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  • 1
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    GeneTIER: prioritization of candidate disease genes using tissue-specific gene expression profiles (2015)
    Oxford University Press
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    Publication Date: 2015-08-08
    Description: Motivation: In attempts to determine the genetic causes of human disease, researchers are often faced with a large number of candidate genes. Linkage studies can point to a genomic region containing hundreds of genes, while the high-throughput sequencing approach will often identify a great number of non-synonymous genetic variants. Since systematic experimental verification of each such candidate gene is not feasible, a method is needed to decide which genes are worth investigating further. Computational gene prioritization presents itself as a solution to this problem, systematically analyzing and sorting each gene from the most to least likely to be the disease-causing gene, in a fraction of the time it would take a researcher to perform such queries manually. Results: Here, we present Gene TIssue Expression Ranker (GeneTIER), a new web-based application for candidate gene prioritization. GeneTIER replaces knowledge-based inference traditionally used in candidate disease gene prioritization applications with experimental data from tissue-specific gene expression datasets and thus largely overcomes the bias toward the better characterized genes/diseases that commonly afflict other methods. We show that our approach is capable of accurate candidate gene prioritization and illustrate its strengths and weaknesses using case study examples. Availability and Implementation: Freely available on the web at http://dna.leeds.ac.uk/GeneTIER/. Contact: umaan@leeds.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 2
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    OVA: integrating molecular and physical phenotype data from multiple biomedical domain ontologies with variant filtering for enhanced variant prioritization (2015)
    Oxford University Press
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    Publication Date: 2015-11-21
    Description: Motivation: Exome sequencing has become a de facto standard method for Mendelian disease gene discovery in recent years, yet identifying disease-causing mutations among thousands of candidate variants remains a non-trivial task. Results: Here we describe a new variant prioritization tool, OVA (ontology variant analysis), in which user-provided phenotypic information is exploited to infer deeper biological context. OVA combines a knowledge-based approach with a variant-filtering framework. It reduces the number of candidate variants by considering genotype and predicted effect on protein sequence, and scores the remainder on biological relevance to the query phenotype. We take advantage of several ontologies in order to bridge knowledge across multiple biomedical domains and facilitate computational analysis of annotations pertaining to genes, diseases, phenotypes, tissues and pathways. In this way, OVA combines information regarding molecular and physical phenotypes and integrates both human and model organism data to effectively prioritize variants. By assessing performance on both known and novel disease mutations, we show that OVA performs biologically meaningful candidate variant prioritization and can be more accurate than another recently published candidate variant prioritization tool. Availability and implementation: OVA is freely accessible at http://dna2.leeds.ac.uk:8080/OVA/index.jsp Supplementary information : Supplementary data are available at Bioinformatics online. Contact: umaan@leeds.ac.uk
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 3
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    DNase hypersensitive sites and association with multiple sclerosis (2014)
    Oxford University Press
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    Publication Date: 2014-01-24
    Description: Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P 〈 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL ( CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1 ). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the etiology of MS. Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype (2014)
    Oxford University Press
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    Publication Date: 2014-03-20
