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  • Computational Methods, Genomics  (140)
  • Natural Disasters  (42)
  • Oxford University Press  (182)
  • MDPI Publishing
  • 1
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    The Value of Heterogeneous Property Rights and the Costs of Water Volatility (2017)
    Oxford University Press
    Details
    Publication Date: 2017-01-05
    Description: The system of prior appropriation in the Western Unites States prioritizes property rights for water based on the establishment of beneficial use, creating a hierarchy where rights initiated first are more secure. I estimate the demand for security in water rights through their capitalization in agricultural property markets in the Yakima River Basin, a major watershed in Washington State. All water rights are satisfied in an average year, so the relative value of secure property rights is a function of water supply volatility and the costs of droughts are predominantly born by those with weak rights. In aggregate, security in water rights does not capitalize into property values at the irrigation district level; however, there is heterogeneity in the premium for secure water rights. The lack of a premium for district-level water security is robust to a variety of econometric methods to account for correlated district unobservables, and the null result produces an economically significant upper bound on the value to water security for the district. The ability for farmers to adapt to water supply volatility, as well as expectations about water markets and government infrastructure investment, are leading explanations for the lack of an aggregate premium. These explanations are supported by the pattern of heterogeneity in the water security premium.
    Keywords: Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q21 - Demand and Supply, Q24 - Land, Q25 - Water, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
    Published by Oxford University Press
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  • 2
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    Enabling the democratization of the genomics revolution with a fully integrated web-based bioinformatics platform (2017)
    Oxford University Press
    Details
    Publication Date: 2017-01-10
    Description: Continued advancements in sequencing technologies have fueled the development of new sequencing applications and promise to flood current databases with raw data. A number of factors prevent the seamless and easy use of these data, including the breadth of project goals, the wide array of tools that individually perform fractions of any given analysis, the large number of associated software/hardware dependencies, and the detailed expertise required to perform these analyses. To address these issues, we have developed an intuitive web-based environment with a wide assortment of integrated and cutting-edge bioinformatics tools in pre-configured workflows. These workflows, coupled with the ease of use of the environment, provide even novice next-generation sequencing users with the ability to perform many complex analyses with only a few mouse clicks and, within the context of the same environment, to visualize and further interrogate their results. This bioinformatics platform is an initial attempt at Empowering the Development of Genomics Expertise (EDGE) in a wide range of applications for microbial research.
    Keywords: Computational Methods, 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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    Methods to increase reproducibility in differential gene expression via meta-analysis (2017)
    Oxford University Press
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    Publication Date: 2017-01-10
    Description: Findings from clinical and biological studies are often not reproducible when tested in independent cohorts. Due to the testing of a large number of hypotheses and relatively small sample sizes, results from whole-genome expression studies in particular are often not reproducible. Compared to single-study analysis, gene expression meta-analysis can improve reproducibility by integrating data from multiple studies. However, there are multiple choices in designing and carrying out a meta-analysis. Yet, clear guidelines on best practices are scarce. Here, we hypothesized that studying subsets of very large meta-analyses would allow for systematic identification of best practices to improve reproducibility. We therefore constructed three very large gene expression meta-analyses from clinical samples, and then examined meta-analyses of subsets of the datasets (all combinations of datasets with up to N/2 samples and K/2 datasets) compared to a ‘silver standard’ of differentially expressed genes found in the entire cohort. We tested three random-effects meta-analysis models using this procedure. We showed relatively greater reproducibility with more-stringent effect size thresholds with relaxed significance thresholds; relatively lower reproducibility when imposing extraneous constraints on residual heterogeneity; and an underestimation of actual false positive rate by Benjamini–Hochberg correction. In addition, multivariate regression showed that the accuracy of a meta-analysis increased significantly with more included datasets even when controlling for sample size.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Temperature Changes, Household Consumption, and Internal Migration: Evidence from Tanzania (2016)
    Oxford University Press
    Details
    Publication Date: 2016-07-09
    Description: Large rural-urban wage gaps observed in many developing countries are suggestive of barriers to migration that keep potential migrants in rural areas. Using long panel data spanning nearly two decades, I study the extent to which migration rates are constrained by liquidity constraints in rural Tanzania. The analysis begins by quantifying the impact of weather variation on household welfare. The results show how household consumption co-moves with temperature, rendering households vulnerable to local weather events. These temperature-induced income shocks are then found to inhibit long-term migration among men, thus preventing them from tapping into the opportunities brought about by geographical mobility.
    Keywords: O12 - Microeconomic Analyses of Economic Development, O15 - Human Resources ; Human Development ; Income Distribution ; Migration, Q54 - Climate ; Natural Disasters ; Global Warming, R23 - Regional Migration ; Regional Labor Markets ; Population
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
    Published by Oxford University Press
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  • 5
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    A new molecular signature method for prediction of driver cancer pathways from transcriptional data (2016)
    Oxford University Press
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    Publication Date: 2016-06-21
    Description: Assigning cancer patients to the most effective treatments requires an understanding of the molecular basis of their disease. While DNA-based molecular profiling approaches have flourished over the past several years to transform our understanding of driver pathways across a broad range of tumors, a systematic characterization of key driver pathways based on RNA data has not been undertaken. Here we introduce a new approach for predicting the status of driver cancer pathways based on signature functions derived from RNA sequencing data. To identify the driver cancer pathways of interest, we mined DNA variant data from TCGA and nominated driver alterations in seven major cancer pathways in breast, ovarian and colon cancer tumors. The activation status of these driver pathways were then characterized using RNA sequencing data by constructing classification signature functions in training datasets and then testing the accuracy of the signatures in test datasets. The signature functions differentiate well tumors with nominated pathway activation from tumors with no signs of activation: average AUC equals to 0.83. Our results confirm that driver genomic alterations are distinctively displayed at the transcriptional level and that the transcriptional signatures can generally provide an alternative to DNA sequencing methods in detecting specific driver pathways.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    DanQ: a hybrid convolutional and recurrent deep neural network for quantifying the function of DNA sequences (2016)
    Oxford University Press
    Details
    Publication Date: 2016-06-21
    Description: Modeling the properties and functions of DNA sequences is an important, but challenging task in the broad field of genomics. This task is particularly difficult for non-coding DNA, the vast majority of which is still poorly understood in terms of function. A powerful predictive model for the function of non-coding DNA can have enormous benefit for both basic science and translational research because over 98% of the human genome is non-coding and 93% of disease-associated variants lie in these regions. To address this need, we propose DanQ, a novel hybrid convolutional and bi-directional long short-term memory recurrent neural network framework for predicting non-coding function de novo from sequence. In the DanQ model, the convolution layer captures regulatory motifs, while the recurrent layer captures long-term dependencies between the motifs in order to learn a regulatory ‘grammar’ to improve predictions. DanQ improves considerably upon other models across several metrics. For some regulatory markers, DanQ can achieve over a 50% relative improvement in the area under the precision-recall curve metric compared to related models. We have made the source code available at the github repository http://github.com/uci-cbcl/DanQ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Phylogeny-aware identification and correction of taxonomically mislabeled sequences (2016)
    Oxford University Press
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    Publication Date: 2016-06-21
    Description: Molecular sequences in public databases are mostly annotated by the submitting authors without further validation. This procedure can generate erroneous taxonomic sequence labels. Mislabeled sequences are hard to identify, and they can induce downstream errors because new sequences are typically annotated using existing ones. Furthermore, taxonomic mislabelings in reference sequence databases can bias metagenetic studies which rely on the taxonomy. Despite significant efforts to improve the quality of taxonomic annotations, the curation rate is low because of the labor-intensive manual curation process. Here, we present SATIVA, a phylogeny-aware method to automatically identify taxonomically mislabeled sequences (‘mislabels’) using statistical models of evolution. We use the Evolutionary Placement Algorithm (EPA) to detect and score sequences whose taxonomic annotation is not supported by the underlying phylogenetic signal, and automatically propose a corrected taxonomic classification for those. Using simulated data, we show that our method attains high accuracy for identification (96.9% sensitivity/91.7% precision) as well as correction (94.9% sensitivity/89.9% precision) of mislabels. Furthermore, an analysis of four widely used microbial 16S reference databases (Greengenes, LTP, RDP and SILVA) indicates that they currently contain between 0.2% and 2.5% mislabels. Finally, we use SATIVA to perform an in-depth evaluation of alternative taxonomies for Cyanobacteria. SATIVA is freely available at https://github.com/amkozlov/sativa .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    iGEMS: an integrated model for identification of alternative exon usage events (2016)
    Oxford University Press
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    Publication Date: 2016-06-21
    Description: DNA microarrays and RNAseq are complementary methods for studying RNA molecules. Current computational methods to determine alternative exon usage (AEU) using such data require impractical visual inspection and still yield high false-positive rates. Integrated Gene and Exon Model of Splicing (iGEMS) adapts a gene-level residuals model with a gene size adjusted false discovery rate and exon-level analysis to circumvent these limitations. iGEMS was applied to two new DNA microarray datasets, including the high coverage Human Transcriptome Arrays 2.0 and performance was validated using RT-qPCR. First, AEU was studied in adipocytes treated with ( n = 9) or without ( n = 8) the anti-diabetes drug, rosiglitazone. iGEMS identified 555 genes with AEU, and robust verification by RT-qPCR (~90%). Second, in a three-way human tissue comparison (muscle, adipose and blood, n = 41) iGEMS identified 4421 genes with at least one AEU event, with excellent RT-qPCR verification (95%, n = 22). Importantly, iGEMS identified a variety of AEU events, including 3'UTR extension, as well as exon inclusion/exclusion impacting on protein kinase and extracellular matrix domains. In conclusion, iGEMS is a robust method for identification of AEU while the variety of exon usage between human tissues is 5–10 times more prevalent than reported by the Genotype-Tissue Expression consortium using RNA sequencing.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 9
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    TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-06
    Description: The Cancer Genome Atlas (TCGA) research network has made public a large collection of clinical and molecular phenotypes of more than 10 000 tumor patients across 33 different tumor types. Using this cohort, TCGA has published over 20 marker papers detailing the genomic and epigenomic alterations associated with these tumor types. Although many important discoveries have been made by TCGA's research network, opportunities still exist to implement novel methods, thereby elucidating new biological pathways and diagnostic markers. However, mining the TCGA data presents several bioinformatics challenges, such as data retrieval and integration with clinical data and other molecular data types (e.g. RNA and DNA methylation). We developed an R/Bioconductor package called TCGAbiolinks to address these challenges and offer bioinformatics solutions by using a guided workflow to allow users to query, download and perform integrative analyses of TCGA data. We combined methods from computer science and statistics into the pipeline and incorporated methodologies developed in previous TCGA marker studies and in our own group. Using four different TCGA tumor types (Kidney, Brain, Breast and Colon) as examples, we provide case studies to illustrate examples of reproducibility, integrative analysis and utilization of different Bioconductor packages to advance and accelerate novel discoveries.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    Robust detection of alternative splicing in a population of single cells (2016)
    Oxford University Press
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    Publication Date: 2016-05-06
    Description: Single cell RNA-seq experiments provide valuable insight into cellular heterogeneity but suffer from low coverage, 3' bias and technical noise. These unique properties of single cell RNA-seq data make study of alternative splicing difficult, and thus most single cell studies have restricted analysis of transcriptome variation to the gene level. To address these limitations, we developed SingleSplice, which uses a statistical model to detect genes whose isoform usage shows biological variation significantly exceeding technical noise in a population of single cells. Importantly, SingleSplice is tailored to the unique demands of single cell analysis, detecting isoform usage differences without attempting to infer expression levels for full-length transcripts. Using data from spike-in transcripts, we found that our approach detects variation in isoform usage among single cells with high sensitivity and specificity. We also applied SingleSplice to data from mouse embryonic stem cells and discovered a set of genes that show significant biological variation in isoform usage across the set of cells. A subset of these isoform differences are linked to cell cycle stage, suggesting a novel connection between alternative splicing and the cell cycle.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 11
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    CARGO: effective format-free compressed storage of genomic information (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: The recent super-exponential growth in the amount of sequencing data generated worldwide has put techniques for compressed storage into the focus. Most available solutions, however, are strictly tied to specific bioinformatics formats, sometimes inheriting from them suboptimal design choices; this hinders flexible and effective data sharing. Here, we present CARGO (Compressed ARchiving for GenOmics), a high-level framework to automatically generate software systems optimized for the compressed storage of arbitrary types of large genomic data collections. Straightforward applications of our approach to FASTQ and SAM archives require a few lines of code, produce solutions that match and sometimes outperform specialized format-tailored compressors and scale well to multi-TB datasets. All CARGO software components can be freely downloaded for academic and non-commercial use from http://bio-cargo.sourceforge.net .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 12
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    InPhaDel: integrative shotgun and proximity-ligation sequencing to phase deletions with single nucleotide polymorphisms (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: Phasing of single nucleotide (SNV), and structural variations into chromosome-wide haplotypes in humans has been challenging, and required either trio sequencing or restricting phasing to population-based haplotypes. Selvaraj et al . demonstrated single individual SNV phasing is possible with proximity ligated (HiC) sequencing. Here, we demonstrate HiC can phase structural variants into phased scaffolds of SNVs. Since HiC data is noisy, and SV calling is challenging, we applied a range of supervised classification techniques, including Support Vector Machines and Random Forest, to phase deletions. Our approach was demonstrated on deletion calls and phasings on the NA12878 human genome. We used three NA12878 chromosomes and simulated chromosomes to train model parameters. The remaining NA12878 chromosomes withheld from training were used to evaluate phasing accuracy. Random Forest had the highest accuracy and correctly phased 86% of the deletions with allele-specific read evidence. Allele-specific read evidence was found for 76% of the deletions. HiC provides significant read evidence for accurately phasing 33% of the deletions. Also, eight of eight top ranked deletions phased by only HiC were validated using long range polymerase chain reaction and Sanger. Thus, deletions from a single individual can be accurately phased using a combination of shotgun and proximity ligation sequencing. InPhaDel software is available at: http://l337x911.github.io/inphadel/.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 13
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    Redundans: an assembly pipeline for highly heterozygous genomes (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: Many genomes display high levels of heterozygosity (i.e. presence of different alleles at the same loci in homologous chromosomes), being those of hybrid organisms an extreme such case. The assembly of highly heterozygous genomes from short sequencing reads is a challenging task because it is difficult to accurately recover the different haplotypes. When confronted with highly heterozygous genomes, the standard assembly process tends to collapse homozygous regions and reports heterozygous regions in alternative contigs. The boundaries between homozygous and heterozygous regions result in multiple assembly paths that are hard to resolve, which leads to highly fragmented assemblies with a total size larger than expected. This, in turn, causes numerous problems in downstream analyses such as fragmented gene models, wrong gene copy number, or broken synteny. To circumvent these caveats we have developed a pipeline that specifically deals with the assembly of heterozygous genomes by introducing a step to recognise and selectively remove alternative heterozygous contigs. We tested our pipeline on simulated and naturally-occurring heterozygous genomes and compared its accuracy to other existing tools. Our method is freely available at https://github.com/Gabaldonlab/redundans .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 14
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    Drought Index Insurance for the Central Valley Project in California (2016)
    Oxford University Press
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    Publication Date: 2016-08-20
    Description: A multi-year drought has taken a severe toll on the agricultural economy of California’s Central Valley. Index insurance is an instrument with the potential to protect water users from economic losses due to periodic water shortages. An index insurance product based on the Sacramento Index and adapted to the Central Valley Project water supply is proposed. To address the potential for intertemporal adverse selection, three product designs are suggested: (1) "early bird" insurance; (2) variable premium insurance; and (3) variable deductible insurance. The performance of the designs are assessed using loss functions from the Westlands Water District in the San Joaquin Valley.
