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  • Articles  (229)
  • Latest Papers from Table of Contents or Articles in Press  (229)
  • Computational Methods, Genomics  (140)
  • Pathogens & Pathogenicity  (51)
  • Land Use  (38)
  • Oxford University Press  (229)
  • Springer
  • 1
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    Supply Response, Marginal Cost, and Soil Erosion Implications of Stover-based Biofuels (2015)
    Oxford University Press
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    Publication Date: 2015-08-11
    Description: Existing economic analysis of corn stover as an energy feedstock has not considered potential changes in land use associated with different stover prices. We estimate the response of corn stover supply density to its price driven by changes in land use and examine its implications for a processing plant's pricing strategy and marginal cost, as well as associated changes in soil erosion. We find that plants will exploit the intensive margin as well as the extensive margin to secure additional amounts of stover. Our results show, counterintuitively, that a market for stover may result in lower soil erosion due to reallocations of land to continuous corn with removal, which, combined with no-till farming, results in lower soil erosion than the baseline without stover removal. Also contrary to expectations, using cover crops with stover removal may result in higher soil erosion due to land use changes within the fuel shed associated with optimal pricing.
    Keywords: Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q24 - Land, Q42 - Alternative Energy Sources
    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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  • 2
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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
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    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
    Published by Oxford University Press
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  • 3
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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
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    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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  • 4
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    A thesaurus of genetic variation for interrogation of repetitive genomic regions (2015)
    Oxford University Press
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    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
    Published by Oxford University Press
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  • 5
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    A human pathogenic bacterial infection model using the two-spotted cricket, Gryllus bimaculatus (2016)
    Oxford University Press
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    Publication Date: 2016-07-15
    Description: Invertebrate animal species that can withstand temperatures as high as 37°C, the human body temperature, are limited. In the present study, we utilized the two-spotted cricket, Gryllus bimaculatus , which lives in tropical and subtropical regions, as an animal model of human pathogenic bacterial infection. Injection of Pseudomonas aeruginosa or Staphylococcus aureus into the hemolymph killed crickets. Injected P. aeruginosa or S. aureus proliferated in the hemolymph until the cricket died. The ability of these pathogenic bacteria to kill the crickets was blocked by the administration of antibiotics. S. aureus gene-knockout mutants of virulence factors, including cvfA, agr and srtA , exhibited decreased killing ability compared with the parent strain. The dose at which 50% of crickets were killed by P. aeruginosa or S. aureus was not decreased at 37°C compared with that at 27°C. Injection of Listeria monocytogenes , which upregulates toxin expression at 37°C, killed crickets, and the dose at which 50% of crickets were killed was decreased at 37°C compared with that at 27°C. These findings suggest that the two-spotted cricket is a useful model animal for evaluating the virulence properties of various human pathogenic bacteria at variable temperature including 37°C.
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    A conserved OmpA-like protein in Legionella pneumophila required for efficient intracellular replication (2016)
    Oxford University Press
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    Publication Date: 2016-07-31
    Description: The OmpA-like protein domain has been associated with peptidoglycan-binding proteins, and is often found in virulence factors of bacterial pathogens. The intracellular pathogen Legionella pneumophila encodes for six proteins that contain the OmpA-like domain, among them the highly conserved uncharacterized protein we named CmpA. Here we set out to characterize the CmpA protein and determine its contribution to intracellular survival of L. pneumophila . Secondary structure analysis suggests that CmpA is an inner membrane protein with a peptidoglycan-binding domain at the C-teminus. A cmpA mutant was able to replicate normally in broth, but failed to compete with an isogenic wild-type strain in an intracellular growth competition assay. The cmpA mutant also displayed significant intracellular growth defects in both the protozoan host Acanthamoeba castellanii and in primary bone marrow-derived macrophages, where uptake into the cells was also impaired. The cmpA phenotypes were completely restored upon expression of CmpA in trans . The data presented here establish CmpA as a novel virulence factor of L. pneumophila that is required for efficient intracellular replication in both mammalian and protozoan hosts.
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    A secretome view of colonisation factors in Shiga toxin-encoding Escherichia coli (STEC): from enterohaemorrhagic E. coli (EHEC) to related enteropathotypes (2016)
    Oxford University Press
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    Publication Date: 2016-08-05
    Description: Shiga toxin-encoding Escherichia coli (STEC) regroup strains that carry genes encoding Shiga toxin (Stx). Among intestinal pathogenic E. coli , enterohaemorrhagic E. coli (EHEC) constitute the major subgroup of virulent STEC. EHEC cause serious human disease such as haemorrhagic colitis and haemolytic-uremic syndrome. While EHEC have evolved from enteropathogenic E. coli , hybrids with enteroaggregative E. coli have recently emerged. Of note, some enteroinvasive E. coli also belong to the STEC group. While the LEE (locus of enterocyte effacement) is a key and prominent molecular determinant in the pathogenicity, neither all EHEC nor STEC contain the LEE, suggesting that they possess additional virulence and colonisation factors. Currently, nine protein secretion systems have been described in diderm-lipopolysaccharide bacteria (archetypal Gram-negative) and can be involved in the secretion of extracellular effectors, cell-surface proteins or assembly of cell-surface organelles, such as flagella or pili. In this review, we focus on the secretome of STEC and related enteropathotypes, which are relevant to the colonisation of biotic and abiotic surfaces. Considering the wealth of potential protein trafficking mechanisms, the different combinations of colonisation factors and modulation of their expression is further emphasised with regard to the ecophysiology of STEC.
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
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  • 8
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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
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  • 9
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    DanQ: a hybrid convolutional and recurrent deep neural network for quantifying the function of DNA sequences (2016)
    Oxford University Press
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    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
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    Topics: Biology
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  • 10
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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
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    Topics: Biology
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  • 11
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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
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    Topics: Biology
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  • 12
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    In vitro activity of levofloxacin against planktonic and biofilm Stenotrophomonas maltophilia lifestyles under conditions relevant to pulmonary infection in cystic fibrosis, and relationship with SmeDEF multidrug efflux pump expression (2016)
    Oxford University Press
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    Publication Date: 2016-06-23
    Description: The activity of levofloxacin against planktonic and biofilm Stenotrophomonas maltophilia cells and the role played by the multidrug efflux pump SmeDEF were evaluated under conditions relevant to the cystic fibrosis (CF) lung. MIC, MBC and MBEC of levofloxacin were assessed, against five CF strains, under ‘standard’ (CLSI-recommended) and ‘CF-like’ (pH 6.8, 5% CO 2 , in a synthetic CF sputum) conditions. Levofloxacin was tested against biofilms at concentrations (10, 50 and 100 μg mL –1 ) corresponding to achievable serum levels and sputum levels by aerosolisation. smeD expression was evaluated, under both conditions, in planktonic and biofilm cells by RT-PCR. The bactericidal effect of levofloxacin was decreased, in three out of five strains tested, under ‘CF-like’ conditions (MBC: 2–4 vs 8–16 μg mL –1 , under ‘standard’ and ‘CF-like’ conditions, respectively). Biofilm was intrinsically resistant to levofloxacin, regardless of conditions tested (MBECs ≥ 100 μg mL –1 for all strains). Only under ‘CF-like’ conditions, smeD expression increased during planktonic-to-biofilm transition, and in biofilm cells compared to stationary planktonic cells. Our findings confirmed that S. maltophilia biofilm is intrinsically resistant to therapeutic concentrations of levofloxacin. Under conditions relevant to CF, smeD overexpression could contribute to levofloxacin resistance. Further studies are warranted to define the clinical relevance of our findings .
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
    Published by Oxford University Press
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  • 13
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    Auranofin and N-heterocyclic carbene gold-analogs are potent inhibitors of the bacteria Helicobacter pylori (2016)
    Oxford University Press
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    Publication Date: 2016-06-23
    Description: Auranofin is an FDA-approved gold-containing compound used for the treatment of rheumatoid arthritis. Recent reports of antimicrobial activity against protozoa and bacteria indicate that auranofin targets the reductive enzyme thioredoxin reductase (TrxR). We evaluated auranofin as well as five auranofin analogs containing N- heterocyclic carbenes (instead of the triethylphosphane present in auranofin) and five gold-carbene controls for their ability to inhibit or kill Helicobacter pylori in vitro . Auranofin completely inhibited bacterial growth at 1.2 μM. Purified H. pylori TrxR was inhibited by auranofin in a cell-free assay (IC 50 ~88 nM). The most active gold(I)- N- heterocyclic carbene compounds exhibited MICs comparable to auranofin against H. pylori (2 μM), while also exhibiting lower toxicities for human embryonic kidney cells (HEK-293T cells). Median toxic concentrations (TC 50 ) were 13–20-fold higher compared to auranofin indicating that they were less cytotoxic. The N- heterocyclic carbene analogs maybe well tolerated, but further evaluation is needed in vivo . Finally, auranofin was synergistic with the antibiotic amoxicillin, suggesting that targeting both the reductive enzyme TrxR and cell wall synthesis may be effective against H. pylori infections.
