adding of the hardening accelerator can accelerate the cement hydration, and what’s more, when the dosage was 0.04%, the setting time was the shortest while the initial setting time and final setting time were 130 min and 180 min, respectively. The initial fluidity of cement paste of adding accelerator was roughly equivalent compared with that of blank. After 30 min, fluidity loss would decrease with the dosage increasing, but fluidity may increase. The application of the hardening accelerator can make the early workability of concrete enhance, especially the slump loss of 30 min can improve more significantly. The bleeding rate of concrete significantly decreases after adding TEA·HCl. The conclusion is that the new hardening accelerator can meet the need of the workability of cement-based materials in the optimum dosage range.

The Advanced Composition Explorer Shock Database and Application to Particle Acceleration Theory

NASA Technical Reports Server (NTRS)

Parker, L. Neergaard; Zank, G. P.

2015-01-01

The theory of particle acceleration via diffusive shock acceleration (DSA) has been studied in depth by Gosling et al. (1981), van Nes et al. (1984), Mason (2000), Desai et al. (2003), Zank et al. (2006), among many others. Recently, Parker and Zank (2012, 2014) and Parker et al. (2014) using the Advanced Composition Explorer (ACE) shock database at 1 AU explored two questions: does the upstream distribution alone have enough particles to account for the accelerated downstream distribution and can the slope of the downstream accelerated spectrum be explained using DSA? As was shown in this research, diffusive shock acceleration can account for a large population of the shocks. However, Parker and Zank (2012, 2014) and Parker et al. (2014) used a subset of the larger ACE database. Recently, work has successfully been completed that allows for the entire ACE database to be considered in a larger statistical analysis. We explain DSA as it applies to single and multiple shocks and the shock criteria used in this statistical analysis. We calculate the expected injection energy via diffusive shock acceleration given upstream parameters defined from the ACE Solar Wind Electron, Proton, and Alpha Monitor (SWEPAM) data to construct the theoretical upstream distribution. We show the comparison of shock strength derived from diffusive shock acceleration theory to observations in the 50 keV to 5 MeV range from an instrument on ACE. Parameters such as shock velocity, shock obliquity, particle number, and time between shocks are considered. This study is further divided into single and multiple shock categories, with an additional emphasis on forward-forward multiple shock pairs. Finally with regard to forward-forward shock pairs, results comparing injection energies of the first shock, second shock, and second shock with previous energetic population will be given.

The Advanced Composition Explorer Shock Database and Application to Particle Acceleration Theory

NASA Technical Reports Server (NTRS)

Parker, L. Neergaard; Zank, G. P.

2015-01-01

The theory of particle acceleration via diffusive shock acceleration (DSA) has been studied in depth by Gosling et al. (1981), van Nes et al. (1984), Mason (2000), Desai et al. (2003), Zank et al. (2006), among many others. Recently, Parker and Zank (2012, 2014) and Parker et al. (2014) using the Advanced Composition Explorer (ACE) shock database at 1 AU explored two questions: does the upstream distribution alone have enough particles to account for the accelerated downstream distribution and can the slope of the downstream accelerated spectrum be explained using DSA? As was shown in this research, diffusive shock acceleration can account for a large population of the shocks. However, Parker and Zank (2012, 2014) and Parker et al. (2014) used a subset of the larger ACE database. Recently, work has successfully been completed that allows for the entire ACE database to be considered in a larger statistical analysis. We explain DSA as it applies to single and multiple shocks and the shock criteria used in this statistical analysis. We calculate the expected injection energy via diffusive shock acceleration given upstream parameters defined from the ACE Solar Wind Electron, Proton, and Alpha Monitor (SWEPAM) data to construct the theoretical upstream distribution. We show the comparison of shock strength derived from diffusive shock acceleration theory to observations in the 50 keV to 5 MeV range from an instrument on ACE. Parameters such as shock velocity, shock obliquity, particle number, and time between shocks are considered. This study is further divided into single and multiple shock categories, with an additional emphasis on forward-forward multiple shock pairs. Finally with regard to forwardforward shock pairs, results comparing injection energies of the first shock, second shock, and second shock with previous energetic population will be given.

Stability analysis of multigrid acceleration methods for the solution of partial differential equations

NASA Technical Reports Server (NTRS)

Fay, John F.

1990-01-01

A calculation is made of the stability of various relaxation schemes for the numerical solution of partial differential equations. A multigrid acceleration method is introduced, and its effects on stability are explored. A detailed stability analysis of a simple case is carried out and verified by numerical experiment. It is shown that the use of multigrids can speed convergence by several orders of magnitude without adversely affecting stability.

Early Experiences Porting the NAMD and VMD Molecular Simulation and Analysis Software to GPU-Accelerated OpenPOWER Platforms

PubMed Central

Stone, John E.; Hynninen, Antti-Pekka; Phillips, James C.; Schulten, Klaus

2017-01-01

All-atom molecular dynamics simulations of biomolecules provide a powerful tool for exploring the structure and dynamics of large protein complexes within realistic cellular environments. Unfortunately, such simulations are extremely demanding in terms of their computational requirements, and they present many challenges in terms of preparation, simulation methodology, and analysis and visualization of results. We describe our early experiences porting the popular molecular dynamics simulation program NAMD and the simulation preparation, analysis, and visualization tool VMD to GPU-accelerated OpenPOWER hardware platforms. We report our experiences with compiler-provided autovectorization and compare with hand-coded vector intrinsics for the POWER8 CPU. We explore the performance benefits obtained from unique POWER8 architectural features such as 8-way SMT and its value for particular molecular modeling tasks. Finally, we evaluate the performance of several GPU-accelerated molecular modeling kernels and relate them to other hardware platforms. PMID:29202130

Overview of RICOR's reliability theoretical analysis, accelerated life demonstration test results and verification by field data

NASA Astrophysics Data System (ADS)

Vainshtein, Igor; Baruch, Shlomi; Regev, Itai; Segal, Victor; Filis, Avishai; Riabzev, Sergey

2018-05-01

The growing demand for EO applications that work around the clock 24hr/7days a week, such as in border surveillance systems, emphasizes the need for a highly reliable cryocooler having increased operational availability and optimized system's Integrated Logistic Support (ILS). In order to meet this need, RICOR developed linear and rotary cryocoolers which achieved successfully this goal. Cryocoolers MTTF was analyzed by theoretical reliability evaluation methods, demonstrated by normal and accelerated life tests at Cryocooler level and finally verified by field data analysis derived from Cryocoolers operating at system level. The following paper reviews theoretical reliability analysis methods together with analyzing reliability test results derived from standard and accelerated life demonstration tests performed at Ricor's advanced reliability laboratory. As a summary for the work process, reliability verification data will be presented as a feedback from fielded systems.

Dynamic deformation analysis of light-weight mirror

NASA Astrophysics Data System (ADS)

Zhang, Yingtao; Cao, Xuedong; Kuang, Long; Yang, Wei

2012-10-01

In the process of optical dynamic target work, under the effort of the arm of dynamic target, the mirror needs to do circular motion, additional accelerated motion and uniform motion. The maximum acceleration is 10°/s2 and the maximum velocity is 30°/s. In this paper, we mostly analyze the dynamic deformation of a 600 mm honeycomb light-weight mirror of a certain dynamic target. Using the FEA (finite element analysis) method, first of all, we analyze the deformation of the light-weight mirror induced in gravity at different position; later, the dynamic deformation of light-weight mirror is analyzed in detailed. The analysis results indicate that, when the maximum acceleration is 10°/s2 and the maximum velocity is 30°/s, the centripetal force is 5% of the gravity at the equal mass, and the dynamic deformation of the mirror is 6.1% of the deformation induced by gravity.

