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  • 1.
    Atkinson, Gemma Catherine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Nooruse 1, Tartu, 50411, Estonia.
    The evolutionary and functional diversity of classical and lesser-known cytoplasmic and organellar translational GTPases across the tree of life2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 78Article in journal (Refereed)
    Abstract [en]

    Background: The ribosome translates mRNA to protein with the aid of a number of accessory protein factors. Translational GTPases (trGTPases) are an integral part of the 'core set' of essential translational factors, and are some of the most conserved proteins across life. This study takes advantage of the wealth of available genomic data, along with novel functional information that has come to light for a number of trGTPases to address the full evolutionary and functional diversity of this superfamily across all domains of life. 

    Results: Through sensitive sequence searching combined with phylogenetic analysis, 57 distinct subfamilies of trGTPases are identified: 14 bacterial, 7 archaeal and 35 eukaryotic (of which 21 are known or predicted to be organellar). The results uncover the functional evolution of trGTPases from before the last common ancestor of life on earth to the current day. 

    Conclusions: While some trGTPases are universal, others are limited to certain taxa, suggesting lineage-specific translational control mechanisms that exist on a base of core factors. These lineage-specific features may give organisms the ability to tune their translation machinery to respond to their environment. Only a fraction of the diversity of the trGTPase superfamily has been subjected to experimental analyses; this comprehensive classification brings to light novel and overlooked translation factors that are worthy of further investigation.

  • 2. Berglund, Eva C.
    et al.
    Lindqvist, Carl Mårten
    Hayat, Shahina
    Övernäs, Elin
    Henriksson, Niklas
    Nordlund, Jessica
    Wahlberg, Per
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lönnerholm, Gudmar
    Syvänen, Ann-Christine
    Accurate detection of subclonal single nucleotide variants in whole genome amplified and pooled cancer samples using HaloPlex target enrichment2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 856-Article in journal (Refereed)
    Abstract [en]

    Background: Target enrichment and resequencing is a widely used approach for identification of cancer genes and genetic variants associated with diseases. Although cost effective compared to whole genome sequencing, analysis of many samples constitutes a significant cost, which could be reduced by pooling samples before capture. Another limitation to the number of cancer samples that can be analyzed is often the amount of available tumor DNA. We evaluated the performance of whole genome amplified DNA and the power to detect subclonal somatic single nucleotide variants in non-indexed pools of cancer samples using the HaloPlex technology for target enrichment and next generation sequencing. Results: We captured a set of 1528 putative somatic single nucleotide variants and germline SNPs, which were identified by whole genome sequencing, with the HaloPlex technology and sequenced to a depth of 792-1752. We found that the allele fractions of the analyzed variants are well preserved during whole genome amplification and that capture specificity or variant calling is not affected. We detected a large majority of the known single nucleotide variants present uniquely in one sample with allele fractions as low as 0.1 in non-indexed pools of up to ten samples. We also identified and experimentally validated six novel variants in the samples included in the pools. Conclusion: Our work demonstrates that whole genome amplified DNA can be used for target enrichment equally well as genomic DNA and that accurate variant detection is possible in non-indexed pools of cancer samples. These findings show that analysis of a large number of samples is feasible at low cost, even when only small amounts of DNA is available, and thereby significantly increases the chances of indentifying recurrent mutations in cancer samples.

  • 3. Doublet, Vincent
    et al.
    Poeschl, Yvonne
    Gogol-Doering, Andreas
    Alaux, Cedric
    Annoscia, Desiderato
    Aurori, Christian
    Barribeau, Seth M.
    Bedoya-Reina, Oscar C.
    Brown, Mark J. F.
    Bull, James C.
    Flenniken, Michelle L.
    Galbraith, David A.
    Genersch, Elke
    Gisder, Sebastian
    Grosse, Ivo
    Holt, Holly L.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lattorff, H. Michael G.
    Le Conte, Yves
    Manfredini, Fabio
    McMahon, Dino P.
    Moritz, Robin F. A.
    Nazzi, Francesco
    Nino, Elina L.
    Nowick, Katja
    van Rij, Ronald P.
    Paxton, Robert J.
    Grozinger, Christina M.
    Unity in defence: honeybee workers exhibit conserved molecular responses to diverse pathogens2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 207Article in journal (Refereed)
    Abstract [en]

    Background: Organisms typically face infection by diverse pathogens, and hosts are thought to have developed specific responses to each type of pathogen they encounter. The advent of transcriptomics now makes it possible to test this hypothesis and compare host gene expression responses to multiple pathogens at a genome-wide scale. Here, we performed a meta-analysis of multiple published and new transcriptomes using a newly developed bioinformatics approach that filters genes based on their expression profile across datasets. Thereby, we identified common and unique molecular responses of a model host species, the honey bee (Apis mellifera), to its major pathogens and parasites: the Microsporidia Nosema apis and Nosema ceranae, RNA viruses, and the ectoparasitic mite Varroa destructor, which transmits viruses.