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
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    Topics: Biology
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  • 14
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    TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data (2016)
    Oxford University Press
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    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
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  • 15
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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
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    Topics: Biology
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  • 16
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    Colony types and virulence traits of Legionella feeleii determined by exopolysaccharide materials (2016)
    Oxford University Press
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    Publication Date: 2016-05-08
    Description: Legionella feeleii is a Gram-negative pathogenic bacterium that causes Pontiac fever and pneumonia in humans. When L. feeleii serogroup 1 (ATCC 35072) was cultured on BCYE agar plates, two types of colonies were observed and exhibited differences in color, opacity and morphology. Since the two colony types are white rugose and brown translucent, they were termed as white rugose L. feeleii (WRLf) and brown translucent L. feeleii (BTLf), respectively. They exhibited different growth capacities in BYE broth in vitro , and it was found that WRLf could transform to BTLf. Under the electron microscope, it was observed that WRLf secreted materials which could be stained with ruthenium red, which was absent in BTLf. When U937 macrophages and HeLa cells were infected with the bacteria, WRLf manifested stronger internalization ability than BTLf. Intracellular growth in murine macrophages and Acanthamoeba cells was affected by the level of initial phagocytosis. WRLf was more resistant to human serum bactericidal action than BTLf. After being inoculated to guinea pigs, both organisms caused fever in the animals. These results suggest that ruthenium red-stained materials secreted in the surroundings may play a crucial role in determining L. feeleii colony morphology and virulence traits.
    Keywords: Pathogens & Pathogenicity
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  • 17
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    Resistance-nodulation-division efflux pump acrAB is modulated by florfenicol and contributes to drug resistance in the fish pathogen Piscirickettsia salmonis (2016)
    Oxford University Press
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    Publication Date: 2016-05-12
    Description: Piscirickettsia salmonis is a fastidious intracellular pathogen responsible for high mortality rates in farmed salmonids, with serious economic consequences for the Chilean aquaculture industry. Oxytetracycline and florfenicol are the most frequently used antibiotics against P. salmonis , but routine use could contribute to drug resistance. This study identified differentiated florfenicol susceptibilities in two P. salmonis strains, LF-89 and AUSTRAL-005. The less susceptible isolate, AUSTRAL-005, also showed a high ethidium bromide efflux rate, indicating a higher activity of general efflux pump genes than LF-89. The P. salmonis genome presented resistance nodulation division (RND) family members, a family containing typical multidrug resistance-related efflux pumps in Gram-negative bacteria. Additionally, efflux pump acrAB genes were overexpressed in AUSTRAL-005 following exposure to the tolerated maximal concentration of florfenicol, in contrast to LF-89. These results indicate that tolerated maximum concentrations of florfenicol can modulate RND gene expression and increase efflux pump activity. We propose that the acrAB efflux pump is essential for P. salmonis survival at critical florfenicol concentrations and for the generation of antibiotic-resistant bacterial strains.
    Keywords: Pathogens & Pathogenicity
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  • 18
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    The ferrichrome receptor A as a new target for Pseudomonas aeruginosa virulence attenuation (2016)
    Oxford University Press
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    Publication Date: 2016-05-12
    Description: Pseudomonas aeruginosa is an opportunistic pathogen, known to develop robust biofilms. Its biofilm development increases when antibiotics are presented at subminimal inhibitory concentrations (MICs) for reasons that remain unclear. In order to identify genes that affect biofilm development under such a sublethal antibiotic stress condition, we screened a transposon (Tn) mutant library of PAO1, a prototype P. aeruginosa strain. Among ~5000 mutants, a fiuA gene mutant was verified to form very defective biofilms in the presence of sub-MIC carbenicillin. The fiuA gene encodes ferrichrome receptor A, involved in the iron acquisition process. Of note, biofilm formation was not decreased in the pchpvd mutant defective in the production of pyochelin and pyoverdine, two well-characterized P. aeruginosa siderophore molecules. Moreover, fiuA , a non-polar fiuA deletion mutant, produced a significantly decreased level of elastase, a major virulence determinant. Mouse airway infection experiments revealed that the mutant expressed significantly less pathogenicity. Our results suggest that the fiuA gene has pleiotropic functions that affect P. aeruginosa biofilm development and virulence. The targeting of FiuA could enable the attenuation of P. aeruginosa virulence and may be suitable for the development of a drug that specifically controls the virulence of this important pathogen.
    Keywords: Pathogens & Pathogenicity
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  • 19
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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
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  • 20
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    InPhaDel: integrative shotgun and proximity-ligation sequencing to phase deletions with single nucleotide polymorphisms (2016)
    Oxford University Press
    Details
    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
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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
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    Graph-based modeling of tandem repeats improves global multiple sequence alignment (2013)
    Oxford University Press
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    Publication Date: 2013-09-26
    Description: Tandem repeats (TRs) are often present in proteins with crucial functions, responsible for resistance, pathogenicity and associated with infectious or neurodegenerative diseases. This motivates numerous studies of TRs and their evolution, requiring accurate multiple sequence alignment. TRs may be lost or inserted at any position of a TR region by replication slippage or recombination, but current methods assume fixed unit boundaries, and yet are of high complexity. We present a new global graph-based alignment method that does not restrict TR unit indels by unit boundaries. TR indels are modeled separately and penalized using the phylogeny-aware alignment algorithm. This ensures enhanced accuracy of reconstructed alignments, disentangling TRs and measuring indel events and rates in a biologically meaningful way. Our method detects not only duplication events but also all changes in TR regions owing to recombination, strand slippage and other events inserting or deleting TR units. We evaluate our method by simulation incorporating TR evolution, by either sampling TRs from a profile hidden Markov model or by mimicking strand slippage with duplications. The new method is illustrated on a family of type III effectors, a pathogenicity determinant in agriculturally important bacteria Ralstonia solanacearum. We show that TR indel rate variation contributes to the diversification of this protein family.
    Keywords: Computational Methods, Genomics
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    Meander: visually exploring the structural variome using space-filling curves (2013)
    Oxford University Press
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    Publication Date: 2013-06-08
    Description: The introduction of next generation sequencing methods in genome studies has made it possible to shift research from a gene-centric approach to a genome wide view. Although methods and tools to detect single nucleotide polymorphisms are becoming more mature, methods to identify and visualize structural variation (SV) are still in their infancy. Most genome browsers can only compare a given sequence to a reference genome; therefore, direct comparison of multiple individuals still remains a challenge. Therefore, the implementation of efficient approaches to explore and visualize SVs and directly compare two or more individuals is desirable. In this article, we present a visualization approach that uses space-filling Hilbert curves to explore SVs based on both read-depth and pair-end information. An interactive open-source Java application, called Meander , implements the proposed methodology, and its functionality is demonstrated using two cases. With Meander , users can explore variations at different levels of resolution and simultaneously compare up to four different individuals against a common reference. The application was developed using Java version 1.6 and Processing.org and can be run on any platform. It can be found at http://homes.esat.kuleuven.be/~bioiuser/meander .
    Keywords: Computational Methods, Genomics
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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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    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
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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
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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
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    FOAM (Functional Ontology Assignments for Metagenomes): a Hidden Markov Model (HMM) database with environmental focus (2014)
    Oxford University Press
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    Publication Date: 2014-11-07
    Description: A new functional gene database, FOAM (Functional Ontology Assignments for Metagenomes), was developed to screen environmental metagenomic sequence datasets. FOAM provides a new functional ontology dedicated to classify gene functions relevant to environmental microorganisms based on Hidden Markov Models (HMMs). Sets of aligned protein sequences (i.e. ‘profiles’) were tailored to a large group of target KEGG Orthologs (KOs) from which HMMs were trained. The alignments were checked and curated to make them specific to the targeted KO. Within this process, sequence profiles were enriched with the most abundant sequences available to maximize the yield of accurate classifier models. An associated functional ontology was built to describe the functional groups and hierarchy. FOAM allows the user to select the target search space before HMM-based comparison steps and to easily organize the results into different functional categories and subcategories. FOAM is publicly available at http://portal.nersc.gov/project/m1317/FOAM/ .
    Keywords: Computational Methods, Genomics
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    Is there a term structure in land lease rates? (2015)
    Oxford University Press
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    Publication Date: 2015-12-29
    Description: This article applies the concept of a term structure to agricultural land rental prices. Based on theoretical considerations, we develop a hedonic pricing model that allows for different shapes of the term structure curve while controlling for other price-relevant characteristics. We apply this model to land lease contracts in Saxony-Anhalt. We find an upward-sloping term structure during the agricultural price boom in 2007 and 2008, where market participants expected increasing rental prices. For the subsequent years, however, we detect a single-humped term structure. Hence, market participants revised their expectations and assumed a decline of land rental prices in the long term.
    Keywords: D44 - Auctions, E43 - Determination of Interest Rates ; Term Structure of Interest Rates, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation
    Print ISSN: 0165-1587
    Electronic ISSN: 1464-3618
    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
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    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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    ATF3 provides protection from Staphylococcus aureus and Listeria monocytogenes infections (2016)
    Oxford University Press
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    Publication Date: 2016-04-08
    Description: Activating transcription factor 3 (ATF3) is a stress-induced transcriptional regulator in eukaryote. The role of ATF3 in cancer has been well defined, but how ATF3 functions in bacterial infection is not well understood. Pneumococcal infection has been shown to induce ATF3 expression, which subsequently enhances cytokine production and provides protection from lethal Streptococcus pneumoniae infection, but the role of ATF3 in other Gram-positive (G + ) infections remains unclear. Here, we report that infection with other G + bacteria ( Staphylococcus aureus and Listeria monocytogenes ) and with G – bacteria (uropathogenic Escherichia coli ) also significantly induced ATF3 expression. Moreover, the production of cytokines (tumor necrosis factor alpha [TNF]-α, interleukin [IL]-1β, IL-6 and interferon [IFN]-) was enhanced by ATF3 in S. aureus and L. monocytogenes infection, but decreased in uropathogenic E. coli (UPEC) infection. In addition, in S. aureus and L. monocytogenes infections, ATF3 WT mice cleared bacteria more efficiently and had higher survival rates than ATF3 knockout mice. However, in UPEC infection, no significant difference was found in survival rate. Taken together, these data suggest that ATF3 provides protection from S. aureus and L. monocytogenes infections; however, the role of ATF3 in UPEC infection is more complicated and should be further elucidated.
