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  • 151.
    Martinez Barrio, Alvaro
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Soeria-Atmadja, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Nistér, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Gustafsson, Mats G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Signals and Systems Group.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    EVALLER: a web server for in silico assessment of potential protein allergenicity2007In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, p. W694-W700Article in journal (Refereed)
    Abstract [en]

    Bioinformatics testing approaches for protein allergenicity, involving amino acid sequence comparisons, have evolved appreciably over the last several years to increased sophistication and performance. EVALLER, the web server presented in this article is based on our recently published 'Detection based on Filtered Length-adjusted Allergen Peptides' (DFLAP) algorithm, which affords in silico determination of potential protein allergenicity of high sensitivity and excellent specificity. To strengthen bioinformatics risk assessment in allergology EVALLER provides a comprehensive outline of its judgment on a query protein's potential allergenicity. Each such textual output incorporates a scoring figure, a confidence numeral of the assignment and information on high- or low-scoring matches to identified allergen-related motifs, including their respective location in accordingly derived allergens. The interface, built on a modified Perl Open Source package, enables dynamic and color-coded graphic representation of key parts of the output. Moreover, pertinent details can be examined in great detail through zoomed views. The server can be accessed at http://bioinformatics.bmc.uu.se/evaller.html.

  • 152.
    Martínez Barrio, Álvaro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Novel Bioinformatics Applications for Protein Allergology, Genome-Wide Association and Retrovirology Studies2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Recently, the pace of growth in the amount of data sources within Life Sciences has increased exponentially until pose a difficult problem to efficiently manage their integration. The data avalanche we are experiencing may be significant for a turning point in science, with a change of orientation from proprietary to publicly available data and a concomitant acceptance of studies based on the latter. To investigate these issues, a Network of Excellence (EMBRACE) was launched with the aim to integrate the major databases and the most popular bioinformatics software tools. The focus of this thesis is therefore to approach the problem of seamlessly integrating varied data sources and/or distributed research tools.

    In paper I, we have developed a web service to facilitate allergenicity risk assessment, based on allergen descriptors, in order to characterize proteins with the potential for sensitization and cross-reactivity.

    In paper II, a web service was developed which uses a lightweight protocol to integrate human endogenous retrovirus (ERV) data within a public genome browser. This new data catalogue and many other publicly available sources were integrated and tested in a bioinformatics-rich client application.

    In paper III, GeneFinder, a distributed tool for genome-wide association studies, was developed and tested. Useful information based on a particular genomic region can be easily retrieved and assessed.

    Finally, in paper IV, we developed a prototype pipeline to mine the dog genome for endogenous retroviruses and displaying the transcriptional landscape of these retroviral integrations. Moreover, we further characterized a group that until this point was believed to be primate-specific. Our results also revealed that the dog has been very effective in protecting itself from such integrations.

    This work integrates different applications in the fields of protein allergology, biotechnology, genome association studies and endogenous retroviruses.

    List of papers
    1. EVALLER: a web server for in silico assessment of potential protein allergenicity
    Open this publication in new window or tab >>EVALLER: a web server for in silico assessment of potential protein allergenicity
    Show others...
    2007 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, p. W694-W700Article in journal (Refereed) Published
    Abstract [en]

    Bioinformatics testing approaches for protein allergenicity, involving amino acid sequence comparisons, have evolved appreciably over the last several years to increased sophistication and performance. EVALLER, the web server presented in this article is based on our recently published 'Detection based on Filtered Length-adjusted Allergen Peptides' (DFLAP) algorithm, which affords in silico determination of potential protein allergenicity of high sensitivity and excellent specificity. To strengthen bioinformatics risk assessment in allergology EVALLER provides a comprehensive outline of its judgment on a query protein's potential allergenicity. Each such textual output incorporates a scoring figure, a confidence numeral of the assignment and information on high- or low-scoring matches to identified allergen-related motifs, including their respective location in accordingly derived allergens. The interface, built on a modified Perl Open Source package, enables dynamic and color-coded graphic representation of key parts of the output. Moreover, pertinent details can be examined in great detail through zoomed views. The server can be accessed at http://bioinformatics.bmc.uu.se/evaller.html.

