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  • 1
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    Likelihood-based complex trait association testing for arbitrary depth sequencing data (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-11
    Description: : In next generation sequencing (NGS)-based genetic studies, researchers typically perform genotype calling first and then apply standard genotype-based methods for association testing. However, such a two-step approach ignores genotype calling uncertainty in the association testing step and may incur power loss and/or inflated type-I error. In the recent literature, a few robust and efficient likelihood based methods including both likelihood ratio test (LRT) and score test have been proposed to carry out association testing without intermediate genotype calling. These methods take genotype calling uncertainty into account by directly incorporating genotype likelihood function (GLF) of NGS data into association analysis. However, existing LRT methods are computationally demanding or do not allow covariate adjustment; while existing score tests are not applicable to markers with low minor allele frequency (MAF). We provide an LRT allowing flexible covariate adjustment, develop a statistically more powerful score test and propose a combination strategy (UNC combo) to leverage the advantages of both tests. We have carried out extensive simulations to evaluate the performance of our proposed LRT and score test. Simulations and real data analysis demonstrate the advantages of our proposed combination strategy: it offers a satisfactory trade-off in terms of computational efficiency, applicability (accommodating both common variants and variants with low MAF) and statistical power, particularly for the analysis of quantitative trait where the power gain can be up to ~60% when the causal variant is of low frequency (MAF 〈 0.01). Availability and implementation : UNC combo and the associated R files, including documentation, examples, are available at http://www.unc.edu/~yunmli/UNCcombo/ Contact: yunli@med.unc.edu 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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    CRISPR-CAS9 D10A nickase target-specific fluorescent labeling of double strand DNA for whole genome mapping and structural variation analysis (2016)
    Oxford University Press
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    Publication Date: 2016-01-30
    Description: We have developed a new, sequence-specific DNA labeling strategy that will dramatically improve DNA mapping in complex and structurally variant genomic regions, as well as facilitate high-throughput automated whole-genome mapping. The method uses the Cas9 D10A protein, which contains a nuclease disabling mutation in one of the two nuclease domains of Cas9, to create a guide RNA-directed DNA nick in the context of an in vitro -assembled CRISPR-CAS9-DNA complex. Fluorescent nucleotides are then incorporated adjacent to the nicking site with a DNA polymerase to label the guide RNA-determined target sequences. This labeling strategy is very powerful in targeting repetitive sequences as well as in barcoding genomic regions and structural variants not amenable to current labeling methods that rely on uneven distributions of restriction site motifs in the DNA. Importantly, it renders the labeled double-stranded DNA available in long intact stretches for high-throughput analysis in nanochannel arrays as well as for lower throughput targeted analysis of labeled DNA regions using alternative methods for stretching and imaging the labeled long DNA molecules. Thus, this method will dramatically improve both automated high-throughput genome-wide mapping as well as targeted analyses of complex regions containing repetitive and structurally variant DNA.
    Keywords: Targeted gene modification, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Overexpression of {alpha} (1,6) fucosyltransferase associated with aggressive prostate cancer (2014)
    Oxford University Press
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    Publication Date: 2014-09-04
    Description: Aberrant protein glycosylation is known to be associated with the development of cancers. The aberrant glycans are produced by the combined actions of changed glycosylation enzymes, substrates and transporters in glycosylation synthesis pathways in cancer cells. To identify glycosylation enzymes associated with aggressive prostate cancer (PCa), we analyzed the difference in the expression of glycosyltransferase genes between aggressive and non-aggressive PCa. Three candidate genes encoding glycosyltransferases that were elevated in aggressive PCa were subsequently selected. The expression of the three candidates was then further evaluated in androgen-dependent (LNCaP) and androgen-independent (PC3) PCa cell lines. We found that the protein expression of one of the glycosyltransferases, α (1,6) fucosyltransferase (FUT8), was only detected in PC3 cells, but not in LNCaP cells. We further showed that FUT8 protein expression was elevated in metastatic PCa tissues compared to normal prostate tissues. In addition, using tissue microarrays, we found that FUT8 overexpression was statistically associated with PCa with a high Gleason score. Using PC3 and LNCaP cells as models, we found that FUT8 overexpression in LNCaP cells increased PCa cell migration, while loss of FUT8 in PC3 cells decreased cell motility. Our results suggest that FUT8 may be associated with aggressive PCa and thus is potentially useful for its prognosis.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    A Study of Semantic Web Services Network (2015)
    Oxford University Press
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    Publication Date: 2015-06-02
    Description: Loosely coupled and cross-platform features make Web services accessible and increasingly popular on the Internet. However, efficient service discovery and automated service composition are still challenges under the conventional practice where services are organized into categories. In this paper, we propose a graph-based method to organize Web services into a service ecosystem interlaced with service relationships at the semantic level. First, Web services are modelled as a set of interfaces, whose input and output parameters are annotated with well-defined ontologies. Secondly, semantic associations and interactions between Web services are mined, and services are constructed into a Web services network (SN), a variant of bipartite graph, by projecting the functional aspects of concrete Web services onto the abstract service layer. Thirdly, from the complex network perspective, the services relations are investigated and the structure of SN is analysed. To demonstrate the basic topological properties of SN, an empirical study is conducted on two data sets for comparative purposes, 10 000+ Web services collected from the Internet and 1231 Web services provided by Titan system of Zhejiang University. The experimental results reveal that SNs, which are built by different data sets on the semantic level, exhibit the same features such as small-world and scale-free. In addition, our results yield valuable insight for developing service discovery and automated composition algorithms, and characterizing the evolution of the entire Web service ecosystem.