SHORT ACCELERATION TIMES FROM SUPERDIFFUSIVE SHOCK ACCELERATION IN THE HELIOSPHERE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perri, S.; Zimbardo, G., E-mail: silvia.perri@fis.unical.it

2015-12-10

The analysis of time profiles of particles accelerated at interplanetary shocks allows particle transport properties to be inferred. The frequently observed power-law decay upstream, indeed, implies a superdiffusive particle transport when the level of magnetic field variance does not change as the time interval from the shock front increases. In this context, a superdiffusive shock acceleration (SSA) theory has been developed, allowing us to make predictions of the acceleration times. In this work we estimate for a number of interplanetary shocks, including the solar wind termination shock, the acceleration times for energetic protons in the framework of SSA and wemore » compare the results with the acceleration times predicted by standard diffusive shock acceleration. The acceleration times due to SSA are found to be much shorter than in the classical model, and also shorter than the interplanetary shock lifetimes. This decrease of the acceleration times is due to the scale-free nature of the particle displacements in the framework of superdiffusion. Indeed, very long displacements are possible, increasing the probability for particles far from the front of the shock to return, and short displacements have a high probability of occurrence, increasing the chances for particles close to the front to cross the shock many times.« less

Muscle activation patterns in acceleration-based phases during reach-to-grasp movement.

PubMed

Tokuda, Keisuke; Lee, Bumsuk; Shiihara, Yasufumi; Takahashi, Kazuhiro; Wada, Naoki; Shirakura, Kenji; Watanabe, Hideomi

2016-11-01

[Purpose] An earlier study divided reaching activity into characteristic phases based on hand velocity profiles. By synchronizing muscle activities and the acceleration profile, a phasing approach for reaching movement, based on hand acceleration profiles, was attempted in order to elucidate the roles of individual muscle activities in the different phases of the acceleration profile in reaching movements. [Subjects and Methods] Ten healthy volunteer subjects participated in this study. The aim was to electromyographically evaluate muscles around the shoulder, the upper trapezius, the anterior deltoid, the biceps brachii, and the triceps brachii, most of which have been used to evaluate arm motion, as well as the acceleration of the upper limb during simple reaching movement in the reach-to-grasp task. [Results] Analysis showed the kinematic trajectories of the acceleration during a simple biphasic profile of the reaching movement could be divided into four phases: increasing acceleration (IA), decreasing acceleration (DA), increasing deceleration (ID), and decreasing deceleration (DD). Muscles around the shoulder showed different activity patterns, which were closely associated with these acceleration phases. [Conclusion] These results suggest the important role of the four phases, derived from the acceleration trajectory, in the elucidation of the muscular mechanisms which regulate and coordinate the muscles around the shoulder in reaching movements.

Study of an External Neutron Source for an Accelerator-Driven System using the PHITS Code

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sugawara, Takanori; Iwasaki, Tomohiko; Chiba, Takashi

A code system for the Accelerator Driven System (ADS) has been under development for analyzing dynamic behaviors of a subcritical core coupled with an accelerator. This code system named DSE (Dynamics calculation code system for a Subcritical system with an External neutron source) consists of an accelerator part and a reactor part. The accelerator part employs a database, which is calculated by using PHITS, for investigating the effect related to the accelerator such as the changes of beam energy, beam diameter, void generation, and target level. This analysis method using the database may introduce some errors into dynamics calculations sincemore » the neutron source data derived from the database has some errors in fitting or interpolating procedures. In this study, the effects of various events are investigated to confirm that the method based on the database is appropriate.« less

Giga-electronvolt electrons due to a transition from laser wakefield acceleration to plasma wakefield acceleration

NASA Astrophysics Data System (ADS)

Masson-Laborde, P. E.; Mo, M. Z.; Ali, A.; Fourmaux, S.; Lassonde, P.; Kieffer, J. C.; Rozmus, W.; Teychenné, D.; Fedosejevs, R.

2014-12-01

We show through experiments that a transition from laser wakefield acceleration (LWFA) regime to a plasma wakefield acceleration (PWFA) regime can drive electrons up to energies close to the GeV level. Initially, the acceleration mechanism is dominated by the bubble created by the laser in the nonlinear regime of LWFA, leading to an injection of a large number of electrons. After propagation beyond the depletion length, leading to a depletion of the laser pulse, whose transverse ponderomotive force is not able to sustain the bubble anymore, the high energy dense bunch of electrons propagating inside bubble will drive its own wakefield by a PWFA regime. This wakefield will be able to trap and accelerate a population of electrons up to the GeV level during this second stage. Three dimensional particle-in-cell simulations support this analysis and confirm the scenario.

Giga-electronvolt electrons due to a transition from laser wakefield acceleration to plasma wakefield acceleration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Masson-Laborde, P. E., E-mail: paul-edouard.masson-laborde@cea.fr; Teychenné, D.; Mo, M. Z.

2014-12-15

We show through experiments that a transition from laser wakefield acceleration (LWFA) regime to a plasma wakefield acceleration (PWFA) regime can drive electrons up to energies close to the GeV level. Initially, the acceleration mechanism is dominated by the bubble created by the laser in the nonlinear regime of LWFA, leading to an injection of a large number of electrons. After propagation beyond the depletion length, leading to a depletion of the laser pulse, whose transverse ponderomotive force is not able to sustain the bubble anymore, the high energy dense bunch of electrons propagating inside bubble will drive its ownmore » wakefield by a PWFA regime. This wakefield will be able to trap and accelerate a population of electrons up to the GeV level during this second stage. Three dimensional particle-in-cell simulations support this analysis and confirm the scenario.« less

Heavy ion linear accelerator for radiation damage studies of materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kutsaev, Sergey V.; Mustapha, Brahim; Ostroumov, Peter N.

A new eXtreme MATerial (XMAT) research facility is being proposed at Argonne National Laboratory to enable rapid in situ mesoscale bulk analysis of ion radiation damage in advanced materials and nuclear fuels. This facility combines a new heavy-ion accelerator with the existing high-energy X-ray analysis capability of the Argonne Advanced Photon Source. The heavy-ion accelerator and target complex will enable experimenters to emulate the environment of a nuclear reactor making possible the study of fission fragment damage in materials. Material scientists will be able to use the measured material parameters to validate computer simulation codes and extrapolate the response ofmore » the material in a nuclear reactor environment. Utilizing a new heavy-ion accelerator will provide the appropriate energies and intensities to study these effects with beam intensities which allow experiments to run over hours or days instead of years. The XMAT facility will use a CW heavy-ion accelerator capable of providing beams of any stable isotope with adjustable energy up to 1.2 MeV/u for U-238(50+) and 1.7 MeV for protons. This energy is crucial to the design since it well mimics fission fragments that provide the major portion of the damage in nuclear fuels. The energy also allows damage to be created far from the surface of the material allowing bulk radiation damage effects to be investigated. The XMAT ion linac includes an electron cyclotron resonance ion source, a normal-conducting radio-frequency quadrupole and four normal-conducting multi-gap quarter-wave resonators operating at 60.625 MHz. This paper presents the 3D multi-physics design and analysis of the accelerating structures and beam dynamics studies of the linac.« less

Heavy ion linear accelerator for radiation damage studies of materials

NASA Astrophysics Data System (ADS)

Kutsaev, Sergey V.; Mustapha, Brahim; Ostroumov, Peter N.; Nolen, Jerry; Barcikowski, Albert; Pellin, Michael; Yacout, Abdellatif