    National Category
    Medical and Health Sciences Signal Processing
    Research subject
    Electrical Engineering with specialization in Signal Processing
    Identifiers
    urn:nbn:se:uu:diva-99645 (URN)10.1093/nar/gkm370 (DOI)000255311500128 ()17537818 (PubMedID)
    Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2017-12-13Bibliographically approved
    2. Annotation and visualization of endogenous retroviral sequences using the Distributed Annotation System (DAS) and eBioX
    Open this publication in new window or tab >>Annotation and visualization of endogenous retroviral sequences using the Distributed Annotation System (DAS) and eBioX
    Show others...
    2009 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 10 Suppl. 6, p. S18-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: The Distributed Annotation System (DAS) is a widely used network protocol for sharing biological information. The distributed aspects of the protocol enable the use of various reference and annotation servers for connecting biological sequence data to pertinent annotations in order to depict an integrated view of the data for the final user. RESULTS: An annotation server has been devised to provide information about the endogenous retroviruses detected and annotated by a specialized in silico tool called RetroTector. We describe the procedure to implement the DAS 1.5 protocol commands necessary for constructing the DAS annotation server. We use our server to exemplify those steps. Data distribution is kept separated from visualization which is carried out by eBioX, an easy to use open source program incorporating multiple bioinformatics utilities. Some well characterized endogenous retroviruses are shown in two different DAS clients. A rapid analysis of areas free from retroviral insertions could be facilitated by our annotations. CONCLUSION: The DAS protocol has shown to be advantageous in the distribution of endogenous retrovirus data. The distributed nature of the protocol is also found to aid in combining annotation and visualization along a genome in order to enhance the understanding of ERV contribution to its evolution. Reference and annotation servers are conjointly used by eBioX to provide visualization of ERV annotations as well as other data sources. Our DAS data source can be found in the central public DAS service repository, http://www.dasregistry.org, or at http://loka.bmc.uu.se/das/sources.

    Place, publisher, year, edition, pages
    BioMed Central, 2009
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-106783 (URN)10.1186/1471-2105-10-S6-S18 (DOI)000267522200018 ()19534743 (PubMedID)
    Available from: 2009-07-03 Created: 2009-07-02 Last updated: 2017-12-13Bibliographically approved
    3. GeneFinder: "in silico" positional cloning of trait genes
    Open this publication in new window or tab >>GeneFinder: "in silico" positional cloning of trait genes
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Motivation: Positional cloning of trait genes is extremely laborious and the amount of information available on gene function in different organisms is increasing so rapidly that it is hard for a research group to collect all the relevant information from a number of data sources without performing a large number of manual and time consuming searches.

    Results: A web service application named GeneFinder was designed and implemented. It collects selected available information related to trait loci within a given chromosomal region that control a specific phenotype. The information contains details on gene function, disease conditions, tissue expression as well as predicted gene homologies in several other species. The information gathered is further ordered by a special-purpose ranking algorithm. A web interface to the GeneFinder web service was also developed where the results are presented in a ranked list easing its interpretation. We explain the design of the architecture, show how our web interface works, and finally test a candidate region.

    Availability: GeneFinder is publicly available and free to use. The web interface is available at http://www.genefinder.org/.

