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Search Results: 1 - 10 of 3359 matches for " Claude Beazley "
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Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations
Alexandra C. Nica,Stephen B. Montgomery,Antigone S. Dimas,Barbara E. Stranger,Claude Beazley,Inês Barroso,Emmanouil T. Dermitzakis
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000895
Abstract: The recent success of genome-wide association studies (GWAS) is now followed by the challenge to determine how the reported susceptibility variants mediate complex traits and diseases. Expression quantitative trait loci (eQTLs) have been implicated in disease associations through overlaps between eQTLs and GWAS signals. However, the abundance of eQTLs and the strong correlation structure (LD) in the genome make it likely that some of these overlaps are coincidental and not driven by the same functional variants. In the present study, we propose an empirical methodology, which we call Regulatory Trait Concordance (RTC) that accounts for local LD structure and integrates eQTLs and GWAS results in order to reveal the subset of association signals that are due to cis eQTLs. We simulate genomic regions of various LD patterns with both a single or two causal variants and show that our score outperforms SNP correlation metrics, be they statistical (r2) or historical (D'). Following the observation of a significant abundance of regulatory signals among currently published GWAS loci, we apply our method with the goal to prioritize relevant genes for each of the respective complex traits. We detect several potential disease-causing regulatory effects, with a strong enrichment for immunity-related conditions, consistent with the nature of the cell line tested (LCLs). Furthermore, we present an extension of the method in trans, where interrogating the whole genome for downstream effects of the disease variant can be informative regarding its unknown primary biological effect. We conclude that integrating cellular phenotype associations with organismal complex traits will facilitate the biological interpretation of the genetic effects on these traits.
Modifier Effects between Regulatory and Protein-Coding Variation
Antigone S. Dimas,Barbara E. Stranger,Claude Beazley,Robert D. Finn,Catherine E. Ingle,Matthew S. Forrest,Matthew E. Ritchie,Panos Deloukas,Simon Tavaré,Emmanouil T. Dermitzakis
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000244
Abstract: Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for. Analyzing genetic interactions between variants (epistasis) is one of the potential ways forward. We investigated the abundance and functional impact of a specific type of epistasis, namely the interaction between regulatory and protein-coding variants. Using genotype and gene expression data from the 210 unrelated individuals of the original four HapMap populations, we have explored the combined effects of regulatory and protein-coding single nucleotide polymorphisms (SNPs). We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in cis. Furthermore, we show that such interactions in cis can affect the expression of downstream targets of the gene containing the protein-coding SNP. In this way, a cis interaction between regulatory and protein-coding variants has a trans impact on gene expression. Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants.
Fast-evolving noncoding sequences in the human genome
Christine P Bird, Barbara E Stranger, Maureen Liu, Daryl J Thomas, Catherine E Ingle, Claude Beazley, Webb Miller, Matthew E Hurles, Emmanouil T Dermitzakis
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-6-r118
Abstract: Here we identify 1,356 CNC sequences that appear to have undergone dramatic human-specific changes in selective pressures, at least 15% of which have substitution rates significantly above that expected under neutrality. The 1,356 'accelerated CNC' (ANC) sequences are enriched in recent segmental duplications, suggesting a recent change in selective constraint following duplication. In addition, single nucleotide polymorphisms within ANC sequences have a significant excess of high frequency derived alleles and high FSTvalues relative to controls, indicating that acceleration and positive selection are recent in human populations. Finally, a significant number of single nucleotide polymorphisms within ANC sequences are associated with changes in gene expression. The probability of variation in an ANC sequence being associated with a gene expression phenotype is fivefold higher than variation in a control CNC sequence.Our analysis suggests that ANC sequences have until very recently played a role in human evolution, potentially through lineage-specific changes in gene regulation.The manner in which the expression of genes is regulated defines and determines many of the cellular and developmental processes in an organism. It has been hypothesized that variation in gene regulation is responsible for much of the phenotypic diversity within and between species [1]. In particular, it was proposed a few decades ago that the phenotypic divergence between human and chimpanzees is largely due to changes in gene regulation rather than changes in the protein-coding sequences of genes [2]. Although it has been long recognized that regulatory sequences play an important role in genome function, the fine structure and evolutionary patterns of such sequences are not well understood [3], mainly because such sequences have a much more complex functional code and appear not to be restricted to particular sequence motifs. One of the most powerful approaches with which to identify regula
Eprints Institutional Repository Software: A Review
Mike R. Beazley
Partnership : the Canadian Journal of Library and Information Practice and Research , 2011,
Abstract: Setting up an institutional repository (IR) can be a daunting task. There are many software packages out there, some commercial, some open source, all of which offer different features and functionality. This article will provide some thoughts about one of these software packages: Eprints. Eprints was one of the first IR software packages to appear and has been available for 10 years. It is under continual development by its creators at the University of Southampton and the current version is v3.2.3. Eprints is open-source, meaning that anyone can download and make use of the software for free and the software can be modified however the user likes. This presents clear advantages for institutions will smaller budgets and also for institutions that have programmers on staff. Eprints requires some additional software to run: Linux, Apache, MySQL, and Perl. This software is all open-source and already present on the servers of many institutions. There is now a version of Eprints that will run on Windows servers as well, which will make the adoption of Eprints even easier for some. In brief, Eprints is an excellent choice for any institution looking to get an IR up and running quickly and easily. Installation is straightforward as is the initial configuration. Once the IR is up and running, users may upload documents and provide the necessary metadata for the records by filling out a simple web form. Embargoes on published documents are handled elegantly by the software, and the software links to the SHERPA/RoMEO database so authors can easily verify their rights regarding IR submissions. Eprints has some drawbacks, which will be discussed later in the review, but on the whole it is easy to recommend to anyone looking to start an IR. However, It is less clear that an institution with an existing IR based on another software package should migrate to Eprints.