    Print ISSN: 0010-4620
    Electronic ISSN: 1460-2067
    Topics: Computer Science
    Published by Oxford University Press
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  • 5
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    Fast multiscale regularization methods for high-order numerical differentiation (2016)
    Oxford University Press
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    Publication Date: 2016-07-13
    Description: The first-order and higher-order derivatives of a function can be viewed as the solutions of Volterra integral equations of the first kind. In this paper we propose a fast multiscale solver for the numerical solution of the Tikhonov regularization of the Volterra equations. In association with the special form of the kernels, the matrices resulting from the discretization by multiscale bases are sparse. Moreover, they can be truncated using proper strategies with only a minor loss of accuracy. In the best case, the number of nonzero entries of the truncated matrices is linear with respect to the dimensions of the matrices. The accuracy of the solution from the solver is analysed theoretically and verified by numerical experiments.
    Print ISSN: 0272-4979
    Electronic ISSN: 1464-3642
    Topics: Mathematics
    Published by Oxford University Press
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  • 6
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    Growth, biomass allocation and photosynthetic responses are related to intensity of root severance and soil moisture conditions in the plantation tree Cunninghamia lanceolata (2016)
    Oxford University Press
    Details
    Publication Date: 2016-08-03
    Description: We employed the warm temperate conifer Cunninghamia lanceolata (Lamb.) Hook. as a model of plantation forest species to investigate ecophysiological responses to root treatments (control (0%), and ~25, 50 or 75% of the initial root mass) under well-watered and water-limited conditions. Our results indicated that total root dry mass accumulation was negatively associated with the severity of root pruning, but there was evidence of multiple compensatory responses. The plants exhibited higher instantaneous and long-term (assessed by carbon isotope composition, 13 C) water-use efficiency in pruning treatments, especially under low water availability. Root pruning also increased the fine root/total root mass ratio, specific root length and fine root vitality in both water availability treatments. As a result of the compensatory responses, under well-watered conditions, height, stem dry mass accumulation, leaf/fine root biomass ratio (L/FR), transpiration rate, photosynthetic capacity and photosynthetic nitrogen-use efficiency ( E N ) were the highest under 25% pruning. Yet, all these traits except L/FR and foliage nitrogen content were severely reduced under 75% pruning. Drought negatively affected growth and leaf gas exchange rates, and there was a greater negative effect on growth, water potential, gas exchange and E N when 〉25% of total root biomass was removed. The stem/aboveground mass ratio was the highest under 25% pruning in both watering conditions. These results indicate that the responses to root severance are related to the excision intensity and soil moisture content. A moderate root pruning proved to be an effective means to improve stem dry mass accumulation.
    Print ISSN: 0829-318X
    Electronic ISSN: 1758-4469
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Published by Oxford University Press
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  • 7
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    ARGs-OAP: online analysis pipeline for antibiotic resistance genes detection from metagenomic data using an integrated structured ARG-database (2016)
    Oxford University Press
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    Publication Date: 2016-07-30
    Description: Motivation: Environmental dissemination of antibiotic resistance genes (ARGs) has become an increasing concern for public health. Metagenomics approaches can effectively detect broad profiles of ARGs in environmental samples; however, the detection and subsequent classification of ARG-like sequences are time consuming and have been severe obstacles in employing metagenomic methods. We sought to accelerate quantification of ARGs in metagenomic data from environmental samples. Results: A Structured ARG reference database (SARG) was constructed by integrating ARDB and CARD, the two most commonly used databases. SARG was curated to remove redundant sequences and optimized to facilitate query sequence identification by similarity. A database with a hierarchical structure (type-subtype-reference sequence) was then constructed to facilitate classification (assigning ARG-like sequence to type, subtype and reference sequence) of sequences identified through similarity search. Utilizing SARG and a previously proposed hybrid functional gene annotation pipeline, we developed an online pipeline called ARGs-OAP for fast annotation and classification of ARG-like sequences from metagenomic data. We also evaluated and proposed a set of criteria important for efficiently conducting metagenomic analysis of ARGs using ARGs-OAP. Availability and Implementation: Perl script for ARGs-OAP can be downloaded from https://github.com/biofuture/Ublastx_stageone . ARGs-OAP can be accessed through http://smile.hku.hk/SARGs . Contact: zhangt@hku.hk or tiedjej@msu.edu 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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  • 8
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    Target-Driven Positive Selection at Hot Spots of Scorpion Toxins Uncovers Their Potential in Design of Insecticides (2016)
    Oxford University Press
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    Publication Date: 2016-07-19