    Keywords
    data integration, web services, GWAS, genome-wide association studies
    National Category
    Medical Genetics Bioinformatics and Systems Biology
    Research subject
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-112124 (URN)
    Projects
    EMBRACE
    Available from: 2010-01-09 Created: 2010-01-09 Last updated: 2018-01-12
    4. Data mining of the dog genome reveals novel Canine Endogenous Retroviruses(CfERVs)
    Open this publication in new window or tab >>Data mining of the dog genome reveals novel Canine Endogenous Retroviruses(CfERVs)
    Show others...
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Mining the dog genome for canine endogenous retroviruses (CfERV) using the program RetroTector© identified 407 CfERVs (0.15% of the total genome size). Phylogenetic analysis showed that the majority of these CfERVs belong to the gammaretroviridae (n=313) genus. In this group, we found 33 integrated CfERVs with similarity to the human HERV-Fc1. Eighteen of them had conserved open reading frames open and seven of the 18 were recent integrations (≤ 5% LTR divergence). Some of these CfERVs may have potential for active retrotransposition and could actively contribute to the plasticity of canine genomes. Similar to other vertebrates, betaretroviruses (n=28) was the second most common group. In addition, four spuma-like and four gypsy-like CfERVs were identified, the latter group being rare in vertebrate genomes. Moreover, we identified 55 CfERVs that could not be classified unambiguously to any known retroviral genera. The integration landscape shows that all dog chromosomes have CfERV integrations with non-uniform distribution both along and across chromosomes. Some regions were essentially devoid of CfERVs whereas other regions had large numbers. Notably, in a comparison between dog and human genomes, CfERV were approximately one fifth of the amount of HERVs found. Species-specific mechanisms for purging and protection against retroviral infections are suggested to act in the dog genome. The CfERV integration pattern showed that a substantial fraction of annotated genes were found within 100 kb distance from annotated proviruses. The majority of such integrations were placed in antisense orientation relative to the transcriptional direction of the neighboring chromosomal genes. In conclusion, our results from Canis familiaris genome analysis support the notion that different mammals may interact distinctively with endogenous retroviruses.

    Keywords
    endogenous retroviruses, ERV, dog, canine
    National Category
    Bioinformatics and Systems Biology Microbiology in the medical area
    Research subject
    Medical Virology
    Identifiers
    urn:nbn:se:uu:diva-112125 (URN)
    Projects
    EMBRACE
    Available from: 2010-01-09 Created: 2010-01-09 Last updated: 2018-01-12
  • 153.
    Mellberg, Sofie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bahram, Fuad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hayashi, Makoto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rennel, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Orzechowski Westholm, Jakub
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindahl, Per
    Cross, Michael J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis2009In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 5, p. 1490-1502Article in journal (Refereed)
    Abstract [en]

    To define molecular events accompanying formation of the 3-dimensional   (3D) vascular tube, we have characterized gene expression during vascular endothelial growth factor (VEGF)-induced tubular morphogenesis of endothelial cells. Microarray analyses were performed comparing gene induction in growth-arrested, tube-forming endothelial cells harvested from 3D collagen cultures to that in proliferating endothelial cells cultured on fibronectin. Differentially expressed genes were clustered and analyzed for specific endothelial expression through publicly  available datasets. We validated the contribution of one of the identified genes vascular endothelial protein tyrosine phosphatase   (VE-PTP), to endothelial morphogenesis. Silencing of VE-PTP expression was accompanied by increased VEGF receptor-2 (VEGFR2) tyrosine  phosphorylation and activation of downstream signaling pathways. The  increased VEGFR2 activity promoted endothelial cell cycle progression,   overcoming the G(0)/G(1) arrest associated with organization into   tubular structures in the 3D cultures. Proximity ligation showed close   association between VEGFR2 and VE-PTP in resting cells. Activation of   VEGFR2 by VEGF led to rapid loss of association, which was resumed with   time in parallel with decreased receptor activity. In conclusion, we   have identified genes, which may serve critical functions in formation  of the vascular tube. One of these, VE-PTP, regulates VEGFR2 activity  thereby modulating the VEGF-response during angiogenesis.-Mellberg, S.,  Dimberg, A., Bahram, F., Hayashi, M., Rennel, E., Ameur, A., Westholm,   J. O., Larsson, E., Lindahl, P., Cross, M. J., Claesson-Welsh, L.   Transcriptional profiling reveals a critical role for tyrosine   phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis. FASEB J. 23, 1490-1502 (2009)

  • 154. Midelfart, H
    et al.
    Komorowski, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, The Linnaeus Centre for Bioinformatics.
    Nørsett, K
    Yadetie, F
    Sandvik, A.K.
    Learning rough set classifiers from gene expressions and clinical data2002In: Fundamenta Informaticae, Vol. 53, no 2, p. 155-183Article in journal (Refereed)
    Abstract [en]

    Biological research is currently undergoing a revolution. With the advent of microarray technology the behavior of thousands of genes can be measured simultaneously. This capability opens a wide range of research opportunities in biology, but the technology generates a vast amount of data that cannot be handled manually. Computational analysis is thus a prerequisite for the success of this technology, and research and development of computational tools for microarray analysis are of great importance.