    Keywords: Q14 - Agricultural Finance, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 2040-5790
    Electronic ISSN: 2040-5804
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
    Published by Oxford University Press
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  • 15
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    Mixed Integer Linear Programming based machine learning approach identifies regulators of telomerase in yeast (2016)
    Oxford University Press
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    Publication Date: 2016-06-03
    Description: Understanding telomere length maintenance mechanisms is central in cancer biology as their dysregulation is one of the hallmarks for immortalization of cancer cells. Important for this well-balanced control is the transcriptional regulation of the telomerase genes. We integrated Mixed Integer Linear Programming models into a comparative machine learning based approach to identify regulatory interactions that best explain the discrepancy of telomerase transcript levels in yeast mutants with deleted regulators showing aberrant telomere length, when compared to mutants with normal telomere length. We uncover novel regulators of telomerase expression, several of which affect histone levels or modifications. In particular, our results point to the transcription factors Sum1, Hst1 and Srb2 as being important for the regulation of EST1 transcription, and we validated the effect of Sum1 experimentally. We compiled our machine learning method leading to a user friendly package for R which can straightforwardly be applied to similar problems integrating gene regulator binding information and expression profiles of samples of e.g. different phenotypes, diseases or treatments.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 16
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    f-divergence cutoff index to simultaneously identify differential expression in the integrated transcriptome and proteome (2016)
    Oxford University Press
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    Publication Date: 2016-06-03
    Description: The ability to integrate ‘omics’ (i.e. transcriptomics and proteomics) is becoming increasingly important to the understanding of regulatory mechanisms. There are currently no tools available to identify differentially expressed genes (DEGs) across different ‘omics’ data types or multi-dimensional data including time courses. We present fCI (f-divergence Cut-out Index), a model capable of simultaneously identifying DEGs from continuous and discrete transcriptomic, proteomic and integrated proteogenomic data. We show that fCI can be used across multiple diverse sets of data and can unambiguously find genes that show functional modulation, developmental changes or misregulation. Applying fCI to several proteogenomics datasets, we identified a number of important genes that showed distinctive regulation patterns. The package fCI is available at R Bioconductor and http://software.steenlab.org/fCI/ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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  • 17
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    CLASS2: accurate and efficient splice variant annotation from RNA-seq reads (2016)
    Oxford University Press
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    Publication Date: 2016-06-03
    Description: Next generation sequencing of cellular RNA is making it possible to characterize genes and alternative splicing in unprecedented detail. However, designing bioinformatics tools to accurately capture splicing variation has proven difficult. Current programs can find major isoforms of a gene but miss lower abundance variants, or are sensitive but imprecise. CLASS2 is a novel open source tool for accurate genome-guided transcriptome assembly from RNA-seq reads based on the model of splice graph. An extension of our program CLASS, CLASS2 jointly optimizes read patterns and the number of supporting reads to score and prioritize transcripts, implemented in a novel, scalable and efficient dynamic programming algorithm. When compared against reference programs, CLASS2 had the best overall accuracy and could detect up to twice as many splicing events with precision similar to the best reference program. Notably, it was the only tool to produce consistently reliable transcript models for a wide range of applications and sequencing strategies, including ribosomal RNA-depleted samples. Lightweight and multi-threaded, CLASS2 requires 〈3GB RAM and can analyze a 350 million read set within hours, and can be widely applied to transcriptomics studies ranging from clinical RNA sequencing, to alternative splicing analyses, and to the annotation of new genomes.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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  • 18
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    FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing (2016)
    Oxford University Press
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    Publication Date: 2016-09-20
    Description: Allele-specific copy number analysis (ASCN) from next generation sequencing (NGS) data can greatly extend the utility of NGS beyond the identification of mutations to precisely annotate the genome for the detection of homozygous/heterozygous deletions, copy-neutral loss-of-heterozygosity (LOH), allele-specific gains/amplifications. In addition, as targeted gene panels are increasingly used in clinical sequencing studies for the detection of ‘actionable’ mutations and copy number alterations to guide treatment decisions, accurate, tumor purity-, ploidy- and clonal heterogeneity-adjusted integer copy number calls are greatly needed to more reliably interpret NGS-based cancer gene copy number data in the context of clinical sequencing. We developed FACETS, an ASCN tool and open-source software with a broad application to whole genome, whole-exome, as well as targeted panel sequencing platforms. It is a fully integrated stand-alone pipeline that includes sequencing BAM file post-processing, joint segmentation of total- and allele-specific read counts, and integer copy number calls corrected for tumor purity, ploidy and clonal heterogeneity, with comprehensive output and integrated visualization. We demonstrate the application of FACETS using The Cancer Genome Atlas (TCGA) whole-exome sequencing of lung adenocarcinoma samples. We also demonstrate its application to a clinical sequencing platform based on a targeted gene panel.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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  • 19
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    A genome-wide approach for detecting novel insertion-deletion variants of mid-range size (2016)
    Oxford University Press
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    Publication Date: 2016-09-03
    Description: We present SWAN, a statistical framework for robust detection of genomic structural variants in next-generation sequencing data and an analysis of mid-range size insertion and deletions (〈10 Kb) for whole genome analysis and DNA mixtures. To identify these mid-range size events, SWAN collectively uses information from read-pair, read-depth and one end mapped reads through statistical likelihoods based on Poisson field models. SWAN also uses soft-clip/split read remapping to supplement the likelihood analysis and determine variant boundaries. The accuracy of SWAN is demonstrated by in silico spike-ins and by identification of known variants in the NA12878 genome. We used SWAN to identify a series of novel set of mid-range insertion/deletion detection that were confirmed by targeted deep re-sequencing. An R package implementation of SWAN is open source and freely available.
    Keywords: Computational Methods, Genomics
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  • 20
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    Comprehensive analysis of high-throughput screens with HiTSeekR (2016)
    Oxford University Press
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    Publication Date: 2016-08-20
    Description: High-throughput screening (HTS) is an indispensable tool for drug (target) discovery that currently lacks user-friendly software tools for the robust identification of putative hits from HTS experiments and for the interpretation of these findings in the context of systems biology. We developed HiTSeekR as a one-stop solution for chemical compound screens, siRNA knock-down and CRISPR/Cas9 knock-out screens, as well as microRNA inhibitor and -mimics screens. We chose three use cases that demonstrate the potential of HiTSeekR to fully exploit HTS screening data in quite heterogeneous contexts to generate novel hypotheses for follow-up experiments: (i) a genome-wide RNAi screen to uncover modulators of TNFα, (ii) a combined siRNA and miRNA mimics screen on vorinostat resistance and (iii) a small compound screen on KRAS synthetic lethality. HiTSeekR is publicly available at http://hitseekr.compbio.sdu.dk . It is the first approach to close the gap between raw data processing, network enrichment and wet lab target generation for various HTS screen types.
    Keywords: Computational Methods, Genomics
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  • 21
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    Quality Matters More Than Quantity: Asymmetric Temperature Effects on Crop Yield and Quality Grade (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: Climate change affects agriculture by altering not only output quantity, but also crop quality. We quantify the economic impacts of climate change on agriculture through changes in both quantity and quality, where quality is measured by crop grades. Our model controls for methodological issues regarding sample selection, aggregation, phenology, and nonlinearity. The empirical application to Japanese rice production indicates that temperature effects are asymmetric: quantity is especially vulnerable to cold, whereas quality is vulnerable to extremely high temperature. Using these results, we simulate the effect of global warming, and we find that warming (a 3 °C increase) increases farm revenues by improving yield but decreases revenues as a result of deteriorating quality. The net effect is negative, suggesting that quality matters more than quantity. The negative effect, however, can be mitigated by shifting cultivation periods and/or regions. Overall, our results suggest that the estimated impacts of climate change and adaptation strategies could be severely misleading unless quality is considered.
    Keywords: L15 - Information and Product Quality ; Standardization and Compatibility, Q10 - General, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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  • 22
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    Alternative Metrics for Comparing Domestic Climate Change Mitigation Efforts and the Emerging International Climate Policy Architecture (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-03
    Description: The availability of practical mechanisms for comparing domestic efforts aimed at mitigating global climate change is important for the stability, equity, and efficiency of international climate agreements. We examine a variety of metrics that could be used to compare countries’ climate change mitigation efforts and illustrate their potential application to large developed and developing countries. Because there is no single, comprehensive, measurable metric that could be applied to all countries, we suggest using a set of indicators to characterize and compare mitigation effort, akin to using a set of economic statistics to indicate the health of the macroeconomy. Given the iterative pledge-and-review approach that is emerging in the current climate change negotiations, participation, commitment, and compliance could be enhanced if this set of indicators is able to show that all parties are doing their "fair share," both prospectively and retrospectively. The latter, in particular, highlights the need for a well-functioning policy surveillance regime. ( JEL : Q54, Q58, F55)
    Keywords: Q54 - Climate ; Natural Disasters ; Global Warming, Q58 - Government Policy, F55 - International Institutional Arrangements
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    The Economics of Wine, Weather, and Climate Change (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-03
    Description: In this article, we provide an overview of the extensive literature on the impact of weather and climate on grapes and wine, with the goal of identifying how climate change is likely to affect their production. We first discuss the physical impact of weather on vine phenology (i.e., the timing of biological events such as bud break or flowering), berry composition, and yields. Then we examine the economic literature that measures the effects of temperature on wine quality, prices, costs, and profits and, based on this review, infer how climate change will affect these variables. We also describe what has been learned thus far about possible adaptation strategies for grape growers that would allow them to mitigate the economic effects of climate change. We conclude that climate change is likely to produce both winners and losers, with the winners being those located closer to the North and South Poles. There are also likely to be some substantial short-run costs as growers adapt to climate change. Nevertheless, wine making has survived through thousands of years of recorded history, a history that has included significant climate changes. ( JEL : Q13, Q18, Q54)
    Keywords: Q13 - Agricultural Markets and Marketing ; Cooperatives ; Agribusiness, Q18 - Agricultural Policy ; Food Policy, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    The Impact of the European Union Emissions Trading Scheme on Regulated Firms: What Is the Evidence after Ten Years? (2016)
    Oxford University Press
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    Publication Date: 2016-02-03
    Description: This article reviews the recent literature on ex post evaluation of the impacts of the European Union (EU) Emissions Trading Scheme (ETS) on regulated firms in the industrial and power sectors. We summarize the findings from original research papers concerning three broadly defined impacts: carbon dioxide emissions, economic performance and competitiveness, and innovation. We conclude by highlighting gaps in the current literature and suggesting priorities for future research on this landmark policy. ( JEL : Q52, Q54, Q58)
    Keywords: Q52 - Pollution Control Costs ; Distributional Effects ; Employment Effects, Q54 - Climate ; Natural Disasters ; Global Warming, Q58 - Government Policy
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    The European Union Emissions Trading System: Ten Years and Counting (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-03
    Description: This article provides an introduction to the European Union (EU) Emissions Trading System (ETS). First we describe the legislative development of the EU ETS, its evolution from free allocation to auctioning and centralized allocation rules, its relationship to the Kyoto Protocol and other trading systems, and its relationship to other EU climate and energy policies. This is followed by an assessment of the performance of the EU ETS, which focuses in particular on emissions, allowance prices, and the use of offsets. We conclude with a discussion of the current debate about the future of the EU ETS and proposals for changes to both the EU ETS and the climate policy environment in which it operates. ( JEL : Q54, Q58)
    Keywords: Q54 - Climate ; Natural Disasters ; Global Warming, Q58 - Government Policy
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    The Climate Change Adaptation Literature (2016)
    Oxford University Press
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    Publication Date: 2016-02-03
    Description: The December 2015 Conference of the Parties (COP) to the United Nations Framework Convention on Climate Change meetings in Paris are likely to yield a global agreement that will slow the world’s growth of greenhouse gas emissions, but this agreement is unlikely to guarantee a decline in global emissions in the near future. Given this reality, climate change adaptation is an increasingly important topic for discussion and study. Although much research has focused on the macroeconomic relationship between economic growth and temperature at the national and/or annual level, microeconomic analysis also offers valuable insights. This Reflections discusses recent work on household and firm responses to three climate change challenges: increased summer heat, higher food prices, and increased natural disaster risk. ( JEL : Q54)
    Keywords: Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    Beegle: from literature mining to disease-gene discovery (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-30
    Description: Disease-gene identification is a challenging process that has multiple applications within functional genomics and personalized medicine. Typically, this process involves both finding genes known to be associated with the disease (through literature search) and carrying out preliminary experiments or screens (e.g. linkage or association studies, copy number analyses, expression profiling) to determine a set of promising candidates for experimental validation. This requires extensive time and monetary resources. We describe Beegle , an online search and discovery engine that attempts to simplify this process by automating the typical approaches. It starts by mining the literature to quickly extract a set of genes known to be linked with a given query, then it integrates the learning methodology of Endeavour (a gene prioritization tool) to train a genomic model and rank a set of candidate genes to generate novel hypotheses. In a realistic evaluation setup, Beegle has an average recall of 84% in the top 100 returned genes as a search engine, which improves the discovery engine by 12.6% in the top 5% prioritized genes. Beegle is publicly available at http://beegle.esat.kuleuven.be/ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    A computational method for studying the relation between alternative splicing and DNA methylation (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-30
    Description: Alternative splicing is an important mechanism in eukaryotes that expands the transcriptome and proteome significantly. It plays an important role in a number of biological processes. Understanding its regulation is hence an important challenge. Recently, increasing evidence has been collected that supports an involvement of intragenic DNA methylation in the regulation of alternative splicing. The exact mechanisms of regulation, however, are largely unknown, and speculated to be complex: different methylation profiles might exist, each of which could be associated with a different regulation mechanism. We present a computational technique that is able to determine such stable methylation patterns and allows to correlate these patterns with inclusion propensity of exons. Pattern detection is based on dynamic time warping (DTW) of methylation profiles, a sophisticated similarity measure for signals that can be non-trivially transformed. We design a flexible self-organizing map approach to pattern grouping. Exemplary application on available data sets indicates that stable patterns which correlate non-trivially with exon inclusion do indeed exist. To improve the reliability of these predictions, further studies on larger data sets will be required. We have thus taken great care that our software runs efficiently on modern hardware, so that it can support future studies on large-scale data sets.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    BubbleTree: an intuitive visualization to elucidate tumoral aneuploidy and clonality using next generation sequencing data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-03-01
    Description: Tumors are characterized by properties of genetic instability, heterogeneity, and significant oligoclonality. Elucidating this intratumoral heterogeneity is challenging but important. In this study, we propose a framework, BubbleTree, to characterize the tumor clonality using next generation sequencing (NGS) data. BubbleTree simultaneously elucidates the complexity of a tumor biopsy, estimating cancerous cell purity, tumor ploidy, allele-specific copy number, and clonality and represents this in an intuitive graph. We further developed a three-step heuristic method to automate the interpretation of the BubbleTree graph, using a divide-and-conquer strategy. In this study, we demonstrated the performance of BubbleTree with comparisons to similar commonly used tools such as THetA2, ABSOLUTE, AbsCN-seq and ASCAT, using both simulated and patient-derived data. BubbleTree outperformed these tools, particularly in identifying tumor subclonal populations and polyploidy. We further demonstrated BubbleTree's utility in tracking clonality changes from patients’ primary to metastatic tumor and dating somatic single nucleotide and copy number variants along the tumor clonal evolution. Overall, the BubbleTree graph and corresponding model is a powerful approach to provide a comprehensive spectrum of the heterogeneous tumor karyotype in human tumors. BubbleTree is R-based and freely available to the research community ( https://www.bioconductor.org/packages/release/bioc/html/BubbleTree.html ).