    Results: We identified a common suite of genes and conserved molecular pathways that respond to all investigated pathogens, a result that suggests a commonality in response mechanisms to diverse pathogens. We found that genes differentially expressed after infection exhibit a higher evolutionary rate than non-differentially expressed genes. Using our new bioinformatics approach, we unveiled additional pathogen-specific responses of honey bees; we found that apoptosis appeared to be an important response following microsporidian infection, while genes from the immune signalling pathways, Toll and Imd, were differentially expressed after Varroa/virus infection. Finally, we applied our bioinformatics approach and generated a gene co-expression network to identify highly connected (hub) genes that may represent important mediators and regulators of anti-pathogen responses.

    Conclusions: Our meta-analysis generated a comprehensive overview of the host metabolic and other biological processes that mediate interactions between insects and their pathogens. We identified key host genes and pathways that respond to phylogenetically diverse pathogens, representing an important source for future functional studies as well as offering new routes to identify or generate pathogen resilient honey bee stocks. The statistical and bioinformatics approaches that were developed for this study are broadly applicable to synthesize information across transcriptomic datasets. These approaches will likely have utility in addressing a variety of biological questions.

  • 4. Georgiadis, Panagiotis
    et al.
    Liampa, Irene
    Hebels, Dennie G
    Krauskopf, Julian
    Chatziioannou, Aristotelis
    Valavanis, Ioannis
    de Kok, Theo M C M
    Kleinjans, Jos C S
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Spaeth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palli, Domenico
    Vermeulen, R C H
    Vlaanderen, J
    Chadeau-Hyam, Marc
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 728Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.

    RESULTS: We employed peripheral blood buffy coats of 347 apparently healthy subjects, of whom 28 were diagnosed with CLL 2.0-15.7 years after enrollment, to derive for the first time genome-wide DNA methylation, as well as gene and miRNA expression, profiles associated with the risk of future disease. After adjustment for white blood cell composition, we identified 722 differentially methylated CpG sites and 15 differentially expressed genes (Bonferroni-corrected p < 0.05) as well as 2 miRNAs (FDR < 0.05) which were associated with the risk of future CLL. The majority of these signals have also been observed in clinical CLL, suggesting the presence in prediagnostic blood of CLL-like cells. Future CLL cases who, at enrollment, had a relatively low B-cell fraction (<10%), and were therefore less likely to have been suffering from undiagnosed CLL or a precursor condition, showed profiles involving smaller numbers of the same differential signals with intensities, after adjusting for B-cell content, generally smaller than those observed in the full set of cases. A similar picture was obtained when the differential profiles of cases with time-to-diagnosis above the overall median period of 7.4 years were compared with those with shorted time-to-disease. Differentially methylated genes of major functional significance include numerous genes that encode for transcription factors, especially members of the homeobox family, while differentially expressed genes include, among others, multiple genes related to WNT signaling as well as the miRNAs miR-150-5p and miR-155-5p.

    CONCLUSIONS: Our findings demonstrate the presence in prediagnostic blood of future CLL patients, more than 10 years before diagnosis, of CLL-like cells which evolve as preclinical disease progresses, and point to early molecular alterations with a pathogenetic potential.

  • 5. Igwe, Emeka I
    et al.
    Essler, Silke
    Al-Furoukh, Natalie
    1Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt.
    Dehne, Nathalie
    Brüne, Bernhard
    Hypoxic transcription gene profiles under the modulation of nitric oxide in nuclear run on-microarray and proteomics.2009In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Microarray analysis still is a powerful tool to identify new components of the transcriptosome. It helps to increase the knowledge of targets triggered by stress conditions such as hypoxia and nitric oxide. However, analysis of transcriptional regulatory events remain elusive due to the contribution of altered mRNA stability to gene expression patterns as well as changes in the half-life of mRNAs, which influence mRNA expression levels and their turn over rates. To circumvent these problems, we have focused on the analysis of newly transcribed (nascent) mRNAs by nuclear run on (NRO), followed by microarray analysis.

    RESULTS: We identified 196 genes that were significantly regulated by hypoxia, 85 genes affected by nitric oxide and 292 genes induced by the cotreatment of macrophages with both NO and hypoxia. Fourteen genes (Bnip3, Ddit4, Vegfa, Trib3, Atf3, Cdkn1a, Scd1, D4Ertd765e, Sesn2, Son, Nnt, Lst1, Hps6 and Fxyd5) were common to all treatments but with different levels of expression in each group. We observed that 162 transcripts were regulated only when cells were co-treated with hypoxia and NO but not with either treatment alone, pointing to the importance of a crosstalk between hypoxia and NO. In addition, both array and proteomics data supported a consistent repression of hypoxia-regulated targets by NO.

    CONCLUSION: By eliminating the interference of steady state mRNA in gene expression profiling, we obtained a smaller number of significantly regulated transcripts in our study compared to published microarray data and identified previously unknown hypoxia-induced targets. Gene analysis profiling corroborated the interplay between NO- and hypoxia-induced signaling.