    One application of microarray technology is cancer studies where supervised learning may be used for predicting tumor subtypes and clinical parameters. We present a general Rough Set approach for classification of tumor samples analyzed with microarrays. This approach is tested on a data set of gastric tumors, and we develop classifiers for six clinical parameters.

    One major obstacle in training classifiers from microarray data is that the number of objects is much smaller that the number of attributes. We therefore introduce a feature selection method based on bootstrapping for selecting genes that discriminate significantly between the classes, and study the performance of this method.

    Moreover, the efficacy of several learning and discretization methods implemented in the ROSETTA system [18] is examined. Their performance is compared to that of linear and quadratic discrimination analysis. The classifiers are also biologically validated. One of the best classifiers is selected for each clinical parameter, and the connection between the genes used in these classifiers and the parameters are compared to the establish knowledge in the biomedical literature.

  • 155. Mikhail, Fady M.
    et al.
    Descartes, Maria
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bruder, Carl E. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carroll, Andrew J.
    A previously unrecognized microdeletion syndrome on chromosome 22 band q11.2 encompassing the BCR gene2007In: American journal of medical genetics. Part A, ISSN 1552-4825, Vol. 143A, no 18, p. 2178-2184Article in journal (Refereed)
    Abstract [en]

    Susceptibility of the chromosome 22q11.2 region to rearrangements has been recognized on the basis of common clinical disorders such as the DiGeorge/velocardiofacial syndrome (DG/VCFs). Recent evidence has implicated low-copy repeats (LCRs); also known as segmental duplications; on 22q as mediators of nonallelic homologous recombination (NAHR) that result in rearrangements of 22q11.2. It has been shown that both deletion and duplication events can occur as a result of NAHR caused by unequal crossover of LCRs. Here we report on the clinical, cytogenetic and array CGH studies of a 15-year-old Hispanic boy with history of learning and behavior problems. We suggest that he represents a previously unrecognized microdeletion syndrome on chromosome 22 band q11.2 just telomeric to the DG/VCFs typically deleted region and encompassing the BCR gene. Using a 32K BAC array CGH chip we were able to refine and precisely narrow the breakpoints of this microdeletion, which was estimated to be 1.55-1.92 Mb in size and to span approximately 20 genes. This microdeletion region is flanked by LCR clusters containing several modules with a very high degree of sequence homology (>95%), and therefore could play a causal role in its origin.

  • 156. Mikhail, Fady M.
    et al.
    Sathienkijkanchai, Achara
    Robin, Nathaniel H.
    Prucka, Sandra
    Biggerstaff, Julie Sanford
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bruder, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carroll, Andrew J.
    Overlapping phenotype of wolf-hirschhorn and beckwith-wiedemann syndromes in a girl with der(4)t(4; 1 1)(pter;pter)2007In: American Journal of Medical Genetics, Part A, ISSN 1552-4825, Vol. 143, no 15, p. 1760-1766Article in journal (Refereed)
    Abstract [en]

    We report on an 8-month-old girl with a novel unbalanced chromosomal rearrangement, consisting of a terminal deletion of 4p and a paternal duplication of terminal 11p. Each of these is associated with the well-known clinical phenotypes of Wolf-Hirschhorn syndrome (WHS) and Beckwith-Wiedemann syndrome (BWS), respectively. She presented for clinical evaluation of dysmorphic facial features, developmental delay, atrial septal defect (ASD), and left hydro-nephrosis. High-resolution cytogenetic analysis revealed a normal female karyotype, but subtelomeric fluorescence in situ hybridization (FISH) analysis revealed a der(4)t(4;11) (pter;pter). Both FISH and microarray CGH studies clearly demonstrated that the WHS critical regions 1 and 2 were deleted, and that the BWS imprinted domains (ID) 1 and 2 were duplicated on the der(4). Parental chromosome analysis revealed that the father carried a cryptic balanced t(4;11)(pter;pter). As expected, our patient manifests findings of both WHS (a growth retardation syndrome) and BWS (an overgrowth syndrome). We compare her unique phenotypic features with those that have been reported for both syndromes.

