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  • 1.
    Avican, Kemal
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Persistent infection by Yersinia pseudotuberculosis2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Enteropathogenic Yersinia species can infect many mammalian organs such as the small intestine, cecum, Peyer’s patches, liver, spleen, and lung and cause diseases that resemble a typhoid-like syndrome, as seen for other enteropathogens. We found that sublethal infection doses of Y. pseudotuberculosis gave rise to asymptomatic persistent infection in mice and identified the cecal lymphoid follicles as the primary site for colonization during persistence. Persistent Y. pseudotuberculosis is localized in the dome area, often in inflammatory lesions, as foci or as single cells, and also in neutrophil exudates in the cecal lumen. This new mouse model for bacterial persistence in cecum has potential as an investigative tool for deeper understanding of bacterial adaptation and host immune defense mechanisms during persistent infection. Here, we investigated the nature of the persistent infection established by Y. pseudotuberculosis in mouse cecal tissue using in vivo RNA-seq of bacteria during early and persistent stages of infection. Comparative analysis of the bacterial transcriptomes revealed that Y. pseudotuberculosis undergoes transcriptional reprogramming with drastic down-regulation of T3SS virulence genes during persistence in the cecum. At the persistent stage, the expression pattern in many respects resembles the pattern seen in vitro at 26°C. Genes that are up-regulated during persistence are genes involved in anaerobiosis, chemotaxis, and protection against oxidative and acidic stress, which indicates the influence of different environmental cues. We found that the Crp/CsrA/RovA regulatory cascades influence the pattern of bacterial gene expression during persistence. Furthermore, we show that ArcA, Fnr, FrdA, WrbA, RovA, and RfaH play critical roles in persistence. An extended investigation of the transcriptional regulator rfaH employing mouse infection studies, phenotypic characterizations, and RNA-seq transcriptomics analyses indicated that this gene product contributes to establishment of infection and confirmed that it regulates O-antigen biosynthesis genes in Y. pseudotuberculosis. The RNA-seq results also suggest that rfaH has a relatively global effect. Furthermore, we also found that the dynamics of the cecal tissue organization and microbial composition shows changes during different stages of the infection. Taken together, based on our findings, we speculate that this enteropathogen initiates infection by using its virulence factors in meeting the innate immune response in the cecal tissue. Later on, these factors lead to dysbiosis in the local microbiota and altered tissue organization. At later stages of the infection, the pathogen adapts to the environment in the cecum by reprogramming its transcriptome from a highly virulent mode to a more environmentally adaptable mode for survival and shedding. The in vivo transcriptomic analyses for essential genes during infections present strong candidates for novel targets for antimicrobials.

  • 2.
    Avican, Kemal
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Huss, Mikael
    Heroven, Ann Kathrin
    Beckstette, Michael
    Dersch, Petra
    Fällman, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Reprogramming of Yersinia from Virulent to Persistent Mode Revealed by Complex In Vivo RNA-seq Analysis2015In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 11, no 1, article id e1004600Article in journal (Refereed)
    Abstract [en]

    We recently found that Yersinia pseudotuberculosis can be used as a model of persistent bacterial infections. We performed in vivo RNA-seq of bacteria in small cecal tissue biopsies at early and persistent stages of infection to determine strategies associated with persistence. Comprehensive analysis of mixed RNA populations from infected tissues revealed that Y. pseudotuberculosis undergoes transcriptional reprogramming with drastic down-regulation of T3SS virulence genes during persistence when the pathogen resides within the cecum. At the persistent stage, the expression pattern in many respects resembles the pattern seen in vitro at 26oC, with for example, up-regulation of flagellar genes and invA. These findings are expected to have impact on future rationales to identify suitable bacterial targets for new antibiotics. Other genes that are up-regulated during persistence are genes involved in anaerobiosis, chemotaxis, and protection against oxidative and acidic stress, which indicates the influence of different environmental cues. We found that the Crp/CsrA/RovA regulatory cascades influence the pattern of bacterial gene expression during persistence. Furthermore, arcA, fnr, frdA, and wrbA play critical roles in persistence. Our findings suggest a model for the life cycle of this enteropathogen with reprogramming from a virulent to an adapted phenotype capable of persisting and spreading by fecal shedding.

  • 3.
    Avican, Ummehan
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Twin-arginine translocation in Yersinia: the substrates and their role in virulence2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pathogenic Yersinia cause a manifold of diseases in humans ranging from mild gastroenteritis (Y. pseudotuberculosis and Y. enterocolitica) to pneumonic and bubonic plague (Y. pestis), while all three have a common virulence strategy that relies on a well-studied type III secretion system and its effector proteins to colonize the host and evade immune responses. However, the role of other protein secretion and/or translocation systems in virulence of Yersinia species is not well known. In this thesis, we sought to investigate the contribution of twin-arginine translocation (Tat) pathway and its secreted substrates to the physiology and virulence of Y. pseudotuberculosis. Tat pathway uniquely exports folded proteins including virulence factors across the cytoplasmic membranes of bacteria. The proteins exported by Tat pathway contain a highly conserved twin-arginine motif in the N-terminal signal peptide. We found that the loss of Tat pathway causes a drastic change of the transcriptome of Y. pseudotuberculosis in stationary phase at environmental temperature with differential regulation of genes involved in virulence, carbon metabolism and stress responses. Phenotypic analysis revealed novel phenotypes of the Tat-deficient strain with defects in iron acquisition, acid resistance, copper oxidation and envelope integrity, which we were partly able to associate with the related Tat substrates. Moreover, increased glucose consumption and accumulation of intracellular fumarate were observed in response to inactivation of Tat pathway implicating a generic effect in cellular physiology. We evaluated the direct role of 22 in silico predicted Tat substrate mutants in the mouse infection model and found only one strain, ΔsufI, exhibited a similar degree of attenuation as Tat-deficient strain. Comparative in vivo characterization studies demonstrated a minor defect for ΔsufI in colonization of intestinal tissues compared to the Tat-deficient strain during early infection, whereas both SufI and TatC were required for dissemination from mesenteric lymph nodes and further systemic spread during late infection. This verifies that SufI has a major role in attenuation seen for the Tat deficient strain both during late infection and initial colonization. It is possible that other Tat substrates such as those involved in iron acquisition and copper resistance also has a role in establishing infection. Further phenotypic analysis indicated that SufI function is required for cell division and stress-survival. Transcriptomic analysis revealed that the highest number of differentially regulated genes in response to loss of Tat and SufI were involved in metabolism and transport. Taken together, this thesis presents a thorough analysis of the involvement of Tat pathway in the overall physiology and virulence strategies of Y. pseudotuberculosis. Finally, we propose that strong effects in virulence render TatC and SufI as potential targets for development of novel antimicrobial compounds

  • 4.
    Avican, Ummehan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Avican, Kemal
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fällman, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Transcriptomic and phenotypic analysis of sufI and tatC mutants of Yersinia pseudotuberculosisManuscript (preprint) (Other academic)
  • 5.
    Avican, Ummehan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Beckstette, Michael
    Heroven, Ann Kathrin
    Lavander, Moa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Dersch, Petra
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Transcriptomic and phenotypic analysis reveals new functions for the Tat pathway in Yersinia pseudotuberculosis2016In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 198, no 20, p. 2876-2886Article in journal (Refereed)
    Abstract [en]

    The Twin-arginine translocation (Tat) system mediates secretion of folded proteins that in bacteria, plants and archaea are identified via an N-terminal signal peptide. Tat systems are associated with virulence in many bacterial pathogens and our previous studies revealed that Tat deficient Yersinia pseudotuberculosis was severely attenuated for virulence. Aiming to identify Tat-dependent pathways and phenotypes of relevance for in vivo infection, we analysed the global transcriptome of parental and ∆tatC mutant strains of Y. pseudotuberculosis during exponential and stationary growth at 26oC and 37oC. The most significant changes in the transcriptome of the ∆tatC mutant were seen at 26oC during stationary phase growth and these included the altered expression of genes related to virulence, stress responses and metabolism. Subsequent phenotypic analysis based on these transcriptome changes revealed several novel Tat-dependent phenotypes including decreased YadA expression, impaired growth under iron-limiting and high copper conditions as well as acidic pH and SDS. Several functionally related Tat substrates were also verified to contribute to these phenotypes. Interestingly, the phenotypic defects observed in the Tat-deficient strain were generally more pronounced than in mutants lacking the Tat substrate predicted to contribute to that specific function. Altogether, this provides new insight into the impact of Tat deficiency on in vivo fitness and survival/replication of Y. pseudotuberculosis during infection.

  • 6. Baison, John
    et al.
    Vidalis, Amaryllis
    Zhou, Linghua
    Chen, Zhi-Qiang
    Li, Zitong
    Sillanpaeae, Mikko J.
    Bernhardsson, Carolina
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Scofield, Douglas
    Forsberg, Nils
    Grahn, Thomas
    Olsson, Lars
    Karlsson, Bo
    Wu, Harry
    Ingvarsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Lundqvist, Sven-Olof
    Niittylae, Totte
    Garcia-Gil, M. Rosario
    Genome-wide association study identified novel candidate loci affecting wood formation in Norway spruce2019In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313XArticle in journal (Refereed)
    Abstract [en]

    Norway spruce is a boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics underlying important wood quality traits in the species. We performed a functional genome-wide association study (GWAS) of 17 wood traits in Norway spruce using 178 101 single nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood traits were defined using functional modelling of wood properties across annual growth rings. We applied a Least Absolute Shrinkage and Selection Operator (LASSO-based) association mapping method using a functional multilocus mapping approach that utilizes latent traits, with a stability selection probability method as the hypothesis testing approach to determine a significant quantitative trait locus. The analysis provided 52 significant SNPs from 39 candidate genes, including genes previously implicated in wood formation and tree growth in spruce and other species. Our study represents a multilocus GWAS for complex wood traits in Norway spruce. The results advance our understanding of the genetics influencing wood traits and identifies candidate genes for future functional studies.