    Keywords: Pathogens & Pathogenicity
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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
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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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    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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    The Economic Costs of Environmental Regulation in U.S. Dairy Farming: A Directional Distance Function Approach (2015)
    Oxford University Press
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    Publication Date: 2015-07-10
    Description: Analyses of the costs of regulating greenhouse gas emissions from dairy production, which could be used to assess the effectiveness of alternative policy measures, is a missing link in the literature. This article addresses this gap by establishing the economic impact associated with a hypothetical greenhouse gas environmental regulatory regime across major dairy producing counties in the United States. In doing so, the article makes three important contributions to the literature. First, it develops a comprehensive pollution index based on Environmental Protection Agency methodologies, which contrasts with previous studies that rely on partial measures based only on surplus nitrogen stemming from the over-application of fertilizer. Second, the article uses a directional output distance function, an approach that has not been employed previously to evaluate polluting technologies in the U.S. dairy sector. Third, the article incorporates a four-way error approach that accounts for unobserved county heterogeneity, time-invariant persistent technical efficiency, time-varying transient technical efficiency, and a random error. The results indicate that regulating greenhouse gas emissions from dairy farming would induce a 5-percentage point increase in average technical efficiency. In addition, the economic costs of implementing this hypothetical regulatory framework exhibit significant spatial variation across counties in the United States.
    Keywords: D22 - Firm Behavior: Empirical Analysis, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q52 - Pollution Control Costs ; Distributional Effects ; Employment Effects
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Molecular dissection of blaKPC-2-bearing plasmids evolving in Klebsiella pneumoniae isolated at one teaching hospital in Shanghai, China (2016)
    Oxford University Press
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    Publication Date: 2016-07-02
    Description: The presence of carbapenemase gene bla KPC-2 in a wide variety of plasmids, especially conjugative plasmids, is key to the rapid, worldwide spread of carbapenemase enzymes. Thirty-eight, non-duplicated, carbapenem-resistant, clinical Klebsiella pneumoniae isolates were collected, all carrying bla KPC-2 -bearing plasmids. Relaxase analysis was used to classify these plasmids; 8 and 30 plasmids belonged to the MOB P3 and MOB F12 subfamilies, respectively. Phylogenetic analysis revealed two genetic subclades in the MOB F12 subfamily and suggested that these subclades might not have originated from the same ancestor. Crossing PCR, used to sequence fully the type IV secretion system (T4SS, essential structures for conjugative plasmids) of the MOB F12 plasmids, found that T4SSs were distinctively different in certain functional genes, e.g. traS and traG. In conclusion, this study delineated the evolution of bla KPC-2 -bearing plasmids at Huashan Hospital, Shanghai, China. The plasmids bearing bla KPC-2 were diverse and the MOB F12 plasmids were dominant in clinical K. pneumoniae isolates.
    Keywords: Pathogens & Pathogenicity
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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
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    Virulence determinants in enteroaggregative Escherichia coli from North India and their interaction in in vitro organ culture system (2016)
    Oxford University Press
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    Publication Date: 2016-08-28
    Description: Enteroaggregative Escherichia coli (EAEC) is an important diarrhoeal pathogen causing diseases in multiple epidemiological and clinical settings. In developing countries like India, diarrhoeal diseases are one of the major killers among paediatric population and oddly, few studies are available from Indian paediatric population on the variability of EAEC virulence genes. In this study, we examined the distribution of plasmid and chromosomal-encoded virulence determinants in EAEC isolates, and analysed cytokines response generated against EAEC with specific aggregative adherence fimbriae (AAF) type in duodenal biopsies using in vitro organ culture (IVOC) mimicking in vivo conditions. Different virulence marker combinations among strains were reflected as a function of specific adhesins signifying EAEC heterogeneity. fis gene emerged as an important genetic marker apart from aggA and aap . Further, EAEC infection in IVOC showed upregulation of IL-8, IL-1β, IL-6, TNF-α and TLR-5 expression. EAEC with AAFII induced significant TLR-5 and IL-8 response, conceivably owing to more pathogenicity markers. This study sheds light on the pattern of EAEC pathotypes prevalent in North Indian paediatric population and highlights the presence of unique virulence combinations in pathogenic strains. Thus, evident diversity in EAEC virulence and multifaceted bacteria-host crosstalk can provide useful insights for the strategic management of diarrhoeal diseases in India, where diarrhoeal outbreaks are more frequent.
    Keywords: Pathogens & Pathogenicity
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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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    Mixed Integer Linear Programming based machine learning approach identifies regulators of telomerase in yeast (2016)
    Oxford University Press
    Details
    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
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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
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    CLASS2: accurate and efficient splice variant annotation from RNA-seq reads (2016)
    Oxford University Press
    Details
    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
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    Transfer of mupirocin resistance from Staphylococcus haemolyticus clinical strains to Staphylococcus aureus through conjugative and mobilizable plasmids (2016)
    Oxford University Press
    Details
    Publication Date: 2016-06-17
    Description: Coagulase-negative staphylococci are thought to act as reservoirs of antibiotic resistance genes that can be transferred to Staphylococcus aureus , thus hindering the combat of this bacterium. In this work, we analyzed the presence of plasmids conferring resistance to the antibiotic mupirocin—widely used to treat and prevent S. aureus infections in hospital environments—in nosocomial S. haemolyticus strains. About 12% of the 75 strains tested were resistant to mupirocin, and this phenotype was correlated with the presence of plasmids. These plasmids were shown to be diverse, being either conjugative or mobilizable, and capable of transferring mupirocin resistance to S. aureus . Our findings reinforce that S. haemolyticus , historically and mistakenly considered as a less important pathogen, is a reservoir of resistance genes which can be transferred to other bacteria, such as S. aureus , emphasizing the necessity of more effective strategies to detect and combat this emergent opportunistic pathogen.
    Keywords: Pathogens & Pathogenicity
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    A new biotype of Fusarium oxysporum f. sp. lycopersici race 2 emerged by a transposon-driven mutation of avirulence gene AVR1 (2016)
    Oxford University Press
    Details
    Publication Date: 2016-06-17
    Description: Emergence of races in Fusarium oxysporum f. sp. lycopersici ( Fol ) is caused by loss or mutation of at least one avirulence ( AVR ) gene. The product of AVR1 is a small protein (Avr1) secreted by Fol in tomato xylem sap during infection. This protein triggers Fol race 1 specific resistance (I) in tomato, indicating that AVR1 is an AVR gene. Deletion of AVR1 in race 1 resulted in the emergence of race 2, and an additional mutation in AVR2 generated race 3. Previously, we reported a new biotype of race 3, KoChi-1, in which AVR1 was truncated by a transposon Hormin , which suggested a new route to evolution of races in Fol . However, to date no race 2 isolate carrying Hormin -truncated AVR1 has been reported. In this report, we describe such isolates, represented by Chiba-5, in which Hormin insertion occurred in AVR1 at a position different from that in KoChi-1. AVR1 truncation in both isolates resulted in production of defective Avr1 proteins. Chiba-5 and KoChi-1 belong to different phylogenetic clades, A1 and A2, respectively, suggesting that insertion of Hormin in AVR1 in Chiba-5 and KoChi-1 occurred as independent evolutionary events.
    Keywords: Pathogens & Pathogenicity
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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
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    Characterization of a highly toxic strain of Bacillus thuringiensis serovar kurstaki very similar to the HD-73 strain (2016)
    Oxford University Press
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    Publication Date: 2016-09-02
    Description: The LBIT-1200 strain of Bacillus thuringiensis was recently isolated from soil, and showed a 6.4 and 9.5 increase in toxicity, against Manduca sexta and Trichoplusia ni , respectively, compared to HD-73. However, LBIT-1200 was still highly similar to HD-73, including the production of bipyramidal crystals containing only one protein of ~130 000 kDa, its flagellin gene sequence related to the kurstaki serotype, plasmid and RepPCR patterns similar to HD-73, no production of β-exotoxin and no presence of VIP genes. Sequencing of its cry gene showed the presence of a cry1Ac -type gene with four amino acid differences, including two amino acid replacements in domain III, compared to Cry1Ac1, which may explain its higher toxicity. In conclusion, the LBIT-1200 strain is a variant of the HD-73 strain but shows a much higher toxicity, which makes this new strain an important candidate to be developed as a bioinsecticide, once it passes other tests, throughout its biotechnological development.