    Description: Ischemia caused by coronary artery disease and myocardial infarction leads to aberrant ventricular remodeling and cardiac fibrosis. This occurs partly through accumulation of gene expression changes in resident fibroblasts, resulting in an overactive fibrotic phenotype. Long-term adaptation to a hypoxic insult is likely to require significant modification of chromatin structure in order to maintain the fibrotic phenotype. Epigenetic changes may play an important role in modulating hypoxia-induced fibrosis within the heart. Therefore, the aim of the study was to investigate the potential pro-fibrotic impact of hypoxia on cardiac fibroblasts and determine whether alterations in DNA methylation could play a role in this process. This study found that within human cardiac tissue, the degree of hypoxia was associated with increased expression of collagen 1 and alpha-smooth muscle actin (ASMA). In addition, human cardiac fibroblast cells exposed to prolonged 1% hypoxia resulted in a pro-fibrotic state. These hypoxia-induced pro-fibrotic changes were associated with global DNA hypermethylation and increased expression of the DNA methyltransferase (DNMT) enzymes DNMT1 and DNMT3B. Expression of these methylating enzymes was shown to be regulated by hypoxia-inducible factor (HIF)-1α. Using siRNA to block DNMT3B expression significantly reduced collagen 1 and ASMA expression. In addition, application of the DNMT inhibitor 5-aza-2'-deoxycytidine suppressed the pro-fibrotic effects of TGFβ. Epigenetic modifications and changes in the epigenetic machinery identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu. Targeting up-regulated expression of DNMTs in ischemic heart disease may prove to be a valuable therapeutic approach.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    The spotty donor star in the X-ray transient Cen X-4 (2014)
    Oxford University Press
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    Publication Date: 2014-04-02
    Description: We accurately determine the fundamental system parameters of the neutron star X-ray transient Cen X–4 solely using phase-resolved high-resolution UV–Visual Echelle Spectrograph spectroscopy. We first determine the radial-velocity curve of the secondary star and then model the shape of the phase-resolved absorption line profiles using an X-ray binary model. The model computes the exact rotationally broadened, phase-resolved spectrum and does not depend on assumptions about the rotation profile, limb-darkening coefficients and the effects of contamination from an accretion disc. We determine the secondary star-to-neutron star binary mass ratio to be 0.1755 ± 0.0025, which is an order of magnitude more accurate than previous estimates. We also constrain the inclination angle to be 32 ${^{\circ }} ^{+8^{\circ }}_{-2^{\circ }}$ . Combining these values with the results of the radial-velocity study gives a neutron star mass of 1.94 $^{+0.37}_{-0.85}$ M consistent with previous estimates. Finally, we perform the first Roche tomography reconstruction of the secondary star in an X-ray binary. The tomogram reveals surface inhomogeneities that are due to the presence of cool starspots. A large cool polar spot, similar to that seen in Doppler images of rapidly rotating isolated stars, is present on the Northern hemisphere of the K7 secondary star and we estimate that ~4 per cent of the total surface area of the donor star is covered with spots. This evidence for starspots supports the idea that magnetic braking plays an important role in the evolution of low-mass X-ray binaries.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 6
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    Geodetic vertical velocities affected by recent rapid changes in polar motion (2014)
    Oxford University Press
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    Publication Date: 2014-09-20
    Description: Secular motion of Earth's rotation pole results in large-scale secular deformation of Earth. Here, we investigate the magnitude of the deformation that has resulted from the rapid motion of the rotation pole to the east since ~2005. We show that geodetic (GNSS, DORIS, VLBI and SLR) estimates of vertical velocity since ~2005 have been biased by up to ±0.38 mm yr –1 relative to the longer-term deformation pattern. The largest signals occur within regions that include the U.S. Pacific Coast, Europe and South Pacific islands where geodetic measurements provide essential measurements of tide-gauge vertical movement and important constraints on models of glacial isostatic adjustment. Consequently, geodetic vertical velocities based on recent data should not be interpreted as being identical to centennial or longer term vertical land movement. Since 2010 the effect is further amplified by the overprediction of the IERS polar motion model relative to the ongoing secular change in pole position—during this time geodetic vertical velocities based on the IERS pole tide model are not just biased relative to the long-term rates but also from actual post-2010 Earth deformation. For geophysical or reference frame studies seeking geodetic vertical velocities that are representative of decadal timescales, where interannual variation is considered noise, the correction for this non-linear effect is straightforward, requiring an elastic computation using a reference rate of polar motion that is linear over the timescales of interest.