  • 7. Banerjee, M.
    et al.
    Zhang, Lai
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Stabilizing Role of Nonlocal Interaction on Spatio-temporal Pattern Formation2016In: Mathematical Modelling of Natural Phenomena, ISSN 0973-5348, E-ISSN 1760-6101, Vol. 11, no 5, p. 103-118Article in journal (Refereed)
    Abstract [en]

    Here we study a spatio-temporal prey-predator model with ratio-dependent functional response and nonlocal interaction term in the prey growth. For a clear understanding of the effect of nonlocal interaction on the resulting stationary and non-stationary patterns, we consider the nonlocal interaction term in prey growth only to describe the nonlocal intra-specific competition due to limited resources for the prey. First we obtain the patterns exhibited by the basic model in the absence of nonlocal interaction and then explore the effect of nonlocal interaction on the resulting patterns. We demonstrate the stabilizing role of nonlocal interaction as it induces stationary pattern from periodic and chaotic regimes with an increase in the range of nonlocal interaction. The existence of multiple branches of stationary solutions, bifurcating from homogeneous steady-state as well as non-stationary patterns, is illustrated with the help of numerical continuation technique.

  • 8.
    Boija, Ann
    et al.
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Holmqvist, Per-Henrik
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå, Sweden.
    Zare, Aman
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå, Sweden.
    Meyers, David J.
    Dept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Cole, Philip A.
    Dept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Mannervik, Mattias
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, SwedenDept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Drosophila CBP cooperates with GAGA factor to induce high levels of Pol II promoter-proximal pausingManuscript (preprint) (Other academic)
  • 9.
    Borgmästars, Emmy
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    de Weerd, Hendrik Arnold
    Lubovac-Pilav, Zelmina
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    miRFA: an automated pipeline for microRNA functional analysis with correlation support from TCGA and TCPA expression data in pancreatic cancer2019In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 20, article id 393Article in journal (Refereed)
    Abstract [en]

    Background: MicroRNAs (miRNAs) are small RNAs that regulate gene expression at a post-transcriptional level and are emerging as potentially important biomarkers for various disease states, including pancreatic cancer. In silico-based functional analysis of miRNAs usually consists of miRNA target prediction and functional enrichment analysis of miRNA targets. Since miRNA target prediction methods generate a large number of false positive target genes, further validation to narrow down interesting candidate miRNA targets is needed. One commonly used method correlates miRNA and mRNA expression to assess the regulatory effect of a particular miRNA.

    The aim of this study was to build a bioinformatics pipeline in R for miRNA functional analysis including correlation analyses between miRNA expression levels and its targets on mRNA and protein expression levels available from the cancer genome atlas (TCGA) and the cancer proteome atlas (TCPA). TCGA-derived expression data of specific mature miRNA isoforms from pancreatic cancer tissue was used.

    Results: Fifteen circulating miRNAs with significantly altered expression levels detected in pancreatic cancer patients were queried separately in the pipeline. The pipeline generated predicted miRNA target genes, enriched gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes (KEGG) pathways. Predicted miRNA targets were evaluated by correlation analyses between each miRNA and its predicted targets. MiRNA functional analysis in combination with Kaplan-Meier survival analysis suggest that hsa-miR-885-5p could act as a tumor suppressor and should be validated as a potential prognostic biomarker in pancreatic cancer.

    Conclusions: Our miRNA functional analysis (miRFA) pipeline can serve as a valuable tool in biomarker discovery involving mature miRNAs associated with pancreatic cancer and could be developed to cover additional cancer types. Results for all mature miRNAs in TCGA pancreatic adenocarcinoma dataset can be studied and downloaded through a shiny web application at https://emmbor.shinyapps.io/mirfa/.

  • 10.
    Buckland, Philip I.
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies, Environmental Archaeology Lab. Umeå University, Faculty of Arts, Humlab.
    SEAD - The Strategic Environmental Archaeology Database Inter-linking Multiproxy Environmental Data with Archaeological Investigations and Ecology2013In: Archaeology in the Digital Era: Papers from the 40th Annual Conference of Computer Applications and Quantitative Methods in Archaeology (CAA), Southampton, 26-29 March 2012 / [ed] Graeme Earl, Tim Sly, Angeliki Chrysanthi, Patricia Murrieta-Flores, Constantinos Papadopoulos, Iza Romanowska & David Wheatley, Amsterdam University Press, 2013, Vol. 1, p. 320-331Conference paper (Refereed)
    Abstract [en]

    The volume of data on past environmental and climate changes, as well as human interactions with these, has long since passed the level where it is manageable outside of large scale database systems. The Strategic Environmental Archaeology Database project aims to not only store and disseminate such data, but also provide tools for querying and analysing them, whilst maintaining a close connection with the archaeological and ecological data that are essential for their comprehensive interpretation. Large scale, geographically and chronologically unrestricted databases provide us with essentially unlimited scope for putting individual sites into a broader context and applying locally collated data to the investigation of earth system level changes. By providing integrated access to data from a variety of proxies, including plant macrofossils, pollen, insects and geochemistry, along with dating evidence, more complex questions can be answered where any single proxy would not be able to provide comprehensive answers.

  • 11.
    Buckland, Philip I.
    et al.
    Umeå University, Faculty of Arts, Archaeology and Sami Studies, Environmental Archaeology Lab.
    Buckland, Paul C.
    BugsCEP: Coleopteran Ecology Package (software)2006Other (Other (popular science, discussion, etc.))
    Abstract [en]

    BugsCEP is a research and teaching aid for palaeoentomology, entomology and ecology. As well as habitat and distribution data, it includes tools for climate and environmental reconstruction, and facilities for storing site based abundance/collection data. A variety of searching and reporting functions greatly augment the efficiency of beetle based research.

    Bugs is built around a comprehensive database of beetle ecology and European fossil records which has been accumulated over the past 20 years.

  • 12.
    Buckland, Philip I.
    et al.
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies, Environmental Archaeology Lab.
    Eriksson, Erik J.
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies, Environmental Archaeology Lab.
    Palm, Fredrik
    Umeå University, Faculty of Arts, Humlab.
    SEAD - The Strategic Environmental Archaeology Database: Progress Report Spring 20142014Report (Other academic)
    Abstract [en]

    This report provides an overview of the progress and results of the VR:KFI infrastructure projects 2007-7494 and (825-)2010-5976. It should be considered as a status report in an on-going long-term research infrastructure development project.

  • 13.
    Bylesjö, Max
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Nilsson, Robert
    Umeå University, Faculty of Medicine, Umeå Life Science Centre (ULSC).
    Srivastava, Vaibhav
    Grönlund, Andreas
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Johansson, Annika I
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Karlsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Moritz, Thomas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Wingsle, Gunnar
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Integrated analysis of transcript, protein and metabolite data to study lignin biosynthesis in hybrid aspen2009In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 8, no 1, p. 199-210Article in journal (Refereed)
    Abstract [en]

    Tree biotechnology will soon reach a mature state where it will influence the overall supply of fiber, energy and wood products. We are now ready to make the transition from identifying candidate genes, controlling important biological processes, to discovering the detailed molecular function of these genes on a broader, more holistic, systems biology level. In this paper, a strategy is outlined for informative data generation and integrated modeling of systematic changes in transcript, protein and metabolite profiles measured from hybrid aspen samples. The aim is to study characteristics of common changes in relation to genotype-specific perturbations affecting the lignin biosynthesis and growth. We show that a considerable part of the systematic effects in the system can be tracked across all platforms and that the approach has a high potential value in functional characterization of candidate genes.

  • 14. Caballero-Pérez, Juan
    et al.
    Espinal-Centeno, Annie
    Falcon, Francisco
    García-Ortega, Luis F.
    Curiel-Quesada, Everardo
    Cruz-Hernández, Andrés
    Bako, Laszlo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Chen, Xuemei
    Martínez, Octavio
    Alberto Arteaga-Vázquez, Mario
    Herrera-Estrella, Luis
    Cruz-Ramírez, Alfredo
    Transcriptional landscapes of Axolotl (Ambystoma mexicanum)2018In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 433, no 2, p. 227-239Article in journal (Refereed)
    Abstract [en]

    The axolotl (Ambystoma mexicanum) is the vertebrate model system with the highest regeneration capacity. Experimental tools established over the past 100 years have been fundamental to start unraveling the cellular and molecular basis of tissue and limb regeneration. In the absence of a reference genome for the Axolotl, transcriptomic analysis become fundamental to understand the genetic basis of regeneration.

    Here we present one of the most diverse transcriptomic data sets for Axolotl by profiling coding and non coding RNAs from diverse tissues. We reconstructed a population of 115,906 putative protein coding mRNAs as full ORFs (including isoforms). We also identified 352 conserved miRNAs and 297 novel putative mature miRNAs.

    Systematic enrichment analysis of gene expression allowed us to identify tissue-specific protein-coding transcripts. We also found putative novel and conserved microRNAs which potentially target mRNAs which are reported as important disease candidates in heart and liver.