2017-03-01

A new eXtreme MATerial (XMAT) research facility is being proposed at Argonne National Laboratory to enable rapid in situ mesoscale bulk analysis of ion radiation damage in advanced materials and nuclear fuels. This facility combines a new heavy-ion accelerator with the existing high-energy X-ray analysis capability of the Argonne Advanced Photon Source. The heavy-ion accelerator and target complex will enable experimenters to emulate the environment of a nuclear reactor making possible the study of fission fragment damage in materials. Material scientists will be able to use the measured material parameters to validate computer simulation codes and extrapolate the response of the material in a nuclear reactor environment. Utilizing a new heavy-ion accelerator will provide the appropriate energies and intensities to study these effects with beam intensities which allow experiments to run over hours or days instead of years. The XMAT facility will use a CW heavy-ion accelerator capable of providing beams of any stable isotope with adjustable energy up to 1.2 MeV/u for 238U50+ and 1.7 MeV for protons. This energy is crucial to the design since it well mimics fission fragments that provide the major portion of the damage in nuclear fuels. The energy also allows damage to be created far from the surface of the material allowing bulk radiation damage effects to be investigated. The XMAT ion linac includes an electron cyclotron resonance ion source, a normal-conducting radio-frequency quadrupole and four normal-conducting multi-gap quarter-wave resonators operating at 60.625 MHz. This paper presents the 3D multi-physics design and analysis of the accelerating structures and beam dynamics studies of the linac.

Analysis of the acceleration region in a circulating fluidized bed riser operating above fast fluidization velocities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Monazam, E.R.; Shadle, L.J.

2008-11-05

In commercial circulating fluidized bed (CFB) processes the acceleration zone greatly contributes to solids mixing, gas and solids dispersion, and particle residence times. A new analysis was developed to describe the relative gas-solids concentration in the acceleration region of a transport system with air as the fluidizing agent for Geldart-type B particles. A theoretical expression was derived from a drag relationship and momentum and continuity equations to describe the evolution of the gas-solids profile along the axial direction. The acceleration zone was characterized using nondimensional analysis of the continuum equations (balances of masses and momenta) that described multiphase flows. Inmore » addition to acceleration length, the boundary condition for the solids fraction at the bottom of the riser and the fully developed regions were measured using an industrial scale CFB of 0.3 m diameter and 15 m tall. The operating factors affecting the flow development in the acceleration region were determined for three materials of various sizes and densities in core annular and dilute regimes of the riser. Performance data were taken from statistically designed experiments over a wide range of Fr (0.5-39), Re (8-600), Ar (29-3600), load ratio (0.2-28), riser to particle diameter ratio (375-5000), and gas to solids density ratio (138-1381). In this one-dimensional system of equations, velocities and solid fractions were assumed to be constant over any cross section. The model and engineering correlations were compared with literature expressions to assess their validity and range of applicability. These expressions can be used as tools for simulation and design of a CFB riser and can also be easily coupled to a kinetics model for process simulation.« less

Review of European microgravity measurements

NASA Technical Reports Server (NTRS)

Hamacher, Hans

1994-01-01

AA In a French/Russion cooperation, CNES developed a microgravity detection system for analyzing the Mir space station micro-g-environment for the first time. European efforts to characterize the microgravity (1/9) environment within a space laboratory began in the late seventies with the design of the First Spacelab Mission SL-1. Its Material Science Double Rack was the first payload element to carry its own tri-axial acceleration package. Even though incapable for any frequency analysis, the data provided a wealth of novel information for optimal experiment and hardware design and operations for missions to come. Theoretical investigations under ESA contract demonstrated the significance of the detailed knowledge of micro-g data for a thorough experiment analysis. They especially revealed the high sensitivity of numerous phenomena to low frequency acceleration. Accordingly, the payloads of the Spacelab missions D-1 and D-2 were furnished with state-of-the-art detection systems to ensure frequency analysis between 0.1 and 100 Hz. The Microgravity Measurement Assembly (MMA) of D-2 was a centralized system comprising fixed installed as well as mobile tri-axial packages showing real-time data processing and transmission to ground. ESA's free flyer EURECA carried a system for continuous measurement over the entire mission. All EURECA subsystems and experimental facilities had to meet tough requirements defining the upper acceleration limits. In a French/Russion cooperation, CNES developed a mi crogravity detection system for analyzing the Mir space station micro-g-environment for the first time. An approach to get access to low frequency acceleration between 0 and 0.02 Hz will be realized by QSAM (Quasi-steady Acceleration Measurement) on IML-2, complementary to the NASA system Spacelab Acceleration Measurement System SAMS. A second flight of QSAM is planned for the Russian free flyer FOTON.

Improvement of voltage holding and high current beam acceleration by MeV accelerator for ITER NB

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taniguchi, M.; Kashiwagi, M.; Inoue, T.

Voltage holding of -1 MV is an essential issue in development of a multi-aperture multi-grid (MAMuG) negative ion accelerator, of which target is to accelerate 200 A/m{sup 2} H{sup -} ion beam up to the energy of 1 MeV for several tens seconds. Review of voltage holding results ever obtained with various geometries of the accelerators showed that the voltage holding capability was about a half of designed value based on the experiment obtained from ideal small electrode. This is considered due to local electric field concentration in the accelerators, such as edge and steps between multi-aperture grids and itsmore » support structures. Based on the detailed investigation with electric field analysis, accelerator was modified to reduce the electric field concentration by reshaping the support structures and expanding the gap length between the grid supports. After the modifications, the accelerator succeeded in sustaining -1 MV for more than one hour in vacuum. Improvement of the voltage holding characteristics progressed the energy and current accelerated by the MeV accelerator. Up to 2010, beam parameters achieved by the MAMuG accelerator were increased to 879 keV, 0.36 A (157 A/m{sup 2}) at perveance matched condition and 937 keV, 0.33 A (144 A/m{sup 2}) slightly under perveance.« less

Failure Engineering Study and Accelerated Stress Test Results for the Mars Global Surveyor Spacecraft's Power Shunt Assemblies

NASA Technical Reports Server (NTRS)

Gibbel, Mark; Larson, Timothy

2000-01-01

An Engineering-of-Failure approach to designing and executing an accelerated product qualification test was performed to support a risk assessment of a "work-around" necessitated by an on-orbit failure of another piece of hardware on the Mars Global Surveyor spacecraft. The proposed work-around involved exceeding the previous qualification experience both in terms of extreme cold exposure level and in terms of demonstrated low cycle fatigue life for the power shunt assemblies. An analysis was performed to identify potential failure sites, modes and associated failure mechanisms consistent with the new use conditions. A test was then designed and executed which accelerated the failure mechanisms identified by analysis. Verification of the resulting failure mechanism concluded the effort.

NASTRAN postprocessor program for transient response to input accelerations. [procedure for generating and writing modal input data on tapes using NASTRAN

NASA Technical Reports Server (NTRS)

Wingate, R. T.; Jones, T. C.; Stephens, M. V.

1973-01-01

The description of a transient analysis program for computing structural responses to input base accelerations is presented. A hybrid modal formulation is used and a procedure is demonstrated for generating and writing all modal input data on user tapes via NASTRAN. Use of several new Level 15 modules is illustrated along with a problem associated with reading the postprocessor program input from a user tape. An example application of the program is presented for the analysis of a spacecraft subjected to accelerations initiated by thrust transients. Experience with the program has indicated it to be very efficient and economical because of its simplicity and small central memory storage requirements.