    Description: Positive selection sites (PSSs), a class of amino acid sites with an excess of nonsynonymous to synonymous substitutions, are indicators of adaptive molecular evolution and have been detected in many protein families involved in a diversity of biological processes by statistical approaches. However, few studies are conducted to evaluate their functional significance and the driving force behind the evolution (i.e., agent of selection). Scorpion α-toxins are a class of multigene family of peptide neurotoxins affecting voltage-gated Na + (Na v ) channels, whose members exhibit differential potency and preference for insect and mammalian Na v channels. In this study, we undertook a systematical molecular dissection of nearly all the PSSs newly characterized in the Mesobuthus α-toxin family and a two-residue insertion ( 19 AlaPhe 20 ) located within a positively selected loop via mutational analysis of α-like MeuNaTxα-5, one member affecting both insect and mammalian Na v channels. This allows to identify hot-spot residues on its functional face involved in interaction with the receptor site of Na v channels, which comprises two PSSs (Ile 40 and Leu 41 ) and the small insertion, both located on two spatially separated functional loops. Mutations at these hot-spots resulted in a remarkably decreased anti-mammalian activity in MeuNaTxα-5 with partially impaired or enhanced insecticide activity, suggesting the potential of PSSs in designing promising candidate insecticides from scorpion α-like toxins. Based on an experiment-guided toxin-channel complex model and high evolutionary variability in the receptor site of predators and prey of scorpions, we provide new evidence for target-driven adaptive evolution of scorpion toxins to deal with their targets’ diversity.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    A functional screen identifies miRNAs that inhibit DNA repair and sensitize prostate cancer cells to ionizing radiation (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: MicroRNAs (miRNAs) have been implicated in DNA repair pathways through transcriptional responses to DNA damaging agents or through predicted miRNA regulation of DNA repair genes. We hypothesized that additional DNA damage regulating miRNAs could be identified by screening a library of 810 miRNA mimetics for the ability to alter cellular sensitivity to ionizing radiation (IR). A prostate cancer Metridia luciferase cell model was applied to examine the effects of individual miRNAs on IR sensitivity. A large percentage of miRNA mimetics were found to increase cellular sensitivity to IR, while a smaller percentage were protective. Two of the most potent IR sensitizing miRNAs, miR-890 and miR-744–3p, significantly delayed IR induced DNA damage repair. Both miRNAs inhibited the expression of multiple components of DNA damage response and DNA repair. miR-890 directly targeted MAD2L2, as well as WEE1 and XPC, where miR-744–3p directly targeted RAD23B. Knock-down of individual miR-890 targets by siRNA was not sufficient to ablate miR-890 radiosensitization, signifying that miR-890 functions by regulating multiple DNA repair genes. Intratumoral delivery of miR-890 mimetics prior to IR therapy significantly enhanced IR therapeutic efficacy. These results reveal novel miRNA regulation of DNA repair and identify miR-890 as a potent IR sensitizing agent.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    A large spectroscopic sample of L and T dwarfs from UKIDSS LAS: peculiar objects, binaries, and space density (2015)
    Oxford University Press
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    Publication Date: 2015-04-12
    Description: We present the spectroscopic analysis of a large sample of late-M, L, and T dwarfs from the United Kingdom Deep Infrared Sky Survey. Using the YJHK photometry from the Large Area Survey and the red-optical photometry from the Sloan Digital Sky Survey we selected a sample of 262 brown dwarf candidates and we have followed-up 196 of them using the echelle spectrograph X-shooter on the Very Large Telescope. The large wavelength coverage (0.30–2.48 μm) and moderate resolution ( R ~ 5000–9000) of X-shooter allowed us to identify peculiar objects including 22 blue L dwarfs, 2 blue T dwarfs, and 2 low-gravity M dwarfs. Using a spectral indices-based technique, we identified 27 unresolved binary candidates, for which we have determined the spectral type of the potential components via spectral deconvolution. The spectra allowed us to measure the equivalent width of the prominent absorption features and to compare them to atmospheric models. Cross-correlating the spectra with a radial velocity standard, we measured the radial velocity of our targets, and we determined the distribution of the sample, which is centred at –1.7 ± 1.2 km s –1 with a dispersion of 31.5 km s –1 . Using our results, we estimated the space density of field brown dwarfs and compared it with the results of numerical simulations. Depending on the binary fraction, we found that there are (0.85 ± 0.55) x 10 –3 to (1.00 ± 0.64) x 10 –3 objects per cubic parsec in the L4–L6.5 range, (0.73 ± 0.47) x 10 –3 to (0.85 ± 0.55) x 10 –3 objects per cubic parsec in the L7–T0.5 range, and (0.74 ± 0.48) x 10 –3 to (0.88 ± 0.56) x 10 –3 objects per cubic parsec in the T1–T4.5 range. We notice that there seems to be an excess of objects in the L–T transition with respect to the late-T dwarfs, a discrepancy that could be explained assuming a higher binary fraction than expected for the L–T transition, or that objects in the high-mass end and low-mass end of this regime form in different environments, i.e. following different initial mass functions.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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