  • 15. Cole, Christopher T.
    et al.
    Ingvarsson, Pär K.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Pathway position constrains the evolution of an ecologically important pathway in aspens (Populus tremula L.)2018In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 27, no 16, p. 3317-3330Article in journal (Refereed)
    Abstract [en]

    Many ecological interactions of aspens and their relatives (Populus spp.) are affected by products of the phenylpropanoid pathway synthesizing condensed tannins (CTs), whose production involves trade-offs with other ecologically important compounds and with growth. Genes of this pathway are candidates for investigating the role of selection on ecologically important, polygenic traits. We analysed sequences from 25 genes representing 10 steps of the CT synthesis pathway, which produces CTs used in defence and lignins used for growth, in 12 individuals of European aspen (Populus tremula). We compared these to homologs from P.trichocarpa, to a control set of 77 P. tremula genes, to genome-wide resequencing data and to RNA-seq expression levels, in order to identify signatures of selection distinct from those of demography. In Populus, pathway position exerts a strong influence on the evolution of these genes. Nonsynonymous diversity, divergence and allele frequency shifts (Tajima's D) were much lower than for synonymous measures. Expression levels were higher, and the direction of selection more negative, for upstream genes than for those downstream. Selective constraints act with increasing intensity on upstream genes, despite the presence of multiple paralogs in most gene families. Pleiotropy, expression level, flux control and codon bias appear to interact in determining levels and patterns of variation in genes of this pathway, whose products mediate a wide array of ecological interactions for this widely distributed species.

  • 16. Delhomme, Nicolas
    et al.
    Padioleau, Ismaël
    Furlong, Eileen E
    Steinmetz, Lars M
    easyRNASeq: a bioconductor package for processing RNA-Seq data.2012In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 28, no 19Article in journal (Refereed)
    Abstract [en]

    MOTIVATION: RNA sequencing is becoming a standard for expression profiling experiments and many tools have been developed in the past few years to analyze RNA-Seq data. Numerous 'Bioconductor' packages are available for next-generation sequencing data loading in R, e.g. ShortRead and Rsamtools as well as to perform differential gene expression analyses, e.g. DESeq and edgeR. However, the processing tasks lying in between these require the precise interplay of many Bioconductor packages, e.g. Biostrings, IRanges or external solutions are to be sought.

    RESULTS: We developed 'easyRNASeq', an R package that simplifies the processing of RNA sequencing data, hiding the complex interplay of the required packages behind a single functionality.

    AVAILABILITY: The package is implemented in R (as of version 2.15) and is available from Bioconductor (as of version 2.10) at the URL: http://bioconductor.org/packages/release/bioc/html/easyRNASeq.html, where installation and usage instructions can be found.

    CONTACT: delhomme@embl.de.

  • 17.
    Figueiredo, Margarida L. A.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kim, Maria
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, SE-90187 Umeå, Sweden.
    Allgardsson, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå UniversityUmeå, Sweden; Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Non-coding roX RNAs prevent the binding of the MSL-complex to heterochromatic regions2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, p. e1004865-Article in journal (Refereed)
    Abstract [en]

    Long non-coding RNAs contribute to dosage compensation in both mammals and Drosophila by inducing changes in the chromatin structure of the X-chromosome. In Drosophila melanogaster, roX1 and roX2 are long non-coding RNAs that together with proteins form the male-specific lethal (MSL) complex, which coats the entire male X-chromosome and mediates dosage compensation by increasing its transcriptional output. Studies on polytene chromosomes have demonstrated that when both roX1 and roX2 are absent, the MSL-complex becomes less abundant on the male X-chromosome and is relocated to the chromocenter and the 4thchromosome. Here we address the role of roX RNAs in MSL-complex targeting and the evolution of dosage compensation in Drosophila. We performed ChIP-seq experiments which showed that MSL-complex recruitment to high affinity sites (HAS) on the X-chromosome is independent of roX and that the HAS sequence motif is conserved in D. simulans. Additionally, a complete and enzymatically active MSL-complex is recruited to six specific genes on the 4thchromosome. Interestingly, our sequence analysis showed that in the absence of roX RNAs, the MSL-complex has an affinity for regions enriched in Hoppel transposable elements and repeats in general. We hypothesize that roX mutants reveal the ancient targeting of the MSL-complex and propose that the role of roX RNAs is to prevent the binding of the MSL-complex to heterochromatin.

  • 18.
    Freyhult, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Önskog, Jenny
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Social Sciences, Department of Statistics.
    Challenges in microarray class discovery: a comprehensive examination of normalization, gene selection and clustering2010In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 11, article id 503Article in journal (Refereed)
    Abstract [en]

    Background: Cluster analysis, and in particular hierarchical clustering, is widely used to extract information from gene expression data. The aim is to discover new classes, or sub-classes, of either individuals or genes. Performing a cluster analysis commonly involve decisions on how to; handle missing values, standardize the data and select genes. In addition, pre processing, involving various types of filtration and normalization procedures, can have an effect on the ability to discover biologically relevant classes. Here we consider cluster analysis in a broad sense and perform a comprehensive evaluation that covers several aspects of cluster analyses, including normalization.

    Result: We evaluated 2780 cluster analysis methods on seven publicly available 2-channel microarray data sets with common reference designs. Each cluster analysis method differed in data normalization (5 normalizations were considered), missing value imputation (2), standardization of data (2), gene selection (19) or clustering method (11). The cluster analyses are evaluated using known classes, such as cancer types, and the adjusted Rand index. The performances of the different analyses vary between the data sets and it is difficult to give general recommendations. However, normalization, gene selection and clustering method are all variables that have a significant impact on the performance. In particular, gene selection is important and it is generally necessary to include a relatively large number of genes in order to get good performance. Selecting genes with high standard deviation or using principal component analysis are shown to be the preferred gene selection methods. Hierarchical clustering using Ward's method, k-means clustering and Mclust are the clustering methods considered in this paper that achieves the highest adjusted Rand. Normalization can have a significant positive impact on the ability to cluster individuals, and there are indications that background correction is preferable, in particular if the gene selection is successful. However, this is an area that needs to be studied further in order to draw any general conclusions.

    Conclusions: The choice of cluster analysis, and in particular gene selection, has a large impact on the ability to cluster individuals correctly based on expression profiles. Normalization has a positive effect, but the relative performance of different normalizations is an area that needs more research. In summary, although clustering, gene selection and normalization are considered standard methods in bioinformatics, our comprehensive analysis shows that selecting the right methods, and the right combinations of methods, is far from trivial and that much is still unexplored in what is considered to be the most basic analysis of genomic data.

  • 19. Giacomello, Stefania
    et al.
    Salmen, Fredrik
    Terebieniec, Barbara K.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Vickovic, Sanja
    Navarro, José Fernandez
    Alexeyenko, Andrey
    Reimegard, Johan
    McKee, Lauren S.
    Mannapperuma, Chanaka
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Bulone, Vincent
    Ståhl, Patrik L.
    Sundström, Jens F.
    Street, Nathaniel
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Lundeberg, Joakim
    Spatially resolved transcriptome profiling in model plant species2017In: Nature Plants, ISSN 2055-026X, Vol. 3, no 6, article id 17061Article in journal (Refereed)
    Abstract [en]

    Understanding complex biological systems requires functional characterization of specialized tissue domains. However, existing strategies for generating and analysing high-throughput spatial expression profiles were developed for a limited range of organisms, primarily mammals. Here we present the first available approach to generate and study highresolution, spatially resolved functional profiles in a broad range of model plant systems. Our process includes highthroughput spatial transcriptome profiling followed by spatial gene and pathway analyses. We first demonstrate the feasibility of the technique by generating spatial transcriptome profiles from model angiosperms and gymnosperms microsections. In Arabidopsis thaliana we use the spatial data to identify differences in expression levels of 141 genes and 189 pathways in eight inflorescence tissue domains. Our combined approach of spatial transcriptomics and functional profiling offers a powerful new strategy that can be applied to a broad range of plant species, and is an approach that will be pivotal to answering fundamental questions in developmental and evolutionary biology.

  • 20.
    Grönlund, Andreas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Lötstedt, Per
    Elf, Johan
    Transcription factor binding kinetics constrain noise suppression via negative feedback2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 1864-Article in journal (Refereed)
    Abstract [en]

    Negative autoregulation, where a transcription factor regulates its own expression by preventing transcription, is commonly used to suppress fluctuations in gene expression. Recent single molecule in vivo imaging has shown that it takes significant time for a transcription factor molecule to bind its chromosomal binding site. Given the slow association kinetics, transcription factor mediated feedback cannot at the same time be fast and strong. Here we show that with a limited association rate follows an optimal transcription factor binding strength where noise is maximally suppressed. At the optimal binding strength the binding site is free a fixed fraction of the time independent of the transcription factor concentration. One consequence is that high-copy number transcription factors should bind weakly to their operators, which is observed for transcription factors in Escherichia coli. The results demonstrate that a binding site's strength may be uncorrelated to its functional importance.