    Keywords: Pathogens & Pathogenicity
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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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    Evaluation of gastrointestinal leakage using serum (1-〉3)-{beta}-D-glucan in a Clostridium difficile murine model (2016)
    Oxford University Press
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    Publication Date: 2016-09-14
    Description: Gastrointestinal (GI) leakage in Clostridium difficile -associated diarrhea (CDAD) is well known but is not routinely assessed in clinical practice. Serum (1-〉3)-β-D-glucan (BG), a fungal cell wall component used as a biomarker for invasive fungal disease, was tested in a CDAD mouse model with and without probiotics. Higher serum fluorescein isothiocyanate-dextran (FITC-dextran) and spontaneous gram-negative bacteremia, GI leakage indicators, were frequently found in CDAD mice, which died compared with those which survived. BG, serum macrophage inflammatory protein-2 and FITC-dextran but not quantitative blood bacterial count differentiated the clinical severity. Interestingly, a specific dose of Lactobacillus rhamnosus L34 attenuated CDAD and decreased serum BG and FITC-dextran, but not other parameters. BG also showed a higher area under the receiver operating characteristic curve for 7-day mortality than FITC-dextran. Fifty-five percent of CDAD mice with BG ≥ 60 pg/ml (the human negative cut-off value for invasive fungal disease) at 1 day after C. difficile gavage died within 7 days. In conclusion, s erum BG was elevated in mice with severe CDAD, an established model of GI leakage with a strong association with mortality rate. BG monitoring in patients with CDAD is of interest as both a potential prognostic tool and a therapeutic efficacy indicator.
    Keywords: Pathogens & Pathogenicity
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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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    The role of NOD1 and NOD2 in host defense against chlamydial infection (2016)
    Oxford University Press
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    Publication Date: 2016-08-28
    Description: Chlamydial species are common intracellular parasites that cause various diseases, mainly characterized by persistent infection, which lead to inflammatory responses modulated by pattern recognition receptors (PRRs). The best understood PRRs are the extracellular Toll-like receptors, but recent significant advances have focused on two important proteins, NOD1 and NOD2, which are members of the intracellular nucleotide-binding oligomerization domain receptor family and are capable of triggering the host innate immune signaling pathways. This results in the production of pro-inflammatory cytokines, which is vital for an adequate host defense against intracellular chlamydial infection. NOD1/2 ligands are known to derive from peptidoglycan, and the latest research has resolved the paradox of whether chlamydial species possess this bacterial cell wall component; this finding is likely to promote in-depth investigations into the interaction between the NOD proteins and chlamydial pathogens. In this review, we summarize the basic characteristics and signal transduction functions of NOD1 and NOD2 and highlight the new research on the roles of NOD1 and NOD2 in the host defense against chlamydial infection.
    Keywords: Pathogens & Pathogenicity
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    Aeromonas salmonicida subsp. salmonicida strains isolated from Chinese freshwater fish contain a novel genomic island and possible regional-specific mobile genetic elements profiles (2016)
    Oxford University Press
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    Publication Date: 2016-08-28
    Description: Two strains of Aeromonas salmonicida , YK and BG, were isolated from largemouth bronze gudgeon and northern whitefish in China, and identified as A. salmonicida subsp. salmonicida based on phylogenetic analysis of vapA and 16S rRNA gene sequences. YK and BG originated from freshwater fish, one of which belonged to the cyprinid family, and the strains showed a difference in virulence. Subsequently, we performed whole genome sequencing of the strains, and comparison of their genomic sequences to the genome of the A449 reference strain revealed various genomic rearrangements, including a new variant of the genomic island AsaGEI in BG, designated as AsaGEI2c . This is the first report on a GEI of A. salmonicida strain from China. Furthermore, both YK and BG strains contained a Tn7 transposon inserted at the same position in the chromosome. Finally, IS-dependent rearrangements on pAsa5 are deemed likely to have occurred, with omission of the resD gene in both strains as well as omission of genes related to the IncF conjugal transfer system in the YK isolate. This study demonstrates that A. salmonicida subsp. salmonicida can infect non-salmonids (cyprinids) in addition to salmonids, and that AsaGEI2c might be useful as a geographical indicator of Chinese A. salmonicida subsp. salmonicida isolates.
    Keywords: Pathogens & Pathogenicity
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    Who Really Benefits from Agricultural Subsidies? Evidence from Field-level Data (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: If agricultural subsidies are largely capitalized into farmland values through their effect on rental rates, then expanding support for agriculture may not benefit farmers who rent the land they farm. Existing evidence on the incidence of subsidies on cash rental rates is mixed. Identification is obscured by unobserved or imprecisely measured factors that tend to be correlated with subsidies, especially land quality and time-varying factors like commodity prices and adverse weather events. A problem that has received less attention is the fact that subsidies and land quality on rented land may differ from owned land. Since most farms possess both rented and owned acreage, farm-level measures of subsidies, land values, and rental rates may bias estimated incidence. Using a new, field-level data set that, for the first time, precisely links subsidies to land parcels, we show that this bias is considerable: where farm-level estimates suggest an incidence of 42–49 cents of the marginal subsidy dollar, field-level estimates from the same farms indicate that landlords capture just 20–28 cents. The size of the farm and the duration of the rental arrangement have substantial effects. Incidence falls by 5–15 cents when doubling total operated acres, and the incidence falls by 0.1–0.8 cents with each additional year of the rental arrangement. Low incidence of subsidies on rents combined with the farm-size and duration effects suggest that farmers renting land have monopsony power.
    Keywords: H22 - Incidence, Q14 - Agricultural Finance, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q18 - Agricultural Policy ; Food Policy
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Burkholderia pseudomallei rpoS mediates iNOS suppression in human hepatocyte (HC04) cells (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: Burkholderia pseudomallei is an intracellular Gram-negative bacterial pathogen and the causative agent of melioidosis, a widespread disease in Southeast Asia. Reactive nitrogen, in an intermediate form of nitric oxide (NO), is one of the first lines of defense used by host cells to eliminate intracellular pathogens, through the stimulation of inducible nitric oxide synthase (iNOS). Studies in phagocytotic cells have shown that the iNOS response is muted in B. pseudomallei infection, and implicated the rpoS sigma factor as a key regulatory factor mediating suppression. The liver is a main visceral organ affected by B. pseudomallei , and there is little knowledge about the interaction of liver cells and B. pseudomallei . This study investigated the induction of iNOS, as well as autophagic flux and light-chain 3 (LC3) localization in human liver (HC04) cells in response to infection with B. pseudomallei and its rpoS deficient mutant. Results showed that the rpoS mutant was unable to suppress iNOS induction and that the mutant showed less induction of autophagy and lower co-localization with LC3, and this was coupled with a lower intracellular growth rate. Combining these results suggest that B. pseudomallei rpoS is an important factor in establishing infection in liver cells.
    Keywords: Pathogens & Pathogenicity
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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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    What Drives the Global "Land Rush"? (2015)
    Oxford University Press
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    Publication Date: 2015-05-21
    Description: We review evidence regarding the size and evolution of the "land rush" in the wake of the 2007–8 boom in agricultural commodity prices, and we study the determinants of foreign land acquisition for large-scale agricultural investment. The use of data on bilateral investment relationships to estimate gravity models of transnational land-intensive investments confirms the central role of agro-ecological potential as a pull factor. However, this finding contrasts the standard literature insofar as the quality of the destination country's business climate is insignificant, and weak tenure security is associated with increased interest for investors to acquire land in the country. Policy implications are discussed.
    Keywords: F21 - International Investment ; Long-Term Capital Movements, O13 - Agriculture ; Natural Resources ; Energy ; Environment ; Other Primary Products, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q34 - Natural Resources and Domestic and International Conflicts
    Print ISSN: 0258-6770
    Electronic ISSN: 1564-698X
    Topics: Economics
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    Irrigated Agricultural Adaptation to Water and Climate Variability: The Economic Value of a Water Portfolio (2015)
    Oxford University Press
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    Publication Date: 2015-04-18
    Description: Increasing aridity, more frequent and intense drought, and greater degrees of water scarcity create unique challenges for agriculture. In response to these challenges, which often manifest themselves as lower and more variable surface water supplies, as well as depleted and degraded ground water supplies, growers tend to seek opportunities to adapt. One option for growers to reduce their exposure to water scarcity and heightened uncertainty is to diversify. Indeed, access to a portfolio of supplies is one way in which water and irrigation districts, as well as individual growers, are responding to the changing landscape of water resource availability. This article evaluates the benefits to irrigated agriculture from having access to multiple sources of water. With farm-level information on 1,900 agricultural parcels across California, we use the hedonic property value method to investigate the extent that growers benefit from having access to multiple sources of water (i.e., a water portfolio). Our results suggest that while lower quality waters, less reliable water, and less water all negatively impact agricultural land values, holding a water portfolio has a positive impact on land values through its role in mitigating the negative aspects of these factors and reducing the sensitivity of agriculture to climate-related factors. From a policy perspective, such results identify a valuable adaptation tool that irrigation districts may consider to help offset the negative impacts of climate change, drought, and population increases on water supply availability and reliability.
    Keywords: Q10 - General, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q18 - Agricultural Policy ; Food Policy, Q50 - General, Q51 - Valuation of Environmental Effects
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Pathway analysis from lists of microRNAs: common pitfalls and alternative strategy (2015)
    Oxford University Press
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    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
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    svaseq: removing batch effects and other unwanted noise from sequencing data (2014)
    Oxford University Press
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    Publication Date: 2014-11-28
    Description: It is now known that unwanted noise and unmodeled artifacts such as batch effects can dramatically reduce the accuracy of statistical inference in genomic experiments. These sources of noise must be modeled and removed to accurately measure biological variability and to obtain correct statistical inference when performing high-throughput genomic analysis. We introduced surrogate variable analysis (sva) for estimating these artifacts by (i) identifying the part of the genomic data only affected by artifacts and (ii) estimating the artifacts with principal components or singular vectors of the subset of the data matrix. The resulting estimates of artifacts can be used in subsequent analyses as adjustment factors to correct analyses. Here I describe a version of the sva approach specifically created for count data or FPKMs from sequencing experiments based on appropriate data transformation. I also describe the addition of supervised sva (ssva) for using control probes to identify the part of the genomic data only affected by artifacts. I present a comparison between these versions of sva and other methods for batch effect estimation on simulated data, real count-based data and FPKM-based data. These updates are available through the sva Bioconductor package and I have made fully reproducible analysis using these methods available from: https://github.com/jtleek/svaseq .