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    Endogenous farm-type selection, endogenous irrigation, and spatial effects in Ricardian models of climate change (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-20
    Description: In the estimation of Ricardian models the endogeneity of adaptation measures is typically ignored. In this article we propose a new estimation strategy that explicitly recognises the endogeneity of the farm type and irrigation to climate. Based on the latest census data on over 270,000 farms in Germany, we estimate a cross-sectional, spatial-IV model that decomposes the effects of climate on farm profitability into direct (unmediated) and indirect (mediated by the variables that reflect adaptation). Our results show that neglecting the endogenous nature of adaptation measures may substantially bias the magnitude of the total effect of climate on farm profitability.
    Keywords: C21 - Cross-Sectional Models ; Spatial Models ; Treatment Effect Models, C25 - Discrete Regression and Qualitative Choice Models, C36- Instrumental Variables (IV) Estimation, Q18 - Agricultural Policy ; Food Policy, Q51 - Valuation of Environmental Effects, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0165-1587
    Electronic ISSN: 1464-3618
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
    Published by Oxford University Press
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    Quantification of read species behavior within whole genome sequencing of cancer genomes for the stratification and visualization of genomic variation (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-20
    Description: The cancer genome is abnormal genome, and the ability to monitor its sequence had undergone a technological revolution. Yet prognosis and diagnosis remain an expert-based decision, with only limited abilities to provide machine-based decisions. We introduce a heterogeneity-based method for stratifying and visualizing whole-genome sequencing (WGS) reads. This method uses the heterogeneity within WGS reads to markedly reduce the dimensionality of next-generation sequencing data; it is available through the tool HiBS (Heterogeneity-Based Subclassification) that allows cancer sample classification. We validated HiBS using 〉200 WGS samples from nine different cancer types from The Cancer Genome Atlas (TCGA). With HiBS, we show progress with two WGS related issues: (i) differentiation between normal (NB) and tumor (TP) samples based solely on the information structure of their WGS data, and (ii) identification of specific regions of chromosomal amplification/deletion and their association with tumor stage. By comparing results to those obtained through available WGS analyses tools, we demonstrate some of the novelties obtained by the approach implemented in HiBS and also show nearly perfect normal/tumor classification, used to identify known and unknown chromosomal aberrations. Finally, the HiBS index has been associated with breast cancer tumor stage.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    Circular RNA profile in gliomas revealed by identification tool UROBORUS (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-20
    Description: Recent evidence suggests that many endogenous circular RNAs (circRNAs) may play roles in biological processes. However, the expression patterns and functions of circRNAs in human diseases are not well understood. Computationally identifying circRNAs from total RNA-seq data is a primary step in studying their expression pattern and biological roles. In this work, we have developed a computational pipeline named UROBORUS to detect circRNAs in total RNA-seq data. By applying UROBORUS to RNA-seq data from 46 gliomas and normal brain samples, we detected thousands of circRNAs supported by at least two read counts, followed by successful experimental validation on 24 circRNAs from the randomly selected 27 circRNAs. UROBORUS is an efficient tool that can detect circRNAs with low expression levels in total RNA-seq without RNase R treatment. The circRNAs expression profiling revealed more than 476 circular RNAs differentially expressed in control brain tissues and gliomas. Together with parental gene expression, we found that circRNA and its parental gene have diversified expression patterns in gliomas and control brain tissues. This study establishes an efficient and sensitive approach for predicting circRNAs using total RNA-seq data. The UROBORUS pipeline can be accessed freely for non-commercial purposes at http://uroborus.openbioinformatics.org/ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    Modeling the combined effect of RNA-binding proteins and microRNAs in post-transcriptional regulation (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-20
    Description: Recent studies show that RNA-binding proteins (RBPs) and microRNAs (miRNAs) function in coordination with each other to control post-transcriptional regulation (PTR). Despite this, the majority of research to date has focused on the regulatory effect of individual RBPs or miRNAs. Here, we mapped both RBP and miRNA binding sites on human 3'UTRs and utilized this collection to better understand PTR. We show that the transcripts that lack competition for HuR binding are destabilized more after HuR depletion. We also confirm this finding for PUM1(2) by measuring genome-wide expression changes following the knockdown of PUM1(2) in HEK293 cells. Next, to find potential cooperative interactions, we identified the pairs of factors whose sites co-localize more often than expected by random chance. Upon examining these results for PUM1(2), we found that transcripts where the sites of PUM1(2) and its interacting miRNA form a stem-loop are more stabilized upon PUM1(2) depletion. Finally, using dinucleotide frequency and counts of regulatory sites as features in a regression model, we achieved an AU-ROC of 0.86 in predicting mRNA half-life in BEAS-2B cells. Altogether, our results suggest that future studies of PTR must consider the combined effects of RBPs and miRNAs, as well as their interactions.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    Using intron position conservation for homology-based gene prediction (2016)
    Oxford University Press
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    Publication Date: 2016-05-20
    Description: Annotation of protein-coding genes is very important in bioinformatics and biology and has a decisive influence on many downstream analyses. Homology-based gene prediction programs allow for transferring knowledge about protein-coding genes from an annotated organism to an organism of interest. Here, we present a homology-based gene prediction program called GeMoMa. GeMoMa utilizes the conservation of intron positions within genes to predict related genes in other organisms. We assess the performance of GeMoMa and compare it with state-of-the-art competitors on plant and animal genomes using an extended best reciprocal hit approach. We find that GeMoMa often makes more precise predictions than its competitors yielding a substantially increased number of correct transcripts. Subsequently, we exemplarily validate GeMoMa predictions using Sanger sequencing. Finally, we use RNA-seq data to compare the predictions of homology-based gene prediction programs, and find again that GeMoMa performs well. Hence, we conclude that exploiting intron position conservation improves homology-based gene prediction, and we make GeMoMa freely available as command-line tool and Galaxy integration.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    Comparison of circular RNA prediction tools (2016)
    Oxford University Press
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    Publication Date: 2016-04-08
    Description: CircRNAs are novel members of the non-coding RNA family. For several decades circRNAs have been known to exist, however only recently the widespread abundance has become appreciated. Annotation of circRNAs depends on sequencing reads spanning the backsplice junction and therefore map as non-linear reads in the genome. Several pipelines have been developed to specifically identify these non-linear reads and consequently predict the landscape of circRNAs based on deep sequencing datasets. Here, we use common RNAseq datasets to scrutinize and compare the output from five different algorithms; circRNA_finder, find_circ, CIRCexplorer, CIRI, and MapSplice and evaluate the levels of bona fide and false positive circRNAs based on RNase R resistance. By this approach, we observe surprisingly dramatic differences between the algorithms specifically regarding the highly expressed circRNAs and the circRNAs derived from proximal splice sites. Collectively, this study emphasizes that circRNA annotation should be handled with care and that several algorithms should ideally be combined to achieve reliable predictions.
    Keywords: Computational Methods, Genomics
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    Comprehensive evaluation of fusion transcript detection algorithms and a meta-caller to combine top performing methods in paired-end RNA-seq data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-03-19
    Description: Background: Fusion transcripts are formed by either fusion genes (DNA level) or trans-splicing events (RNA level). They have been recognized as a promising tool for diagnosing, subtyping and treating cancers. RNA-seq has become a precise and efficient standard for genome-wide screening of such aberration events. Many fusion transcript detection algorithms have been developed for paired-end RNA-seq data but their performance has not been comprehensively evaluated to guide practitioners. In this paper, we evaluated 15 popular algorithms by their precision and recall trade-off, accuracy of supporting reads and computational cost. We further combine top-performing methods for improved ensemble detection. Results: Fifteen fusion transcript detection tools were compared using three synthetic data sets under different coverage, read length, insert size and background noise, and three real data sets with selected experimental validations. No single method dominantly performed the best but SOAPfuse generally performed well, followed by FusionCatcher and JAFFA. We further demonstrated the potential of a meta-caller algorithm by combining top performing methods to re-prioritize candidate fusion transcripts with high confidence that can be followed by experimental validation. Conclusion: Our result provides insightful recommendations when applying individual tool or combining top performers to identify fusion transcript candidates.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    EMERGE: a flexible modelling framework to predict genomic regulatory elements from genomic signatures (2016)
    Oxford University Press
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    Publication Date: 2016-03-19
    Description: Regulatory DNA elements, short genomic segments that regulate gene expression, have been implicated in developmental disorders and human disease. Despite this clinical urgency, only a small fraction of the regulatory DNA repertoire has been confirmed through reporter gene assays. The overall success rate of functional validation of candidate regulatory elements is low. Moreover, the number and diversity of datasets from which putative regulatory elements can be identified is large and rapidly increasing. We generated a flexible and user-friendly tool to integrate the information from different types of genomic datasets, e.g. ATAC-seq, ChIP-seq, conservation, aiming to increase the ease and success rate of functional prediction. To this end, we developed the EMERGE program that merges all datasets that the user considers informative and uses a logistic regression framework, based on validated functional elements, to set optimal weights to these datasets. ROC curve analysis shows that a combination of datasets leads to improved prediction of tissue-specific enhancers in human, mouse and Drosophila genomes. Functional assays based on this prediction can be expected to have substantially higher success rates. The resulting integrated signal for prediction of functional elements can be plotted in a build-in genome browser or exported for further analysis.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    Modeling co-occupancy of transcription factors using chromatin features (2016)
    Oxford University Press
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    Publication Date: 2016-03-19
    Description: Regulation of gene expression requires both transcription factor (TFs) and epigenetic modifications, and interplays between the two types of factors have been discovered. However study of relationships between chromatin features and TF–TF co-occupancy remains limited. Here, we revealed the relationship by first illustrating distinct profile patterns of chromatin features related to different binding events, including single TF binding and TF–TF co-occupancy of 71 TFs from five human cell lines. We further implemented statistical analyses to demonstrate the relationship by accurately predicting co-occupancy genome-widely using chromatin features including DNase I hypersensitivity, 11 histone modifications (HMs) and GC content. Remarkably, our results showed that the combination of chromatin features enables accurate predictions across the five cells. For individual chromatin features, DNase I enables high and consistent predictions. H3K27ac, H3K4me 2, H3K4me3 and H3K9ac are more reliable predictors than other HMs. Although the combination of 11 HMs achieves accurate predictions, their predictive ability varies considerably when a model obtained from one cell is applied to others, indicating relationship between HMs and TF–TF co-occupancy is cell type dependent. GC content is not a reliable predictor, but the addition of GC content to any other features enhances their predictive ability. Together, our results elucidate a strong relationship between TF–TF co-occupancy and chromatin features.