  • 21. Grüning, Björn
    et al.
    Dale, Ryan
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Division of CBRN Security and Defence, FOI – Swedish Defence Research Agency, Umeå, Sweden.
    Chapman, Brad A.
    Rowe, Jillian
    Tomkins-Tinch, Christopher H.
    Valieris, Renan
    Köster, Johannes
    Bioconda: sustainable and comprehensive software distribution for the life sciences2018In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 15, no 7, p. 475-476Article in journal (Refereed)
  • 22. Hibar, Derrek P.
    et al.
    Adams, Hieab H. H.
    Jahanshad, Neda
    Chauhan, Ganesh
    Stein, Jason L.
    Hofer, Edith
    Renteria, Miguel E.
    Bis, Joshua C.
    Arias-Vasquez, Alejandro
    Ikram, M. Kamran
    Desrivieres, Sylvane
    Vernooij, Meike W.
    Abramovic, Lucija
    Alhusaini, Saud
    Amin, Najaf
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Arfanakis, Konstantinos
    Aribisala, Benjamin S.
    Armstrong, Nicola J.
    Athanasiu, Lavinia
    Axelsson, Tomas
    Beecham, Ashley H.
    Beiser, Alexa
    Bernard, Manon
    Blanton, Susan H.
    Bohlken, Marc M.
    Boks, Marco P.
    Bralten, Janita
    Brickman, Adam M.
    Carmichael, Owen
    Chakravarty, M. Mallar
    Chen, Qiang
    Ching, Christopher R. K.
    Chouraki, Vincent
    Cuellar-Partida, Gabriel
    Crivello, Fabrice
    Den Braber, Anouk
    Doan, Nhat Trung
    Ehrlich, Stefan
    Giddaluru, Sudheer
    Goldman, Aaron L.
    Gottesman, Rebecca F.
    Grimm, Oliver
    Griswold, Michael E.
    Guadalupe, Tulio
    Gutman, Boris A.
    Hass, Johanna
    Haukvik, Unn K.
    Hoehn, David
    Holmes, Avram J.
    Hoogman, Martine
    Janowitz, Deborah
    Jia, Tianye
    Jorgensen, Kjetil N.
    Karbalai, Nazanin
    Kasperaviciute, Dalia
    Kim, Sungeun
    Klein, Marieke
    Kraemer, Bernd
    Lee, Phil H.
    Liewald, David C. M.
    Lopez, Lorna M.
    Luciano, Michelle
    Macare, Christine
    Marquand, Andre F.
    Matarin, Mar
    Mather, Karen A.
    Mattheisen, Manuel
    McKay, David R.
    Milaneschi, Yuri
    Maniega, Susana Munoz
    Nho, Kwangsik
    Nugent, Allison C.
    Nyquist, Paul
    Loohuis, Loes M. Olde
    Oosterlaan, Jaap
    Papmeyer, Martina
    Pirpamer, Lukas
    Puetz, Benno
    Ramasamy, Adaikalavan
    Richards, Jennifer S.
    Risacher, Shannon L.
    Roiz-Santianez, Roberto
    Rommelse, Nanda
    Ropele, Stefan
    Rose, Emma J.
    Royle, Natalie A.
    Rundek, Tatjana
    Saemann, Philipp G.
    Saremi, Arvin
    Satizabal, Claudia L.
    Schmaal, Lianne
    Schork, Andrew J.
    Shen, Li
    Shin, Jean
    Shumskaya, Elena
    Smith, Albert V.
    Sprooten, Emma
    Strike, Lachlan T.
    Teumer, Alexander
    Tordesillas-Gutierrez, Diana
    Toro, Roberto
    Trabzuni, Daniah
    Trompet, Stella
    Vaidya, Dhananjay
    Van der Grond, Jeroen
    Van der Lee, Sven J.
    Van der Meer, Dennis
    Van Donkelaar, Marjolein M. J.
    Van Eijk, Kristel R.
    Van Erp, Theo G. M.
    Van Rooij, Daan
    Walton, Esther
    Westlye, Lars T.
    Whelan, Christopher D.
    Windham, Beverly G.
    Winkler, Anderson M.
    Wittfeld, Katharina
    Woldehawariat, Girma
    Wolf, Christiane
    Wolfers, Thomas
    Yanek, Lisa R.
    Yang, Jingyun
    Zijdenbos, Alex
    Zwiers, Marcel P.
    Agartz, Ingrid
    Almasy, Laura
    Ames, David
    Amouyel, Philippe
    Andreassen, Ole A.
    Arepalli, Sampath
    Assareh, Amelia A.
    Barral, Sandra
    Bastin, Mark E.
    Becker, Diane M.
    Becker, James T.
    Bennett, David A.
    Blangero, John
    van Bokhoven, Hans
    Boomsma, Dorret I.
    Brodaty, Henry
    Brouwer, Rachel M.
    Brunner, Han G.
    Buckner, Randy L.
    Buitelaar, Jan K.
    Bulayeva, Kazima B.
    Cahn, Wiepke
    Calhoun, Vince D.
    Cannon, Dara M.
    Cavalleri, Gianpiero L.
    Cheng, Ching-Yu
    Cichon, Sven
    Cookson, Mark R.
    Corvin, Aiden
    Crespo-Facorro, Benedicto
    Curran, Joanne E.
    Czisch, Michael
    Dale, Anders M.
    Davies, Gareth E.
    De Craen, Anton J. M.
    De Geus, Eco J. C.
    De Jager, Philip L.
    De Zubicaray, Greig I.
    Deary, Ian J.
    Debette, Stephanie
    DeCarli, Charles
    Delanty, Norman
    Depondt, Chantal
    DeStefano, Anita
    Dillman, Allissa
    Djurovic, Srdjan
    Donohoe, Gary
    Drevets, Wayne C.
    Duggirala, Ravi
    Dyer, Thomas D.
    Enzinger, Christian
    Erk, Susanne
    Espeseth, Thomas
    Fedko, Iryna O.
    Fernandez, Guillen
    Ferrucci, Luigi
    Fisher, Simon E.
    Fleischman, Debra A.
    Ford, Ian
    Fornage, Myriam
    Foroud, Tatiana M.
    Fox, Peter T.
    Francks, Clyde
    Fukunaga, Masaki
    Gibbs, J. Raphael
    Glahn, David C.
    Gollub, Randy L.
    Goring, Harald H. H.
    Green, Robert C.
    Gruber, Oliver
    Gudnason, Vilmundur
    Guelfi, Sebastian
    Haberg, Asta K.
    Hansell, Narelle K.
    Hardy, John
    Hartman, Catharina A.
    Hashimoto, Ryota
    Hegenscheid, Katrin
    Heinz, Andreas
    Le Hellard, Stephanie
    Hernandez, Dena G.
    Heslenfeld, Dirk J.
    Ho, Beng-Choon
    Hoekstra, Pieter J.
    Hoffmann, Wolfgang
    Hofman, Albert
    Holsboer, Florian
    Homuth, Georg
    Hosten, Norbert
    Hottenga, Jouke-Jan
    Huentelman, Matthew
    Pol, Hilleke E. Hulshoff
    Ikeda, Masashi
    Jack, Clifford R., Jr.
    Jenkinson, Mark
    Johnson, Robert
    Joensson, Erik G.
    Jukema, J. Wouter
    Kahn, Rene S.
    Kanai, Ryota
    Kloszewska, Iwona
    Knopman, David S.
    Kochunov, Peter
    Kwok, John B.
    Lawrie, Stephen M.
    Lemaitre, Herve
    Liu, Xinmin
    Longo, Dan L.
    Lopez, Oscar L.
    Lovestone, Simon
    Martinez, Oliver
    Martinot, Jean-Luc
    Mattay, Venkata S.
    McDonald, Colm
    McIntosh, Andrew M.
    McMahon, Francis J.
    McMahon, Katie L.
    Mecocci, Patrizia
    Melle, Ingrid
    Meyer-Lindenberg, Andreas
    Mohnke, Sebastian
    Montgomery, Grant W.
    Morris, Derek W.
    Mosley, Thomas H.
    Muhleisen, Thomas W.
    Mueller-Myhsok, Bertram
    Nalls, Michael A.
    Nauck, Matthias
    Nichols, Thomas E.
    Niessen, Wiro J.
    Nothen, Markus M.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Ohi, Kazutaka
    Olvera, Rene L.
    Ophoff, Roel A.
    Pandolfo, Massimo
    Paus, Tomas
    Pausova, Zdenka
    Penninx, Brenda W. J. H.
    Pike, G. Bruce
    Potkin, Steven G.
    Psaty, Bruce M.
    Reppermund, Simone
    Rietschel, Marcella
    Roffman, Joshua L.
    Romanczuk-Seiferth, Nina
    Rotter, Jerome I.
    Ryten, Mina
    Sacco, Ralph L.
    Sachdev, Perminder S.
    Saykin, Andrew J.
    Schmidt, Reinhold
    Schmidt, Helena
    Schofield, Peter R.
    Sigursson, Sigurdur
    Simmons, Andrew
    Singleton, Andrew
    Sisodiya, Sanjay M.
    Smith, Colin
    Smoller, Jordan W.
    Soininen, Hilkka
    Steen, Vidar M.
    Stott, David J.
    Sussmann, Jessika E.
    Thalamuthu, Anbupalam
    Toga, Arthur W.
    Traynor, Bryan J.
    Troncoso, Juan
    Tsolaki, Magda
    Tzourio, Christophe
    Uitterlinden, Andre G.
    Hernandez, Maria C. Valdes
    Van der Brug, Marcel
    van der Lugt, Aad
    van der Wee, Nic J. A.
    Van Haren, Neeltje E. M.
    van't Ent, Dennis
    Van Tol, Marie-Jose
    Vardarajan, Badri N.
    Vellas, Bruno
    Veltman, Dick J.
    Voelzke, Henry
    Walter, Henrik
    Wardlaw, Joanna M.
    Wassink, Thomas H.
    Weale, Michael E.
    Weinberger, Daniel R.
    Weiner, Michael W.
    Wen, Wei
    Westman, Eric
    White, Tonya
    Wong, Tien Y.
    Wright, Clinton B.
    Zielke, Ronald H.
    Zonderman, Alan B.
    Martin, Nicholas G.
    Van Duijn, Cornelia M.
    Wright, Margaret J.
    Longstreth, W. T.
    Schumann, Gunter
    Grabe, Hans J.
    Franke, Barbara
    Launer, Lenore J.
    Medland, Sarah E.
    Seshadri, Sudha
    Thompson, Paul M.
    Ikram, M. Arfan
    Novel genetic loci associated with hippocampal volume2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 13624Article in journal (Refereed)
    Abstract [en]

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

  • 23.
    Jokipii-Lukkari, Soile
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology,Swedish University of Agricultural Sciences, SE-901 84 Umeå, Sweden.
    Sundell, David
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Nilsson, Ove
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, 1430 Ås, Norway.
    Street, Nathaniel R.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Tuominen, Hannele
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    NorWood: a gene expression resource for evo-devo studies of conifer wood development2017In: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 216, no 2, p. 482-494Article in journal (Refereed)
    Abstract [en]

    The secondary xylem of conifers is composed mainly of tracheids that differ anatomically and chemically from angiosperm xylem cells. There is currently no high-spatial-resolution data available profiling gene expression during wood formation for any coniferous species, which limits insight into tracheid development.