    Keywords: Computational Methods, Genomics
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    Insyght: navigating amongst abundant homologues, syntenies and gene functional annotations in bacteria, it's that symbol! (2014)
    Oxford University Press
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    Publication Date: 2014-11-28
    Description: High-throughput techniques have considerably increased the potential of comparative genomics whilst simultaneously posing many new challenges. One of those challenges involves efficiently mining the large amount of data produced and exploring the landscape of both conserved and idiosyncratic genomic regions across multiple genomes. Domains of application of these analyses are diverse: identification of evolutionary events, inference of gene functions, detection of niche-specific genes or phylogenetic profiling. Insyght is a comparative genomic visualization tool that combines three complementary displays: (i) a table for thoroughly browsing amongst homologues, (ii) a comparator of orthologue functional annotations and (iii) a genomic organization view designed to improve the legibility of rearrangements and distinctive loci. The latter display combines symbolic and proportional graphical paradigms. Synchronized navigation across multiple species and interoperability between the views are core features of Insyght. A gene filter mechanism is provided that helps the user to build a biologically relevant gene set according to multiple criteria such as presence/absence of homologues and/or various annotations. We illustrate the use of Insyght with scenarios. Currently, only Bacteria and Archaea are supported. A public instance is available at http://genome.jouy.inra.fr/Insyght . The tool is freely downloadable for private data set analysis.
    Keywords: Computational Methods, Genomics
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    iPro54-PseKNC: a sequence-based predictor for identifying sigma-54 promoters in prokaryote with pseudo k-tuple nucleotide composition (2014)
    Oxford University Press
    Details
    Publication Date: 2014-11-28
    Description: The 54 promoters are unique in prokaryotic genome and responsible for transcripting carbon and nitrogen-related genes. With the avalanche of genome sequences generated in the postgenomic age, it is highly desired to develop automated methods for rapidly and effectively identifying the 54 promoters. Here, a predictor called ‘ iPro54-PseKNC ’ was developed. In the predictor, the samples of DNA sequences were formulated by a novel feature vector called ‘pseudo k -tuple nucleotide composition’, which was further optimized by the incremental feature selection procedure. The performance of iPro54-PseKNC was examined by the rigorous jackknife cross-validation tests on a stringent benchmark data set. As a user-friendly web-server, iPro54-PseKNC is freely accessible at http://lin.uestc.edu.cn/server/iPro54-PseKNC . For the convenience of the vast majority of experimental scientists, a step-by-step protocol guide was provided on how to use the web-server to get the desired results without the need to follow the complicated mathematics that were presented in this paper just for its integrity. Meanwhile, we also discovered through an in-depth statistical analysis that the distribution of distances between the transcription start sites and the translation initiation sites were governed by the gamma distribution, which may provide a fundamental physical principle for studying the 54 promoters.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Binding site discovery from nucleic acid sequences by discriminative learning of hidden Markov models (2014)
    Oxford University Press
    Details
    Publication Date: 2014-11-28
    Description: We present a discriminative learning method for pattern discovery of binding sites in nucleic acid sequences based on hidden Markov models. Sets of positive and negative example sequences are mined for sequence motifs whose occurrence frequency varies between the sets. The method offers several objective functions, but we concentrate on mutual information of condition and motif occurrence. We perform a systematic comparison of our method and numerous published motif-finding tools. Our method achieves the highest motif discovery performance, while being faster than most published methods. We present case studies of data from various technologies, including ChIP-Seq, RIP-Chip and PAR-CLIP, of embryonic stem cell transcription factors and of RNA-binding proteins, demonstrating practicality and utility of the method. For the alternative splicing factor RBM10, our analysis finds motifs known to be splicing-relevant. The motif discovery method is implemented in the free software package Discrover. It is applicable to genome- and transcriptome-scale data, makes use of available repeat experiments and aside from binary contrasts also more complex data configurations can be utilized.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Spatial localization of co-regulated genes exceeds genomic gene clustering in the Saccharomyces cerevisiae genome (2013)
    Oxford University Press
    Details
    Publication Date: 2013-02-20
    Description: While it has been long recognized that genes are not randomly positioned along the genome, the degree to which its 3D structure influences the arrangement of genes has remained elusive. In particular, several lines of evidence suggest that actively transcribed genes are spatially co-localized, forming transcription factories; however, a generalized systematic test has hitherto not been described. Here we reveal transcription factories using a rigorous definition of genomic structure based on Saccharomyces cerevisiae chromosome conformation capture data, coupled with an experimental design controlling for the primary gene order. We develop a data-driven method for the interpolation and the embedding of such datasets and introduce statistics that enable the comparison of the spatial and genomic densities of genes. Combining these, we report evidence that co-regulated genes are clustered in space, beyond their observed clustering in the context of gene order along the genome and show this phenomenon is significant for 64 out of 117 transcription factors. Furthermore, we show that those transcription factors with high spatially co-localized targets are expressed higher than those whose targets are not spatially clustered. Collectively, our results support the notion that, at a given time, the physical density of genes is intimately related to regulatory activity.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    PanOCT: automated clustering of orthologs using conserved gene neighborhood for pan-genomic analysis of bacterial strains and closely related species (2012)
    Oxford University Press
    Details
    Publication Date: 2012-12-14
    Description: Pan-genome ortholog clustering tool ( PanOCT ) is a tool for pan-genomic analysis of closely related prokaryotic species or strains. PanOCT uses conserved gene neighborhood information to separate recently diverged paralogs into orthologous clusters where homology-only clustering methods cannot. The results from PanOCT and three commonly used graph-based ortholog-finding programs were compared using a set of four publicly available strains of the same bacterial species. All four methods agreed on ~70% of the clusters and ~86% of the proteins. The clusters that did not agree were inspected for evidence of correctness resulting in 85 high-confidence manually curated clusters that were used to compare all four methods.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    A novel ab initio identification system of transcriptional regulation motifs in genome DNA sequences based on direct comparison scheme of signal/noise distributions (2012)
    Oxford University Press
    Details
    Publication Date: 2012-10-10
    Description: A novel ab initio parameter-tuning-free system to identify transcriptional factor (TF) binding motifs (TFBMs) in genome DNA sequences was developed. It is based on the comparison of two types of frequency distributions with respect to the TFBM candidates in the target DNA sequences and the non-candidates in the background sequence, with the latter generated by utilizing the intergenic sequences. For benchmark tests, we used DNA sequence datasets extracted by ChIP-on-chip and ChIP-seq techniques and identified 65 yeast and four mammalian TFBMs, with the latter including gaps. The accuracy of our system was compared with those of other available programs (i.e. MEME, Weeder, BioProspector, MDscan and DME) and was the best among them, even without tuning of the parameter set for each TFBM and pre-treatment/editing of the target DNA sequences. Moreover, with respect to some TFs for which the identified motifs are inconsistent with those in the references, our results were revealed to be correct, by comparing them with other existing experimental data. Thus, our identification system does not need any other biological information except for gene positions, and is also expected to be applicable to genome DNA sequences to identify unknown TFBMs as well as known ones.
    Keywords: Computational Methods, Genomics
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    Identification of new microRNA-regulated genes by conserved targeting in plant species (2012)
    Oxford University Press
    Details
    Publication Date: 2012-10-10
    Description: MicroRNAs (miRNAs) are major regulators of gene expression in multicellular organisms. They recognize their targets by sequence complementarity and guide them to cleavage or translational arrest. It is generally accepted that plant miRNAs have extensive complementarity to their targets and their prediction usually relies on the use of empirical parameters deduced from known miRNA–target interactions. Here, we developed a strategy to identify miRNA targets which is mainly based on the conservation of the potential regulation in different species. We applied the approach to expressed sequence tags datasets from angiosperms. Using this strategy, we predicted many new interactions and experimentally validated previously unknown miRNA targets in Arabidopsis thaliana . Newly identified targets that are broadly conserved include auxin regulators, transcription factors and transporters. Some of them might participate in the same pathways as the targets known before, suggesting that some miRNAs might control different aspects of a biological process. Furthermore, this approach can be used to identify targets present in a specific group of species, and, as a proof of principle, we analyzed Solanaceae -specific targets. The presented strategy can be used alone or in combination with other approaches to find miRNA targets in plants.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    Decoupling of agricultural support payments: the impact on land market participation decisions (2012)
    Oxford University Press
    Details
    Publication Date: 2012-08-03
    Description: This paper analyses the impact of the recent decision by the European Union to ‘decouple’ agricultural support payments from agricultural production on Irish farmers' land market decisions. The land market participation decisions of Irish farmers are modelled using a dynamic probit model, while the extent of participation decisions is modelled using a dynamic tobit model. Decoupling does not appear to have significantly altered farmers' land market decisions. One likely explanation for this is the cross-compliance obligation for farmers to maintain land in a state fit for agricultural production in order to receive their full payments.