Assessment of MCRM Boost Assist from Orbit for Deep Space Missions

NASA Technical Reports Server (NTRS)

2000-01-01

Report provides results of analysis for the beamed energy driven MHD Chemical Rocket Motor (MCRM) for application to boost from orbit to escape for deep space and interplanetary missions. Parametric analyses were performed in the mission to determine operating regime for which the MCRM provides significant propulsion performance enhancement. Analysis of the MHD accelerator was performed numerical computational methods to determine design and operational features necessary to achieve Isp on the order of 2,000 to 3,000 seconds. Algorithms were developed to scale weights for the accelerator and power supply. Significant improvement in propulsion system performance can be achieved with the beamed energy driven MCRM. The limiting factor on achievable vehicle acceleration is the specific power of the rectenna.

Acceleration of convergence of vector sequences

NASA Technical Reports Server (NTRS)

Sidi, A.; Ford, W. F.; Smith, D. A.

1983-01-01

A general approach to the construction of convergence acceleration methods for vector sequence is proposed. Using this approach, one can generate some known methods, such as the minimal polynomial extrapolation, the reduced rank extrapolation, and the topological epsilon algorithm, and also some new ones. Some of the new methods are easier to implement than the known methods and are observed to have similar numerical properties. The convergence analysis of these new methods is carried out, and it is shown that they are especially suitable for accelerating the convergence of vector sequences that are obtained when one solves linear systems of equations iteratively. A stability analysis is also given, and numerical examples are provided. The convergence and stability properties of the topological epsilon algorithm are likewise given.

The study of two-dimensional oscillations using a smartphone acceleration sensor: example of Lissajous curves

NASA Astrophysics Data System (ADS)

Tuset-Sanchis, Luis; Castro-Palacio, Juan C.; Gómez-Tejedor, José A.; Manjón, Francisco J.; Monsoriu, Juan A.

2015-08-01

A smartphone acceleration sensor is used to study two-dimensional harmonic oscillations. The data recorded by the free android application, Accelerometer Toy, is used to determine the periods of oscillation by graphical analysis. Different patterns of the Lissajous curves resulting from the superposition of harmonic motions are illustrated for three experiments. This work introduces an example of how two-dimensional oscillations can be easily studied with a smartphone acceleration sensor.

Laparoscopic surgery skills evaluation: analysis based on accelerometers.

PubMed

Sánchez, Alexis; Rodríguez, Omaira; Sánchez, Renata; Benítez, Gustavo; Pena, Romina; Salamo, Oriana; Baez, Valentina

2014-01-01

Technical skills assessment is considered an important part of surgical training. Subjective assessment is not appropriate for training feedback, and there is now increased demand for objective assessment of surgical performance. Economy of movement has been proposed as an excellent alternative for this purpose. The investigators describe a readily available method to evaluate surgical skills through motion analysis using accelerometers in Apple's iPod Touch device. Two groups of individuals with different minimally invasive surgery skill levels (experts and novices) were evaluated. Each group was asked to perform a given task with an iPod Touch placed on the dominant-hand wrist. The Accelerometer Data Pro application makes it possible to obtain movement-related data detected by the accelerometers. Average acceleration and maximum acceleration for each axis (x, y, and z) were determined and compared. The analysis of average acceleration and maximum acceleration showed statistically significant differences between groups on both the y (P = .04, P = .03) and z (P = .04, P = .04) axes. This demonstrates the ability to distinguish between experts and novices. The analysis of the x axis showed no significant differences between groups, which could be explained by the fact that the task involves few movements on this axis. Accelerometer-based motion analysis is a useful tool to evaluate laparoscopic skill development of surgeons and should be used in training programs. Validation of this device in an in vivo setting is a research goal of the investigators' team.

Progress report of the innovated KIST ion beam facility

NASA Astrophysics Data System (ADS)

Kim, Joonkon; Eliades, John A.; Yu, Byung-Yong; Lim, Weon Cheol; Chae, Keun Hwa; Song, Jonghan

2017-01-01

The Korea Institute of Science and Technology (KIST, Seoul, Republic of (S.) Korea) ion beam facility consists of three electrostatic accelerators: a 400 kV single ended ion implanter, a 2 MV tandem accelerator system and a 6 MV tandem accelerator system. The 400 kV and 6 MV systems were purchased from High Voltage Engineering Europa (HVEE, Netherlands) and commissioned in 2013, while the 2 MV system was purchased from National Electrostatics Corporation (NEC, USA) in 1995. These systems are used to provide traditional ion beam analysis (IBA), isotope ratio analysis (ex. accelerator mass spectrometry, AMS), and ion implantation/irradiation for domestic industrial and academic users. The main facility is the 6 MV HVEE Tandetron system that has an AMS line currently used for 10Be, 14C, 26Al, 36 Cl, 41Ca and 129I analyses, and three lines for IBA that are under construction. Here, these systems are introduced with their specifications and initial performance results.

OARE flight maneuvers and calibration measurements on STS-58

NASA Technical Reports Server (NTRS)

Blanchard, Robert C.; Nicholson, John Y.; Ritter, James R.; Larman, Kevin T.

1994-01-01

The Orbital Acceleration Research Experiment (OARE), which has flown on STS-40, STS-50, and STS-58, contains a three axis accelerometer with a single, nonpendulous, electrostatically suspended proofmass which can resolve accelerations to the nano-g level. The experiment also contains a full calibration station to permit in situ bias and scale factor calibration. This on-orbit calibration capability eliminates the large uncertainty of ground-based calibrations encountered with accelerometers flown in the past on the orbiter, thus providing absolute acceleration measurement accuracy heretofore unachievable. This is the first time accelerometer scale factor measurements have been performed on orbit. A detailed analysis of the calibration process is given along with results of the calibration factors from the on-orbit OARE flight measurements on STS-58. In addition, the analysis of OARE flight maneuver data used to validate the scale factor measurements in the sensor's most sensitive range is also presented. Estimates on calibration uncertainties are discussed. This provides bounds on the STS-58 absolute acceleration measurements for future applications.

Design of an 81.25 MHz continuous-wave radio-frequency quadrupole accelerator for Low Energy Accelerator Facility

NASA Astrophysics Data System (ADS)

Ma, Wei; Lu, Liang; Xu, Xianbo; Sun, Liepeng; Zhang, Zhouli; Dou, Weiping; Li, Chenxing; Shi, Longbo; He, Yuan; Zhao, Hongwei

2017-03-01

An 81.25 MHz continuous wave (CW) radio frequency quadrupole (RFQ) accelerator has been designed for the Low Energy Accelerator Facility (LEAF) at the Institute of Modern Physics (IMP) of the Chinese Academy of Science (CAS). In the CW operating mode, the proposed RFQ design adopted the conventional four-vane structure. The main design goals are providing high shunt impendence with low power losses. In the electromagnetic (EM) design, the π-mode stabilizing loops (PISLs) were optimized to produce a good mode separation. The tuners were also designed and optimized to tune the frequency and field flatness of the operating mode. The vane undercuts were optimized to provide a flat field along the RFQ cavity. Additionally, a full length model with modulations was set up for the final EM simulations. Following the EM design, thermal analysis of the structure was carried out. In this paper, detailed EM design and thermal simulations of the LEAF-RFQ will be presented and discussed. Structure error analysis was also studied.