  • 6. Immanen, Juha
    et al.
    Nieminen, Kaisa
    Duchens Silva, Hector
    Rodriguez Rojas, Fernanda
    Meisel, Lee A.
    Silva, Herman
    Albert, Victor A.
    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).
    Helariutta, Yka
    Characterization of cytokinin signaling and homeostasis gene families in two hardwood tree species: Populus trichocarpa and Prunus persica2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 885-Article in journal (Refereed)
    Abstract [en]

    Background: Through the diversity of cytokinin regulated processes, this phytohormone has a profound impact on plant growth and development. Cytokinin signaling is involved in the control of apical and lateral meristem activity, branching pattern of the shoot, and leaf senescence. These processes influence several traits, including the stem diameter, shoot architecture, and perennial life cycle, which define the development of woody plants. To facilitate research about the role of cytokinin in regulation of woody plant development, we have identified genes associated with cytokinin signaling and homeostasis pathways from two hardwood tree species. Results: Taking advantage of the sequenced black cottonwood (Populus trichocarpa) and peach (Prunus persica) genomes, we have compiled a comprehensive list of genes involved in these pathways. We identified genes belonging to the six families of cytokinin oxidases (CKXs), isopentenyl transferases (IPTs), LONELY GUY genes (LOGs), two-component receptors, histidine containing phosphotransmitters (HPts), and response regulators (RRs). All together 85 Populus and 45 Prunus genes were identified, and compared to their Arabidopsis orthologs through phylogenetic analyses. Conclusions: In general, when compared to Arabidopsis, differences in gene family structure were often seen in only one of the two tree species. However, one class of genes associated with cytokinin signal transduction, the CKI1-like family of two-component histidine kinases, was larger in both Populus and Prunus than in Arabidopsis.

  • 7.
    Jun, He
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kieselbach, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jönsson, Leif J
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Comparative proteome analysis of Saccharomyces cerevisiae: A global overview of in vivo targets of the yeast activator protein 12012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, no 1, p. 230-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: : The activity of the yeast activator protein 1 (Yap1p) increases under stress conditions, which leads to enhanced transcription of a number of genes encoding protective enzymes or other proteins. To obtain a global overview of changes in expression of Yap1p-targeted proteins, we compared a Yap1p-overexpressing transformant with a control transformant by triplicate analysis of the proteome using two-dimensional gel electrophoresis (2-DE). Proteins of interest were identified using MALDI-MS or LC-MS/MS. RESULTS: : The relative quantities of 55 proteins were elevated significantly upon overexpression of Yap1p, and most of these proteins were found to have a Yap1p-binding site upstream of their coding sequences. Interestingly, the main metabolic enzymes in the glycolysis and pyruvate-ethanol pathways showed a significant increase in the Yap1p-overexpressing transformant. Moreover, a comparison of our proteome data with transcriptome data from the literature suggested which proteins were regulated at the level of the proteome, and which proteins were regulated at the level of the transcriptome. Eight proteins involved in stress response, including seven heat-shock and chaperone proteins, were significantly more abundant in the Yap1p-overexpressing transformant. CONCLUSIONS: : We have investigated the general protein composition in Yap1p-overexpressing S. cerevisiae using proteomic techniques, and quantified the changes in the expression of the potential Yap1p-targeted proteins. Identification of the potential Yap1p targets and analysis of their role in cellular processes not only give a global overview of the ubiquitous cellular changes elicited by Yap1p, but also provide the framework for understanding the mechanisms behind Yap1p-regulated stress response in yeast.

  • 8. Kisand, Veljo
    et al.
    Lettieri, Teresa
    Genome sequencing of bacteria: sequencing, de novo assembly and rapid analysis using open source tools2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, article id 211Article in journal (Refereed)
    Abstract [en]

    Background: De novo genome sequencing of previously uncharacterized microorganisms has the potential to open up new frontiers in microbial genomics by providing insight into both functional capabilities and biodiversity. Until recently, Roche 454 pyrosequencing was the NGS method of choice for de novo assembly because it generates hundreds of thousands of long reads(<450 bps), which are presumed to aid in the analysis of uncharacterized genomes. The array of tools for processing NGS data are increasingly free and open source and are often adopted for both their high quality and role in promoting academic freedom. Results: The error rate of pyrosequencing the Alcanivorax borkumensis genome was such that thousands of insertions and deletions were artificially introduced into the finished genome. Despite a high coverage (similar to 30 fold), it did not allow the reference genome to be fully mapped. Reads from regions with errors had low quality, low coverage, or were missing. The main defect of the reference mapping was the introduction of artificial indels into contigs through lower than 100% consensus and distracting gene calling due to artificial stop codons. No assembler was able to perform de novo assembly comparable to reference mapping. Automated annotation tools performed similarly on reference mapped and de novo draft genomes, and annotated most CDSs in the de novo assembled draft genomes. Conclusions: Free and open source software (FOSS) tools for assembly and annotation of NGS data are being developed rapidly to provide accurate results with less computational effort. Usability is not high priority and these tools currently do not allow the data to be processed without manual intervention. Despite this, genome assemblers now readily assemble medium short reads into long contigs (>97-98% genome coverage). A notable gap in pyrosequencing technology is the quality of base pair calling and conflicting base pairs between single reads at the same nucleotide position. Regardless, using draft whole genomes that are not finished and remain fragmented into tens of contigs allows one to characterize unknown bacteria with modest effort.