    Keywords: Express Letters, Gravity, Geodesy and Tides
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 7
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    Vitamin D receptor binding, chromatin states and association with multiple sclerosis (2012)
    Oxford University Press
    Details
    Publication Date: 2012-07-28
    Description: Both genetic and environmental factors contribute to the aetiology of multiple sclerosis (MS). More than 50 genomic regions have been associated with MS susceptibility and vitamin D status also influences the risk of this complex disease. However, how these factors interact in disease causation is unclear. We aimed to investigate the relationship between vitamin D receptor (VDR) binding in lymphoblastoid cell lines (LCLs), chromatin states in LCLs and MS-associated genomic regions. Using the Genomic Hyperbrowser, we found that VDR-binding regions overlapped with active regulatory regions [active promoter (AP) and strong enhancer (SE)] in LCLs more than expected by chance [45.3-fold enrichment for SE ( P 〈 2.0e–05) and 63.41-fold enrichment for AP ( P 〈 2.0e–05)]. Approximately 77% of VDR regions were covered by either AP or SE elements. The overlap between VDR binding and regulatory elements was significantly greater in LCLs than in non-immune cells ( P 〈 2.0e–05). VDR binding also occurred within MS regions more than expected by chance (3.7-fold enrichment, P 〈 2.0e–05). Furthermore, regions of joint overlap SE-VDR and AP-VDR were even more enriched within MS regions and near to several disease-associated genes. These findings provide relevant insights into how vitamin D influences the immune system and the risk of MS through VDR interactions with the chromatin state inside MS regions. Furthermore, the data provide additional evidence for an important role played by B cells in MS. Further analyses in other immune cell types and functional studies are warranted to fully elucidate the role of vitamin D in the immune system.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    A window on exoplanet dynamical histories: Rossiter-McLaughlin observations of WASP-13b and WASP-32b (2014)
    Oxford University Press
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    Publication Date: 2014-04-19
    Description: We present Rossiter–McLaughlin observations of WASP-13b and WASP-32b and determine the sky-projected angle between the normal of the planetary orbit and the stellar rotation axis (). WASP-13b and WASP-32b both have prograde orbits and are consistent with alignment with measured sky-projected angles of $\lambda =8{^{\circ }}^{+13}_{-12}$ and $\lambda =-2{^{\circ }}^{+17}_{-19}$, respectively. Both WASP-13 and WASP-32 have T eff  〈 6250 K, and therefore, these systems support the general trend that aligned planetary systems are preferentially found orbiting cool host stars. A Lomb–Scargle periodogram analysis was carried out on archival SuperWASP data for both systems. A statistically significant stellar rotation period detection (above 99.9 per cent confidence) was identified for the WASP-32 system with P rot  = 11.6 ± 1.0 days. This rotation period is in agreement with the predicted stellar rotation period calculated from the stellar radius, R * , and v sin i if a stellar inclination of i *  = 90° is assumed. With the determined rotation period, the true 3D angle between the stellar rotation axis and the planetary orbit, , was found to be  = 11° ± 14°. We conclude with a discussion on the alignment of systems around cool host stars with T eff  〈 6150 K by calculating the tidal dissipation time-scale. We find that systems with short tidal dissipation time-scales are preferentially aligned and systems with long tidal dissipation time-scales have a broad range of obliquities.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 9
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    Defocused transmission spectroscopy: a potential detection of sodium in the atmosphere of WASP-12b (2014)
    Oxford University Press
    Details
    Publication Date: 2014-11-18
    Description: We report on a pilot study of a novel observing technique, defocused transmission spectroscopy, and its application to the study of exoplanet atmospheres using ground-based platforms. Similar to defocused photometry, defocused transmission spectroscopy has an added advantage over normal spectroscopy in that it reduces systematic errors due to flat-fielding, point spread function variations, slit-jaw imperfections and other effects associated with ground-based observations. For one of the planetary systems studied, WASP-12b, we report a tentative detection of additional Na absorption of 0.12 ± 0.03[+0.03] per cent during transit using a 2 Å wavelength mask. After consideration of a systematic that occurs mid-transit, it is likely that the true depth is actually closer to 0.15 per cent. This is a similar level of absorption reported in the atmosphere of HD 209458b (0.135 ± 0.017 per cent; Snellen et al. 2008 ). Finally, we outline methods that will improve the technique during future observations, based on our findings from this pilot study.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 10
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    Roche tomography of cataclysmic variables - VI. Differential rotation of AE Aqr - not tidally locked! (2014)
    Oxford University Press
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    Publication Date: 2014-08-14
    Description: We present Roche tomograms of the K4V secondary star in the cataclysmic variable AE Aqr, reconstructed from two data sets taken 9 d apart, and measure the differential rotation of the stellar surface. The tomograms show many large, cool starspots, including a large high-latitude spot and a prominent appendage down the trailing hemisphere. We find two distinct bands of spots around 22° and 43° latitude, and estimate a spot coverage of 15.4–17 per cent on the Northern hemisphere. Assuming a solar-like differential rotation law, the differential rotation of AE Aqr was measured using two different techniques. The first method yields an equator–pole lap time of 269 d and the second yields a lap time of 262 d. This shows that the star is not fully tidally locked, as was previously assumed for CVs, but has a co-rotation latitude of ~40°. We discuss the implications that these observations have on stellar dynamo theory, as well as the impact that spot traversal across the L 1 point may have on accretion rates in CVs as well as some of their other observed properties. The entropy landscape technique was applied to determine the system parameters of AE Aqr. For the two independent data sets, we find M 1  = 1.20 and 1.17 M , M 2  = 0.81 and 0.78 M , and orbital inclinations of 50° to 51° at optimal systemic velocities of  = –64.7 and –62.9 km s –1 .
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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