    RNA-sequencing data from replicated, high-spatial-resolution section series throughout the cambial and woody tissues of Picea abies were used to generate the NorWood.conGenIE.org web resource, which facilitates exploration of the associated gene expression profiles and co-expression networks.

    Integration within PlantGenIE.org enabled a comparative regulomics analysis, revealing divergent co-expression networks between P. abies and the two angiosperm species Arabidopsis thaliana and Populus tremula for the secondary cell wall (SCW) master regulator NAC Class IIB transcription factors. The SCW cellulose synthase genes (CesAs) were located in the neighbourhoods of the NAC factors in Athaliana and P. tremula, but not in Pabies. The NorWood co-expression network enabled identification of potential SCW CesA regulators in P. abies.

    The NorWood web resource represents a powerful community tool for generating evo-devo insights into the divergence of wood formation between angiosperms and gymnosperms and for advancing understanding of the regulation of wood development in P. abies.

  • 24. Kokocinski, Felix
    et al.
    Delhomme, Nicolas
    Wrobel, Gunnar
    Hummerich, Lars
    Toedt, Grischa
    Lichter, Peter
    FACT--a framework for the functional interpretation of high-throughput experiments.2005In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Interpreting the results of high-throughput experiments, such as those obtained from DNA-microarrays, is an often time-consuming task due to the high number of data-points that need to be analyzed in parallel. It is usually a matter of extensive testing and unknown beforehand, which of the possible approaches for the functional analysis will be the most informative.

    RESULTS: To address this problem, we have developed the Flexible Annotation and Correlation Tool (FACT). FACT allows for detection of important patterns in large data sets by simplifying the integration of heterogeneous data sources and the subsequent application of different algorithms for statistical evaluation or visualization of the annotated data. The system is constantly extended to include additional annotation data and comparison methods.

    CONCLUSION: FACT serves as a highly flexible framework for the explorative analysis of large genomic and proteomic result sets. The program can be used online; open source code and supplementary information are available at http://www.factweb.de.

  • 25.
    Kumar, Rajendra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Sobhy, Haitham
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). FOI Swedish Def Res Agcy, Div CBRN Secur & Def, S-90621 Umea, Sweden.
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Genome contact map explorer: a platform for the comparison, interactive visualization and analysis of genome contact maps2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 17, article id e152Article in journal (Refereed)
    Abstract [en]

    Hi-C experiments generate data in form of large genome contact maps (Hi-C maps). These show that chromosomes are arranged in a hierarchy of three-dimensional compartments. But to understand how these compartments form and by how much they affect genetic processes such as gene regulation, biologists and bioinformaticians need efficient tools to visualize and analyze Hi-C data. However, this is technically challenging because these maps are big. In this paper, we remedied this problem, partly by implementing an efficient file format and developed the genome contact map explorer platform. Apart from tools to process Hi-C data, such as normalization methods and a programmable interface, we made a graphical interface that let users browse, scroll and zoom Hi-C maps to visually search for patterns in the Hi-C data. In the software, it is also possible to browse several maps simultaneously and plot related genomic data. The software is openly accessible to the scientific community.

  • 26.
    L. Pourbozorgi, Parham
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Delhomme, Nicolas
    Obi, Ikenna
    Mohammad, Jani Basha
    Sabouri, Nasim
    Topoisomerase 1 and the Pfh1 helicase are both required for proper DNA synthesisManuscript (preprint) (Other academic)
  • 27. L. Pourbozorgi, Parham
    et al.
    Delhomme, Nicolas
    Obi, Ikenna
    Sabouri, Nasim
    Top1 and Pfh1Pif1 maintain the S. pombe mitochondrial genomeManuscript (preprint) (Other academic)
  • 28.
    Landfors, Mattias
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Normalization and analysis of high-dimensional genomics data2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the middle of the 1990’s the microarray technology was introduced. The technology allowed for genome wide analysis of gene expression in one experiment. Since its introduction similar high through-put methods have been developed in other fields of molecular biology. These high through-put methods provide measurements for hundred up to millions of variables in a single experiment and a rigorous data analysis is necessary in order to answer the underlying biological questions.

    Further complications arise in data analysis as technological variation is introduced in the data, due to the complexity of the experimental procedures in these experiments. This technological variation needs to be removed in order to draw relevant biological conclusions from the data. The process of removing the technical variation is referred to as normalization or pre-processing. During the last decade a large number of normalization and data analysis methods have been proposed.

    In this thesis, data from two types of high through-put methods are used to evaluate the effect pre-processing methods have on further analyzes. In areas where problems in current methods are identified, novel normalization methods are proposed. The evaluations of known and novel methods are performed on simulated data, real data and data from an in-house produced spike-in experiment.

  • 29.
    Landfors, Mattias
    et al.
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Normalization of high dimensional genomics data where the distribution of the altered variables is skewed2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e27942-Article in journal (Refereed)
    Abstract [en]

    Genome-wide analysis of gene expression or protein binding patterns using different array or sequencing based technologies is now routinely performed to compare different populations, such as treatment and reference groups. It is often necessary to normalize the data obtained to remove technical variation introduced in the course of conducting experimental work, but standard normalization techniques are not capable of eliminating technical bias in cases where the distribution of the truly altered variables is skewed, i.e. when a large fraction of the variables are either positively or negatively affected by the treatment. However, several experiments are likely to generate such skewed distributions, including ChIP-chip experiments for the study of chromatin, gene expression experiments for the study of apoptosis, and SNP-studies of copy number variation in normal and tumour tissues. A preliminary study using spike-in array data established that the capacity of an experiment to identify altered variables and generate unbiased estimates of the fold change decreases as the fraction of altered variables and the skewness increases. We propose the following work-flow for analyzing high-dimensional experiments with regions of altered variables: (1) Pre-process raw data using one of the standard normalization techniques. (2) Investigate if the distribution of the altered variables is skewed. (3) If the distribution is not believed to be skewed, no additional normalization is needed. Otherwise, re-normalize the data using a novel HMM-assisted normalization procedure. (4) Perform downstream analysis. Here, ChIP-chip data and simulated data were used to evaluate the performance of the work-flow. It was found that skewed distributions can be detected by using the novel DSE-test (Detection of Skewed Experiments). Furthermore, applying the HMM-assisted normalization to experiments where the distribution of the truly altered variables is skewed results in considerably higher sensitivity and lower bias than can be attained using standard and invariant normalization methods.

  • 30.
    Lavander, Moa
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Medical Countermeasures, Division of NBC Defense, Swedish Defense Research Agency, SE-901 82 Umeå, Sweden.
    Ericsson, Solveig K.
    Bröms, Jeanette E
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Medical Countermeasures, Division of NBC Defense, Swedish Defense Research Agency, SE-901 82 Umeå, Sweden.
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Countermeasures, Division of NBC Defense, Swedish Defense Research Agency, SE-901 82 Umeå, Sweden.
    The Twin Arginine Translocation System is Essential for Virulence of Yersinia pseudotuberculosis2006In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 74, no 3, p. 1768-1776Article in journal (Refereed)
    Abstract [en]

    Yersinia species pathogenic to humans have been extensively characterized with respect to type III secretion and its essential role in virulence. This study concerns the twin arginine translocation (Tat) pathway utilized by gram-negative bacteria to secrete folded proteins across the bacterial inner membrane into the periplasmic compartment. We have shown that the Yersinia Tat system is functional and required for motility and contributes to acid resistance. A Yersinia pseudotuberculosis mutant strain with a disrupted Tat system (tatC) was, however, not affected in in vitro growth or more susceptible to high osmolarity, oxidative stress, or high temperature, nor was it impaired in type III secretion. Interestingly, the tatC mutant was severely attenuated via both the oral and intraperitoneal routes in the systemic mouse infection model and highly impaired in colonization of lymphoid organs like Peyer's patches and the spleen. Our work highlights that Tat secretion plays a key role in the virulence of Y. pseudotuberculosis.

  • 31.
    Lavander, Moa
    et al.
    Diseases, Swedish Defence Research Agency, Sweden.
    Ericsson, Solveig K.
    Department of Medical Countermeasures, Division of NBC Defence, Swedish Defence Research Agency, Sweden.
    Bröms, Jeanette E.
    Department of Medical Countermeasures, Division of NBC Defence, Swedish Defence Research Agency, Sweden.
    Forsberg, Åke
    Department of Medical Countermeasures, Division of NBC Defence, Swedish Defence Research Agency, Sweden.
    Twin arginine translocation in Yersinia2007In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 603, p. 258-267Article in journal (Refereed)
    Abstract [en]

    Bacteria utilise Twin arginine translocation (Tat) to deliver folded proteins across the cytoplasmic membrane. Disruption of Tat typically results in pleiotropic effects on e.g. growth, stress resistance, bacterial membrane biogenesis, motility and cell morphology. Further, Tat is coupled to virulence in a range of pathogenic bacteria, including species of Pseudomonas, Legionella, Agrobacterium and Mycobacterium. We have investigated this, for Yersinia, previously unexplored system, and have shown that the Tat pathway is functional and absolutely required for virulence of Yersinia pseudotuberculosis. A range of putative Yersinia Tat substrates have been predicted in silico, which together with the Tat system itself may be interesting targets for future development of antimicrobial treatments. Here we present a brief review of bacterial Tat and discuss our results concerning this system in Yersinia.