    Keywords: Q12 - Micro Analysis of Farm Firms, Farm Households, and Farm Input Markets, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q18 - Agricultural Policy ; Food Policy
    Print ISSN: 0165-1587
    Electronic ISSN: 1464-3618
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Use of ChIP-Seq data for the design of a multiple promoter-alignment method (2012)
    Oxford University Press
    Details
    Publication Date: 2012-04-15
    Description: We address the challenge of regulatory sequence alignment with a new method, Pro-Coffee, a multiple aligner specifically designed for homologous promoter regions. Pro-Coffee uses a dinucleotide substitution matrix estimated on alignments of functional binding sites from TRANSFAC. We designed a validation framework using several thousand families of orthologous promoters. This dataset was used to evaluate the accuracy for predicting true human orthologs among their paralogs. We found that whereas other methods achieve on average 73.5% accuracy, and 77.6% when trained on that same dataset, the figure goes up to 80.4% for Pro-Coffee. We then applied a novel validation procedure based on multi-species ChIP-seq data. Trained and untrained methods were tested for their capacity to correctly align experimentally detected binding sites. Whereas the average number of correctly aligned sites for two transcription factors is 284 for default methods and 316 for trained methods, Pro-Coffee achieves 331, 16.5% above the default average. We find a high correlation between a method's performance when classifying orthologs and its ability to correctly align proven binding sites. Not only has this interesting biological consequences, it also allows us to conclude that any method that is trained on the ortholog data set will result in functionally more informative alignments.
    Keywords: Computational Methods, Genomics
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    MCScanX: a toolkit for detection and evolutionary analysis of gene synteny and collinearity (2012)
    Oxford University Press
    Details
    Publication Date: 2012-04-15
    Description: MCScan is an algorithm able to scan multiple genomes or subgenomes in order to identify putative homologous chromosomal regions, and align these regions using genes as anchors. The MCScanX toolkit implements an adjusted MCScan algorithm for detection of synteny and collinearity that extends the original software by incorporating 14 utility programs for visualization of results and additional downstream analyses. Applications of MCScanX to several sequenced plant genomes and gene families are shown as examples. MCScanX can be used to effectively analyze chromosome structural changes, and reveal the history of gene family expansions that might contribute to the adaptation of lineages and taxa. An integrated view of various modes of gene duplication can supplement the traditional gene tree analysis in specific families. The source code and documentation of MCScanX are freely available at http://chibba.pgml.uga.edu/mcscan2/ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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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
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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
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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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    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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    The role of temperate bacteriophages in bacterial infection (2016)
    Oxford University Press
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    Publication Date: 2016-02-20
    Description: Bacteriophages are viruses that infect bacteria. There are an estimated 10 31 phage on the planet, making them the most abundant form of life. We are rapidly approaching the centenary of their identification, and yet still have only a limited understanding of their role in the ecology and evolution of bacterial populations. Temperate prophage carriage is often associated with increased bacterial virulence. The rise in use of technologies, such as genome sequencing and transcriptomics, has highlighted more subtle ways in which prophages contribute to pathogenicity. This review discusses the current knowledge of the multifaceted effects that phage can exert on their hosts and how this may contribute to bacterial adaptation during infection.
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
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    Pleiotropic consequences of gene knockouts in the phthiocerol dimycocerosate and phenolic glycolipid biosynthetic gene cluster of the opportunistic human pathogen Mycobacterium marinum (2016)
    Oxford University Press
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    Publication Date: 2016-02-20
    Description: Phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs) contribute to the pathogenicity of several mycobacteria. Biosynthesis of these virulence factors requires polyketide synthases and other enzymes that represent potential targets for the development of adjuvant antivirulence drugs. We used six isogenic Mycobacterium marinum mutants, each with a different gene knockout in the PDIM/PGL biosynthetic pathway, to probe the pleiotropy of mutations leading to PDIM – PGL – , PDIM + PGL – or PDIM – PGL + phenotypes. We evaluated the M. marinum mutants for changes in antibiotic susceptibility, cell envelope permeability, biofilm formation, surface properties, sliding motility and virulence in an amoeba model. The analysis also permitted us to begin exploring the hypothesis that different gene knockouts rendering the same PDIM and/or PGL deficiency phenotypes lead to M. marinum mutants with equivalent pleiotropic profiles. Overall, the results of our study revealed a complex picture of pleiotropic patterns emerging from different gene knockouts, uncovered unexpected phenotypic inequalities between mutants, and provided new insight into the phenotypic consequences of gene knockouts in the PDIM/PGL biosynthetic pathway.
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
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    Isolation and identification of nematode-antagonistic compounds from the fungus Aspergillus candidus (2016)
    Oxford University Press
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    Publication Date: 2016-02-20
    Description: Culture medium from an isolate of the fungus Aspergillus candidus was extracted, fractionated and examined to discover compounds antagonistic to plant-parasitic nematodes that are important pathogens of agricultural crops. Column, thin layer and preparative chromatographies and spectral and elemental analyses, were used to isolate and identify two major constituents of an active fraction (Fraction F) obtained from the medium. Compound 1 was identified as 2-hydroxypropane-1, 2, 3-tricarboxylic acid (citric acid). Compound 2 was identified as 3-hydroxy-5-methoxy-3-(methoxycarbonyl)-5-oxopentanoic acid, an isomer of 1, 2-dimethyl citrate. Compound 1 and a citric acid standard, each tested at 50 mg mL –1 in water, decreased hatch from eggs of the plant-parasitic nematode Meloidogyne incognita by more than 94%, and completely immobilized second-stage juveniles after 4–6 days exposure. Fraction F and Compounds 1 and 2 decreased the mobility of adults of the plant-parasitic nematode Ditylenchus destructor in vitro . Fraction F (25 mg mL –1 ) inhibited mobility 〉99% at 72 hrs. Compounds 1 and 2 (50 mg mL –1 ) each inhibited mobility more than 25% at 24 hr and more than 50% at 72 hr. This is the first assignment of nematode-antagonistic properties to specifically identified A. candidus metabolites.
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
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    Antibiotic resistance: the emergence of plasmid-mediated colistin resistance enhances the need of a proactive one-health approach (2016)
    Oxford University Press
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    Publication Date: 2016-02-27
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
    Topics: Biology
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    T7-RNA polymerase dependent RNAi system in Aspergillus fumigatus: a proof of concept study (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-25
    Description: An RNAi system based on T7 RNA polymerase (TRNAP) was designed and examined in Aspergillus fumigatus . This system consists of two elements; an inducible T7RNAP expressing cassette and an AMA1-based episomal RNAi plasmid. These constructs were transformed into the A. fumigatus protoplasts and the efficiency of this system was tested in downregulation of alb1 gene. Upon the induction of T7RNAP expression, the recombinant T7RNAP was able to recognize T7 promoters, which were located on the episomal plasmid and in opposite direction. As a result, the bidirectional transcription of alb1 fragment led to the silencing of the target gene. However, our results demonstrated that this silencing system is unstable and may not be applicable in preparation of RNAi libraries.
    Keywords: Pathogens & Pathogenicity
    Print ISSN: 0378-1097
    Electronic ISSN: 1574-6968
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    Discovery and characterization of Alu repeat sequences via precise local read assembly (2015)
    Oxford University Press
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    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
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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
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    A mostly traditional approach improves alignment of bisulfite-converted DNA (2012)
    Oxford University Press
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    Publication Date: 2012-07-22
    Description: Cytosines in genomic DNA are sometimes methylated. This affects many biological processes and diseases. The standard way of measuring methylation is to use bisulfite, which converts unmethylated cytosines to thymines, then sequence the DNA and compare it to a reference genome sequence. We describe a method for the critical step of aligning the DNA reads to the correct genomic locations. Our method builds on classic alignment techniques, including likelihood-ratio scores and spaced seeds. In a realistic benchmark, our method has a better combination of sensitivity, specificity and speed than nine other high-throughput bisulfite aligners. This study enables more accurate and rational analysis of DNA methylation. It also illustrates how to adapt general-purpose alignment methods to a special case with distorted base patterns: this should be informative for other special cases such as ancient DNA and AT-rich genomes.
    Keywords: Computational Methods, Genomics
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    PhiSpy: a novel algorithm for finding prophages in bacterial genomes that combines similarity- and composition-based strategies (2012)
    Oxford University Press
    Details
    Publication Date: 2012-09-13
    Description: Prophages are phages in lysogeny that are integrated into, and replicated as part of, the host bacterial genome. These mobile elements can have tremendous impact on their bacterial hosts’ genomes and phenotypes, which may lead to strain emergence and diversification, increased virulence or antibiotic resistance. However, finding prophages in microbial genomes remains a problem with no definitive solution. The majority of existing tools rely on detecting genomic regions enriched in protein-coding genes with known phage homologs, which hinders the de novo discovery of phage regions. In this study, a weighted phage detection algorithm, PhiSpy was developed based on seven distinctive characteristics of prophages, i.e. protein length, transcription strand directionality, customized AT and GC skew, the abundance of unique phage words, phage insertion points and the similarity of phage proteins. The first five characteristics are capable of identifying prophages without any sequence similarity with known phage genes. PhiSpy locates prophages by ranking genomic regions enriched in distinctive phage traits, which leads to the successful prediction of 94% of prophages in 50 complete bacterial genomes with a 6% false-negative rate and a 0.66% false-positive rate.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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    Exploiting mid-range DNA patterns for sequence classification: binary abstraction Markov models (2012)
    Oxford University Press
    Details
    Publication Date: 2012-06-06
    Description: Messenger RNA sequences possess specific nucleotide patterns distinguishing them from non-coding genomic sequences. In this study, we explore the utilization of modified Markov models to analyze sequences up to 44 bp, far beyond the 8-bp limit of conventional Markov models, for exon/intron discrimination. In order to analyze nucleotide sequences of this length, their information content is first reduced by conversion into shorter binary patterns via the application of numerous abstraction schemes. After the conversion of genomic sequences to binary strings, homogenous Markov models trained on the binary sequences are used to discriminate between exons and introns. We term this approach the Binary Abstraction Markov Model (BAMM). High-quality abstraction schemes for exon/intron discrimination are selected using optimization algorithms on supercomputers. The best MM classifiers are then combined using support vector machines into a single classifier. With this approach, over 95% classification accuracy is achieved without taking reading frame into account. With further development, the BAMM approach can be applied to sequences lacking the genetic code such as ncRNAs and 5'-untranslated regions.
