Distortion of genealogical properties when the sample is very large

Study sample sizes in human genetics are growing rapidly, and in due course it will become routine to analyze samples with hundreds of thousands if not millions of individuals. In addition to posing computational challenges, such large sample sizes call for carefully re-examining the theoretical foundation underlying commonly-used analytical tools. Here, we study the accuracy of the coalescent, a central model for studying the ancestry of a sample of individuals. The coalescent arises as a limit of a large class of random mating models and it is an accurate approximation to the original model provided that the population size is sufficiently larger than the sample size. We develop a method for performing exact computation in the discrete-time Wright-Fisher (DTWF) model and compare several key genealogical quantities of interest with the coalescent predictions. For realistic demographic scenarios, we find that there are a significant number of multiple- and simultaneous-merger events under the DTWF model, which are absent in the coalescent by construction. Furthermore, for large sample sizes, there are noticeable differences in the expected number of rare variants between the coalescent and the DTWF model. To balance the tradeoff between accuracy and computational efficiency, we propose a hybrid algorithm that utilizes the DTWF model for the recent past and the coalescent for the more distant past. Our results demonstrate that the hybrid method with only a handful of generations of the DTWF model leads to a frequency spectrum that is quite close to the prediction of the full DTWF model.Comment: 27 pages, 2 tables, 14 figure

The long-term prognostic significance of 6-minute walk test distance in patients with chronic heart failure

Background. The 6-minute walk test (6-MWT) is used to assess patients with chronic heart failure (CHF). The prognostic significance of the 6-MWT distance during long-term followup ( > 5 years) is unclear. Methods. 1,667 patients (median [inter-quartile range, IQR]) (age 72 [65-77] ; 75% males) with heart failure due to left ventricular systolic impairment undertook a 6-MWT as part of their baseline assessment and were followed up for 5 years. Results. At 5 years' followup, those patients who died (n = 959) were older at baseline and had a higher log NT pro-BNP than those who survived to 5 years (n = 708). 6-MWT distance was lower in those who died [163 (153) m versus 269 (160) m; P 360 m. 6-MWT distance was a predictor of all-cause mortality (HR 0.97; 95% CI 0.96-0.97; Chi-square = 184.1; P < 0.0001). Independent predictors of all-cause mortality were decreasing 6-MWT distance, increasing age, increasing NYHA classification, increasing log NT pro-BNP, decreasing diastolic blood pressure, decreasing sodium, and increasing urea. Conclusion. The 6-MWT is an important independent predictor of all-cause mortality following long-term followup in patients with CHF. © 2014 Lee Ingle et al

Evolution of genes and genomes on the Drosophila phylogeny

Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species

Comparative profiling of the transcriptional response to infection in two species of Drosophila by short-read cDNA sequencing

<p>Abstract</p> <p>Background</p> <p>Homology-based comparisons of the genes involved in innate immunity across many insect taxa with fully sequenced genomes has revealed a striking pattern of gene gain and loss, particularly among genes that encode proteins involved in clearing pathogens (effectors). However, limited functional annotation in non-model systems has hindered understanding of evolutionary novelties in the insect innate immune system.</p> <p>Results</p> <p>We use short read sequencing technology (Illumina/Solexa) to compare the transcriptional response to infection between the well studied model system <it>Drosophila melanogaster </it>and the distantly related drosophilid <it>D. virilis</it>. We first demonstrate that Illumina/Solexa sequencing of cDNA from infected and uninfected <it>D. melanogaster </it>recapitulates previously published microarray studies of the transcriptional response to infection in this species, validating our approach. We then show that patterns of transcription of homologous genes differ considerably between <it>D. melanogaster </it>and <it>D. virilis</it>, and identify potential candidates for novel components of the <it>D. virilis </it>immune system based on transcriptional data. Finally, we use a proteomic approach to characterize the protein constituents of the <it>D. virilis </it>hemolymph and validate our transcriptional data.</p> <p>Conclusion</p> <p>These results suggest that the acquisition of novel components of the immune system, and particularly novel effector proteins, may be a common evolutionary phenomenon.</p

Chemistry by Mobile Phone (or how to justify more time at the bar)

By combining automatic environment monitoring with Java smartphones a system has been produced for the real-time monitoring of experiments whilst away from the lab. Changes in the laboratory environment are encapsulated as simple XML messages, which are published using an MQTT compliant broker. Clients subscribe to the MQTT stream, and produce a user display. An MQTT client written for the Java MIDP platform, can be run on a smartphone with a GPRS Internet connection, freeing us from the constraints of the lab. We present an overview of the technologies used, and how these are helping chemists make the best use of their time

18F-FAC PET Visualizes Brain-Infiltrating Leukocytes in a Mouse Model of Multiple Sclerosis.

Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for noninvasively visualizing these cells in a living organism. 1-(2'-deoxy-2'-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a PET radiotracer that measures deoxyribonucleoside salvage and accumulates preferentially in immune cells. We hypothesized that 18F-FAC PET could noninvasively image brain-infiltrating leukocytes. Methods: Healthy mice were imaged with 18F-FAC PET to quantify if this radiotracer crosses the blood-brain barrier (BBB). Experimental autoimmune encephalomyelitis (EAE) is a mouse disease model with brain-infiltrating leukocytes. To determine whether 18F-FAC accumulates in brain-infiltrating leukocytes, EAE mice were analyzed with 18F-FAC PET, digital autoradiography, and immunohistochemistry, and deoxyribonucleoside salvage activity in brain-infiltrating leukocytes was analyzed ex vivo. Fingolimod-treated EAE mice were imaged with 18F-FAC PET to assess if this approach can monitor the effect of an immunomodulatory drug on brain-infiltrating leukocytes. PET scans of individuals injected with 2-chloro-2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosyl-adenine (18F-CFA), a PET radiotracer that measures deoxyribonucleoside salvage in humans, were analyzed to evaluate whether 18F-CFA crosses the human BBB. Results: 18F-FAC accumulates in the healthy mouse brain at levels similar to 18F-FAC in the blood (2.54 ± 0.2 and 3.04 ± 0.3 percentage injected dose per gram, respectively) indicating that 18F-FAC crosses the BBB. EAE mice accumulate 18F-FAC in the brain at 180% of the levels of control mice. Brain 18F-FAC accumulation localizes to periventricular regions with significant leukocyte infiltration, and deoxyribonucleoside salvage activity is present at similar levels in brain-infiltrating T and innate immune cells. These data suggest that 18F-FAC accumulates in brain-infiltrating leukocytes in this model. Fingolimod-treated EAE mice accumulate 18F-FAC in the brain at 37% lower levels than control-treated EAE mice, demonstrating that 18F-FAC PET can monitor therapeutic interventions in this mouse model. 18F-CFA accumulates in the human brain at 15% of blood levels (0.08 ± 0.01 and 0.54 ± 0.07 SUV, respectively), indicating that 18F-CFA does not cross the BBB in humans. Conclusion: 18F-FAC PET can visualize brain-infiltrating leukocytes in a mouse MS model and can monitor the response of these cells to an immunomodulatory drug. Translating this strategy into humans will require exploring additional radiotracers

Development of a composite model derived from cardiopulmonary exercise tests to predict mortality risk in patients with mild-to-moderate heart failure

Objective: Cardiopulmonary exercise testing (CPET) is used to predict outcome in patients with mild-to-moderate heart failure (HF). Single CPET-derived variables are often used, but we wanted to see if a composite score achieved better predictive power. Methods: Retrospective analysis of patient records at the Department of Cardiology, Castle Hill Hospital, Kingston-upon-Hull. 387 patients [median (25th-75th percentile)] [age 65 (56-72) years; 79% males; LVEF 34 (31-37) %] were included. Patients underwent a symptomlimited, maximal CPET on a treadmill. During a median follow up of 8.6 ± 2.1 years in survivors, 107 patients died. Survival models were built and validated using a hybrid approach between the bootstrap and Cox regression. Nine CPET-derived variables were included. Z-score defined each variable's predictive strength. Model coefficients were converted to a risk score. Results: Four CPET-related variables were independent predictors of all-cause mortality in the survival model: the presence of exertional oscillatory ventilation (EOV), increasing slope of the relation between ventilation and carbon dioxide production (VE/VCO2 slope), decreasing oxygen uptake efficiency slope (OUES), and an increase in the lowest ventilatory equivalent for carbon dioxide (VEqCO2 nadir). Individual predictors of mortality ranged from 0.60 to 0.71 using Harrell’s C-statistic, but the optimal combination of EOV + VE/VCO2 slope + OUES + VEqCO2 nadir reached 0.75. The Hull CPET risk score had a significantly higher area under the curve (0.78) when compared to the Heart Failure Survival Score (AUC=0.70;

Simple models of genomic variation in human SNP density

<p>Abstract</p> <p>Background</p> <p>Descriptive hierarchical Poisson models and population-genetic coalescent mixture models are used to describe the observed variation in single-nucleotide polymorphism (SNP) density from samples of size two across the human genome.</p> <p>Results</p> <p>Using empirical estimates of recombination rate across the human genome and the observed SNP density distribution, we produce a maximum likelihood estimate of the genomic heterogeneity in the scaled mutation rate <it>θ</it>. Such models produce significantly better fits to the observed SNP density distribution than those that ignore the empirically observed recombinational heterogeneities.</p> <p>Conclusion</p> <p>Accounting for mutational and recombinational heterogeneities can allow for empirically sound null distributions in genome scans for "outliers", when the alternative hypotheses include fundamentally historical and unobserved phenomena.</p

Size and Exhumation Rate of Ultrahigh-Pressure Terranes Linked to Orogenic Stage

A growing set of data indicates a stark contrast between the evolution of two types of ultrahigh-pressure (UHP) terranes: large terranes that evolved slowly (over 10–30 Myr), and small terranes that formed and were exhumed on timescales of \u3c 10 Myr. Here we compare the characteristics – area, thickness, formation rate, exhumation rate, age, and tectonic setting – of these two endmember types of UHP terrane worldwide. We suggest that the two UHP terrane types may form during different orogenic stages because of variations in the buoyancy and traction forces due to different proportions of subducting crust and mantle lithosphere or to different rates of subduction. The initial stages of continent collision involve the subduction of thin continental crust or microcontinents, and thus tectonic forces are dominated by the density of the oceanic slab; subduction rates are rapid and subduction angles are initially steep. However, as collision matures, thicker and larger pieces of continental material are subducted, and the positive buoyancy of the down-going slab becomes more prominent; subduction angles become gentle and convergence slows. Assessing the validity of this hypothesis is critical to understanding the physical and chemical evolution of Earth\u27s crust and mantle. Included here is the post-print copy of this article. The final publication is available via ScienceDirect at http://www.sciencedirect.com/science/article/pii/S0012821X1100756