  • 9.
    Klevebring, Daniel
    et al.
    School of Biotechnology, Division of Gene Technology, AlbaNova University Center, Royal Institute of Technology, 106 91 Stockholm, Sweden.
    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).
    Fahlgren, Noah
    Center for Genome Research and Biocomputing, Oregon State University, Corvallis, Oregon 97331, USA.
    Kasschau, Kristin D
    Center for Genome Research and Biocomputing, Oregon State University, Corvallis, Oregon 97331, USA.
    Carrington, James C
    Center for Genome Research and Biocomputing, Oregon State University, Corvallis, Oregon 97331, USA.
    Lundeberg, Joakim
    School of Biotechnology, Division of Gene Technology, AlbaNova University Center, Royal Institute of Technology, 106 91 Stockholm, Sweden.
    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).
    Genome-wide profiling of populus small RNAs2009In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 10, p. 620-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Short RNAs, and in particular microRNAs, are important regulators of gene expression both within defined regulatory pathways and at the epigenetic scale. We investigated the short RNA (sRNA) population (18-24 nt) of the transcriptome of green leaves from the sequenced Populus trichocarpa using a concatenation strategy in combination with 454 sequencing. RESULTS: The most abundant size class of sRNAs were 24 nt. Long Terminal Repeats were particularly associated with 24 nt sRNAs. Additionally, some repetitive elements were associated with 22 nt sRNAs. We identified an sRNA hot-spot on chromosome 19, overlapping a region containing both the proposed sex-determining locus and a major cluster of NBS-LRR genes. A number of phased siRNA loci were identified, a subset of which are predicted to target PPR and NBS-LRR disease resistance genes, classes of genes that have been significantly expanded in Populus. Additional loci enriched for sRNA production were identified and characterised. We identified 15 novel predicted microRNAs (miRNAs), including miRNA*sequences, and identified a novel locus that may encode a dual miRNA or a miRNA and short interfering RNAs (siRNAs). CONCLUSIONS: The short RNA population of P. trichocarpa is at least as complex as that of Arabidopsis thaliana. We provide a first genome-wide view of short RNA production for P. trichocarpa and identify new, non-conserved miRNAs.

  • 10. Lundberg, Max
    et al.
    Boss, John
    Canbäck, Björn
    Liedvogel, Miriam
    Larson, Keith W.
    Grahn, Mats
    Åkesson, Susanne
    Bensch, Staffan
    Wright, Anthony
    Characterisation of a transcriptome to find sequence differences between two differentially migrating subspecies of the willow warbler Phylloscopus trochilus2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, no 1, p. 1-11, article id 330Article in journal (Refereed)
    Abstract [en]

    Background: Animal migration requires adaptations in morphological, physiological and behavioural traits. Several of these traits have been shown to possess a strong heritable component in birds, but little is known about their genetic architecture. Here we used 454 sequencing of brain-derived transcriptomes from two differentially migrating subspecies of the willow warbler Phylloscopus trochilus to detect genes potentially underlying traits associated with migration. Results: The transcriptome sequencing resulted in 1.8 million reads following filtering steps. Most of the reads (84%) were successfully mapped to the genome of the zebra finch Taeniopygia gutatta. The mapped reads were situated within at least 12,101 predicted zebra finch genes, with the greatest sequencing depth in exons. Reads that were mapped to intergenic regions were generally located close to predicted genes and possibly located in uncharacterized untranslated regions (UTRs). Out of 85,000 single nucleotide polymorphisms (SNPs) with a minimum sequencing depth of eight reads from each of two subspecies-specific pools, only 55 showed high differentiation, confirming previous studies showing that most of the genetic variation is shared between the subspecies. Validation of a subset of the most highly differentiated SNPs using Sanger sequencing demonstrated that several of them also were differentiated between an independent set of individuals of each subspecies. These SNPs were clustered in two chromosome regions that are likely to be influenced by divergent selection between the subspecies and that could potentially be associated with adaptations to their different migratory strategies. Conclusions: Our study represents the first large-scale sequencing analysis aiming at detecting genes underlying migratory phenotypes in birds and provides new candidates for genes potentially involved in migration.

  • 11. Moghadam, Behrooz Torabi
    et al.
    Zamani, Neda
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Department of Medical Biochemistry and Microbiology/BILS, Genomics, Uppsala University, Uppsala, Sweden.
    Komorowski, Jan
    Grabherr, Manfred
    PiiL: visualization of DNA methylation and gene expression data in gene pathways2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 571Article in journal (Refereed)
    Abstract [en]

    Background: DNA methylation is a major mechanism involved in the epigenetic state of a cell. It has been observed that the methylation status of certain CpG sites close to or within a gene can directly affect its expression, either by silencing or, in some cases, up-regulating transcription. However, a vertebrate genome contains millions of CpG sites, all of which are potential targets for methylation, and the specific effects of most sites have not been characterized to date. To study the complex interplay between methylation status, cellular programs, and the resulting phenotypes, we present PiiL, an interactive gene expression pathway browser, facilitating analyses through an integrated view of methylation and expression on multiple levels.