  • 32.
    Lundström, Niklas L. P.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Zhang, Hong
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Department of Financial Mathematics, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
    Brännström, Åke
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Evolution and Ecology Program, International Institute for Applied Systems Analysis, 2361 Laxenburg, Austria.
    Pareto-efficient biological pest control enable high efficacy at small costs2017In: Ecological Modelling, ISSN 0304-3800, E-ISSN 1872-7026, Vol. 364, p. 89-97Article in journal (Refereed)
    Abstract [en]

    Biological pest control is increasingly used in agriculture as an alternative to traditional chemical pest control. In many cases, this involves a one-off or periodic release of naturally occurring and/or genetically modified enemies such as predators, parasitoids, or pathogens. As the interaction between these enemies and the pest is complex and the production of natural enemies potentially expensive, it is not surprising that both the efficacy and economic viability of biological pest control are debated. Here, we investigate the performance of very simple control strategies. In particular, we show how Pareto-efficient one-off or periodic release strategies, that optimally trade off between efficacy and economic viability, can be devised and used to enable high efficacy at small economic costs. We demonstrate our method on a pest–pathogen–crop model with a tunable immigration rate of pests. By analyzing this model, we demonstrate that simple Pareto-efficient one-off and periodic release strategies are efficacious and simultaneously have profits that are close to the theoretical maximum obtained by strategies optimizing only the profit. When the immigration rate of pests is low to intermediate, one-off control strategies are sufficient, and when the immigration of pests is high, periodic release strategies are preferable. The methods presented here can be extended to more complex scenarios and be used to identify promising biological pest control strategies in many circumstances.

  • 33.
    Masuda, Naoki
    et al.
    University of Tokyo.
    Holme, Petter
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Predicting and controlling infectious disease epidemics using temporal networks2013In: F1000 Prime Reports, ISSN 2051-7599, Vol. 5, p. 6-Article, review/survey (Refereed)
    Abstract [en]

    Infectious diseases can be considered to spread over social networks of people or animals. Mainly owing to the development of data recording and analysis techniques, an increasing amount of social contact data with time stamps has been collected in the last decade. Such temporal data capture the dynamics of social networks on a timescale relevant to epidemic spreading and can potentially lead to better ways to analyze, forecast, and prevent epidemics. However, they also call for extended analysis tools for network epidemiology, which has, to date, mostly viewed networks as static entities. We review recent results of network epidemiology for such temporal network data and discuss future developments.

  • 34. Myburg, Alexander A.
    et al.
    Hussey, Steven G.
    Street, Nathaniel
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Street, Nathaniel R.
    Mizrachi, Eshchar
    Systems and Synthetic Biology of Forest Trees: A Bioengineering Paradigm for Woody Biomass Feedstocks2019In: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 10, article id 775Article, review/survey (Refereed)
    Abstract [en]

    Fast-growing forest plantations are sustainable feedstocks of plant biomass that can serve as alternatives to fossil carbon resources for materials, chemicals, and energy. Their ability to efficiently harvest light energy and carbon from the atmosphere and sequester this into metabolic precursors for lignocellulosic biopolymers and a wide range of plant specialized metabolites make them excellent biochemical production platforms and living biorefineries. Their large sizes have facilitated multi-omics analyses and systems modeling of key biological processes such as lignin biosynthesis in trees. High-throughput 'omics' approaches have also been applied in segregating tree populations where genetic variation creates abundant genetic perturbations of system components allowing construction of systems genetics models linking genes and pathways to complex trait variation. With this information in hand, it is now possible to start using synthetic biology and genome editing techniques in a bioengineering approach based on a deeper understanding and rational design of biological parts, devices, and integrated systems. However, the complexity of the biology and interacting components will require investment in big data informatics, machine learning, and intuitive visualization to fully explore multi-dimensional patterns and identify emergent properties of biological systems. Predictive systems models could be tested rapidly through high-throughput synthetic biology approaches and multigene editing. Such a bioengineering paradigm, together with accelerated genomic breeding, will be crucial for the development of a new generation of woody biorefinery crops.

  • 35.
    Mörén, Lina
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information2015In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 5, no 3, p. 502-520Article in journal (Refereed)
    Abstract [en]

    Glioma grading and classification, today based on histological features, is not always easy to interpret and diagnosis partly relies on the personal experience of the neuropathologists. The most important feature of the classification is the aimed correlation between tumor grade and prognosis. However, in the clinical reality, large variations exist in the survival of patients concerning both glioblastomas and low-grade gliomas. Thus, there is a need for biomarkers for a more reliable classification of glioma tumors as well as for prognosis. We analyzed relative metabolite concentrations in serum samples from 96 fasting glioma patients and 81 corresponding tumor samples with different diagnosis (glioblastoma, oligodendroglioma) and grade (World Health Organization (WHO) grade II, III and IV) using gas chromatography-time of flight mass spectrometry (GC-TOFMS). The acquired data was analyzed and evaluated by pattern recognition based on chemometric bioinformatics tools. We detected feature patterns in the metabolomics data in both tumor and serum that distinguished glioblastomas from oligodendrogliomas (p(tumor) = 2.46 × 10(-8), p(serum) = 1.3 × 10(-5)) and oligodendroglioma grade II from oligodendroglioma grade III (p(tumor) = 0.01, p(serum) = 0.0008). Interestingly, we also found patterns in both tumor and serum with individual metabolite features that were both elevated and decreased in patients that lived long after being diagnosed with glioblastoma compared to those who died shortly after diagnosis (p(tum)(o)(r) = 0.006, p(serum) = 0.004; AUROCC(tumor) = 0.846 (0.647-1.000), AUROCC(serum) = 0.958 (0.870-1.000)). Metabolic patterns could also distinguish long and short survival in patients diagnosed with oligodendroglioma (p(tumor) = 0.01, p(serum) = 0.001; AUROCC(tumor) = 1 (1.000-1.000), AUROCC(serum) = 1 (1.000-1.000)). In summary, we found different metabolic feature patterns in tumor tissue and serum for glioma diagnosis, grade and survival, which indicates that, following further verification, metabolomic profiling of glioma tissue as well as serum may be a valuable tool in the search for latent biomarkers for future characterization of malignant glioma.

  • 36.
    Nilsson-Örtman, Viktor
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Nilsson, Anders N.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Using taxonomic revision data to estimate the global species richness and characteristics of undescribed species of diving beetles (Coleoptera: Dytiscidae)2010In: Biodiversity Informatics, ISSN 1546-9735, Vol. 7, no 1, p. 1-16Article in journal (Refereed)
    Abstract [en]

    Many methods used for estimating species richness are either difficult to use on poorly known taxa or require input data that are laborious and expensive to collect. In this paper we apply a method which takes advantage of the carefully conducted tests of how the described diversity compares to real species richness that are inherent in taxonomic revisions. We analyze the quantitative outcome from such revisions with respect to body size, zoogeographical region and phylogenetic relationship. The best fitting model is used to predict the diversity of unrevised groups if these would have been subject to as rigorous species level hypothesis-testing as the revised groups. The sensitivity of the predictive model to single observations is estimated by bootstrapping over resampled subsets of the original data. The Dytiscidae is with its 4080 described species (end of May 2009) the most diverse group of aquatic beetles and have a world-wide distribution. Extensive taxonomic work has been carried out on the family but still the number of described species increases exponentially in most zoogeographical regions making many commonly used methods of estimation difficult to apply. We provide independent species richness estimates of subsamples for which species richness estimates can be reached through extrapolation and compare these to the species richness estimates obtained through the method using revision data. We estimate there to be 5405 species of dytiscids, a 1.32-fold increase over the present number of described species. The undescribed diversity is likely to be biased towards species with small body size from tropical regions outside of Africa.

  • 37.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Mining DNA elements involved in targeting of chromatin modifiers2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: In all higher organisms, the nuclear DNA is condensed into nucleosomes that consist of DNA wrapped around a core of highly conserved histone proteins. DNA bound to histones and other structural proteins form the chromatin. Generally, only few regions of DNA are accessible and most of the time RNA polymerase and other DNA binding proteins have to overcome this compaction to initiate transcription. Several proteins are involved in making the chromatin more compact or open. Such chromatin-modifying proteins make distinct post-translational modifications of histones – especially in the histone tails – to alter their affinity to DNA. Aim: The main aim of my thesis work is to study the targeting of chromatin modifiers important for correct gene expression in Drosophila melanogaster (fruit flies). Primary DNA sequences, chromatin associated proteins, transcription, and non-coding RNAs are all likely to be involved in targeting mechanisms. This thesis work involves the development of new computational methods for identification of DNA motifs and protein factors involved in the targeting of chromatin modifiers. Targeting and functional analysis of two chromatin modifiers, namely male-specific lethal (MSL) complex and CREB-binding protein (CBP) are specifically studied. The MSL complex is a protein complex that mediates dosage compensation in flies. CBP protein is known as a transcriptional co-regulator in metazoans and it has histone acetyl transferase activity and CBP has been used to predict novel enhancers. Results: My studies of the binding sites of MSL complex shows that promoters and coding sequences of MSL-bound genes on the X-chromosome of Drosophila melanogaster can influence the spreading of the complex along the X-chromosome. Analysis of MSL binding sites when two non-coding roX RNAs are mutated shows that MSL-complex recruitment to high-affinity sites on the Xchromosome is independent of roX, and the role of roX RNAs is to prevent binding to repeats in autosomal sites. Functional analysis of MSL-bound genes using their dosage compensation status shows that the function of the MSL complex is to enhance the expression of short housekeeping genes, but MSL-independent mechanisms exist to achieve complete dosage compensation. Studies of the binding sites of the CBP protein show that, in early embryos, Dorsal in cooperation with GAGA factor (GAF) and factors like Medea and Dichaete target CBP to its binding sites. In the S2 cell line, GAF is identified as the targeting factor of CBP at promoters and enhancers, and GAF and CBP together are found to induce high levels of polymerase II pausing at promoters. In another study using integrated data analysis, CBP binding sites could be classified into polycomb protein binding sites, repressed enhancers, insulator protein-bound regions, active promoters, and active enhancers, and this suggested different potential roles for CBP. A new approach was also developed to eliminate technical bias in skewed experiments. Our study shows that in the case of skewed datasets it is always better to identify non-altered variables and to normalize the data using only such variables.