    Keywords: Computational Methods, Genomics
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    New methods for finding common insertion sites and co-occurring common insertion sites in transposon- and virus-based genetic screens (2012)
    Oxford University Press
    Details
    Publication Date: 2012-05-13
    Description: Insertional mutagenesis screens in mice are used to identify individual genes that drive tumor formation. In these screens, candidate cancer genes are identified if their genomic location is proximal to a common insertion site (CIS) defined by high rates of transposon or retroviral insertions in a given genomic window. In this article, we describe a new method for defining CISs based on a Poisson distribution, the Poisson Regression Insertion Model, and show that this new method is an improvement over previously described methods. We also describe a modification of the method that can identify pairs and higher orders of co-occurring common insertion sites. We apply these methods to two data sets, one generated in a transposon-based screen for gastrointestinal tract cancer genes and another based on the set of retroviral insertions in the Retroviral Tagged Cancer Gene Database. We show that the new methods identify more relevant candidate genes and candidate gene pairs than found using previous methods. Identification of the biologically relevant set of mutations that occur in a single cell and cause tumor progression will aid in the rational design of single and combinatorial therapies in the upcoming age of personalized cancer therapy.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    Cooperation against theft: A test of incentives for water management In Tunisia (2014)
    Oxford University Press
    Details
    Publication Date: 2014-01-22
    Description: Water theft carried out by manipulating water meters constrains volumetric pricing in semi-arid regions. Cooperative management can reduce theft and improve incentives for efficient water use by inducing peer monitoring. Using a theoretical model, we show that theft is more likely when prices are high, punishments are weak, and cooperatives are large. We also show how cooperative membership and punishment levels are determined endogenously by constraints on monitoring. We test the model on data from Tunisia for the years 2001–2003, relying on instruments that proxy for unobservable monitoring costs. The results confirm that well-designed incentives can reduce theft, and that constraints on monitoring costs affect institutional design.
    Keywords: D82 - Asymmetric and Private Information, Q13 - Agricultural Markets and Marketing ; Cooperatives ; Agribusiness, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q25 - Water
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    A Natural Resource Theory of U.S. Crop Insurance Contract Choice (2014)
    Oxford University Press
    Details
    Publication Date: 2014-01-22
    Description: A large variety of subsidized crop insurance products are available to U.S. crop growers. Distinct and perhaps puzzling patterns in the choices of insurance products and coverage levels can be discerned. Where production conditions are better and yields are less risky then ( a ) higher insurance coverage levels are chosen; and ( b ) revenue insurance is preferred over yield insurance. Also, ( c ) the extent of preference for revenue insurance is stronger in more productive areas. Assuming, as many do, that growers seek to maximize subsidy transfers, point ( a ) can be explained by the interaction between yield technology and natural resource endowments. Points ( b ) and ( c ) can be explained by location in conjunction with the "natural hedge" and a contract design bias in how revenue insurance guarantees are computed. Empirical study of Risk Management Agency data on corn, soybean, and wheat yields, and insurance contract choices lend support to our model inferences.
    Keywords: Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q18 - Agricultural Policy ; Food Policy, Q24 - Land
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Isoform-level gene signature improves prognostic stratification and accurately classifies glioblastoma subtypes (2014)
    Oxford University Press
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    Publication Date: 2014-05-01
    Description: Molecular stratification of tumors is essential for developing personalized therapies. Although patient stratification strategies have been successful; computational methods to accurately translate the gene-signature from high-throughput platform to a clinically adaptable low-dimensional platform are currently lacking. Here, we describe PIGExClass (platform-independent isoform-level gene-expression based classification-system), a novel computational approach to derive and then transfer gene-signatures from one analytical platform to another. We applied PIGExClass to design a reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) based molecular-subtyping assay for glioblastoma multiforme (GBM), the most aggressive primary brain tumors. Unsupervised clustering of TCGA (the Cancer Genome Altas Consortium) GBM samples, based on isoform-level gene-expression profiles, recaptured the four known molecular subgroups but switched the subtype for 19% of the samples, resulting in significant ( P = 0.0103) survival differences among the refined subgroups. PIGExClass derived four-class classifier, which requires only 121 transcript-variants, assigns GBM patients’ molecular subtype with 92% accuracy. This classifier was translated to an RT-qPCR assay and validated in an independent cohort of 206 GBM samples. Our results demonstrate the efficacy of PIGExClass in the design of clinically adaptable molecular subtyping assay and have implications for developing robust diagnostic assays for cancer patient stratification.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    fourSig: a method for determining chromosomal interactions in 4C-Seq data (2014)
    Oxford University Press
    Details
    Publication Date: 2014-05-01
    Description: The ability to correlate chromosome conformation and gene expression gives a great deal of information regarding the strategies used by a cell to properly regulate gene activity. 4C-Seq is a relatively new and increasingly popular technology where the set of genomic interactions generated by a single point in the genome can be determined. 4C-Seq experiments generate large, complicated data sets and it is imperative that signal is properly distinguished from noise. Currently, there are a limited number of methods for analyzing 4C-Seq data. Here, we present a new method, fourSig , which in addition to being precise and simple to use also includes a new feature that prioritizes detected interactions. Our results demonstrate the efficacy of fourSig with previously published and novel 4C-Seq data sets and show that our significance prioritization correlates with the ability to reproducibly detect interactions among replicates.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
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    Topics: Biology
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    High-resolution functional annotation of human transcriptome: predicting isoform functions by a novel multiple instance-based label propagation method (2014)
    Oxford University Press
    Details
    Publication Date: 2014-04-03
    Description: Alternative transcript processing is an important mechanism for generating functional diversity in genes. However, little is known about the precise functions of individual isoforms. In fact, proteins (translated from transcript isoforms), not genes, are the function carriers. By integrating multiple human RNA-seq data sets, we carried out the first systematic prediction of isoform functions, enabling high-resolution functional annotation of human transcriptome. Unlike gene function prediction, isoform function prediction faces a unique challenge: the lack of the training data—all known functional annotations are at the gene level. To address this challenge, we modelled the gene–isoform relationships as multiple instance data and developed a novel label propagation method to predict functions. Our method achieved an average area under the receiver operating characteristic curve of 0.67 and assigned functions to 15 572 isoforms. Interestingly, we observed that different functions have different sensitivities to alternative isoform processing, and that the function diversity of isoforms from the same gene is positively correlated with their tissue expression diversity. Finally, we surveyed the literature to validate our predictions for a number of apoptotic genes. Strikingly, for the famous ‘TP53’ gene, we not only accurately identified the apoptosis regulation function of its five isoforms, but also correctly predicted the precise direction of the regulation.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    Capitalized Costs of Habitat Conservation Easements (2014)
    Oxford University Press
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    Publication Date: 2014-04-05
    Description: Perpetual conservation easements permanently remove the option to convert existing habitat to more intensive agricultural production. If existing habitat is at threat of conversion, removing the option to convert will reduce land values. In this article, we estimate the land value discount resulting from perpetual habitat conservation easements by using propensity score matching. We find that on the average eased parcel, land values fall by approximately $86 per acre for every acre of eased habitat. On average, our results suggest that landowners have been adequately compensated and conservation agencies have successfully secured habitat at risk of conversion.
    Keywords: Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q24 - Land, Q57 - Ecological Economics: Ecosystem Services ; Biodiversity Conservation ; Bioeconomics
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Agri-environmental Policy and Urban Development Patterns: A General Equilibrium Analysis (2014)
    Oxford University Press
    Details
    Publication Date: 2014-04-05
    Description: This paper investigates the spatial effects that the provision of environmental public goods have on residential location choices in a suburban context. Specifically, a spatial general equilibrium framework is developed to analyze the consequences of adopting an agri-environmental policy promoting the provision of positive farming externalities. We use a static monocentric model of an open city where agricultural bid-rents and agricultural amenities vary endogenously in space, and where the positive externalities associated with agricultural production are valued by households. Consistent with empirical evidence of the potential side effects that conservation policies may have in terms of urbanization patterns and land price changes, we show that under certain conditions implementing an agri-environmental policy may promote additional suburban development. Moreover, we demonstrate that the emergence of disconnected suburban areas may be significantly influenced by the location of land regulated by an agri-environmental policy. Finally, we discuss distributional aspects and show that while introducing an agri-environmental policy has a negative impact on most residential land value, it can have positive effects on farmland and residential land located within the regulated areas, suggesting the non-neutrality of such policies regarding the agents’ assets.
    Keywords: Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q18 - Agricultural Policy ; Food Policy, R13 - General Equilibrium and Welfare Economic Analysis of Regional Economies, R14 - Land Use Patterns, R21 - Housing Demand
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Agricultural Rodent Control Using Barn Owls: Is It Profitable? (2014)
    Oxford University Press
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    Publication Date: 2014-04-05
    Description: We develop a model to evaluate the profitability of controlling rodent damage by placing barn owl nesting boxes in agricultural areas. The model incorporates the spatial patterns of barn owl predation pressure on rodents, and the impact of this predation pressure on nesting choices and agricultural output. We apply the model to data collected in Israel and find the installation of nesting boxes profitable. While this finding indicates that economic policy instruments to enhance the adoption of this biological control method are redundant, it does support stricter regulations on rodent control using rodenticides.