    Results: PiiL allows for specific hypothesis testing by quickly assessing pathways or gene networks, where the data is projected onto pathways that can be downloaded directly from the online KEGG database. PiiL provides a comprehensive set of analysis features that allow for quick and specific pattern searches. Individual CpG sites and their impact on host gene expression, as well as the impact on other genes present in the regulatory network, can be examined. To exemplify the power of this approach, we analyzed two types of brain tumors, Glioblastoma multiform and lower grade gliomas.

    Conclusion: At a glance, we could confirm earlier findings that the predominant methylation and expression patterns separate perfectly by mutations in the IDH genes, rather than by histology. We could also infer the IDH mutation status for samples for which the genotype was not known. By applying different filtering methods, we show that a subset of CpG sites exhibits consistent methylation patterns, and that the status of sites affect the expression of key regulator genes, as well as other genes located downstream in the same pathways.

    PiiL is implemented in Java with focus on a user-friendly graphical interface. The source code is available under the GPL license from https://github.com/behroozt/PiiL.git.

  • 12.
    Netotea, Sergiu
    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).
    Sundell, David
    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.
    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).
    ComPlEx: conservation and divergence of co-expression networks in A. thaliana, Populus and O. sativa2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 106-Article in journal (Refereed)
    Abstract [en]

    Background: Divergence in gene regulation has emerged as a key mechanism underlying species differentiation. Comparative analysis of co-expression networks across species can reveal conservation and divergence in the regulation of genes. Results: We inferred co-expression networks of A. thaliana, Populus spp. and O. sativa using state-of-the-art methods based on mutual information and context likelihood of relatedness, and conducted a comprehensive comparison of these networks across a range of co-expression thresholds. In addition to quantifying gene-gene link and network neighbourhood conservation, we also applied recent advancements in network analysis to do cross-species comparisons of network properties such as scale free characteristics and gene centrality as well as network motifs. We found that in all species the networks emerged as scale free only above a certain co-expression threshold, and that the high-centrality genes upholding this organization tended to be conserved. Network motifs, in particular the feed-forward loop, were found to be significantly enriched in specific functional subnetworks but where much less conserved across species than gene centrality. Although individual gene-gene co-expression had massively diverged, up to similar to 80% of the genes still had a significantly conserved network neighbourhood. For genes with multiple predicted orthologs, about half had one ortholog with conserved regulation and another ortholog with diverged or non-conserved regulation. Furthermore, the most sequence similar ortholog was not the one with the most conserved gene regulation in over half of the cases. Conclusions: We have provided a comprehensive analysis of gene regulation evolution in plants and built a web tool for Comparative analysis of Plant co-Expression networks (ComPlEx, http:// complex. plantgenie. org/). The tool can be particularly useful for identifying the ortholog with the most conserved regulation among several sequence-similar alternatives and can thus be of practical importance in e. g. finding candidate genes for perturbation experiments.

  • 13.
    Niemiec, Maria Joanna
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). HKI, Leibniz Inst Nat Product Res & Infect Biol, Jena, Germany.
    Grumaz, Christian
    Ermert, David
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Lund Univ, Div Med Prot Chem, Dept Translat Med, Malmo, Sweden.
    Desel, Christiane
    Shankar, Madhu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lopes, Jose Pedro
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Mills, Ian G.
    Stevens, Philip
    Sohn, Kai
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Dual transcriptome of the immediate neutrophil and Candida albicans interplay2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 696Article in journal (Refereed)
    Abstract [en]

    Background: Neutrophils are traditionally considered transcriptionally inactive. Compared to other immune cells, little is known about their transcriptional profile during interaction with pathogens. Methods: We analyzed the meta-transcriptome of the neutrophil-Candida albicans interplay and the transcriptome of C. albicans challenged with neutrophil extracellular traps (NETs) by RNA-Seq, considering yeast and hypha individually in each approach. Results: The neutrophil response to C. albicans yeast and hyphae was dominated by a morphotype-independent core response. However, 11 % of all differentially expressed genes were regulated in a specific manner when neutrophils encountered the hyphal form of C. albicans. While involving genes for transcriptional regulators, receptors, and cytokines, the neutrophil core response lacked typical antimicrobial effectors genes. Genes of the NOD-like receptor pathway, including NLRP3, were enriched. Neutrophil-and NET-provoked responses in C. albicans differed. At the same time, the Candida transcriptome upon neutrophil encounter and upon NET challenge included genes from various metabolic processes and indicate a mutual role of the regulators Tup1p, Efg1p, Hap43p, and Cap1p. Upon challenge with neutrophils and NETs, the overall Candida response was partially morphotype-specific. Yet again, actual oppositional regulation in yeasts and hyphae was only detected for the arginine metabolism in neutrophil-infecting C. albicans. Conclusions: Taken together, our study provides a comprehensive and quantitative transcript profile of the neutrophil-C. albicans interaction. By considering the two major appearances of both, neutrophils and C. albicans, our study reveals yet undescribed insights into this medically relevant encounter. Hence, our findings will facilitate future research and potentially inspire novel therapy developments.

