Using Population Mixtures to Optimize the Utility of Genomic Databases: Linkage Disequilibrium and Association Study Design in India

When performing association studies in populations that have not been the focus of large-scale investigations of haplotype variation, it is often helpful to rely on genomic databases in other populations for study design and analysis – such as in the selection of tag SNPs and in the imputation of missing genotypes. One way of improving the use of these databases is to rely on a mixture of database samples that is similar to the population of interest, rather than using the single most similar database sample. We demonstrate the effectiveness of the mixture approach in the application of African, European, and East Asian HapMap samples for tag SNP selection in populations from India, a genetically intermediate region underrepresented in genomic studies of haplotype variation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65949/1/j.1469-1809.2008.00457.x.pd

Lump correction and identification in the combined thermal/epithermal neutron (CTEN) method

The authors present a model for self shielding in lumps of fissile material in active-neutron assays. The model combines the formula for self-attenuation of gamma-ray in lumpy sources with the multi-group analysis techniques used in neutron transport calculations. Models for thin foils and for spheres are examined in terms of error multiplication in determining lump corrections and the basic accuracy of the model

Contributions of Fire Refugia to Resilient Ponderosa Pine and Dry Mixed‐Conifer Forest Landscapes

Altered fire regimes can drive major and enduring compositional shifts or losses of forest ecosystems. In western North America, ponderosa pine and dry mixed‐conifer forest types appear increasingly vulnerable to uncharacteristically extensive, high‐severity wildfire. However, unburned or only lightly impacted forest stands that persist within burn mosaics—termed fire refugia—may serve as tree seed sources and promote landscape recovery. We sampled tree regeneration along gradients of fire refugia proximity and density at 686 sites within the perimeters of 12 large wildfires that occurred between 2000 and 2005 in the interior western United States. We used generalized linear mixed‐effects models to elucidate statistical relationships between tree regeneration and refugia pattern, including a new metric that incorporates patch proximity and proportional abundance. These relationships were then used to develop a spatially explicit landscape simulation model. We found that regeneration by ponderosa pine and obligate‐seeding mixed‐conifer tree species assemblages was strongly and positively predicted by refugia proximity and density. Simulation models revealed that for any given proportion of the landscape occupied by refugia, small patches produced greater landscape recovery than large patches. These results highlight the disproportionate importance of small, isolated islands of surviving trees, which may not be detectable with coarse‐scale satellite imagery. Findings also illustrate the interplay between patch‐scale resistance and landscape‐scale resilience: Disturbance‐resistant settings (fire refugia) can entrain resilience (forest regeneration) across the burn matrix. Implications and applications for land managers and conservation practitioners include strategies for the promotion and maintenance of fire refugia as components of resilient forest landscapes

Political brand image: an investigation into the operationalisation of the external orientation of David Cameron’s Conservative brand

This paper seeks to address the limited understanding of how to operationalise the external brand image of a political brand. More specifically, this research critically assesses the transfer potential of the six variables of brand image by Bosch, Venter, Han and Boshoff to deconstruct the UK Conservative Party brand from the perspective of young people aged 18–24 years during the 2010 UK General Election campaign. This research demonstrates the applicability of the six variables otherwise known as the ‘brand image framework’ to the political environment. However, the application of the brand image framework in its original conceptualisation proved problematic. Many of the brand image variables were clarified, rearticulated and simplified to address the political context. This refined conceptualisation provided an in-depth understanding of how to investigate the political brand image of David Cameron’s Conservative Party. This study addresses the paucity of research that operationalises external brand image and provides practitioners and academics within and beyond the context of political branding a mechanism to understand the external orientation of brands. This research may also be used by political and non-political brands as a basis to explore external brand image and compare its consistency with internal brand identity

Haplotypes versus genotypes on pedigrees

Abstract. Genome sequencing will soon produce haplotype data for individuals. For pedigrees of related individuals, sequencing appears to be an attractive alternative to genotyping. However, methods for pedigree analysis with haplotype data have not yet been developed, and the computational complexity of such problems has been an open question. Furthermore, it is not clear in which scenarios haplotype data would provide better estimates than genotype data for quantities such as recombination rates. To answer these questions, a reduction is given from genotype problem instances to haplotype problem instances, and it is shown that solving the haplotype problem yields the solution to the genotype problem, up to constant factors or coefficients. The pedigree analysis problems we will consider are the likelihood, maximum probability haplotype, and minimum recombination haplotype problems. Two algorithms are introduced: an exponential-time hidden Markov model (HMM) for haplotype data where some individuals are untyped, and a linear-time algorithm for pedigrees having haplotype data for all individuals. Recombination estimates from the general haplotype HMM algorithm are compared to recombination estimates produced by a genotype HMM. Having haplotype data on all individuals produces better estimates. However, having several untyped individuals can drastically reduce the utility of haplotype data. Pedigree analysis, both linkage and association studies, has a long history of important contributions to genetics, including disease-gene finding and some of the first genetic maps for humans. Recent contributions include fine-scale recombination maps in humans [4], regions linked to Schizophrenia that might be missed by genome-wide association studies [11], and insights into the relationship between cystic fibrosis and fertility [13]. Algorithms for pedigree problems are of great interest to the computer science community, in part because of connections to machine learning algorithms, optimization methods, and combinatorics [7, 16

Learning intrinsic excitability in medium spiny neurons

We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single-compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parametrization of individual ion channels on the neuronal activation function. We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal variability on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how variability and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic variability determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction.Comment: 20 pages, 8 figure

DEM of triaxial tests on crushable sand

This paper presents simulations of high-pressure triaxial shear tests on a crushable sand. The discrete element method is used, featuring a large number of particles and avoiding the use of agglomerates. The triaxial model features a flexible membrane, therefore allowing realistic deformation, and a simple breakage mechanism is implemented using the octahedral shear stress induced in the particles. The simulations show that particle crushing is essential to replicate the realistic behaviour of sand (in particular the volumetric contraction) in high-pressure shear tests. The general effects of crushing during shear are explored, including its effects on critical states, and the influence of particle strength and confining pressure on the degree of crushing are discussed

Inference of population splits and mixtures from genome-wide allele frequency data

Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In this model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication, and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and "ancient" Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.comComment: 28 pages, 6 figures in main text. Attached supplement is 22 pages, 15 figures. This is an updated version of the preprint available at http://precedings.nature.com/documents/6956/version/

A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes

GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available. © 2013 Capra et al