    Keywords: Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q18 - Agricultural Policy ; Food Policy, Q57 - Ecological Economics: Ecosystem Services ; Biodiversity Conservation ; Bioeconomics
    Print ISSN: 0002-9092
    Electronic ISSN: 1467-8276
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Efficient large-scale protein sequence comparison and gene matching to identify orthologs and co-orthologs (2012)
    Oxford University Press
    Details
    Publication Date: 2012-03-29
    Description: Broadly, computational approaches for ortholog assignment is a three steps process: (i) identify all putative homologs between the genomes, (ii) identify gene anchors and (iii) link anchors to identify best gene matches given their order and context. In this article, we engineer two methods to improve two important aspects of this pipeline [specifically steps (ii) and (iii)]. First, computing sequence similarity data [step (i)] is a computationally intensive task for large sequence sets, creating a bottleneck in the ortholog assignment pipeline. We have designed a fast and highly scalable sort-join method (afree) based on k -mer counts to rapidly compare all pairs of sequences in a large protein sequence set to identify putative homologs. Second, availability of complex genomes containing large gene families with prevalence of complex evolutionary events, such as duplications, has made the task of assigning orthologs and co-orthologs difficult. Here, we have developed an iterative graph matching strategy where at each iteration the best gene assignments are identified resulting in a set of orthologs and co-orthologs. We find that the afree algorithm is faster than existing methods and maintains high accuracy in identifying similar genes. The iterative graph matching strategy also showed high accuracy in identifying complex gene relationships. Standalone afree available from http://vbc.med.monash.edu.au/~kmahmood/afree . EGM2, complete ortholog assignment pipeline (including afree and the iterative graph matching method) available from http://vbc.med.monash.edu.au/~kmahmood/EGM2 .
    Keywords: Computational Methods, Genomics
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    The allele distribution in next-generation sequencing data sets is accurately described as the result of a stochastic branching process (2012)
    Oxford University Press
    Details
    Publication Date: 2012-03-29
    Description: With the availability of next-generation sequencing (NGS) technology, it is expected that sequence variants may be called on a genomic scale. Here, we demonstrate that a deeper understanding of the distribution of the variant call frequencies at heterozygous loci in NGS data sets is a prerequisite for sensitive variant detection. We model the crucial steps in an NGS protocol as a stochastic branching process and derive a mathematical framework for the expected distribution of alleles at heterozygous loci before measurement that is sequencing. We confirm our theoretical results by analyzing technical replicates of human exome data and demonstrate that the variance of allele frequencies at heterozygous loci is higher than expected by a simple binomial distribution. Due to this high variance, mutation callers relying on binomial distributed priors are less sensitive for heterozygous variants that deviate strongly from the expected mean frequency. Our results also indicate that error rates can be reduced to a greater degree by technical replicates than by increasing sequencing depth.
    Keywords: Computational Methods, Genomics
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    Unsupervised discovery of microbial population structure within metagenomes using nucleotide base composition (2012)
    Oxford University Press
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    Publication Date: 2012-03-14
    Description: An approach to infer the unknown microbial population structure within a metagenome is to cluster nucleotide sequences based on common patterns in base composition, otherwise referred to as binning. When functional roles are assigned to the identified populations, a deeper understanding of microbial communities can be attained, more so than gene-centric approaches that explore overall functionality. In this study, we propose an unsupervised, model-based binning method with two clustering tiers, which uses a novel transformation of the oligonucleotide frequency-derived error gradient and GC content to generate coarse groups at the first tier of clustering; and tetranucleotide frequency to refine these groups at the secondary clustering tier. The proposed method has a demonstrated improvement over PhyloPythia, S-GSOM, TACOA and TaxSOM on all three benchmarks that were used for evaluation in this study. The proposed method is then applied to a pyrosequenced metagenomic library of mud volcano sediment sampled in southwestern Taiwan, with the inferred population structure validated against complementary sequencing of 16S ribosomal RNA marker genes. Finally, the proposed method was further validated against four publicly available metagenomes, including a highly complex Antarctic whale-fall bone sample, which was previously assumed to be too complex for binning prior to functional analysis.
    Keywords: Computational Methods, Genomics
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    How do agricultural policies influence farm size inequality? The example of France (2011)
    Oxford University Press
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    Publication Date: 2011-12-27
    Description: We investigate farm size inequality in France using agricultural censuses and farm structure surveys at the NUTS3 level (‘départements’) during the period 1970–2007. Using calculated Gini coefficients, we show that farm size inequality has not systematically increased in France. An econometric analysis of the determinants of farm size inequality reveals that policy measures significantly affected farm size inequality, with most of the measures considered decreasing it. Empirical results suggest that the main contributor was the activity of the SAFER (Société d'Aménagement Foncier et d'Etablissement Rural), a specific feature of the French farm structural policy aimed at regulating rural land management. Besides, this research highlights the great complexity of the dynamics underlying the evolution of farm size distribution.
    Keywords: D30 - General, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q18 - Agricultural Policy ; Food Policy
    Print ISSN: 0165-1587
    Electronic ISSN: 1464-3618
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    Optimisation of implementation policies of environmental quota trade (2011)
    Oxford University Press
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    Publication Date: 2011-12-27
    Description: This paper analyses implementation policies of environmental quota trade, with the Flemish nutrient production rights as an example. Implementation policies concern the transaction quantity, quota reduction and prevention of speculation. They are analysed with a static and a dynamic multi-agent quota trade model. The static model with discrete non-auctioned quota trade shows that the obligation for quota sellers to entirely stop their production stimulates structural change. The dynamic model version indicates that a flat rate reduction on traded quota and measures taken to prevent speculation combined with too low penalties for overuse stimulate the total production.
    Keywords: Q12 - Micro Analysis of Farm Firms, Farm Households, and Farm Input Markets, Q15 - Land Ownership and Tenure ; Land Reform ; Land Use ; Irrigation, Q18 - Agricultural Policy ; Food Policy
    Print ISSN: 0165-1587
    Electronic ISSN: 1464-3618
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Economics
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    NTRFinder: a software tool to find nested tandem repeats (2012)
    Oxford University Press
    Details
    Publication Date: 2012-02-17
    Description: We introduce the software tool NTRFinder to search for a complex repetitive structure in DNA we call a nested tandem repeat (NTR). An NTR is a recurrence of two or more distinct tandem motifs interspersed with each other. We propose that NTRs can be used as phylogenetic and population markers. We have tested our algorithm on both real and simulated data, and present some real NTRs of interest. NTRFinder can be downloaded from http://www.maths.otago.ac.nz/~aamatroud/ .
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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    sPARTA: a parallelized pipeline for integrated analysis of plant miRNA and cleaved mRNA data sets, including new miRNA target-identification software (2014)
    Oxford University Press
    Details
    Publication Date: 2014-10-10
    Description: Parallel analysis of RNA ends (PARE) is a technique utilizing high-throughput sequencing to profile uncapped, mRNA cleavage or decay products on a genome-wide basis. Tools currently available to validate miRNA targets using PARE data employ only annotated genes, whereas important targets may be found in unannotated genomic regions. To handle such cases and to scale to the growing availability of PARE data and genomes, we developed a new tool, ‘ sPARTA ’ (small RNA-PARE target analyzer) that utilizes a built-in, plant-focused target prediction module (aka ‘ miRferno ’). sPARTA not only exhibits an unprecedented gain in speed but also it shows greater predictive power by validating more targets, compared to a popular alternative. In addition, the novel ‘seed-free’ mode, optimized to find targets irrespective of complementarity in the seed-region, identifies novel intergenic targets. To fully capitalize on the novelty and strengths of sPARTA , we developed a web resource, ‘ comPARE ’, for plant miRNA target analysis; this facilitates the systematic identification and analysis of miRNA-target interactions across multiple species, integrated with visualization tools. This collation of high-throughput small RNA and PARE datasets from different genomes further facilitates re-evaluation of existing miRNA annotations, resulting in a ‘cleaner’ set of microRNAs.
    Keywords: Computational Methods, Genomics
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    A statistical model of ChIA-PET data for accurate detection of chromatin 3D interactions (2014)
    Oxford University Press
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    Publication Date: 2014-10-10
    Description: Identification of three-dimensional (3D) interactions between regulatory elements across the genome is crucial to unravel the complex regulatory machinery that orchestrates proliferation and differentiation of cells. ChIA-PET is a novel method to identify such interactions, where physical contacts between regions bound by a specific protein are quantified using next-generation sequencing. However, determining the significance of the observed interaction frequencies in such datasets is challenging, and few methods have been proposed. Despite the fact that regions that are close in linear genomic distance have a much higher tendency to interact by chance, no methods to date are capable of taking such dependency into account. Here, we propose a statistical model taking into account the genomic distance relationship, as well as the general propensity of anchors to be involved in contacts overall. Using both real and simulated data, we show that the previously proposed statistical test, based on Fisher's exact test, leads to invalid results when data are dependent on genomic distance. We also evaluate our method on previously validated cell-line specific and constitutive 3D interactions, and show that relevant interactions are significant, while avoiding over-estimating the significance of short nearby interactions.
    Keywords: Computational Methods, Genomics
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    Topics: Biology
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