  • 14.
    Obudulu, Ogonna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bygdell, Joakim
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sundberg, Bjorn
    Moritz, Thomas
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. 5 Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Norway.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wingsle, Gunnar
    Quantitative proteomics reveals protein profiles underlying major transitions in aspen wood development2016In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, article id 119Article in journal (Refereed)
    Abstract [en]

    Background: Wood development is of outstanding interest both to basic research and industry due to the associated cellulose and lignin biomass production. Efforts to elucidate wood formation (which is essential for numerous aspects of both pure and applied plant science) have been made using transcriptomic analyses and/or low-resolution sampling. However, transcriptomic data do not correlate perfectly with levels of expressed proteins due to effects of post-translational modifications and variations in turnover rates. In addition, high-resolution analysis is needed to characterize key transitions. In order to identify protein profiles across the developmental region of wood formation, an in-depth and tissue specific sampling was performed. Results: We examined protein profiles, using an ultra-performance liquid chromatography/quadrupole time of flight mass spectrometry system, in high-resolution tangential sections spanning all wood development zones in Populus tremula from undifferentiated cambium to mature phloem and xylem, including cell expansion and cell death zones. In total, we analyzed 482 sections, 20-160 mu m thick, from four 47-year-old trees growing wild in Sweden. We obtained high quality expression profiles for 3,082 proteins exhibiting consistency across the replicates, considering that the trees were growing in an uncontrolled environment. A combination of Principal Component Analysis (PCA), Orthogonal Projections to Latent Structures (OPLS) modeling and an enhanced stepwise linear modeling approach identified several major transitions in global protein expression profiles, pinpointing (for example) locations of the cambial division leading to phloem and xylem cells, and secondary cell wall formation zones. We also identified key proteins and associated pathways underlying these developmental landmarks. For example, many of the lignocellulosic related proteins were upregulated in the expansion to the early developmental xylem zone, and for laccases with a rapid decrease in early xylem zones. We observed upregulation of two forms of xylem cysteine protease (Potri.002G005700.1 and Potri.005G256000.2; Pt-XCP2.1) in early xylem and their downregulation in late maturing xylem. Our data also show that Pt-KOR1.3 (Potri.003G151700.2) exhibits an expression pattern that supports the hypothesis put forward in previous studies that this is a key xyloglucanase involved in cellulose biosynthesis in primary cell walls and reduction of cellulose crystallinity in secondary walls. Conclusion: Our novel multivariate approach highlights important processes and provides confirmatory insights into the molecular foundations of wood development.

  • 15.
    Obudulu, Ogonna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 90183 Umeå, Sweden.
    Mähler, Niklas
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Faculty of Chemistry, Biotechnology and Food Science, Norwegian, University of Life Sciences, 1432 Ås, Norway.
    Skotare, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bygdell, Joakim
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Abreu, Ilka N.
    Ahnlund, Maria
    Latha Gandla, Madhavi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Petterle, Anna
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Moritz, Thomas
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Faculty of Chemistry, Biotechnology and Food Science, Norwegian, University of Life Sciences, 1432 Ås, Norway.
    Jönsson, Leif J.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wingsle, Gunnar
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tuominen, Hannele
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    A multi-omics approach reveals function of Secretory Carrier-Associated Membrane Proteins in wood formation of​ ​​Populus​​ ​trees2018In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 19, article id 11Article in journal (Refereed)
    Abstract [en]

    Background: Secretory Carrier-Associated Membrane Proteins (SCAMPs) are highly conserved 32–38 kDa proteins that are involved in membrane trafficking. A systems approach was taken to elucidate function of SCAMPs in wood formation of Populus trees. Phenotypic and multi-omics analyses were performed in woody tissues of transgenic Populus trees carrying an RNAi construct for Populus tremula x tremuloides SCAMP3 (PttSCAMP3;Potri.019G104000).

    Results: The woody tissues of the transgenic trees displayed increased amounts of both polysaccharides and lignin oligomers, indicating increased deposition of both the carbohydrate and lignin components of the secondary cell walls. This coincided with a tendency towards increased wood density as well as significantly increased thickness of the suberized cork in the transgenic lines. Multivariate OnPLS (orthogonal projections to latent structures) modeling of five different omics datasets (the transcriptome, proteome, GC-MS metabolome, LC-MS metabolome and pyrolysis-GC/MS metabolome) collected from the secondary xylem tissues of the stem revealed systemic variation in the different variables in the transgenic lines, including changes that correlated with the changes in the secondary cell wall composition. The OnPLS model also identified a rather large number of proteins that were more abundant in the transgenic lines than in the wild type. Several of these were related to secretion and/or endocytosis as well as both primary and secondary cell wall biosynthesis.