Experimental and analytical studies on the vibration serviceability of long-span prestressed concrete floor

NASA Astrophysics Data System (ADS)

Cao, Liang; Liu, Jiepeng; Li, Jiang; Zhang, Ruizhi

2018-04-01

An extensive experimental and theoretical research study was undertaken to study the vibration serviceability of a long-span prestressed concrete floor system to be used in the lounge of a major airport. Specifically, jumping impact tests were carried out to obtain the floor's modal parameters, followed by an analysis of the distribution of peak accelerations. Running tests were also performed to capture the acceleration responses. The prestressed concrete floor was found to have a low fundamental natural frequency (≈ 8.86 Hz) corresponding to the average modal damping ratio of ≈ 2.17%. A coefficients β rp is proposed for convenient calculation of the maximum root-mean-square acceleration for running. In the theoretical analysis, the prestressed concrete floor under running excitation is treated as a two-span continuous anisotropic rectangular plate with simply-supported edges. The calculated analytical results (natural frequencies and root-mean-square acceleration) agree well with the experimental ones. The analytical approach is thus validated.

Brane with variable tension as a possible solution to the problem of the late cosmic acceleration

NASA Astrophysics Data System (ADS)

García-Aspeitia, Miguel A.; Hernandez-Almada, A.; Magaña, Juan; Amante, Mario H.; Motta, V.; Martínez-Robles, C.

2018-05-01

Braneworld models have been proposed as a possible solution to the problem of the accelerated expansion of the Universe. The idea is to dispense the dark energy (DE) and drive the late-time cosmic acceleration with a five-dimensional geometry. We investigate a brane model with variable brane tension as a function of redshift called chrono-brane. We propose the polynomial λ =(1 +z )n function inspired in tracker-scalar-field potentials. To constrain the n exponent we use the latest observational Hubble data from cosmic chronometers, Type Ia Supernovae from the full joint-light-analysis sample, baryon acoustic oscillations and the posterior distance from the cosmic microwave background of Planck 2015 measurements. A joint analysis of these data estimates n ≃6.19 ±0.12 which generates a DE-like (cosmological-constantlike at late times) term, in the Friedmann equation arising from the extra dimensions. This model is consistent with these data and can drive the Universe to an accelerated phase at late times.

SIRIUS - A new 6 MV accelerator system for IBA and AMS at ANSTO

NASA Astrophysics Data System (ADS)

Pastuovic, Zeljko; Button, David; Cohen, David; Fink, David; Garton, David; Hotchkis, Michael; Ionescu, Mihail; Long, Shane; Levchenko, Vladimir; Mann, Michael; Siegele, Rainer; Smith, Andrew; Wilcken, Klaus

2016-03-01

The Centre for Accelerator Science (CAS) facility at ANSTO has been expanded with a new 6 MV tandem accelerator system supplied by the National Electrostatic Corporation (NEC). The beamlines, end-stations and data acquisition software for the accelerator mass spectrometry (AMS) were custom built by NEC for rare isotope mass spectrometry, while the beamlines with end-stations for the ion beam analysis (IBA) are largely custom designed at ANSTO. An overview of the 6 MV system and its performance during testing and commissioning phase is given with emphasis on the IBA end-stations and their applications for materials modification and characterisation.

Progress on the Multiphysics Capabilities of the Parallel Electromagnetic ACE3P Simulation Suite

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kononenko, Oleksiy

2015-03-26

ACE3P is a 3D parallel simulation suite that is being developed at SLAC National Accelerator Laboratory. Effectively utilizing supercomputer resources, ACE3P has become a key tool for the coupled electromagnetic, thermal and mechanical research and design of particle accelerators. Based on the existing finite-element infrastructure, a massively parallel eigensolver is developed for modal analysis of mechanical structures. It complements a set of the multiphysics tools in ACE3P and, in particular, can be used for the comprehensive study of microphonics in accelerating cavities ensuring the operational reliability of a particle accelerator.

PRISM software—Processing and review interface for strong-motion data

USGS Publications Warehouse

Jones, Jeanne M.; Kalkan, Erol; Stephens, Christopher D.; Ng, Peter

2017-11-28

Rapidly available and accurate ground-motion acceleration time series (seismic recordings) and derived data products are essential to quickly providing scientific and engineering analysis and advice after an earthquake. To meet this need, the U.S. Geological Survey National Strong Motion Project has developed a software package called PRISM (Processing and Review Interface for Strong-Motion data). PRISM automatically processes strong-motion acceleration records, producing compatible acceleration, velocity, and displacement time series; acceleration, velocity, and displacement response spectra; Fourier amplitude spectra; and standard earthquake-intensity measures. PRISM is intended to be used by strong-motion seismic networks, as well as by earthquake engineers and seismologists.

A new IBA-AMS laboratory at the Comenius University in Bratislava (Slovakia)

NASA Astrophysics Data System (ADS)

Povinec, Pavel P.; Masarik, Jozef; Kúš, Peter; Holý, Karol; Ješkovský, Miroslav; Breier, Robert; Staníček, Jaroslav; Šivo, Alexander; Richtáriková, Marta; Kováčik, Andrej; Szarka, Ján; Steier, Peter; Priller, Alfred

2015-01-01

A Centre for Nuclear and Accelerator Technologies (CENTA) has been established at the Comenius University in Bratislava comprising of a tandem laboratory designed for Ion Beam Analysis (IBA), Ion Beam Modification (IBM) of materials and Accelerator Mass Spectrometry (AMS). The main equipment of the laboratory, i.e. Alphatross and MC-SNICS ion sources, 3 MV Pelletron tandem accelerator, and analyzers of accelerated ions are described. Optimization of ion beam characteristics for different ion sources with gas and solid targets, for transmission of accelerated ions with different energy and charge state, for different parameters of the high-energy ion analyzers, as well as first AMS results are presented. The scientific program of the CENTA will be devoted mainly to nuclear, environmental, life and material sciences.

Noninvasive acceleration measurements to characterize knee arthritis and chondromalacia.

PubMed

Reddy, N P; Rothschild, B M; Mandal, M; Gupta, V; Suryanarayanan, S

1995-01-01

Devising techniques and instrumentation for early detection of knee arthritis and chondromalacia presents a challenge in the domain of biomedical engineering. The purpose of the present investigation was to characterize normal knees and knees affected by osteoarthritis, rheumatoid arthritis, and chondromalacia using a set of noninvasive acceleration measurements. Ultraminiature accelerometers were placed on the skin over the patella in four groups of subjects, and acceleration measurements were obtained during leg rotation. Acceleration measurements were significantly different in the four groups of subjects in the time and frequency domains. Power spectral analysis revealed that the average power was significantly different for these groups over a 100-500 Hz range. Noninvasive acceleration measurements can characterize the normal, arthritis, and chondromalacia knees. However, a study on a larger group of subjects is indicated.

Reaction time in pilots at sustained acceleration of +4.5 G(z).

PubMed

Truszczynski, Olaf; Wojtkowiak, Mieczyslaw; Lewkowicz, Rafal; Biernacki, Marcin P; Kowalczuk, Krzysztof

2013-08-01

Pilots flying at very high speed are exposed to the effects of prolonged accelerations while changing their flight path. The aim of this research was to assess the impact of sustained accelerations on the visual-motor response times of pilots and the acceleration tolerance level (ATL) as a measure of pilots' endurance to applied +G(z). The study involved 18 young pilots, 23-25 yr of age. The subjects' task was to quickly and accurately respond to the light stimuli presented on a light bar during exposure to acceleration at +4.5 G(z) and until reaching the ATL. Simple response time (SRT) measurements were performed using a visual-motor analysis system throughout the exposures, which allowed the assessment of a pilot's ATL. The pilots' ATL ranged from 270 to 366 s (Mean = 317.7 +/- 26.15 SD). The analysis of the SRT indicated a significant effect of duration of acceleration on the visual response time. The results of the post hoc comparisons showed that SRT increased with longer durations of the same level of +G(z) load and then decreased, reaching values similar to the controls. Exposure to prolonged acceleration of +4.5 G(z) significantly increases SRT. There was no statistically significant difference in SRT between the pilots with "short" and "long" time exposures. A pilot's SRT during a prolonged +4.5 G(z) exposure could be a reliable indicator of pilot G performance in the fast jet. Deterioration of SRT may be used to predict imminent +G(z) endurance limits between pilots with widely varying endurance abilities.