    Keywords: Computational Methods, Genomics
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    Discovering hotspots in functional genomic data superposed on 3D chromatin configuration reconstructions (2016)
    Oxford University Press
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    Publication Date: 2016-03-19
    Description: The spatial organization of the genome influences cellular function, notably gene regulation. Recent studies have assessed the three-dimensional (3D) co-localization of functional annotations (e.g. centromeres, long terminal repeats) using 3D genome reconstructions from Hi-C (genome-wide chromosome conformation capture) data; however, corresponding assessments for continuous functional genomic data (e.g. chromatin immunoprecipitation-sequencing (ChIP-seq) peak height) are lacking. Here, we demonstrate that applying bump hunting via the patient rule induction method (PRIM) to ChIP-seq data superposed on a Saccharomyces cerevisiae 3D genome reconstruction can discover ‘functional 3D hotspots’, regions in 3-space for which the mean ChIP-seq peak height is significantly elevated. For the transcription factor Swi6, the top hotspot by P -value contains MSB2 and ERG11 – known Swi6 target genes on different chromosomes. We verify this finding in a number of ways. First, this top hotspot is relatively stable under PRIM across parameter settings. Second, this hotspot is among the top hotspots by mean outcome identified by an alternative algorithm, k -Nearest Neighbor ( k -NN) regression. Third, the distance between MSB2 and ERG11 is smaller than expected (by resampling) in two other 3D reconstructions generated via different normalization and reconstruction algorithms. This analytic approach can discover functional 3D hotspots and potentially reveal novel regulatory interactions.
    Keywords: Computational Methods, Genomics
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    Simultaneous characterization of sense and antisense genomic processes by the double-stranded hidden Markov model (2016)
    Oxford University Press
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    Publication Date: 2016-03-19
    Description: Hidden Markov models (HMMs) have been extensively used to dissect the genome into functionally distinct regions using data such as RNA expression or DNA binding measurements. It is a challenge to disentangle processes occurring on complementary strands of the same genomic region. We present the double-stranded HMM (dsHMM), a model for the strand-specific analysis of genomic processes. We applied dsHMM to yeast using strand specific transcription data, nucleosome data, and protein binding data for a set of 11 factors associated with the regulation of transcription.The resulting annotation recovers the mRNA transcription cycle (initiation, elongation, termination) while correctly predicting strand-specificity and directionality of the transcription process. We find that pre-initiation complex formation is an essentially undirected process, giving rise to a large number of bidirectional promoters and to pervasive antisense transcription. Notably, 12% of all transcriptionally active positions showed simultaneous activity on both strands. Furthermore, dsHMM reveals that antisense transcription is specifically suppressed by Nrd1, a yeast termination factor.
    Keywords: Computational Methods, Genomics
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    csaw: a Bioconductor package for differential binding analysis of ChIP-seq data using sliding windows (2016)
    Oxford University Press
    Details
    Publication Date: 2016-03-19
    Description: Chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) is widely used to identify binding sites for a target protein in the genome. An important scientific application is to identify changes in protein binding between different treatment conditions, i.e. to detect differential binding. This can reveal potential mechanisms through which changes in binding may contribute to the treatment effect. The csaw package provides a framework for the de novo detection of differentially bound genomic regions. It uses a window-based strategy to summarize read counts across the genome. It exploits existing statistical software to test for significant differences in each window. Finally, it clusters windows into regions for output and controls the false discovery rate properly over all detected regions. The csaw package can handle arbitrarily complex experimental designs involving biological replicates. It can be applied to both transcription factor and histone mark datasets, and, more generally, to any type of sequencing data measuring genomic coverage. csaw performs favorably against existing methods for de novo DB analyses on both simulated and real data. csaw is implemented as a R software package and is freely available from the open-source Bioconductor project.
    Keywords: Computational Methods, Genomics
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    Estimate of within population incremental selection through branch imbalance in lineage trees (2016)
    Oxford University Press
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    Publication Date: 2016-03-19
    Description: Incremental selection within a population, defined as limited fitness changes following mutation, is an important aspect of many evolutionary processes. Strongly advantageous or deleterious mutations are detected using the synonymous to non-synonymous mutations ratio. However, there are currently no precise methods to estimate incremental selection. We here provide for the first time such a detailed method and show its precision in multiple cases of micro-evolution. The proposed method is a novel mixed lineage tree/sequence based method to detect within population selection as defined by the effect of mutations on the average number of offspring. Specifically, we propose to measure the log of the ratio between the number of leaves in lineage trees branches following synonymous and non-synonymous mutations. The method requires a high enough number of sequences, and a large enough number of independent mutations. It assumes that all mutations are independent events. It does not require of a baseline model and is practically not affected by sampling biases. We show the method's wide applicability by testing it on multiple cases of micro-evolution. We show that it can detect genes and inter-genic regions using the selection rate and detect selection pressures in viral proteins and in the immune response to pathogens.
    Keywords: Computational Methods, Genomics
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    COSMOS: accurate detection of somatic structural variations through asymmetric comparison between tumor and normal samples (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-06
    Description: An important challenge in cancer genomics is precise detection of structural variations (SVs) by high-throughput short-read sequencing, which is hampered by the high false discovery rates of existing analysis tools. Here, we propose an accurate SV detection method named COSMOS, which compares the statistics of the mapped read pairs in tumor samples with isogenic normal control samples in a distinct asymmetric manner. COSMOS also prioritizes the candidate SVs using strand-specific read-depth information. Performance tests on modeled tumor genomes revealed that COSMOS outperformed existing methods in terms of F-measure. We also applied COSMOS to an experimental mouse cell-based model, in which SVs were induced by genome engineering and gamma-ray irradiation, followed by polymerase chain reaction-based confirmation. The precision of COSMOS was 84.5%, while the next best existing method was 70.4%. Moreover, the sensitivity of COSMOS was the highest, indicating that COSMOS has great potential for cancer genome analysis.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Dynamic Adjustment in US Agriculture under Climate Change (2016)
    Oxford University Press
    Details
    Publication Date: 2016-04-24
    Description: We construct a stochastic dynamic dual model to investigate the structural adjustment of two aggregate output and three aggregate input categories in US agriculture under stochastic climatic change. More than a century of national annual data (1910–2011) is used in the empirical analysis. No constraints on asset fixity are imposed. Results indicate that, with rational expectations, both output categories as well as all input categories exhibit quasi-fixity in response to market change and stochastic climate change. Crops adjust more than twice as fast as livestock—49% versus 20% of the way toward their long-run equilibrium in one year. Fertilizer adjusts most rapidly toward equilibrium levels (88% in one year), and capital adjusts most slowly (5% in one year). Labor oscillates rather than converging smoothly toward equilibrium; its distance from equilibrium is the same as if it adjusted 59% of the way toward its optimal level in one year. Failing to anticipate climate change dramatically slows the estimated rate of adjustment for two netputs and modestly speeds the rate for two others, thus likely increasing overall adjustment costs. Failing to account for uncertainty in anticipated climate change has little impact on adjustment rates.
    Keywords: Q11 - Aggregate Supply and Demand Analysis ; Prices, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
    Published by Oxford University Press
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    Prioritizing and selecting likely novel miRNAs from NGS data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-04-08
    Description: Small non-coding RNAs play a key role in many physiological and pathological processes. Since 2004, miRNA sequences have been catalogued in miRBase, which is currently in its 21st version. We investigated sequence and structural features of miRNAs annotated in the miRBase and compared them between different versions of this reference database. We have identified that the two most recent releases (v20 and v21) are influenced by next-generation sequencing based miRNA predictions and show significant deviation from miRNAs discovered prior to the high-throughput profiling period. From the analysis of miRBase, we derived a set of key characteristics to predict new miRNAs and applied the implemented algorithm to evaluate novel blood-borne miRNA candidates. We carried out 705 individual whole miRNA sequencings of blood cells and collected a total of 9.7 billion reads. Using miRDeep2 we initially predicted 1452 potentially novel miRNAs. After excluding false positives, 518 candidates remained. These novel candidates were ranked according to their distance to the features in the early miRBase versions allowing for an easier selection of a subset of putative miRNAs for validation. Selected candidates were successfully validated by qRT-PCR and northern blotting. In addition, we implemented a web-server for ranking potential miRNA candidates, which is available at: www.ccb.uni-saarland.de/novomirank .
    Keywords: Computational Methods, Genomics
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    Gene integrated set profile analysis: a context-based approach for inferring biological endpoints (2016)
    Oxford University Press
    Details
    Publication Date: 2016-04-21
    Description: The identification of genes with specific patterns of change (e.g. down-regulated and methylated) as phenotype drivers or samples with similar profiles for a given gene set as drivers of clinical outcome, requires the integration of several genomic data types for which an ‘integrate by intersection’ (IBI) approach is often applied. In this approach, results from separate analyses of each data type are intersected, which has the limitation of a smaller intersection with more data types. We introduce a new method, GISPA (Gene Integrated Set Profile Analysis) for integrated genomic analysis and its variation, SISPA (Sample Integrated Set Profile Analysis) for defining respective genes and samples with the context of similar, a priori specified molecular profiles. With GISPA, the user defines a molecular profile that is compared among several classes and obtains ranked gene sets that satisfy the profile as drivers of each class. With SISPA, the user defines a gene set that satisfies a profile and obtains sample groups of profile activity. Our results from applying GISPA to human multiple myeloma (MM) cell lines contained genes of known profiles and importance, along with several novel targets, and their further SISPA application to MM coMMpass trial data showed clinical relevance.
    Keywords: Computational Methods, Genomics
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    CrossHub: a tool for multi-way analysis of The Cancer Genome Atlas (TCGA) in the context of gene expression regulation mechanisms (2016)
    Oxford University Press
    Details
    Publication Date: 2016-04-21
    Description: The contribution of different mechanisms to the regulation of gene expression varies for different tissues and tumors. Complementation of predicted mRNA–miRNA and gene–transcription factor (TF) relationships with the results of expression correlation analyses derived for specific tumor types outlines the interactions with functional impact in the current biomaterial. We developed CrossHub software, which enables two-way identification of most possible TF–gene interactions: on the basis of ENCODE ChIP-Seq binding evidence or Jaspar prediction and co-expression according to the data of The Cancer Genome Atlas (TCGA) project, the largest cancer omics resource. Similarly, CrossHub identifies mRNA–miRNA pairs with predicted or validated binding sites (TargetScan, mirSVR, PicTar, DIANA microT, miRTarBase) and strong negative expression correlations. We observed partial consistency between ChIP-Seq or miRNA target predictions and gene–TF/miRNA co-expression, demonstrating a link between these indicators. Additionally, CrossHub expression-methylation correlation analysis can be used to identify hypermethylated CpG sites or regions with the greatest potential impact on gene expression. Thus, CrossHub is capable of outlining molecular portraits of a specific gene and determining the three most common sources of expression regulation: promoter/enhancer methylation, miRNA interference and TF-mediated activation or repression. CrossHub generates formatted Excel workbooks with the detailed results. CrossHub is freely available at https://sourceforge.net/projects/crosshub/ .
    Keywords: Computational Methods, Genomics
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    Agriculture Afforestation for Carbon Sequestration Under Carbon Markets in the United States: Leakage Behavior from Regional Allowance Programs (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-10
    Description: This study quantifies how leakage behavior from afforesting agricultural land affects the intensification of agricultural production. In particular, we examine the leakage percentage from carbon offset allowance at specific southern regions in the United States as a part of a carbon market. We use the Forest and Agriculture Sector Optimization Model-Greenhouse Gases model to examine responses between sectors as part of the regional afforestation policy analysis. Regional characteristics and a policy's time frame are found to play important roles in achieving net gains, in terms of greenhouse gases stored, from such regional policies. In some cases, however, leakage greater than 100% is evident.
    Keywords: Q23 - Forestry, Q54 - Climate ; Natural Disasters ; Global Warming, R14 - Land Use Patterns
    Print ISSN: 2040-5790
    Electronic ISSN: 2040-5804
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Robust lineage reconstruction from high-dimensional single-cell data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-08-20
    Description: Single-cell gene expression data provide invaluable resources for systematic characterization of cellular hierarchy in multi-cellular organisms. However, cell lineage reconstruction is still often associated with significant uncertainty due to technological constraints. Such uncertainties have not been taken into account in current methods. We present ECLAIR (Ensemble Cell Lineage Analysis with Improved Robustness), a novel computational method for the statistical inference of cell lineage relationships from single-cell gene expression data. ECLAIR uses an ensemble approach to improve the robustness of lineage predictions, and provides a quantitative estimate of the uncertainty of lineage branchings. We show that the application of ECLAIR to published datasets successfully reconstructs known lineage relationships and significantly improves the robustness of predictions. ECLAIR is a powerful bioinformatics tool for single-cell data analysis. It can be used for robust lineage reconstruction with quantitative estimate of prediction accuracy.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    The exon quantification pipeline (EQP): a comprehensive approach to the quantification of gene, exon and junction expression from RNA-seq data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-09-20
    Description: The quantification of transcriptomic features is the basis of the analysis of RNA-seq data. We present an integrated alignment workflow and a simple counting-based approach to derive estimates for gene, exon and exon–exon junction expression. In contrast to previous counting-based approaches, EQP takes into account only reads whose alignment pattern agrees with the splicing pattern of the features of interest. This leads to improved gene expression estimates as well as to the generation of exon counts that allow disambiguating reads between overlapping exons. Unlike other methods that quantify skipped introns, EQP offers a novel way to compute junction counts based on the agreement of the read alignments with the exons on both sides of the junction, thus providing a uniformly derived set of counts. We evaluated the performance of EQP on both simulated and real Illumina RNA-seq data and compared it with other quantification tools. Our results suggest that EQP provides superior gene expression estimates and we illustrate the advantages of EQP's exon and junction counts. The provision of uniformly derived high-quality counts makes EQP an ideal quantification tool for differential expression and differential splicing studies. EQP is freely available for download at https://github.com/Novartis/EQP-cluster .