  • 38.
    Philip, Philge
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, Sweden.
    Boija, Ann
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Mannervik, Mattias
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, Sweden.
    CBP functions outside of promoters and enhancers in Drosophila melanogasterManuscript (preprint) (Other academic)
  • 39.
    Philip, Philge
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Centre for Cellular and Molecular Biology, Uppal Road, Telangana, India .
    Boija, Ann
    Vaid, Roshan
    Churcher, Allison M
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Meyers, David J
    Cole, Philip A
    Mannervik, Mattias
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Security and Defence, FOI–Swedish Defence Research Agency, Umeå, Sweden.
    CBP binding outside of promoters and enhancers in Drosophila melanogaster2015In: Epigenetics & Chromatin, ISSN 1756-8935, E-ISSN 1756-8935, Vol. 8, article id 48Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: CREB-binding protein (CBP, also known as nejire) is a transcriptional co-activator that is conserved in metazoans. CBP plays an important role in embryonic development and cell differentiation and mutations in CBP can lead to various diseases in humans. In addition, CBP and the related p300 protein have successfully been used to predict enhancers in both humans and flies when they occur with monomethylation of histone H3 on lysine 4 (H3K4me1).

    RESULTS: Here, we compare CBP chromatin immunoprecipitation sequencing data from Drosophila S2 cells with modENCODE data and show that CBP is bound at genomic sites with a wide range of functions. As expected, we find that CBP is bound at active promoters and enhancers. In addition, we find that the strongest CBP sites in the genome are found at Polycomb response elements embedded in histone H3 lysine 27 trimethylated (H3K27me3) chromatin, where they correlate with binding of the Pho repressive complex. Interestingly, we find that CBP also binds to most insulators in the genome. At a subset of these, CBP may regulate insulating activity, measured as the ability to prevent repressive H3K27 methylation from spreading into adjacent chromatin.

    CONCLUSIONS: We conclude that CBP could be involved in a much wider range of functions than has previously been appreciated, including Polycomb repression and insulator activity. In addition, we discuss the possibility that a common role for CBP at all functional elements may be to regulate interactions between distant chromosomal regions and speculate that CBP is controlling higher order chromatin organization.

  • 40.
    Philip, Philge
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Pettersson, Fredrik
    Umbio, 907 19 Umeå, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Sequence signatures involved in targeting the male-specific lethal complex to X-chromosomal genes in Drosophila melanogaster2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 97-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In Drosophila melanogaster, the dosage-compensation system that equalizes X-linked gene expression between males and females, thereby assuring that an appropriate balance is maintained between the expression of genes on the X chromosome(s) and the autosomes, is at least partially mediated by the Male-Specific Lethal (MSL) complex. This complex binds to genes with a preference for exons on the male X chromosome with a 3' bias, and it targets most expressed genes on the X chromosome. However, a number of genes are expressed but not targeted by the complex. High affinity sites seem to be responsible for initial recruitment of the complex to the X chromosome, but the targeting to and within individual genes is poorly understood.

    RESULTS: We have extensively examined X chromosome sequence variation within five types of gene features (promoters, 5' UTRs, coding sequences, introns, 3' UTRs) and intergenic sequences, and assessed its potential involvement in dosage compensation. Presented results show that: the X chromosome has a distinct sequence composition within its gene features; some of the detected variation correlates with genes targeted by the MSL-complex; the insulator protein BEAF-32 preferentially binds upstream of MSL-bound genes; BEAF-32 and MOF co-localizes in promoters; and that bound genes have a distinct sequence composition that shows a 3' bias within coding sequence.

    CONCLUSIONS: Although, many strongly bound genes are close to a high affinity site neither our promoter motif nor our coding sequence signatures show any correlation to HAS. Based on the results presented here, we believe that there are sequences in the promoters and coding sequences of targeted genes that have the potential to direct the secondary spreading of the MSL-complex to nearby genes.

  • 41.
    Pourbozorgi Langroudi, Parham
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Insights into the roles of the essential Pfh1 DNA helicase in the nuclear and mitochondrial genomes2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Eukaryotic cells have two sets of genomes, the nuclear and mitochondrial, and both need to be accurately maintained. Also, the rate of transcription must be precisely regulated in these genomes. However, there are many natural barriers that dysregulate these processes. The aim of this thesis was to enhance our understanding of the Schizosaccharomyces pombe, Pif1 family helicase, Pfh1, and its roles in the nuclear and mitochondrial genomes. The S. pombe genome contains 446 predicted Gquadruplex (G4) structures. By circular dichroism and Thioflavin-T assay we demonstrated that sequences from the ribosomal DNA (rDNA) and telomeres form G4 structures in vitro. The recombinant nuclear isoform of Pfh1 bound and unwound these G4 structures. Also, by chromatin immunoprecipitation combined with quantitative PCR (ChIP-qPCR), we showed that Pfh1 binds these sequences in vivo. This work provides evidence that G4 structure formation in the rDNA and telomere regions is biologically important and that unwinding of G4 structures is a conserved property of Pif1 family helicases. Using ChIP-seq we found that Pfh1 binds to natural fork barriers, such as highly transcribed genes, and nucleosome depleted regions, and that replication through these sites were dependent on Pfh1. By immunoaffinity precipitation combined with mass spectrometry, Pfh1 interacted with several replisome components, as well as DNA repair proteins, and mitochondrial proteins. Furthermore, Pfh1 moved with similar kinetics as the leading strand polymerase. These findings suggest that Pfh1 is needed at natural fork barriers to promote fork progression, and that it is not just recruited to its target sites but moves with the replisome. Based on these findings, we anticipated that lack of Pfh1 would affect expression of highly transcribed genes. By performing genome-wide transcriptome analysis of S. pombe in the absence of Pfh1, we showed that highly transcribed genes are downregulated more often than other genes. Furthermore, combining absence of Pfh1 together with Topoisomerase 1 (Top1), resulted in slower cell growth, reduced DNA synthesis rate compared to single mutants, and upregulation of genes associated with DNA repair and apoptosis. These data suggest that, cells lacking both Pfh1 and Top1 have severe problem in maintaining their genomes. By ChIP-qPCR analysis we showed that Pfh1 and Top1 directly bind to mitochondrial DNA. In addition, these cells upregulated many metabolic pathways and lost about 80% of their mtDNA. These data suggest that both Pfh1 and Top1 are required for maintenance of mtDNA. This is the first evidence showing that Top1 is present in S. pombe mitochondria. In conclusion, Pfh1 directly binds mitochondrial DNA, and natural fork barriers in the nuclear DNA, such as G4 structures. In the nucleus, Pfh1 is part of the replisome. Cells lacking Pfh1 and Top1 grow slower, rapidly lose their mitochondrial DNA, have slower nuclear DNA synthesis, and induce apoptotic pathways. Finally, this thesis emphasizes the importance of both Pfh1 and Top1 in maintaining the nuclear and mitochondrial genomes.

  • 42. Regnell, Simon E.
    et al.
    Hessner, Martin J.
    Åkesson, Lina
    Stenlund, Hans
    Swedish Metabolomics Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Moritz, Thomas
    La Torre, Daria
    Lernmark, Åke
    Longitudinal analysis of hepatic transcriptome and serum metabolome demonstrates altered lipid metabolism following the onset of hyperglycemia in spontaneously diabetic biobreeding rats2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0171372Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes is associated with abberations of fat metabolism before and after the clinical onset of disease. It has been hypothesized that the absence of the effect of insulin in the liver contributes to reduced hepatic fat synthesis. We measured hepatic gene expression and serum metabolites before and after the onset of hyperglycemia in a BioBreeding rat model of type 1 diabetes. Functional pathway annotation identified that lipid metabolism was differentially expressed in hyperglycemic rats and that these pathways significantly overlapped with genes regulated by insulin. 17 serum metabolites significantly changed in concentration. All but 2 of the identified metabolites had previously been reported in type 1 diabetes, and carbohydrates were overall the most upregulated class of metabolites. We conclude that lack of insulin in the liver contributes to the changes in fat metabolism observed in type 1 diabetes. Further studies are needed to understand the clinical consequences of a lack of insulin in the liver in patients with type 1 diabetes.

  • 43.
    Rios, Javier
    et al.
    Department of Computer Architecture, Malaga University.
    Karlsson, Johan
    Department of Computer Architecture, Malaga University.
    Trelles, Oswaldo
    Department of Computer Architecture, Malaga University.
    Magallanes: a web services discovery and automatic workflow composition tool2009In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 10, no 334Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:To aid in bioinformatics data processing and analysis, an increasing number of web-based applications are being deployed. Although this is a positive circumstance in general, the proliferation of tools makes it difficult to find the right tool, or more importantly, the right set of tools that can work together to solve real complex problems.

    RESULTS:Magallanes (Magellan) is a versatile, platform-independent Java library of algorithms aimed at discovering bioinformatics web services and associated data types. A second important feature of Magallanes is its ability to connect available and compatible web services into workflows that can process data sequentially to reach a desired output given a particular input. Magallanes’ capabilities can be exploited both as an API or directly accessed through a graphic user interface.The Magallanes’ API is freely available for academic use, and together with Magallanes application has been tested in MS-WindowsTM XP and Unix-like operating systems. Detailed implementation information, including user manuals and tutorials, is available at http://www.bitlab-es.com/magallanes.

    CONCLUSION:Different implementations of the same client (web page, desktop applications, web services, etc.) have been deployed and are currently in use in real installations such as the National Institute of Bioinformatics (Spain) and the ACGT-EU project. This shows the potential utility and versatility of the software library, including the integration of novel tools in the domain and with strong evidences in the line of facilitate the automatic discovering and composition of workflows.