    Conclusions: Populus SCAMP proteins were shown to influence accumulation of secondary cell wall components, including polysaccharides and phenolic compounds, in the woody tissues of Populus tree stems. Our multi-omics analyses combined with the OnPLS modelling suggest that this function is mediated by changes in membrane trafficking to fine-tune the abundance of cell wall precursors and/or proteins involved in cell wall biosynthesis and transport. The data provides a multi-level source of information for future studies on the function of the SCAMP proteins in plant stem tissues.

  • 16.
    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.

  • 17.
    Richter, Karin
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Wirta, Valtteri
    Dahl, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Bruce, Sara
    Lundeberg, Joakim
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Williams, Cecilia
    Global gene expression analyses of hematopoietic stem cell-like cell lines with inducible Lhx2 expression2006In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 7, p. 75-Article in journal (Refereed)
    Abstract [en]

    Background Expression of the LIM-homeobox gene Lhx2 in murine hematopoietic cells allows for the generation of hematopoietic stem cell (HSC)-like cell lines. To address the molecular basis of Lhx2 function, we generated HSC-like cell lines where Lhx2 expression is regulated by a tet-on system and hence dependent on the presence of doxycyclin (dox). These cell lines efficiently down-regulate Lhx2 expression upon dox withdrawal leading to a rapid differentiation into various myeloid cell types.

    Results Global gene expression of these cell lines cultured in dox was compared to different time points after dox withdrawal using microarray technology. We identified 267 differentially expressed genes. The majority of the genes overlapping with HSC-specific databases were those down-regulated after turning off Lhx2 expression and a majority of the genes overlapping with those defined as late progenitor-specific genes were the up-regulated genes, suggesting that these cell lines represent a relevant model system for normal HSCs also at the level of global gene expression. Moreover, in situ hybridisations of several genes down-regulated after dox withdrawal showed overlapping expression patterns with Lhx2 in various tissues during embryonic development.

    Conclusion Global gene expression analysis of HSC-like cell lines with inducible Lhx2 expression has identified genes putatively linked to self-renewal / differentiation of HSCs, and function of Lhx2 in organ development and stem / progenitor cells of non-hematopoietic origin.

  • 18. Sjödin, Andreas
    et al.
    Svensson, Kerstin
    FOI.
    Öhrman, Caroline
    Ahlinder, Jon
    Lindgren, Petter
    Duodu, Samuel
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Colquhoun, Duncan J.
    Larsson, Pär
    Swedish Defense Research Agency, Umea, Sweden.
    Forsman, Mats
    Genome characterisation of the genus Francisella reveals insight into similar evolutionary paths in pathogens of mammals and fish2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 268-Article in journal (Refereed)
    Abstract [en]

    Background: Prior to this study, relatively few strains of Francisella had been genome-sequenced. Previously published Francisella genome sequences were largely restricted to the zoonotic agent F. tularensis. Only limited data were available for other members of the Francisella genus, including F. philomiragia, an opportunistic pathogen of humans, F. noatunensis, a serious pathogen of farmed fish, and other less well described endosymbiotic species. Results: We determined the phylogenetic relationships of all known Francisella species, including some for which the phylogenetic positions were previously uncertain. The genus Francisella could be divided into two main genetic clades: one included F. tularensis, F. novicida, F. hispaniensis and Wolbachia persica, and another included F. philomiragia and F. noatunensis. Some Francisella species were found to have significant recombination frequencies. However, the fish pathogen F. noatunensis subsp. noatunensis was an exception due to it exhibiting a highly clonal population structure similar to the human pathogen F. tularensis. Conclusions: The genus Francisella can be divided into two main genetic clades occupying both terrestrial and marine habitats. However, our analyses suggest that the ancestral Francisella species originated in a marine habitat. The observed genome to genome variation in gene content and IS elements of different species supports the view that similar evolutionary paths of host adaptation developed independently in F. tularensis (infecting mammals) and F. noatunensis subsp. noatunensis (infecting fish).