Double temporal sparsity based accelerated reconstruction of compressively sensed resting-state fMRI.

PubMed

Aggarwal, Priya; Gupta, Anubha

2017-12-01

A number of reconstruction methods have been proposed recently for accelerated functional Magnetic Resonance Imaging (fMRI) data collection. However, existing methods suffer with the challenge of greater artifacts at high acceleration factors. This paper addresses the issue of accelerating fMRI collection via undersampled k-space measurements combined with the proposed method based on l 1 -l 1 norm constraints, wherein we impose first l 1 -norm sparsity on the voxel time series (temporal data) in the transformed domain and the second l 1 -norm sparsity on the successive difference of the same temporal data. Hence, we name the proposed method as Double Temporal Sparsity based Reconstruction (DTSR) method. The robustness of the proposed DTSR method has been thoroughly evaluated both at the subject level and at the group level on real fMRI data. Results are presented at various acceleration factors. Quantitative analysis in terms of Peak Signal-to-Noise Ratio (PSNR) and other metrics, and qualitative analysis in terms of reproducibility of brain Resting State Networks (RSNs) demonstrate that the proposed method is accurate and robust. In addition, the proposed DTSR method preserves brain networks that are important for studying fMRI data. Compared to the existing methods, the DTSR method shows promising potential with an improvement of 10-12 dB in PSNR with acceleration factors upto 3.5 on resting state fMRI data. Simulation results on real data demonstrate that DTSR method can be used to acquire accelerated fMRI with accurate detection of RSNs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acceleration effects in solid propellant rocket motors

NASA Technical Reports Server (NTRS)

Langhenry, M. T.

1986-01-01

The performance variations due to acceleration loads imposed on spinning solid propellant rocket motors are investigated. The four potentially most significant modes of acceleration-induced phenomena are identified from a study of the literature and modeled. The four modes are a mechanical mode which deals with deformations of the propellant and case: a thermodynamic mode which covers acceleration-induced combustion phenomena; a stress mode which covers the stressed propellant's effect on burn rate; and a gas dynamic mode which deals with changes in gas flow in the chamber and through the nozzle. Simplified models of each mode are developed or taken from the literature and are added to an internal ballistics evaluation computer program. The resulting analysis is the first to include all of the modes. In order to do this an original analysis of the mechanical and stress modes was necessary. However, the analysis shows that the stress mode is not important for the circular perforated grains studied. The other effects are shown to have a significant influence on solid rocket motor performance. The magnitude of the different mode effects are such that one may not be ignored over the others as has been done in the past. The results of the analysis are compared to published rocket motor data. The comparisons indicate an erosive burning effect that is a function of spin rate. A qualitative explanation of the erosive effect is presented.

Arc-driven rail accelerator research

NASA Technical Reports Server (NTRS)

Ray, Pradosh K.

1987-01-01

Arc-driven rail accelerator research is analyzed by considering wall ablation and viscous drag in the plasma. Plasma characteristics are evaluated through a simple fluid-mechanical analysis considering only wall ablation. By equating the energy dissipated in the plasma with the radiation heat loss, the average properties of the plasma are determined as a function of time and rate of ablation. Locations of two simultaneously accelerating arcs were determined by optical and magnetic probes and fron streak camera photographs. All three measurements provide consistent results.

IRGM Variants and Susceptibility to Inflammatory Bowel Disease in the German Population

PubMed Central

Bues, Stephanie; Stallhofer, Johannes; Fries, Christoph; Olszak, Torsten; Tsekeri, Eleni; Wetzke, Martin; Beigel, Florian; Steib, Christian; Friedrich, Matthias; Göke, Burkhard; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

2013-01-01

Background & Aims Genome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study. Methodology/Principal Findings Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05–1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06–1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01–1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (p<0.05). Genotype-phenotype analysis revealed no significant associations with a specific IBD phenotype or ileal CD involvement. There was evidence for weak gene-gene-interaction between several SNPs of the autophagy genes IRGM and ATG16L1 (p<0.05), which, however, did not remain significant after Bonferroni correction. Conclusions/Significance Our results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD. PMID:23365659

Maintenance therapy with sucralfate in duodenal ulcer: genuine prevention or accelerated healing of ulcer recurrence?

PubMed

Bynum, T E; Koch, G G

1991-08-08

We sought to compare the efficacy of sucralfate to placebo for the prevention of duodenal ulcer recurrence and to determine that the efficacy of sucralfate was due to a true reduction in ulcer prevalence and not due to secondary effects such as analgesic activity or accelerated healing. This was a double-blind, randomized, placebo-controlled, parallel groups, multicenter clinical study with 254 patients. All patients had a past history of at least two duodenal ulcers with at least one ulcer diagnosed by endoscopic examination 3 months or less before the start of the study. Complete ulcer healing without erosions was required to enter the study. Sucralfate or placebo were dosed as a 1-g tablet twice a day for 4 months, or until ulcer recurrence. Endoscopic examinations once a month and when symptoms developed determined the presence or absence of duodenal ulcers. If a patient developed an ulcer between monthly scheduled visits, the patient was dosed with a 1-g sucralfate tablet twice a day until the next scheduled visit. Statistical analyses of the results determined the efficacy of sucralfate compared with placebo for preventing duodenal ulcer recurrence. Comparisons of therapeutic agents for preventing duodenal ulcers have usually been made by testing for statistical differences in the cumulative rates for all ulcers developed during a follow-up period, regardless of the time of detection. Statistical experts at the United States Food and Drug Administration (FDA) and on the FDA Advisory Panel expressed doubts about clinical study results based on this type of analysis. They suggested three possible mechanisms for reducing the number of observed ulcers: (a) analgesic effects, (b) accelerated healing, and (c) true ulcer prevention. Traditional ulcer analysis could miss recurring ulcers due to an analgesic effect or accelerated healing. Point-prevalence analysis could miss recurring ulcers due to accelerated healing between endoscopic examinations. Maximum ulcer analyses, a novel statistical method, eliminated analgesic effects by regularly scheduled endoscopies and accelerated healing of recurring ulcers by frequent endoscopies and an open-label phase. Maximum ulcer analysis reflects true ulcer recurrence and prevention. Sucralfate was significantly superior to placebo in reducing ulcer prevalence by all analyses. Significance (p less than 0.05) was found at months 3 and 4 for all analyses. All months were significant in the traditional analysis, months 2-4 in point-prevalence analysis, and months 3-4 in the maximal ulcer prevalence analysis. Sucralfate was shown to be effective for the prevention of duodenal ulcer recurrence by a true reduction in new ulcer development.

Focal spot motion of linear accelerators and its effect on portal image analysis.