  • 157. Mischak, Harald
    et al.
    Kolch, Walter
    Aivaliotis, Michalis
    Bouyssie, David
    Court, Magali
    Dihazi, Hassan
    Dihazi, Gry H.
    Franke, Julia
    Garin, Jerome
    de Peredo, Anne Gonzalez
    Iphoefer, Alexander
    Jaensch, Lothar
    Lacroix, Chrystelle
    Makridakis, Manousos
    Masselon, Christophe
    Metzger, Jochen
    Monsarrat, Bernard
    Mrug, Michal
    Norling, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Novak, Jan
    Pich, Andreas
    Pitt, Andrew
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Siwy, Justyna
    Suzuki, Hitoshi
    Thongboonkerd, Visith
    Wang, Li-Shun
    Zoidakis, Jerome
    Zuerbig, Petra
    Schanstra, Joost P.
    Vlahou, Antonia
    Comprehensive human urine standards for comparability and standardization in clinical proteome analysis2010In: Proteomics - Clinical Applications, ISSN 1862-8346, Vol. 4, no 4, p. 464-478Article in journal (Refereed)
    Abstract [en]

    Purpose: Urine proteomics is emerging as a powerful tool for biomarker discovery. The purpose of this study is the development of a well-characterized "real life" sample that can be used as reference standard in urine clinical proteomics studies. Experimental design: We report on the generation of male and female urine samples that are extensively characterized by different platforms and methods (CE-MS, LC-MS, LC-MS/MS, 1-D gel analysis in combination with nano-LC MS/MS (using LTQ-FT ultra), and 2-DE-MS) for their proteome and peptidome. In several cases analysis involved a definition of the actual biochemical entities, i.e. proteins/peptides associated with molecular mass and detected PTMs and the relative abundance of these compounds. Results: The combination of different technologies allowed coverage of a wide mass range revealing the advantages and complementarities of the different technologies. Application of these samples in "inter-laboratory" and "inter-platform" data comparison is also demonstrated. Conclusions and clinical relevance: These well-characterized urine samples are freely available upon request to enable data comparison especially in the context of biomarker discovery and validation studies. It is also expected that they will provide the basis for the comprehensive characterization of the urinary proteome.

  • 158. Mishchenko, Kateryna
    et al.
    Holmgren, Sverker
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Rönnegård, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Newton-type methods for REML estimation in genetic analysis of quantitative traits2008In: Journal of Computational Methods in Sciences and Engineering, ISSN 1472-7978, E-ISSN 1875-8983, Vol. 8, p. 53-67Article in journal (Refereed)
  • 159.
    Motallebipour, Mehdi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bysani, Madhusudhan Reddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Patra, Kalicharan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Mangion, Jonathan
    Barker, Melissa
    McKernan, Kevin
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq2009In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 10, no 11, p. R129-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The forkhead box/winged helix family members FOXA1, FOXA2, and FOXA3 are of high importance in development and specification of the hepatic linage and the continued expression of liver-specific genes. RESULTS: Here, we present a genome-wide location analysis of FOXA1 and FOXA3 binding sites in HepG2 cells through chromatin immunoprecipitation with detection by sequencing (ChIP-seq) studies and compare these with our previous results on FOXA2. We found that these factors often bind close to each other in different combinations and consecutive immunoprecipitation of chromatin for one and then a second factor (ChIP-reChIP) shows that this occurs in the same cell and on the same DNA molecule, suggestive of molecular interactions. Using co-immunoprecipitation, we further show that FOXA2 interacts with both FOXA1 and FOXA3 in vivo, while FOXA1 and FOXA3 do not appear to interact. Additionally, we detected diverse patterns of trimethylation of lysine 4 on histone H3 (H3K4me3) at transcriptional start sites and directionality of this modification at FOXA binding sites. Using the sequence reads at polymorphic positions, we were able to predict allele specific binding for FOXA1, FOXA3, and H3K4me3. Finally, several SNPs associated with diseases and quantitative traits were located in the enriched regions. CONCLUSIONS: We find that ChIP-seq can be used not only to create gene regulatory maps but also to predict molecular interactions and to inform on the mechanisms for common quantitative variation.