Codimensions of Newton Strata for SL_3 in the Iwahori Case
E. T. Beazley
Mathematics , 2007,
Abstract: We study the Newton stratification on SL_3(F), where F is a Laurent power series field. We provide a formula for the codimensions of the Newton strata inside each component of the affine Bruhat decomposition on SL_3(F). These calculations are related to the study of certain affine Deligne-Lusztig varieties. In particular, we describe a method for determining which of these varieties is non-empty in the case of SL_3(F).
Affine Deligne-Lusztig varieties associated to additive affine Weyl group elements
E. T. Beazley
Mathematics , 2010,
Abstract: Affine Deligne-Lusztig varieties can be thought of as affine analogs of classical Deligne-Lusztig varieties, or Frobenius-twisted analogs of Schubert varieties. We provide a method for proving a non-emptiness statement for affine Deligne-Lusztig varieties inside the affine flag variety associated to affine Weyl group elements satisfying a certain length additivity hypothesis. In particular, we prove that non-emptiness holds whenever it is conjectured to do so for alcoves in the shrunken dominant Weyl chamber, providing a partial converse to the emptiness results of Goertz, Haines, Kottwitz, and Reuman. Our technique involves the work of Geck and Pfeiffer on cuspidal conjugacy classes, in addition to an analysis of the combinatorics of certain fully commutative elements in the finite Weyl group.
Message-Passing Multi-Cell Molecular Dynamics on the Connection Machine 5
D. M. Beazley,P. S. Lomdahl
Physics , 1993,
Abstract: We present a new scalable algorithm for short-range molecular dynamics simulations on distributed memory MIMD multicomputer based on a message-passing multi-cell approach. We have implemented the algorithm on the Connection Machine 5 (CM-5) and demonstrate that meso-scale molecular dynamics with more than $10^8$ particles is now possible on massively parallel MIMD computers. Typical runs show single particle update-times of $0.15 \mu s$ in 2 dimensions (2D) and approximately $1 \mu s$ in 3 dimensions (3D) on a 1024 node CM-5 without vector units, corresponding to more than 1.8 GFlops overall performance. We also present a scaling equation which agrees well with actually observed timings.
Equivariant Quantum Cohomology of the Grassmannian via the Rim Hook Rule
Elizabeth Beazley,Anna Bertiger,Kaisa Taipale
Mathematics , 2014,
Abstract: A driving question in (quantum) cohomology of flag varieties is to find non-recursive, positive combinatorial formulas for expressing the product of two classes in a particularly nice basis, called the Schubert basis. Bertram, Ciocan-Fontanine and Fulton provided a way to compute quantum products of Schubert classes in the Grassmannian of k-planes in complex n-space by doing classical multiplication and then applying a combinatorial rim hook rule which yields the quantum parameter. In this paper, we provide a generalization of this rim hook rule to the setting in which there is also an action of the complex torus. Combining this result with Knutson and Tao's puzzle rule then gives an effective algorithm for computing the equivariant quantum Littlewood-Richardson coefficients. Interestingly, this rule requires a specialization of torus weights modulo n, providing an explicit connection to the Peterson isomorphism relating quantum and affine Schubert calculus.
Patterns of Cis Regulatory Variation in Diverse Human Populations
Barbara E. Stranger equal contributor,Stephen B. Montgomery equal contributor,Antigone S. Dimas equal contributor,Leopold Parts,Oliver Stegle,Catherine E. Ingle,Magda Sekowska,George Davey Smith,David Evans,Maria Gutierrez-Arcelus,Alkes Price,Towfique Raj,James Nisbett,Alexandra C. Nica,Claude Beazley,Richard Durbin,Panos Deloukas,Emmanouil T. Dermitzakis
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002639
Abstract: The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations.
Generating Net Forces from Backgrounds of Randomly Created Waves  [PDF]
Claude Gauthier
Journal of Modern Physics (JMP) , 2014, DOI: 10.4236/jmp.2014.516158
Abstract: We examine the possibility of generating net forces on concave isolated objects from backgrounds consisting of randomly created waves carrying momentum. This issue is examined first for waves at the surface of a liquid, and second for quantum vacuum electromagnetic waves, both in relation with a one-side-open rectangular structure whose interior embodies a large number of parallel reflecting plates. Using known results about the Casimir-like effect and the original Casimir effect for parallel plates, we explain why and how such rectangular hollow structures should feel net oriented forces. We briefly describe real systems that would allow testing these theoretical results.
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