PubMed

Sonke, Jan-Jakob; Brand, Bob; van Herk, Marcel

2003-06-01

The focal spot of a linear accelerator is often considered to have a fully stable position. In practice, however, the beam control loop of a linear accelerator needs to stabilize after the beam is turned on. As a result, some motion of the focal spot might occur during the start-up phase of irradiation. When acquiring portal images, this motion will affect the projected position of anatomy and field edges, especially when low exposures are used. In this paper, the motion of the focal spot and the effect of this motion on portal image analysis are quantified. A slightly tilted narrow slit phantom was placed at the isocenter of several linear accelerators and images were acquired (3.5 frames per second) by means of an amorphous silicon flat panel imager positioned approximately 0.7 m below the isocenter. The motion of the focal spot was determined by converting the tilted slit images to subpixel accurate line spread functions. The error in portal image analysis due to focal spot motionwas estimated by a subtraction of the relative displacement of the projected slit from the relative displacement of the field edges. It was found that the motion of the focal spot depends on the control system and design of the accelerator. The shift of the focal spot at the start of irradiation ranges between 0.05-0.7 mm in the gun-target (GT) direction. In the left-right (AB) direction the shift is generally smaller. The resulting error in portal image analysis due to focal spotmotion ranges between 0.05-1.1 mm for a dose corresponding to two monitor units (MUs). For 20 MUs, the effect of the focal spot motion reduces to 0.01-0.3 mm. The error in portal image analysis due to focal spot motion can be reduced by reducing the applied dose rate.

Staging of RF-accelerating Units in a MEMS-based Ion Accelerator

NASA Astrophysics Data System (ADS)

Persaud, A.; Seidl, P. A.; Ji, Q.; Feinberg, E.; Waldron, W. L.; Schenkel, T.; Ardanuc, S.; Vinayakumar, K. B.; Lal, A.

Multiple Electrostatic Quadrupole Array Linear Accelerators (MEQALACs) provide an opportunity to realize compact radio- frequency (RF) accelerator structures that can deliver very high beam currents. MEQALACs have been previously realized with acceleration gap distances and beam aperture sizes of the order of centimeters. Through advances in Micro-Electro-Mechanical Systems (MEMS) fabrication, MEQALACs can now be scaled down to the sub-millimeter regime and batch processed on wafer substrates. In this paper we show first results from using three RF stages in a compact MEMS-based ion accelerator. The results presented show proof-of-concept with accelerator structures formed from printed circuit boards using a 3 × 3 beamlet arrangement and noble gas ions at 10 keV. We present a simple model to describe the measured results. We also discuss some of the scaling behaviour of a compact MEQALAC. The MEMS-based approach enables a low-cost, highly versatile accelerator covering a wide range of currents (10 μA to 100 mA) and beam energies (100 keV to several MeV). Applications include ion-beam analysis, mass spectrometry, materials processing, and at very high beam powers, plasma heating.

Wilson Prize Talk

NASA Astrophysics Data System (ADS)

Symon, Keith R.

2005-04-01

In the late 1950's and the 1960's the MURA (Midwestern Universities Research Association) working group developed fixed field alternating gradient (FFAG) particle accelerators. FFAG accelerators are a natural corollary of the invention of alternating gradient focusing. The fixed guide field accommodates all orbits from the injection to the final energy. For this reason, the transverse motion in the guide field is nearly decoupled from the longitudinal acceleration. This allows a wide variety of acceleration schemes, using betatron or rf accelerating fields, beam stacking, bucket lifts, phase displacement, etc. It also simplifies theoretical and experimental studies of accelerators. Theoretical studies included an extensive analysis of rf acceleration processes, nonlinear orbit dynamics, and collective instabilities. Two FFAG designs, radial sector and spiral sector, were invented. The MURA team built small electron models of each type, and used them to study orbit dynamics, acceleration processes, orbit instabilities, and space charge limits. A practical result of these studies was the invention of the spiral sector cyclotron. Another was beam stacking, which led to the first practical way of achieving colliding beams. A 50 MeV two-way radial sector model was built in which it proved possible to stack a beam of over 10 amperes of electrons.

Staging of RF-accelerating Units in a MEMS-based Ion Accelerator

DOE PAGES

Persaud, A.; Seidl, P. A.; Ji, Q.; ...

2017-10-26

Multiple Electrostatic Quadrupole Array Linear Accelerators (MEQALACs) provide an opportunity to realize compact radio- frequency (RF) accelerator structures that can deliver very high beam currents. MEQALACs have been previously realized with acceleration gap distances and beam aperture sizes of the order of centimeters. Through advances in Micro-Electro-Mechanical Systems (MEMS) fabrication, MEQALACs can now be scaled down to the sub-millimeter regime and batch processed on wafer substrates. In this paper we show first results from using three RF stages in a compact MEMS-based ion accelerator. The results presented show proof-of-concept with accelerator structures formed from printed circuit boards using a 3more » × 3 beamlet arrangement and noble gas ions at 10 keV. We present a simple model to describe the measured results. We also discuss some of the scaling behaviour of a compact MEQALAC. The MEMS-based approach enables a low-cost, highly versatile accelerator covering a wide range of currents (10 μA to 100 mA) and beam energies (100 keV to several MeV). Applications include ion-beam analysis, mass spectrometry, materials processing, and at very high beam powers, plasma heating.« less

Staging of RF-accelerating Units in a MEMS-based Ion Accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Persaud, A.; Seidl, P. A.; Ji, Q.

Multiple Electrostatic Quadrupole Array Linear Accelerators (MEQALACs) provide an opportunity to realize compact radio- frequency (RF) accelerator structures that can deliver very high beam currents. MEQALACs have been previously realized with acceleration gap distances and beam aperture sizes of the order of centimeters. Through advances in Micro-Electro-Mechanical Systems (MEMS) fabrication, MEQALACs can now be scaled down to the sub-millimeter regime and batch processed on wafer substrates. In this paper we show first results from using three RF stages in a compact MEMS-based ion accelerator. The results presented show proof-of-concept with accelerator structures formed from printed circuit boards using a 3more » × 3 beamlet arrangement and noble gas ions at 10 keV. We present a simple model to describe the measured results. We also discuss some of the scaling behaviour of a compact MEQALAC. The MEMS-based approach enables a low-cost, highly versatile accelerator covering a wide range of currents (10 μA to 100 mA) and beam energies (100 keV to several MeV). Applications include ion-beam analysis, mass spectrometry, materials processing, and at very high beam powers, plasma heating.« less

The REVEILLE Clock Genes Inhibit Growth of Juvenile and Adult Plants by Control of Cell Size1[OPEN

PubMed Central

Gray, Jennifer A.; Chu, Dalena Nhu

2017-01-01

The circadian clock is a complex regulatory network that enhances plant growth and fitness in a constantly changing environment. In Arabidopsis (Arabidopsis thaliana), the clock is composed of numerous regulatory feedback loops in which REVEILLE8 (RVE8) and its homologs RVE4 and RVE6 act in a partially redundant manner to promote clock pace. Here, we report that the remaining members of the RVE8 clade, RVE3 and RVE5, play only minor roles in the regulation of clock function. However, we find that RVE8 clade proteins have unexpected functions in the modulation of light input to the clock and the control of plant growth at multiple stages of development. In seedlings, these proteins repress hypocotyl elongation in a daylength- and sucrose-dependent manner. Strikingly, adult rve4 6 8 and rve3 4 5 6 8 mutants are much larger than wild-type plants, with both increased leaf area and biomass. This size phenotype is associated with a faster growth rate and larger cell size and is not simply due to a delay in the transition to flowering. Gene expression and epistasis analysis reveal that the growth phenotypes of rve mutants are due to the misregulation of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and PIF5 expression. Our results show that even small changes in PIF gene expression caused by the perturbation of clock gene function can have large effects on the growth of adult plants. PMID:28254761

High Density Single Nucleotide Polymorphism (SNP) Mapping and Quantitative Trait Loci (QTL) Analysis in a Biparental Spring Triticale Population Localized Major and Minor Effect Fusarium Head Blight Resistance and Associated Traits QTL