    Keywords: Computational Methods, Genomics
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    Boiler: lossy compression of RNA-seq alignments using coverage vectors (2016)
    Oxford University Press
    Details
    Publication Date: 2016-09-20
    Description: We describe Boiler, a new software tool for compressing and querying large collections of RNA-seq alignments. Boiler discards most per-read data, keeping only a genomic coverage vector plus a few empirical distributions summarizing the alignments. Since most per-read data is discarded, storage footprint is often much smaller than that achieved by other compression tools. Despite this, the most relevant per-read data can be recovered; we show that Boiler compression has only a slight negative impact on results given by downstream tools for isoform assembly and quantification. Boiler also allows the user to pose fast and useful queries without decompressing the entire file. Boiler is free open source software available from github.com/jpritt/boiler .
    Keywords: Computational Methods, Genomics
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    Global transcript structure resolution of high gene density genomes through multi-platform data integration (2016)
    Oxford University Press
    Details
    Publication Date: 2016-10-14
    Description: Annotation of herpesvirus genomes has traditionally been undertaken through the detection of open reading frames and other genomic motifs, supplemented with sequencing of individual cDNAs. Second generation sequencing and high-density microarray studies have revealed vastly greater herpesvirus transcriptome complexity than is captured by existing annotation. The pervasive nature of overlapping transcription throughout herpesvirus genomes, however, poses substantial problems in resolving transcript structures using these methods alone. We present an approach that combines the unique attributes of Pacific Biosciences Iso-Seq long-read, Illumina short-read and deepCAGE (Cap Analysis of Gene Expression) sequencing to globally resolve polyadenylated isoform structures in replicating Epstein-Barr virus (EBV). Our method, Transcriptome Resolution through Integration of Multi-platform Data (TRIMD), identifies nearly 300 novel EBV transcripts, quadrupling the size of the annotated viral transcriptome. These findings illustrate an array of mechanisms through which EBV achieves functional diversity in its relatively small, compact genome including programmed alternative splicing (e.g. across the IR1 repeats), alternative promoter usage by LMP2 and other latency-associated transcripts, intergenic splicing at the BZLF2 locus, and antisense transcription and pervasive readthrough transcription throughout the genome.
    Keywords: Computational Methods, Genomics
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    Identification of multi-loci hubs from 4C-seq demonstrates the functional importance of simultaneous interactions (2016)
    Oxford University Press
    Details
    Publication Date: 2016-10-14
    Description: Use of low resolution single cell DNA FISH and population based high resolution chromosome conformation capture techniques have highlighted the importance of pairwise chromatin interactions in gene regulation. However, it is unlikely that associations involving regulatory elements act in isolation of other interacting partners that also influence their impact. Indeed, the influence of multi-loci interactions remains something of an enigma as beyond low-resolution DNA FISH we do not have the appropriate tools to analyze these. Here we present a method that uses standard 4C-seq data to identify multi-loci interactions from the same cell. We demonstrate the feasibility of our method using 4C-seq data sets that identify known pairwise and novel tri-loci interactions involving the Tcrb and Igk antigen receptor enhancers. We further show that the three Igk enhancers, MiE, 3'E and Ed, interact simultaneously in this super-enhancer cluster, which add to our previous findings showing that loss of one element decreases interactions between all three elements as well as reducing their transcriptional output. These findings underscore the functional importance of simultaneous interactions and provide new insight into the relationship between enhancer elements. Our method opens the door for studying multi-loci interactions and their impact on gene regulation in other biological settings.
    Keywords: Computational Methods, Genomics
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    Identify bilayer modules via pseudo-3D clustering: applications to miRNA-gene bilayer networks (2016)
    Oxford University Press
    Details
    Publication Date: 2016-12-01
    Description: Module identification is a frequently used approach for mining local structures with more significance in global networks. Recently, a wide variety of bilayer networks are emerging to characterize the more complex biological processes. In the light of special topological properties of bilayer networks and the accompanying challenges, there is yet no effective method aiming at bilayer module identification to probe the modular organizations from the more inspiring bilayer networks. To this end, we proposed the pseudo-3D clustering algorithm, which starts from extracting initial non-hierarchically organized modules and then iteratively deciphers the hierarchical organization of modules according to a bottom-up strategy. Specifically, a modularity function for bilayer modules was proposed to facilitate the algorithm reporting the optimal partition that gives the most accurate characterization of the bilayer network. Simulation studies demonstrated its robustness and outperformance against alternative competing methods. Specific applications to both the soybean and human miRNA-gene bilayer networks demonstrated that the pseudo-3D clustering algorithm successfully identified the overlapping, hierarchically organized and highly cohesive bilayer modules. The analyses on topology, functional and human disease enrichment and the bilayer subnetwork involved in soybean fat biosynthesis provided both the theoretical and biological evidence supporting the effectiveness and robustness of pseudo-3D clustering algorithm.
    Keywords: Computational Methods, Genomics
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    Finding approximate gene clusters with GECKO 3 (2016)
    Oxford University Press
    Details
    Publication Date: 2016-12-01
    Description: Gene-order-based comparison of multiple genomes provides signals for functional analysis of genes and the evolutionary process of genome organization. Gene clusters are regions of co-localized genes on genomes of different species. The rapid increase in sequenced genomes necessitates bioinformatics tools for finding gene clusters in hundreds of genomes. Existing tools are often restricted to few (in many cases, only two) genomes, and often make restrictive assumptions such as short perfect conservation, conserved gene order or monophyletic gene clusters. We present Gecko 3, an open-source software for finding gene clusters in hundreds of bacterial genomes, that comes with an easy-to-use graphical user interface. The underlying gene cluster model is intuitive, can cope with low degrees of conservation as well as misannotations and is complemented by a sound statistical evaluation. To evaluate the biological benefit of Gecko 3 and to exemplify our method, we search for gene clusters in a dataset of 678 bacterial genomes using Synechocystis sp. PCC 6803 as a reference. We confirm detected gene clusters reviewing the literature and comparing them to a database of operons; we detect two novel clusters, which were confirmed by publicly available experimental RNA-Seq data. The computational analysis is carried out on a laptop computer in 〈40 min.
    Keywords: Computational Methods, Genomics
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    DynaMIT: the dynamic motif integration toolkit (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-09
    Description: De-novo motif search is a frequently applied bioinformatics procedure to identify and prioritize recurrent elements in sequences sets for biological investigation, such as the ones derived from high-throughput differential expression experiments. Several algorithms have been developed to perform motif search, employing widely different approaches and often giving divergent results. In order to maximize the power of these investigations and ultimately be able to draft solid biological hypotheses, there is the need for applying multiple tools on the same sequences and merge the obtained results. However, motif reporting formats and statistical evaluation methods currently make such an integration task difficult to perform and mostly restricted to specific scenarios. We thus introduce here the Dynamic Motif Integration Toolkit (DynaMIT), an extremely flexible platform allowing to identify motifs employing multiple algorithms, integrate them by means of a user-selected strategy and visualize results in several ways; furthermore, the platform is user-extendible in all its aspects. DynaMIT is freely available at http://cibioltg.bitbucket.org .
    Keywords: Computational Methods, Genomics
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    Large-scale profiling of microRNAs for The Cancer Genome Atlas (2016)
    Oxford University Press
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    Publication Date: 2016-01-09
    Description: The comprehensive multiplatform genomics data generated by The Cancer Genome Atlas (TCGA) Research Network is an enabling resource for cancer research. It includes an unprecedented amount of microRNA sequence data: ~11 000 libraries across 33 cancer types. Combined with initiatives like the National Cancer Institute Genomics Cloud Pilots, such data resources will make intensive analysis of large-scale cancer genomics data widely accessible. To support such initiatives, and to enable comparison of TCGA microRNA data to data from other projects, we describe the process that we developed and used to generate the microRNA sequence data, from library construction through to submission of data to repositories. In the context of this process, we describe the computational pipeline that we used to characterize microRNA expression across large patient cohorts.
    Keywords: Computational Methods, Genomics
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    MethylAction: detecting differentially methylated regions that distinguish biological subtypes (2016)
    Oxford University Press
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    Publication Date: 2016-01-09
    Description: DNA methylation differences capture substantial information about the molecular and gene-regulatory states among biological subtypes. Enrichment-based next generation sequencing methods such as MBD-isolated genome sequencing (MiGS) and MeDIP-seq are appealing for studying DNA methylation genome-wide in order to distinguish between biological subtypes. However, current analytic tools do not provide optimal features for analyzing three-group or larger study designs. MethylAction addresses this need by detecting all possible patterns of statistically significant hyper- and hypo- methylation in comparisons involving any number of groups. Crucially, significance is established at the level of differentially methylated regions (DMRs), and bootstrapping determines false discovery rates (FDRs) associated with each pattern. We demonstrate this functionality in a four-group comparison among benign prostate and three clinical subtypes of prostate cancer and show that the bootstrap FDRs are highly useful in selecting the most robust patterns of DMRs. Compared to existing tools that are limited to two-group comparisons, MethylAction detects more DMRs with strong differential methylation measurements confirmed by whole genome bisulfite sequencing and offers a better balance between precision and recall in cross-cohort comparisons. MethylAction is available as an R package at http://jeffbhasin.github.io/methylaction .
    Keywords: Computational Methods, Genomics
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    NanoStringDiff: a novel statistical method for differential expression analysis based on NanoString nCounter data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-12-01
    Description: The advanced medium-throughput NanoString nCounter technology has been increasingly used for mRNA or miRNA differential expression (DE) studies due to its advantages including direct measurement of molecule expression levels without amplification, digital readout and superior applicability to formalin fixed paraffin embedded samples. However, the analysis of nCounter data is hampered because most methods developed are based on t-tests, which do not fit the count data generated by the NanoString nCounter system. Furthermore, data normalization procedures of current methods are either not suitable for counts or not specific for NanoString nCounter data. We develop a novel DE detection method based on NanoString nCounter data. The method, named NanoStringDiff, considers a generalized linear model of the negative binomial family to characterize count data and allows for multifactor design. Data normalization is incorporated in the model framework through data normalization parameters, which are estimated from positive controls, negative controls and housekeeping genes embedded in the nCounter system. We propose an empirical Bayes shrinkage approach to estimate the dispersion parameter in the model and a likelihood ratio test to identify differentially expressed genes. Simulations and real data analysis demonstrate that the proposed method performs better than existing methods.
    Keywords: Computational Methods, Genomics
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    Rethinking the Water-Food-Climate Nexus and Conflict: An Opportunity Cost Approach (2016)
    Oxford University Press
    Details
    Publication Date: 2016-12-07
    Description: Much attention has been paid to the potential role that climate and food security has on conflict, especially in the Middle East. However, there has been little critical examination beyond the statistical correlation of events, which demonstrates whether a causal link exists and if it does, what can be done about it. This paper explores the conceptual linkages between food and conflict and attempts to draw attention to the opportunity cost of conflict as the nexus for decision-making in this context.
    Keywords: D74 - Conflict ; Conflict Resolution ; Alliances, Q18 - Agricultural Policy ; Food Policy, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 2040-5790
    Electronic ISSN: 2040-5804
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    What Is the Social Value of Second Generation Biofuels? (2016)
    Oxford University Press
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    Publication Date: 2016-12-07
    Description: What are second-generation (2G) biofuel technologies worth to global society? A dynamic, economic model is used to assess the impact that introducing 2G biofuels technology has on crops, livestock, biofuels, forestry, and environmental services, as well as greenhouse gas emissions. Under baseline conditions, this amounts to $64 billion and is $84 billion under the optimistic technology case, suggesting that investing in 2G technology could be appropriate. Under greenhouse gas regulation, global valuation more than doubles to $139 and $174 billion, respectively. A flat energy price scenario eliminates the value of 2G technology to society.
    Keywords: Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q42 - Alternative Energy Sources, Q54 - Climate ; Natural Disasters ; Global Warming
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    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    RNA2DNAlign: nucleotide resolution allele asymmetries through quantitative assessment of RNA and DNA paired sequencing data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-12-17
    Description: We introduce RNA2DNAlign, a computational framework for quantitative assessment of allele counts across paired RNA and DNA sequencing datasets. RNA2DNAlign is based on quantitation of the relative abundance of variant and reference read counts, followed by binomial tests for genotype and allelic status at SNV positions between compatible sequences. RNA2DNAlign detects positions with differential allele distribution, suggesting asymmetries due to regulatory/structural events. Based on the type of asymmetry, RNA2DNAlign outlines positions likely to be implicated in RNA editing, allele-specific expression or loss, somatic mutagenesis or loss-of-heterozygosity (the first three also in a tumor-specific setting). We applied RNA2DNAlign on 360 matching normal and tumor exomes and transcriptomes from 90 breast cancer patients from TCGA. Under high-confidence settings, RNA2DNAlign identified 2038 distinct SNV sites associated with one of the aforementioned asymetries, the majority of which have not been linked to functionality before. The performance assessment shows very high specificity and sensitivity, due to the corroboration of signals across multiple matching datasets. RNA2DNAlign is freely available from http://github.com/HorvathLab/NGS as a self-contained binary package for 64-bit Linux systems.