  • 19. Srivastava, Vaibhav
    et al.
    Obudulu, Ogonna
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational life science cluster (CLiC), Umeå University and Swedish University of Agricultural Sciences.
    Bygdell, Joakim
    Löfstedt, Tommy
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational life science cluster (CLiC), Umeå University.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational life science cluster (CLiC), Umeå University.
    Nilsson, Robert
    Ahnlund, Maria
    Johansson, Annika
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational life science cluster (CLiC), Umeå University.
    Freyhult, Eva
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Computational life science cluster (CLiC), Umeå University.
    Qvarnström, Johanna
    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).
    Melzer, Michael
    Moritz, Thomas
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational life science cluster (CLiC), Umeå University.
    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). Umeå University, Faculty of Science and Technology, Department of Chemistry. Computational life science cluster (CLiC), Umeå University and Department of Chemistry, Biotechnology; Food Science, Norwegian, University of Life Sciences, Ås Norwegian, Norway.
    Wingsle, Gunnar
    OnPLS integration of transcriptomic, proteomic and metabolomic data shows multi-level oxidative stress responses in the cambium of transgenic hipI- superoxide dismutase Populus plants2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, article id 893Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Reactive oxygen species (ROS) are involved in the regulation of diverse physiological processes in plants, including various biotic and abiotic stress responses. Thus, oxidative stress tolerance mechanisms in plants are complex, and diverse responses at multiple levels need to be characterized in order to understand them. Here we present system responses to oxidative stress in Populus by integrating data from analyses of the cambial region of wild-type controls and plants expressing high-isoelectric-point superoxide dismutase (hipI-SOD) transcripts in antisense orientation showing a higher production of superoxide. The cambium, a thin cell layer, generates cells that differentiate to form either phloem or xylem and is hypothesized to be a major reason for phenotypic perturbations in the transgenic plants. Data from multiple platforms including transcriptomics (microarray analysis), proteomics (UPLC/QTOF-MS), and metabolomics (GC-TOF/MS, UPLC/MS, and UHPLC-LTQ/MS) were integrated using the most recent development of orthogonal projections to latent structures called OnPLS. OnPLS is a symmetrical multi-block method that does not depend on the order of analysis when more than two blocks are analysed. Significantly affected genes, proteins and metabolites were then visualized in painted pathway diagrams.

    RESULTS: The main categories that appear to be significantly influenced in the transgenic plants were pathways related to redox regulation, carbon metabolism and protein degradation, e.g. the glycolysis and pentose phosphate pathways (PPP). The results provide system-level information on ROS metabolism and responses to oxidative stress, and indicate that some initial responses to oxidative stress may share common pathways.

    CONCLUSION: The proposed data evaluation strategy shows an efficient way of compiling complex, multi-platform datasets to obtain significant biological information.

  • 20.
    Street, Nathaniel Robert
    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).
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Bylesjö, Max
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gustafsson, Petter
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    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).
    A cross-species transcriptomics approach to identify genes involved in leaf development2008In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, no 1, p. 539-Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Background

    We have made use of publicly available gene expression data to identify transcription factors and transcriptional modules (regulons) associated with leaf development in Populus. Different tissue types were compared to identify genes informative in the discrimination of leaf and non-leaf tissues. Transcriptional modules within this set of genes were identified in a much wider set of microarray data collected from leaves in a number of developmental, biotic, abiotic and transgenic experiments.

    Results

    Transcription factors that were over represented in leaf EST libraries and that were useful for discriminating leaves from other tissues were identified, revealing that the C2C2-YABBY, CCAAT-HAP3 and 5, MYB, and ZF-HD families are particularly important in leaves. The expression of transcriptional modules and transcription factors was examined across a number of experiments to select those that were particularly active during the early stages of leaf development. Two transcription factors were found to collocate to previously published Quantitative Trait Loci (QTL) for leaf length. We also found that miRNA family 396 may be important in the control of leaf development, with three members of the family collocating with clusters of leaf development QTL.

    Conclusion

    This work provides a set of candidate genes involved in the control and processes of leaf development. This resource can be used for a wide variety of purposes such as informing the selection of candidate genes for association mapping or for the selection of targets for reverse genetics studies to further understanding of the genetic control of leaf size and shape.

  • 21. Vlaanderen, Jelle
    et al.
    Leenders, Max
    Chadeau-Hyam, Marc
    Portengen, Lutzen
    Kyrtopoulos, Soterios A.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hebels, Dennie D. G. A. J.
    de Kok, Theo M. C. M.
    Vineis, Paolo
    Vermeulen, Roel C. H.
    Exploring the nature of prediagnostic blood transcriptome markers of chronic lymphocytic leukemia by assessing their overlap with the transcriptome at the clinical stage2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 239Article in journal (Refereed)
    Abstract [en]

    Background: We recently identified 700 genes whose expression levels were predictive of chronic lymphocytic leukemia (CLL) in a genome-wide gene expression analysis of prediagnostic blood from future cases and matched controls. We hypothesized that a large fraction of these markers were likely related to early disease manifestations. Here we aim to gain a better understanding of the natural history of the identified markers by comparing results from our prediagnostic analysis, the only prediagnostic analysis to date, to results obtained from a meta-analysis of a series of publically available transcriptomics profiles obtained in incident CLL cases and controls.

    Results: We observed considerable overlap between the results from our prediagnostic study and the clinical CLL signals (p-value for overlap Bonferroni significant markers 0.01; p-value for overlap nominal significant markers < 2.20e-16). We observed similar patterns with time to diagnosis and similar functional annotations for the markers that were identified in both settings compared to the markers that were only identified in the prediagnostic study. These results suggest that both gene sets operate in similar pathways.

    Conclusion: An overlap exists between expression levels of genes predictive of CLL identified in prediagnostic blood and expression levels of genes associated to CLL at the clinical stage. Our analysis provides insight in a set of genes for which expression levels can be used to follow the time-course of the disease; providing an opportunity to study CLL progression in more detail in future studies.

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