PubMed Central

Dhariwal, Raman; Fedak, George; Dion, Yves; Pozniak, Curtis; Laroche, André; Eudes, François; Randhawa, Harpinder Singh

2018-01-01

Triticale (xTriticosecale Wittmack) is an important feed crop which suffers severe yield, grade and end-use quality losses due to Fusarium head blight (FHB). Development of resistant triticale cultivars is hindered by lack of effective genetic resistance sources. To dissect FHB resistance, a doubled haploid spring triticale population produced from the cross TMP16315/AC Ultima using a microspore culture method, was phenotyped for FHB incidence, severity, visual rating index (VRI), deoxynivalenol (DON) and some associated traits (ergot, grain protein content, test weight, yield, plant height and lodging) followed by single nucleotide polymorphism (SNP) genotyping. A high-density map consisting of 5274 SNPs, mapped on all 21 chromosomes with a map density of 0.48 cM/SNP, was constructed. Together, 17 major quantitative trait loci were identified for FHB on chromosomes 1A, 2B, 3A, 4A, 4R, 5A, 5R and 6B; two of incidence loci (on 2B and 5R) also co-located with loci for severity and VRI, and two other loci of VRI (on 1A and 4R) with DON accumulation. Major and minor loci were also identified for all other traits in addition to many epistasis loci. This study provides new insight into the genetic basis of FHB resistance and their association with other traits in triticale. PMID:29304028

Cytonuclear Epistasis Controls the Density of Symbiont Wolbachia pipientis in Nongonadal Tissues of Mosquito Culex quinquefasciatus.

PubMed

Emerson, Kevin J; Glaser, Robert L

2017-08-07

Wolbachia pipientis , a bacterial symbiont infecting arthropods and nematodes, is vertically transmitted through the female germline and manipulates its host's reproduction to favor infected females. Wolbachia also infects somatic tissues where it can cause nonreproductive phenotypes in its host, including resistance to viral pathogens. Wolbachia -mediated phenotypes are strongly associated with the density of Wolbachia in host tissues. Little is known, however, about how Wolbachia density is regulated in native or heterologous hosts. Here, we measure the broad-sense heritability of Wolbachia density among families in field populations of the mosquito Culex pipiens , and show that densities in ovary and nongonadal tissues of females in the same family are not correlated, suggesting that Wolbachia density is determined by distinct mechanisms in the two tissues. Using introgression analysis between two different strains of the closely related species C. quinquefasciatus , we show that Wolbachia densities in ovary tissues are determined primarily by cytoplasmic genotype, while densities in nongonadal tissues are determined by both cytoplasmic and nuclear genotypes and their epistatic interactions. Quantitative-trait-locus mapping identified two major-effect quantitative-trait loci in the C. quinquefasciatus genome explaining a combined 23% of variance in Wolbachia density, specifically in nongonadal tissues. A better understanding of how Wolbachia density is regulated will provide insights into how Wolbachia density can vary spatiotemporally in insect populations, leading to changes in Wolbachia -mediated phenotypes such as viral pathogen resistance. Copyright © 2017 Emerson, Glaser.

Distinct Functions of Different scl Isoforms in Zebrafish Definitive Hematopoietic Stem Cell Initiation and Maintenance

NASA Astrophysics Data System (ADS)

Lan, Yahui

2011-07-01

The establishment of entire blood system relies on the multi-potent hematopoietic stem cells (HSCs), thus identifying the molecular mechanism in HSC generation is of importance for not only complementing the fundamental knowledge in stem cell biology, but also providing insights to the regenerative therapies. Recent researches have documented the formation of nascent HSCs through a direct transition from ventral aortic endothelium, named as endothelial hematopoietic transition (EHT) process. However, the precise genetic program engaged in this process remains largely elusive. The transcription factor scl plays pivotal and conserved roles in embryonic and adult hematopoiesis from teleosts to mammals. Our lab have previously identified a new truncated scl isoform, scl-beta, which is indispensible for the specification of HSCs in the ventral wall of dorsal aorta (VDA), the zebrafish equivalent of mammalian fetal hematopoietic organ. Here we observe that, by combining time-lapse confocal imaging of transgenic zebrafish and genetic epistasis analysis, scl-beta is expressed in a subset of ventral aortic endothelial cells and critical for their forthcoming transformation to hemogenic endothelium; in contrast, runx1 is required downstream to govern the successful egress of the hemogenic endothelial cells to become naive HSCs. In addition, the traditional known full-length scl-alpha isoform is firstly evidenced to be required for the maintenance or survival of newly formed HSCs in VDA. Collectively our data has established the genetic hierarchy controlling discrete steps in the consecutive process of HSC formation from endothelial cells and further development in VDA.

Genetic Complexity and Quantitative Trait Loci Mapping of Yeast Morphological Traits

PubMed Central

Nogami, Satoru; Ohya, Yoshikazu; Yvert, Gaël

2007-01-01

Functional genomics relies on two essential parameters: the sensitivity of phenotypic measures and the power to detect genomic perturbations that cause phenotypic variations. In model organisms, two types of perturbations are widely used. Artificial mutations can be introduced in virtually any gene and allow the systematic analysis of gene function via mutants fitness. Alternatively, natural genetic variations can be associated to particular phenotypes via genetic mapping. However, the access to genome manipulation and breeding provided by model organisms is sometimes counterbalanced by phenotyping limitations. Here we investigated the natural genetic diversity of Saccharomyces cerevisiae cellular morphology using a very sensitive high-throughput imaging platform. We quantified 501 morphological parameters in over 50,000 yeast cells from a cross between two wild-type divergent backgrounds. Extensive morphological differences were found between these backgrounds. The genetic architecture of the traits was complex, with evidence of both epistasis and transgressive segregation. We mapped quantitative trait loci (QTL) for 67 traits and discovered 364 correlations between traits segregation and inheritance of gene expression levels. We validated one QTL by the replacement of a single base in the genome. This study illustrates the natural diversity and complexity of cellular traits among natural yeast strains and provides an ideal framework for a genetical genomics dissection of multiple traits. Our results did not overlap with results previously obtained from systematic deletion strains, showing that both approaches are necessary for the functional exploration of genomes. PMID:17319748

Regulation of Hippo signalling by p38 signalling.

PubMed

Huang, Dashun; Li, Xiaojiao; Sun, Li; Huang, Ping; Ying, Hao; Wang, Hui; Wu, Jiarui; Song, Haiyun

2016-08-01

The Hippo signalling pathway has a crucial role in growth control during development, and its dysregulation contributes to tumorigenesis. Recent studies uncover multiple upstream regulatory inputs into Hippo signalling, which affects phosphorylation of the transcriptional coactivator Yki/YAP/TAZ by Wts/Lats. Here we identify the p38 mitogen-activated protein kinase (MAPK) pathway as a new upstream branch of the Hippo pathway. In Drosophila, overexpression of MAPKK gene licorne (lic), or MAPKKK gene Mekk1, promotes Yki activity and induces Hippo target gene expression. Loss-of-function studies show that lic regulates Hippo signalling in ovary follicle cells and in the wing disc. Epistasis analysis indicates that Mekk1 and lic affect Hippo signalling via p38b and wts We further demonstrate that the Mekk1-Lic-p38b cascade inhibits Hippo signalling by promoting F-actin accumulation and Jub phosphorylation. In addition, p38 signalling modulates actin filaments and Hippo signalling in parallel to small GTPases Ras, Rac1, and Rho1. Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton. Upregulation or downregulation of the p38 pathway regulates YAP-mediated transcription. Our work thus reveals a conserved crosstalk between the p38 MAPK pathway and the Hippo pathway in growth regulation. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.