    Keywords: Computational Methods, Genomics
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    Identifying gene regulatory network rewiring using latent differential graphical models (2016)
    Oxford University Press
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    Publication Date: 2016-10-08
    Description: Gene regulatory networks (GRNs) are highly dynamic among different tissue types. Identifying tissue-specific gene regulation is critically important to understand gene function in a particular cellular context. Graphical models have been used to estimate GRN from gene expression data to distinguish direct interactions from indirect associations. However, most existing methods estimate GRN for a specific cell/tissue type or in a tissue-naive way, or do not specifically focus on network rewiring between different tissues. Here, we describe a new method called Latent Differential Graphical Model (LDGM). The motivation of our method is to estimate the differential network between two tissue types directly without inferring the network for individual tissues, which has the advantage of utilizing much smaller sample size to achieve reliable differential network estimation. Our simulation results demonstrated that LDGM consistently outperforms other Gaussian graphical model based methods. We further evaluated LDGM by applying to the brain and blood gene expression data from the GTEx consortium. We also applied LDGM to identify network rewiring between cancer subtypes using the TCGA breast cancer samples. Our results suggest that LDGM is an effective method to infer differential network using high-throughput gene expression data to identify GRN dynamics among different cellular conditions.
    Keywords: Computational Methods, Genomics
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    Trade Liberalization versus Climate Change Policy for Reducing Greenhouse Gas Emissions in Agriculture: Some Insights from Norway (2015)
    Oxford University Press
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    Publication Date: 2015-08-11
    Description: Using a mathematical programming model of Norwegian agriculture, we explore interconnections between trade liberalization and reductions in greenhouse gas (GHG) emissions. We show that the Doha Round proposals for a new agreement on agriculture through the World Trade Organization would not generate significant reductions in emissions. Further trade liberalization would reduce emissions by cutting agricultural production but would not change production methods. Imposing a carbon tax would lead both to a reduction in output and the extensification of production. In contrast, if farmers are allowed to claim a credit for carbon sequestration the effect is to intensify agricultural production.
    Keywords: F18 - Trade and Environment, Q17 - Agriculture in International Trade, Q54 - Climate ; Natural Disasters ; Global Warming
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    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    A low-latency, big database system and browser for storage, querying and visualization of 3D genomic data (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-19
    Description: Recent releases of genome three-dimensional (3D) structures have the potential to transform our understanding of genomes. Nonetheless, the storage technology and visualization tools need to evolve to offer to the scientific community fast and convenient access to these data. We introduce simultaneously a database system to store and query 3D genomic data ( 3DBG ), and a 3D genome browser to visualize and explore 3D genome structures ( 3DGB ). We benchmark 3DBG against state-of-the-art systems and demonstrate that it is faster than previous solutions, and importantly gracefully scales with the size of data. We also illustrate the usefulness of our 3D genome Web browser to explore human genome structures. The 3D genome browser is available at http://3dgb.cs.mcgill.ca/ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Analysis of strand-specific RNA-seq data using machine learning reveals the structures of transcription units in Clostridium thermocellum (2015)
    Oxford University Press
    Details
    Publication Date: 2015-05-29
    Description: Identification of transcription units (TUs) encoded in a bacterial genome is essential to elucidation of transcriptional regulation of the organism. To gain a detailed understanding of the dynamically composed TU structures, we have used four strand-specific RNA-seq (ssRNA-seq) datasets collected under two experimental conditions to derive the genomic TU organization of Clostridium thermocellum using a machine-learning approach. Our method accurately predicted the genomic boundaries of individual TUs based on two sets of parameters measuring the RNA-seq expression patterns across the genome: expression-level continuity and variance. A total of 2590 distinct TUs are predicted based on the four RNA-seq datasets. Among the predicted TUs, 44% have multiple genes. We assessed our prediction method on an independent set of RNA-seq data with longer reads. The evaluation confirmed the high quality of the predicted TUs. Functional enrichment analyses on a selected subset of the predicted TUs revealed interesting biology. To demonstrate the generality of the prediction method, we have also applied the method to RNA-seq data collected on Escherichia coli and achieved high prediction accuracies. The TU prediction program named SeqTU is publicly available at https://code.google.com/p/seqtu/ . We expect that the predicted TUs can serve as the baseline information for studying transcriptional and post-transcriptional regulation in C. thermocellum and other bacteria.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    A thesaurus of genetic variation for interrogation of repetitive genomic regions (2015)
    Oxford University Press
    Details
    Publication Date: 2015-05-29
    Description: Detecting genetic variation is one of the main applications of high-throughput sequencing, but is still challenging wherever aligning short reads poses ambiguities. Current state-of-the-art variant calling approaches avoid such regions, arguing that it is necessary to sacrifice detection sensitivity to limit false discovery. We developed a method that links candidate variant positions within repetitive genomic regions into clusters. The technique relies on a resource, a thesaurus of genetic variation, that enumerates genomic regions with similar sequence. The resource is computationally intensive to generate, but once compiled can be applied efficiently to annotate and prioritize variants in repetitive regions. We show that thesaurus annotation can reduce the rate of false variant calls due to mappability by up to three orders of magnitude. We apply the technique to whole genome datasets and establish that called variants in low mappability regions annotated using the thesaurus can be experimentally validated. We then extend the analysis to a large panel of exomes to show that the annotation technique opens possibilities to study variation in hereto hidden and under-studied parts of the genome.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Following the footprints of polymorphic inversions on SNP data: from detection to association tests (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: Inversion polymorphisms have important phenotypic and evolutionary consequences in humans. Two different methodologies have been used to infer inversions from SNP dense data, enabling the use of large cohorts for their study. One approach relies on the differences in linkage disequilibrium across breakpoints; the other one captures the internal haplotype groups that tag the inversion status of chromosomes. In this article, we assessed the convergence of the two methods in the detection of 20 human inversions that have been reported in the literature. The methods converged in four inversions including inv-8p23, for which we studied its association with low-BMI in American children. Using a novel haplotype tagging method with control on inversion ancestry, we computed the frequency of inv-8p23 in two American cohorts and observed inversion haplotype admixture. Accounting for haplotype ancestry, we found that the European inverted allele in children carries a recessive risk of underweight, validated in an independent Spanish cohort (combined: OR= 2.00, P = 0.001). While the footprints of inversions on SNP data are complex, we show that systematic analyses, such as convergence of different methods and controlling for ancestry, can reveal the contribution of inversions to the ancestral composition of populations and to the heritability of human disease.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    Reconstructing genome-scale metabolic models with merlin (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: The Metabolic Models Reconstruction Using Genome-Scale Information ( merlin ) tool is a user-friendly Java application that aids the reconstruction of genome-scale metabolic models for any organism that has its genome sequenced. It performs the major steps of the reconstruction process, including the functional genomic annotation of the whole genome and subsequent construction of the portfolio of reactions. Moreover, merlin includes tools for the identification and annotation of genes encoding transport proteins, generating the transport reactions for those carriers. It also performs the compartmentalisation of the model, predicting the organelle localisation of the proteins encoded in the genome and thus the localisation of the metabolites involved in the reactions promoted by such enzymes. The gene-proteins-reactions (GPR) associations are automatically generated and included in the model. Finally, merlin expedites the transition from genomic data to draft metabolic models reconstructions exported in the SBML standard format, allowing the user to have a preliminary view of the biochemical network, which can be manually curated within the environment provided by merlin .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Inferential modeling of 3D chromatin structure (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: For eukaryotic cells, the biological processes involving regulatory DNA elements play an important role in cell cycle. Understanding 3D spatial arrangements of chromosomes and revealing long-range chromatin interactions are critical to decipher these biological processes. In recent years, chromosome conformation capture (3C) related techniques have been developed to measure the interaction frequencies between long-range genome loci, which have provided a great opportunity to decode the 3D organization of the genome. In this paper, we develop a new Bayesian framework to derive the 3D architecture of a chromosome from 3C-based data. By modeling each chromosome as a polymer chain, we define the conformational energy based on our current knowledge on polymer physics and use it as prior information in the Bayesian framework. We also propose an expectation-maximization (EM) based algorithm to estimate the unknown parameters of the Bayesian model and infer an ensemble of chromatin structures based on interaction frequency data. We have validated our Bayesian inference approach through cross-validation and verified the computed chromatin conformations using the geometric constraints derived from fluorescence in situ hybridization (FISH) experiments. We have further confirmed the inferred chromatin structures using the known genetic interactions derived from other studies in the literature. Our test results have indicated that our Bayesian framework can compute an accurate ensemble of 3D chromatin conformations that best interpret the distance constraints derived from 3C-based data and also agree with other sources of geometric constraints derived from experimental evidence in the previous studies. The source code of our approach can be found in https://github.com/wangsy11/InfMod3DGen .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    Integrating motif, DNA accessibility and gene expression data to build regulatory maps in an organism (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: Characterization of cell type specific regulatory networks and elements is a major challenge in genomics, and emerging strategies frequently employ high-throughput genome-wide assays of transcription factor (TF) to DNA binding, histone modifications or chromatin state. However, these experiments remain too difficult/expensive for many laboratories to apply comprehensively to their system of interest. Here, we explore the potential of elucidating regulatory systems in varied cell types using computational techniques that rely on only data of gene expression, low-resolution chromatin accessibility, and TF–DNA binding specificities (‘motifs’). We show that static computational motif scans overlaid with chromatin accessibility data reasonably approximate experimentally measured TF–DNA binding. We demonstrate that predicted binding profiles and expression patterns of hundreds of TFs are sufficient to identify major regulators of ~200 spatiotemporal expression domains in the Drosophila embryo. We are then able to learn reliable statistical models of enhancer activity for over 70 expression domains and apply those models to annotate domain specific enhancers genome-wide. Throughout this work, we apply our motif and accessibility based approach to comprehensively characterize the regulatory network of fruitfly embryonic development and show that the accuracy of our computational method compares favorably to approaches that rely on data from many experimental assays.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    Local warming and violent conflict in North and South Sudan (2015)
    Oxford University Press
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    Publication Date: 2015-04-14
    Description: Our article contributes to the emerging micro-level strand of the literature on the link between local variations in weather shocks and conflicts by focusing on a pixel-level analysis for North and South Sudan between 1997 and 2009. Temperature anomalies are found to strongly affect the risk of conflict, whereas the risk is expected to magnify in a range of 24–31% in the future under a median scenario. Our analysis also sheds light on the competition over natural resources, in particular water, as the main driver of such relationship in a region where pastoralism constitutes the dominant livelihood.
    Keywords: D74 - Conflict ; Conflict Resolution ; Alliances, O13 - Agriculture ; Natural Resources ; Energy ; Environment ; Other Primary Products, Q54 - Climate ; Natural Disasters ; Global Warming, R11 - Regional Economic Activity: Growth, Development, and Changes
    Print ISSN: 1468-2702
    Electronic ISSN: 1468-2710
    Topics: Geography , Economics
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    Dealing with Uncertainty in Agent-Based Simulation: Farm-Level Modeling of Adaptation to Climate Change in Southwest Germany (2015)
    Oxford University Press
    Details
    Publication Date: 2015-04-18
    Description: Climate change will most likely confront agricultural producers with natural, economic, and political conditions that have not previously been observed and are largely uncertain. As a consequence, extrapolation from past data reaches its limits, and a process-based analysis of farmer adaptation is required. Simulation of changes in crop yields using crop growth models is a first step in that direction. However, changes in crop yields are only one pathway through which climate change affects agricultural production. A meaningful process-based analysis of farmer adaptation requires a whole-farm analysis at the farm level. We use a highly disaggregated mathematical programming model to analyze farm-level climate change adaptation for a mountainous area in southwest Germany. Regional-level results are obtained by simulating each full-time farm holding in the study area. We address parameter uncertainty and model underdetermination using a cautious calibration approach and a comprehensive uncertainty analysis. We deal with the resulting computational burden using efficient experimental designs and high-performance computing. We show that in our study area, shifted crop management time slots can have potentially significant effects on agricultural supply, incomes, and various policy objectives promoted under German and European environmental policy schemes. The simulated effects are robust against model uncertainty and underline the importance of a comprehensive assessment of climate change impacts beyond merely looking at crop yield changes. Our simulations demonstrate how farm-level models can contribute to a process-based analysis of climate change adaptation if they are embedded into a systematic framework for treating inherent model uncertainty.
    Keywords: C61 - Optimization Techniques ; Programming Models ; Dynamic Analysis, C63 - Computational Techniques, Q12 - Micro Analysis of Farm Firms, Farm Households, and Farm Input Markets, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Irrigation Decisions for Major West Coast Crops: Water Scarcity and Climatic Determinants (2015)
    Oxford University Press
    Details
    Publication Date: 2015-12-13
    Description: This article uses the 2007 Farm and Ranch Irrigation Survey database developed by the U.S. Department of Agriculture to assess the impact of water scarcity and climate on irrigation decisions for producers of specialty crops, wheat, and forage crops. We estimate an irrigation management model for major crops in the West Coast (California, Oregon, and Washington), which includes a farm-level equation of irrigated share and crop-specific equations of technology adoption and water application rate (orchard/vineyard, vegetable, wheat, alfalfa, hay, and pasture). We find that economic and physical water scarcity, climate, and extreme weather, such as frost, extreme heat, and drought, significantly impact producers’ irrigation decisions. Producers use sprinkler technologies or additional water applications to mitigate risk of crop damage from extreme weather. Water application rates are least responsive to surface water cost or groundwater well depth for producers of orchard/vineyard. Water supply institutions influence producers’ irrigation decisions. Producers who receive water from federal agencies use higher water application rates and are less likely to adopt water-saving irrigation technologies for some crops. Institutional arrangements, including access to distinct water sources (surface or ground) and whether surface water cost is fee based, also affect the responsiveness of water application rates to changes in surface water cost. The analysis provides valuable information about how producers in irrigated agricultural production systems would respond and adapt to water pricing policies and climate change.