  • 44.
    Sandberg Hiltunen, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Andersson, Patrik (Contributor)
    Tysklind, Mats (Contributor)
    Wold, Svante (Contributor)
    The Constrained Principal Property (CPP) Space in QSAR: Directional and Non-Directional Modelling Approaches2000In: Molecular Modeling and Prediction of Bioactivity / [ed] Klaus Gundertofte , Flemming Steen Jørgensen , Klaus Gundertofte , Flemming Steen Jørgensen, Dordrecht: Kluwer Academic/Plenum Publishers , 2000, p. 65-70Chapter in book (Refereed)
  • 45.
    Schiffthaler, Bastian
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Terebieniec, Barbara K
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Mähler, Niklas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Robinson, Kathryn M
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Mannapperuma, Chanaka
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Street, Nathaniel R
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    An integrated functional genomics and systems genetics analysis of leaf shape in Populus tremula Manuscript (preprint) (Other academic)
    Abstract [en]

    Leaf shape is an important component of our relationship with the living world, representing a defining feature of how we recognise and classify plant species. There is extensive variation in the form and function of leaves within and between species. In the current study we utilised variation in leaf shape represented among individuals of a collection of Eurasian aspen (Populus tremula L.) sampled across Sweden and the remarkable extent of heterophylly present to establish morphological, cellular and transcriptional developmental time lines. We performed gene expression network and phenotypical regression analyses to identify genes of central importance or that were highly predictive of shape and size phenotypes during leaf development using a systems biology approach. We complemented this developmental study with a genome wide association study of leaf shape variation to identify single nucleotide polymorphisms associated with leaf shape and size, their genomic context and the biological role of associated genes. We then compared these association candidate genes to differentially expressed genes between groups of genotypes with highly contrasting leaf shapes, also considering whether there were expression quantitative trait loci associated with the genes. We demonstrate that our developmental gene expression series captured known biology for homologs of functionally characterised Arabidopsis thaliana genes and biological processes of importance during leaf development. We identified genes of high importance from the developmental series and natural variation analyses. These included genes with characterised functions in leaf development in addition to many novel candidates. Our systems genetics approach identified numerous genes supported by the developmental time series, phenotypic and expression association mapping and differential expression between phenotypic extremes. As such, we describe a rich resource for directing future functional characterisation studies and a comprehensive data resource characterising the role of gene expression during leaf development in aspen.

  • 46.
    Seyfferth, Carolin
    et al.
    Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Wessels, Bernard
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Jokipii-Lukkari, Soile
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Sundberg, Björn
    Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Delhomme, Nicolas
    Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Felten, Judith
    Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Tuominen, Hannele
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Ethylene-Related Gene Expression Networks in Wood Formation2018In: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 9, article id 272Article in journal (Refereed)
    Abstract [en]

    Thickening of tree stems is the result of secondary growth, accomplished by the meristematic activity of the vascular cambium. Secondary growth of the stem entails developmental cascades resulting in the formation of secondary phloem outwards and secondary xylem (i.e., wood) inwards of the stem. Signaling and transcriptional reprogramming by the phytohormone ethylene modifies cambial growth and cell differentiation, but the molecular link between ethylene and secondary growth remains unknown. We addressed this shortcoming by analyzing expression profiles and co-expression networks of ethylene pathway genes using the AspWood transcriptome database which covers all stages of secondary growth in aspen (Populus tremula) stems. ACC synthase expression suggests that the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) is synthesized during xylem expansion and xylem cell maturation. Ethylene-mediated transcriptional reprogramming occurs during all stages of secondary growth, as deduced from AspWood expression profiles of ethylene-responsive genes. A network centrality analysis of the AspWood dataset identified EIN3D and 11 ERFs as hubs. No overlap was found between the co-expressed genes of the EIN3 and ERF hubs, suggesting target diversification and hence independent roles for these transcription factor families during normal wood formation. The EIN3D hub was part of a large co-expression gene module, which contained 16 transcription factors, among them several new candidates that have not been earlier connected to wood formation and a VND-INTERACTING 2 (VNI2) homolog. We experimentally demonstrated Populus EIN3D function in ethylene signaling in Arabidopsis thaliana. The ERF hubs ERF118 and ERF119 were connected on the basis of their expression pattern and gene co-expression module composition to xylem cell expansion and secondary cell wall formation, respectively. We hereby establish data resources for ethylene-responsive genes and potential targets for EIN3D and ERF transcription factors in Populus stem tissues, which can help to understand the range of ethylene targeted biological processes during secondary growth.

  • 47.
    Simon, Philippe
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Undersökning av Nosema hos bin: utbredning och förekomst i Sverige2019Independent thesis Basic level (degree of Bachelor), 180 HE creditsStudent thesis
    Abstract [en]

    This report investigates the presence of Nosema in Sweden. Nosema is an intracellular parasite within the order Microsporidia and is considered a global threat. The most recent academic study on the presence of Nosema in Sweden was published in 2013, however in that study no presence of Nosema in the north of Sweden was reported. The aim of this study was to explore the presence of Nosema in Sweden, particularly in the north of Sweden. Samples were gathered from different locations in Sweden, and thereafter analysed (n=74), 54 samples were analysed under microscope. A geographical map was created to establish the range of Nosema on a global perspective. PCR primers and FISH gene probes for molecular identification were evaluated and tested both in SILVA and in an own database created in the bioinformatics software package ‘ARB’. Main findings of the study were that Nosema were detected in two samples in Sweden and that further studies with more sophisticated methods and better sequencing needs to be developed in order to fully investigate the presence of Nosema in the north of Sweden.

  • 48.
    Sjödin, Andreas
    et al.
    Division of CBRN Security and Defence, FOI - Swedish Defence Research Agency, Umeå, Sweden.
    Svensson, Kerstin
    Division of CBRN Security and Defence, FOI - Swedish Defence Research Agency, Umeå, Sweden.
    Lindgren, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Forsman, Mats
    Division of CBRN Security and Defence, FOI - Swedish Defence Research Agency, Umeå, Sweden.
    Larsson, Pär
    Division of CBRN Security and Defence, FOI - Swedish Defence Research Agency, Umeå, Sweden.
    Whole-genome sequencing reveals distinct mutational patterns in closely related laboratory and naturally propagated Francisella tularensis strains2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 7, p. e11556-Article in journal (Refereed)
    Abstract [en]

    The F. tularensis type A strain FSC198 from Slovakia and a second strain FSC043, which has attenuated virulence, are both considered to be derivatives of the North American F. tularensis type A strain SCHU S4. These strains have been propagated under different conditions: the FSC198 has undergone natural propagation in the environment, while the strain FSC043 has been cultivated on artificial media in laboratories. Here, we have compared the genome sequences of FSC198, FSC043, and SCHU S4 to explore the possibility that the contrasting propagation conditions may have resulted in different mutational patterns. We found four insertion/deletion events (INDELs) in the strain FSC043, as compared to the SCHU S4, while no single nucleotide polymorphisms (SNPs) or variable number of tandem repeats (VNTRs) were identified. This result contrasts with previously reported findings for the strain FSC198, where eight SNPs and three VNTR differences, but no INDELs exist as compared to the SCHU S4 strain. The mutations detected in the laboratory and naturally propagated type A strains, respectively, demonstrate distinct patterns supporting that analysis of mutational spectra might be a useful tool to reveal differences in past growth conditions. Such information may be useful to identify leads in a microbial forensic investigation.

  • 49.
    Sobhy, Haitham
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    A bioinformatics pipeline to search functional motifs within whole-proteome data: a case study of poxviruses2017In: Virus genes, ISSN 0920-8569, E-ISSN 1572-994X, Vol. 53, no 2, p. 173-178Article in journal (Refereed)
    Abstract [en]

    Proteins harbor domains or short linear motifs, which facilitate their functions and interactions. Finding functional motifs in protein sequences could predict the putative cellular roles or characteristics of hypothetical proteins. In this study, we present Shetti-Motif, which is an interactive tool to (i) map UniProt and PROSITE flat files, (ii) search for multiple pre-defined consensus patterns or experimentally validated functional motifs in large datasets protein sequences (proteome-wide), (iii) search for motifs containing repeated residues (low-complexity regions, e.g., Leu-, SR-, PEST-rich motifs, etc.). As proof of principle, using this comparative proteomics pipeline, eleven proteomes encoded by member of Poxviridae family were searched against about 100 experimentally validated functional motifs. The closely related viruses and viruses infect the same host cells (e.g. vaccinia and variola viruses) show similar motif-containing proteins profile. The motifs encoded by these viruses are correlated, which explains why poxviruses are able to interact with wide range of host cells. In conclusion, this in silico analysis is useful to establish a dataset(s) or potential proteins for further investigation or compare between species.

  • 50.
    Sobhy, Haitham
    Dalian Institute of Chemical Physics, CAS, Dalian, PR China.
    Shetti, a simple tool to parse, manipulate and search large datasets of sequences2015In: Microbial Genomics, ISSN 2057-5858, Vol. 1, no 5Article in journal (Refereed)
    Abstract [en]

    Parsing and manipulating long and/or multiple protein or gene sequences can be a challenging process for experimental biologists and microbiologists lacking prior knowledge of bioinformatics and programming. Here we present a simple, easy, user-friendly and versatile tool to parse, manipulate and search within large datasets of long and multiple protein or gene sequences. The Shetti tool can be used to search for a sequence, species, protein/gene or pattern/motif. Moreover, it can also be used to construct a universal consensus or molecular signatures for proteins based on their physical characteristics. Shetti is an efficient and fast tool that can deal with large sets of long sequences efficiently. Shetti parses UniProt Knowledgebase and NCBI GenBank flat files and visualizes them as a table.

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