    Keywords: Q12 - Micro Analysis of Farm Firms, Farm Households, and Farm Input Markets, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q16 - R&D ; Agricultural Technology ; Agricultural Extension Services, Q18 - Agricultural Policy ; Food Policy, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    A statistical framework for revealing signaling pathways perturbed by DNA variants (2015)
    Oxford University Press
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    Publication Date: 2015-06-24
    Description: Much of the inter-individual variation in gene expression is triggered via perturbations of signaling networks by DNA variants. We present a novel probabilistic approach for identifying the particular pathways by which DNA variants perturb the signaling network. Our procedure, called PINE, relies on a systematic integration of established biological knowledge of signaling networks with data on transcriptional responses to various experimental conditions. Unlike previous approaches, PINE provides statistical aspects that are critical for prioritizing hypotheses for followup experiments. Using simulated data, we show that higher accuracy is attained with PINE than with existing methods. We used PINE to analyze transcriptional responses of immune dendritic cells to several pathogenic stimulations. PINE identified statistically significant genetic perturbations in the pathogen-sensing signaling network, suggesting previously uncharacterized regulatory mechanisms for functional DNA variants.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    An Introduction to the Green Paradox: The Unintended Consequences of Climate Policies (2015)
    Oxford University Press
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    Publication Date: 2015-07-18
    Description: How important is the Green Paradox? We address this question in three ways. First, we present a simple model explaining how announcing a future climate policy may increase carbon emissions today – the Green Paradox effect. This effect is a result of fossil fuel producers increasing their extraction today as a response to a reduction in future resource rents. Second, we examine the theoretical and empirical literature to assess whether green paradoxes are likely to occur, and if they are, whether they are big enough to be of concern for policy makers. We consider several factors that affect the existence of the green paradox, including long-term extraction costs, short-term extraction capacities, the mix of policy instruments, and potential spatial carbon leakage to countries that have no climate policy. We find that these and other factors can sometimes strengthen, but mostly weaken, the case for concern about the green paradox. Third, we identify the lessons the literature offers for policy makers. We argue that in designing climate policy, policy makers need to consider the supply side of the fossil fuel market.
    Keywords: H23 - Externalities ; Redistributive Effects ; Environmental Taxes and Subsidies, Q31 - Demand and Supply, Q38 - Government Policy, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    Introductory Comment-The Green Paradox: A Supply-Side View of the Climate Problem (2015)
    Oxford University Press
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    Publication Date: 2015-07-18
    Description: Why have policies aimed at reducing the demand for carbon not succeeded in slowing down global carbon extraction and CO 2 emissions, and why have carbon prices failed to increase over the last three decades? This comment argues that this is because of the Green Paradox, that is, the anticipation of sales by resource owners who try to preempt the destruction of their markets by green policies. Reviewing some of the conditions under which strong and weak versions of the Green Paradox may emerge, it is argued that there is little hope that green replacement technologies will impose hard price constraints that would keep long-run extraction within a fixed carbon budget and that, therefore, even strong versions of the paradox cannot easily be avoided.
    Keywords: O13 - Agriculture ; Natural Resources ; Energy ; Environment ; Other Primary Products, Q32 - Exhaustible Resources and Economic Development, Q54 - Climate ; Natural Disasters ; Global Warming, H23 - Externalities ; Redistributive Effects ; Environmental Taxes and Subsidies
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    The Green Paradox in Open Economies: Lessons from Static and Dynamic Models (2015)
    Oxford University Press
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    Publication Date: 2015-07-18
    Description: This article examines how, in a world with incomplete coordination among countries, well-intentioned unilateral environmental policies may actually harm the global environment. This outcome is known as the "Green Paradox." The incentives for free-riding and the challenge of achieving an effective international environmental agreement are reviewed. I examine the various channels that lead to carbon leakage in static models of open economies, and report some simulation results. This is complemented by a review of the potential for Green Paradox outcomes in dynamic open-economy models in which forward-looking firms exploit an exhaustible resource. I show that border tax adjustments can lead to Green Paradox outcomes. I also discuss priorities for future research on environmental policies in a trading world that lacks a central enforcement agency.
    Keywords: Q54 - Climate ; Natural Disasters ; Global Warming, Q42 - Alternative Energy Sources
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    Reflections-Managing Uncertain Climates: Some Guidance for Policy Makers and Researchers (2015)
    Oxford University Press
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    Publication Date: 2015-07-18
    Description: Climate change—and, by extension, climate policy—is beset with unknowns and unknowables. This "Reflections" article presents an overview of approaches to managing climate uncertainties, in the hopes of providing guidance for current policy decisions as well as future research. We propose the following guidance for policy makers: Treat climate change as a risk management problem; recognize that benefit-cost analysis is only the first of many steps in deciding on optimal climate policy; in assessing abatement choices, use a discount rate that declines over time; recognize the importance of framing, evidence, and connecting the dots; reward modesty. We suggest the following questions for consideration by researchers: Can we improve forecasting? Can we improve the way we address nonlinearities and possible irreversibilities? What other (sub)disciplines merit a closer look? How can we create the right incentives for updating and expanding economic damage functions and climate-economy models? What alternative decision criteria merit further exploration? What does ‘not knowing’ tell us?
    Keywords: Q54 - Climate ; Natural Disasters ; Global Warming, D81 - Criteria for Decision-Making under Risk and Uncertainty
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    Why weight? Modelling sample and observational level variability improves power in RNA-seq analyses (2015)
    Oxford University Press
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    Publication Date: 2015-08-29
    Description: Variations in sample quality are frequently encountered in small RNA-sequencing experiments, and pose a major challenge in a differential expression analysis. Removal of high variation samples reduces noise, but at a cost of reducing power, thus limiting our ability to detect biologically meaningful changes. Similarly, retaining these samples in the analysis may not reveal any statistically significant changes due to the higher noise level. A compromise is to use all available data, but to down-weight the observations from more variable samples. We describe a statistical approach that facilitates this by modelling heterogeneity at both the sample and observational levels as part of the differential expression analysis. At the sample level this is achieved by fitting a log-linear variance model that includes common sample-specific or group-specific parameters that are shared between genes. The estimated sample variance factors are then converted to weights and combined with observational level weights obtained from the mean–variance relationship of the log-counts-per-million using ‘voom’. A comprehensive analysis involving both simulations and experimental RNA-sequencing data demonstrates that this strategy leads to a universally more powerful analysis and fewer false discoveries when compared to conventional approaches. This methodology has wide application and is implemented in the open-source ‘limma’ package.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    RAX2: a genome-wide detection method of condition-associated transcription variation (2015)
    Oxford University Press
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    Publication Date: 2015-08-29
    Description: Most mammalian genes have mRNA variants due to alternative promoter usage, alternative splicing, and alternative cleavage and polyadenylation. Expression of alternative RNA isoforms has been found to be associated with tumorigenesis, proliferation and differentiation. Detection of condition-associated transcription variation requires association methods. Traditional association methods such as Pearson chi-square test and Fisher Exact test are single test methods and do not work on count data with replicates. Although the Cochran Mantel Haenszel (CMH) approach can handle replicated count data, our simulations showed that multiple CMH tests still had very low power. To identify condition-associated variation of transcription, we here proposed a ranking analysis of chi-squares (RAX2) for large-scale association analysis. RAX2 is a nonparametric method and has accurate and conservative estimation of FDR profile. Simulations demonstrated that RAX2 performs well in finding condition-associated transcription variants. We applied RAX2 to primary T-cell transcriptomic data and identified 1610 (16.3%) tags associated in transcription with immune stimulation at FDR 〈 0.05. Most of these tags also had differential expression. Analysis of two and three tags within genes revealed that under immune stimulation short RNA isoforms were preferably used.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    Unique transposon landscapes are pervasive across Drosophila melanogaster genomes (2015)
    Oxford University Press
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    Publication Date: 2015-12-16
    Description: To understand how transposon landscapes (TLs) vary across animal genomes, we describe a new method called the Transposon Insertion and Depletion AnaLyzer (TIDAL) and a database of 〉300 TLs in Drosophila melanogaster (TIDAL-Fly). Our analysis reveals pervasive TL diversity across cell lines and fly strains, even for identically named sub-strains from different laboratories such as the ISO1 strain used for the reference genome sequence. On average, 〉500 novel insertions exist in every lab strain, inbred strains of the Drosophila Genetic Reference Panel (DGRP), and fly isolates in the Drosophila Genome Nexus (DGN). A minority (〈25%) of transposon families comprise the majority (〉70%) of TL diversity across fly strains. A sharp contrast between insertion and depletion patterns indicates that many transposons are unique to the ISO1 reference genome sequence. Although TL diversity from fly strains reaches asymptotic limits with increasing sequencing depth, rampant TL diversity causes unsaturated detection of TLs in pools of flies. Finally, we show novel transposon insertions negatively correlate with Piwi-interacting RNA (piRNA) levels for most transposon families, except for the highly-abundant roo retrotransposon. Our study provides a useful resource for Drosophila geneticists to understand how transposons create extensive genomic diversity in fly cell lines and strains.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    An ensemble strategy that significantly improves de novo assembly of microbial genomes from metagenomic next-generation sequencing data (2015)
    Oxford University Press
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    Publication Date: 2015-04-21
    Description: Next-generation sequencing (NGS) approaches rapidly produce millions to billions of short reads, which allow pathogen detection and discovery in human clinical, animal and environmental samples. A major limitation of sequence homology-based identification for highly divergent microorganisms is the short length of reads generated by most highly parallel sequencing technologies. Short reads require a high level of sequence similarities to annotated genes to confidently predict gene function or homology. Such recognition of highly divergent homologues can be improved by reference-free ( de novo ) assembly of short overlapping sequence reads into larger contigs. We describe an ensemble strategy that integrates the sequential use of various de Bruijn graph and overlap-layout-consensus assemblers with a novel partitioned sub-assembly approach. We also proposed new quality metrics that are suitable for evaluating metagenome de novo assembly. We demonstrate that this new ensemble strategy tested using in silico spike-in, clinical and environmental NGS datasets achieved significantly better contigs than current approaches.
    Keywords: Computational Methods, Genomics
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    Distinguishing between productive and abortive promoters using a random forest classifier in Mycoplasma pneumoniae (2015)
    Oxford University Press
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    Publication Date: 2015-04-21
    Description: Distinguishing between promoter-like sequences in bacteria that belong to true or abortive promoters, or to those that do not initiate transcription at all, is one of the important challenges in transcriptomics. To address this problem, we have studied the genome-reduced bacterium Mycoplasma pneumoniae , for which the RNAs associated with transcriptional start sites have been recently experimentally identified. We determined the contribution to transcription events of different genomic features: the –10, extended –10 and –35 boxes, the UP element, the bases surrounding the –10 box and the nearest-neighbor free energy of the promoter region. Using a random forest classifier and the aforementioned features transformed into scores, we could distinguish between true, abortive promoters and non-promoters with good –10 box sequences. The methods used in this characterization of promoters can be extended to other bacteria and have important applications for promoter design in bacterial genome engineering.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    The Effect of Weather-Induced Internal Migration on Local Labor Markets. Evidence from Uganda (2015)
    Oxford University Press
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    Publication Date: 2015-05-21
    Description: Relying on census data collected in 2002 and historical weather data for Uganda, we estimate the impact of weather-induced internal migration on the probability for non-migrants living in the destination regions to be employed. Consistent with the prediction of a simple theoretical model, our results reveal a larger negative impact than the one documented for developed countries. They further show that this negative impact is significantly stronger in Ugandan regions with lower road density and therefore less conducive to capital mobility: a 10 percentage points increase in the net in-migration rate in these areas decreases the probability of being employed of non-migrants by more than 10 percentage points.
    Keywords: E24 - Employment ; Unemployment ; Wages ; Intergenerational Income Distribution, J21 - Labor Force and Employment, Size, and Structure, J61 - Geographic Labor Mobility ; Immigrant Workers, Q54 - Climate ; Natural Disasters ; Global Warming, R23 - Regional Migration ; Regional Labor Markets ; Population
    Print ISSN: 0258-6770
    Electronic ISSN: 1564-698X
    Topics: Economics
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    Optimal Directions for Directional Distance Functions: An Exploration of Potential Reductions of Greenhouse Gases (2015)
    Oxford University Press
    Details
    Publication Date: 2015-04-18
    Description: This article explores the reduction potential of greenhouse gases for major pollution-emitting countries of the world using nonparametric productivity measurement methods and directional distance functions. In contrast to the existing literature, we apply optimization methods to endogenously determine optimal directions for the efficiency analysis. These directions represent the compromise of output enhancement and emissions reduction. The results show that for reasonable directions the adoption of best practices would lead to sizable emission reductions in a range of approximately 20% compared with current levels.
    Keywords: C14 - Semiparametric and Nonparametric Methods, D24 - Production ; Cost ; Capital and Total Factor Productivity ; Capacity, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
    Published by Oxford University Press
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    Pathway analysis from lists of microRNAs: common pitfalls and alternative strategy (2015)
    Oxford University Press
    Details
    Publication Date: 2015-04-21
    Description: MicroRNAs (miRNAs) are involved in the regulation of gene expression at a post-transcriptional level. As such, monitoring miRNA expression has been increasingly used to assess their role in regulatory mechanisms of biological processes. In large scale studies, once miRNAs of interest have been identified, the target genes they regulate are often inferred using algorithms or databases. A pathway analysis is then often performed in order to generate hypotheses about the relevant biological functions controlled by the miRNA signature. Here we show that the method widely used in scientific literature to identify these pathways is biased and leads to inaccurate results. In addition to describing the bias and its origin we present an alternative strategy to identify potential biological functions specifically impacted by a miRNA signature. More generally, our study exemplifies the crucial need of relevant negative controls when developing, and using, bioinformatics methods.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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    Regulation of Natural Gas in the United States, Canada, and Europe: Prospects for a Low Carbon Fuel (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-29
    Description: The United States and Canada have seen a competitive and technological revolution in unconventional natural gas production in the 21 st Century—dramatically lowering the price of gas and displacing high-carbon coal with low-carbon gas for power generation. This gas revolution came from an earlier revolution in the regulation of gas pipelines, which ended the obstruction of gas markets by pipeline interests. Neither revolution has spread to Europe, where increasingly protectionist EU legislation has effectively blocked competitive pipeline entry and related gas markets. As a result, unconventional gas is untapped, coal displaces gas for power generation, and oil-linked gas prices have cost EU consumers a staggering $425 billion more than their US counterparts have paid since 2009 for about the same quantity of gas. Europe faces a serious institutional challenge to adopting the kind of pipeline regulation that facilitates the competitive flow of natural gas supplies and the accompanying lower carbon emissions. ( JEL : D23, K23, L14, L51, L95, N70, Q54)
    Keywords: D23 - Organizational Behavior ; Transaction Costs ; Property Rights, K23 - Regulated Industries and Administrative Law, L14 - Transactional Relationships ; Contracts and Reputation ; Networks, L51 - Economics of Regulation, L95 - Gas Utilities ; Pipelines ; Water Utilities, N70 - General, International, or Comparative, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
    Published by Oxford University Press
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    A Global Perspective on the Future of Natural Gas: Resources, Trade, and Climate Constraints (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-29
    Description: Natural gas plays an important role in the global energy system as an input to power generation, heating, and industry. This article identifies key drivers and uncertainties for natural gas markets in the coming decades. These include the availability of natural gas from conventional and unconventional sources, the role of international trade, and the impact of climate policies. We build on model-based research as well as an up-to-date survey of natural gas resource availability. We find that natural gas is an abundant fossil fuel and that the Asia-Pacific region will be most important in future global natural gas markets, especially under stringent international climate change mitigation. This means that an increasingly large share of future natural gas trade flows and infrastructure expansions will be directed to the Asia-Pacific region and that the role of liquefied natural gas will continue to increase globally. ( JEL : C61, L71, Q33, Q37, Q54)
    Keywords: C61 - Optimization Techniques ; Programming Models ; Dynamic Analysis, L71 - Mining, Extraction, and Refining: Hydrocarbon Fuels, Q33 - Resource Booms, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 1750-6816
    Electronic ISSN: 1750-6824
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Political Science , Economics
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    Fiscal Responses after Catastrophes and the Enabling Role of Financial Development (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-29
    Description: Natural disasters may constitute a major shock to public finances and debt sustainability because of their impact on output and the need for government response with reconstruction and relief expenses. The question arises of whether governments can use financial development policy as the means to mitigate or insure against this negative fiscal impact. This paper uses a panel vector autoregressive model, estimated on annual data for high- and middle-income countries over 1975–2008, to study the role of debt market development and insurance penetration in enabling fiscal response after catastrophes. The authors find that countries with higher debt market development suffer smaller real consequences from disasters but that their deficits expand further following the mitigating fiscal response. Disasters in countries with high insurance penetration also experience smaller real consequences of disasters but without the need for further deficit expansions. From an ex-post perspective, the availability of insurance could offer the best mitigation approach against the real and fiscal consequences of disasters.
    Keywords: E32 - Business Fluctuations ; Cycles, H50 - General, H60 - General, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0258-6770
    Electronic ISSN: 1564-698X
    Topics: Economics
    Published by Oxford University Press
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    Distributional Implications of Climate Change in Rural India: A General Equilibrium Approach (2015)
    Oxford University Press
    Details
    Publication Date: 2015-07-10
    Description: We develop a general equilibrium framework, based on a specific-factors trade model, to quantify the medium-term household welfare impacts of global warming in rural India. Using an hedonic approach grounded in the theory combined with detailed microdata, we estimate that three decades of warming will reduce agricultural productivity in the range of 7%–13%, with the arid northwest of India especially hard hit. Our analysis shows that the proportional welfare cost of climate change is likely to be both modest and evenly distributed across percentiles of the per capita income distribution, but this latter conclusion emerges only when the flexibility of rural wages is taken into account.
    Keywords: Q17 - Agriculture in International Trade, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-30
    Description: In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource ( larva.gersteinlab.org ).
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Discovery and characterization of Alu repeat sequences via precise local read assembly (2015)
    Oxford University Press
    Details
    Publication Date: 2015-12-02
    Description: Alu insertions have contributed to 〉11% of the human genome and ~30–35 Alu subfamilies remain actively mobile, yet the characterization of polymorphic Alu insertions from short-read data remains a challenge. We build on existing computational methods to combine Alu detection and de novo assembly of WGS data as a means to reconstruct the full sequence of insertion events from Illumina paired end reads. Comparison with published calls obtained using PacBio long-reads indicates a false discovery rate below 5%, at the cost of reduced sensitivity due to the colocation of reference and non-reference repeats. We generate a highly accurate call set of 1614 completely assembled Alu variants from 53 samples from the Human Genome Diversity Project (HGDP) panel. We utilize the reconstructed alternative insertion haplotypes to genotype 1010 fully assembled insertions, obtaining 〉99% agreement with genotypes obtained by PCR. In our assembled sequences, we find evidence of premature insertion mechanisms and observe 5' truncation in 16% of Alu Ya5 and Alu Yb8 insertions. The sites of truncation coincide with stem-loop structures and SRP9/14 binding sites in the Alu RNA, implicating L1 ORF2p pausing in the generation of 5' truncations. Additionally, we identified variable Alu J and Alu S elements that likely arose due to non-retrotransposition mechanisms.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Responsiveness of Crop Yield and Acreage to Prices and Climate (2015)
    Oxford University Press
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    Publication Date: 2015-12-13
    Description: We investigate the effect of crop price and climate variables on rainfed corn and soybean yields and acreage in the United States using a large panel dataset for the 1977–2007 period. Instrumental variables are used to control for endogeneity of prices in yield and acreage regressions, while allowing for spatially auto-correlated errors. We find that an increase in corn price has a statistically significant positive impact on corn yield, but the effect of soybean price on soybean yields is not statistically significant. The estimated price elasticities of corn yield and acreage are 0.23 and 0.45, respectively. Of the increase in corn supply caused by an increase in corn price, we find that 33.8% is due to price-induced yield enhancement and 66.2% is due to price-induced acreage expansion. We also find that the impact of climate change on corn production ranges from $-$ 7% to $-$ 41% and on soybean ranges from $-$ 8% to $-$ 45%, depending on the climate change scenarios, time horizon, and global climate models used to predict climate change. We show that the aggregate net impact of omitting price variables is an overestimation of the effect of climate change on corn yield by up to 9% and on soybean yield by up to 15%.
    Keywords: Q11 - Aggregate Supply and Demand Analysis ; Prices, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q54 - Climate ; Natural Disasters ; Global Warming
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
    Published by Oxford University Press
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    Conditional mutual inclusive information enables accurate quantification of associations in gene regulatory networks (2015)
    Oxford University Press
    Details
    Publication Date: 2015-03-14
    Description: Mutual information (MI), a quantity describing the nonlinear dependence between two random variables, has been widely used to construct gene regulatory networks (GRNs). Despite its good performance, MI cannot separate the direct regulations from indirect ones among genes. Although the conditional mutual information (CMI) is able to identify the direct regulations, it generally underestimates the regulation strength, i.e. it may result in false negatives when inferring gene regulations. In this work, to overcome the problems, we propose a novel concept, namely conditional mutual inclusive information (CMI2), to describe the regulations between genes. Furthermore, with CMI2, we develop a new approach, namely CMI2NI (CMI2-based network inference), for reverse-engineering GRNs. In CMI2NI, CMI2 is used to quantify the mutual information between two genes given a third one through calculating the Kullback–Leibler divergence between the postulated distributions of including and excluding the edge between the two genes. The benchmark results on the GRNs from DREAM challenge as well as the SOS DNA repair network in Escherichia coli demonstrate the superior performance of CMI2NI. Specifically, even for gene expression data with small sample size, CMI2NI can not only infer the correct topology of the regulation networks but also accurately quantify the regulation strength between genes. As a case study, CMI2NI was also used to reconstruct cancer-specific GRNs using gene expression data from The Cancer Genome Atlas (TCGA). CMI2NI is freely accessible at http://www.comp-sysbio.org/cmi2ni .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    CODEX: a normalization and copy number variation detection method for whole exome sequencing (2015)
    Oxford University Press
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    Publication Date: 2015-04-02
    Description: High-throughput sequencing of DNA coding regions has become a common way of assaying genomic variation in the study of human diseases. Copy number variation (CNV) is an important type of genomic variation, but detecting and characterizing CNV from exome sequencing is challenging due to the high level of biases and artifacts. We propose CODEX, a normalization and CNV calling procedure for whole exome sequencing data. The Poisson latent factor model in CODEX includes terms that specifically remove biases due to GC content, exon capture and amplification efficiency, and latent systemic artifacts. CODEX also includes a Poisson likelihood-based recursive segmentation procedure that explicitly models the count-based exome sequencing data. CODEX is compared to existing methods on a population analysis of HapMap samples from the 1000 Genomes Project, and shown to be more accurate on three microarray-based validation data sets. We further evaluate performance on 222 neuroblastoma samples with matched normals and focus on a well-studied rare somatic CNV within the ATRX gene. We show that the cross-sample normalization procedure of CODEX removes more noise than normalizing the tumor against the matched normal and that the segmentation procedure performs well in detecting CNVs with nested structures.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Comprehensive discovery of DNA motifs in 349 human cells and tissues reveals new features of motifs (2015)
    Oxford University Press
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    Publication Date: 2015-01-10
    Description: Comprehensive motif discovery under experimental conditions is critical for the global understanding of gene regulation. To generate a nearly complete list of human DNA motifs under given conditions, we employed a novel approach to de novo discover significant co-occurring DNA motifs in 349 human DNase I hypersensitive site datasets. We predicted 845 to 1325 motifs in each dataset, for a total of 2684 non-redundant motifs. These 2684 motifs contained 54.02 to 75.95% of the known motifs in seven large collections including TRANSFAC. In each dataset, we also discovered 43 663 to 2 013 288 motif modules, groups of motifs with their binding sites co-occurring in a significant number of short DNA regions. Compared with known interacting transcription factors in eight resources, the predicted motif modules on average included 84.23% of known interacting motifs. We further showed new features of the predicted motifs, such as motifs enriched in proximal regions rarely overlapped with motifs enriched in distal regions, motifs enriched in 5' distal regions were often enriched in 3' distal regions, etc. Finally, we observed that the 2684 predicted motifs classified the cell or tissue types of the datasets with an accuracy of 81.29%. The resources generated in this study are available at http://server.cs.ucf.edu/predrem/ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    A framework for improving microRNA prediction in non-human genomes (2015)
    Oxford University Press
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    Publication Date: 2015-11-17
    Description: The prediction of novel pre-microRNA (miRNA) from genomic sequence has received considerable attention recently. However, the majority of studies have focused on the human genome. Previous studies have demonstrated that sensitivity (correctly detecting true miRNA) is sustained when human-trained methods are applied to other species, however they have failed to report the dramatic drop in specificity (the ability to correctly reject non-miRNA sequences) in non-human genomes. Considering the ratio of true miRNA sequences to pseudo-miRNA sequences is on the order of 1:1000, such low specificity prevents the application of most existing tools to non-human genomes, as the number of false positives overwhelms the true predictions. We here introduce a framework (SMIRP) for creating species-specific miRNA prediction systems, leveraging sequence conservation and phylogenetic distance information. Substantial improvements in specificity and precision are obtained for four non-human test species when our framework is applied to three different prediction systems representing two types of classifiers (support vector machine and Random Forest), based on three different feature sets, with both human-specific and taxon-wide training data. The SMIRP framework is potentially applicable to all miRNA prediction systems and we expect substantial improvement in precision and specificity, while sustaining sensitivity, independent of the machine learning technique chosen.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Efficient exploration of pan-cancer networks by generalized covariance selection and interactive web content (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-29
    Description: Statistical network modeling techniques are increasingly important tools to analyze cancer genomics data. However, current tools and resources are not designed to work across multiple diagnoses and technical platforms, thus limiting their applicability to comprehensive pan-cancer datasets such as The Cancer Genome Atlas (TCGA). To address this, we describe a new data driven modeling method, based on generalized Sparse Inverse Covariance Selection (SICS). The method integrates genetic, epigenetic and transcriptional data from multiple cancers, to define links that are present in multiple cancers, a subset of cancers, or a single cancer. It is shown to be statistically robust and effective at detecting direct pathway links in data from TCGA. To facilitate interpretation of the results, we introduce a publicly accessible tool ( cancerlandscapes.org ), in which the derived networks are explored as interactive web content, linked to several pathway and pharmacological databases. To evaluate the performance of the method, we constructed a model for eight TCGA cancers, using data from 3900 patients. The model rediscovered known mechanisms and contained interesting predictions. Possible applications include prediction of regulatory relationships, comparison of network modules across multiple forms of cancer and identification of drug targets.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    A new approach for annotation of transposable elements using small RNA mapping (2015)
    Oxford University Press
    Details
    Publication Date: 2015-07-25
    Description: Transposable elements (TEs) are mobile genomic DNA sequences found in most organisms. They so densely populate the genomes of many eukaryotic species that they are often the major constituents. With the rapid generation of many plant genome sequencing projects over the past few decades, there is an urgent need for improved TE annotation as a prerequisite for genome-wide studies. Analogous to the use of RNA-seq for gene annotation, we propose a new method for de novo TE annotation that uses as a guide 24 nt-siRNAs that are a part of TE silencing pathways. We use this new approach, called TASR (for Transposon Annotation using Small RNAs), for de novo annotation of TEs in Arabidopsis , rice and soybean and demonstrate that this strategy can be successfully applied for de novo TE annotation in plants. Executable PERL is available for download from: http://tasr-pipeline.sourceforge.net/
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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