  • 160.
    Motallebipour, Mehdi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Koch, Christoph
    Wellcome Trust Sanger Institute.
    Dunham, Ian
    Wellcome Trust Sanger Institute.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Ericsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Novel genes in cell cycle control and lipid metabolism with dynamically regulated binding sites for sterol regulatory element-binding protein 1 and RNA polymerase II in HepG2 cells detected by chromatin immunoprecipitation with microarray detection2009In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, no 7, p. 1878-1890Article in journal (Refereed)
    Abstract [en]

    Sterol regulatory element-binding proteins 1 and 2 (SREBP-1 and SREBP-2) are important regulators of genes involved in cholesterol and fatty acid metabolism, but have also been implicated in the regulation of the cell cycle and have been associated with the pathogenesis of type 2 diabetes, atherosclerosis and obesity, among others. In this study, we aimed to characterize the binding sites of SREBP-1 and RNA polymerase II through chromatin immunoprecipitation and microarray analysis in 1% of the human genome, as defined by the Encyclopaedia of DNA Elements consortium, in a hepatocellular carcinoma cell line (HepG2). Our data identified novel binding sites for SREBP-1 in genes directly or indirectly involved in cholesterol metabolism, e.g. apolipoprotein C-III (APOC3). The most interesting biological findings were the binding sites for SREBP-1 in genes for host cell factor C1 (HCFC1), involved in cell cycle regulation, and for filamin A (FLNA). For RNA polymerase II, we found binding sites at classical promoters, but also in intergenic and intragenic regions. Furthermore, we found evidence of sterol-regulated binding of SREBP-1 and RNA polymerase II to HCFC1 and FLNA. From the results of this work, we infer that SREBP-1 may be involved in processes other than lipid metabolism.

  • 161.
    Motallebipour, Mehdi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rada-Iglesias, Alvaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Two polypyrimidine tracts in the nitric oxide synthase 2 gene: similar regulatory sequences with different properties2010In: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 37, no 4, p. 2021-2030Article in journal (Refereed)
    Abstract [en]

    We reported previously that the polymorphic polypyrimidine CCTTT-microsatellite in the regulatory region of nitric oxide synthase 2 (NOS2) bound nuclear proteins in vitro. In the present work, we aimed to characterize and investigate a potential regulatory role of the CCTTT-microsatellite in NOS2 expression. Therefore, we performed gel-shift, S1-nuclease, and chromatin immunoprecipitation (ChIP) assays. In vitro experiments showed that the microsatellite formed triplex-DNA both with and without superhelical constraint. We also found that the CCTTT-microsatellite and an apparently similar CT-repeat in the first intron of NOS2 were specifically cleaved by S1-nuclease, when cloned into a supercoiled plasmid. In vitro data suggested that the CCTTT-microsatellite bound both polypyrimidine tract-binding protein (PTBP1) and heterogeneous nuclear ribonucleoprotein K (hnRNPK). On the contrary, ChIP revealed binding of PTBP1 and hnRNPK rather to the CT-repeat in the first intron than to the CCTTT-microsatellite. Enrichment for RNA polymerase II and acetylated histones H3 and H4 was also detected at the intronic site. We suggest that both PTBP1 and hnRNPK binds the single strand of the triplex-DNA formed at the CT-repeat in the first intron and that this interaction could be involved in the regulation of NOS2 expression.

  • 162.
    Moulton, V
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, The Linnaeus Centre for Bioinformatics.
    Steel, M
    Peeling phylogenetic 'oranges'2004In: Advances in Applied Mathematics, Vol. 33, no 4, p. 710-727Article in journal (Refereed)
    Abstract [en]

    We investigate the combinatorics of a topological space that is generated by the set of edge-weighted finite trees. This space arises by multiplying the weights of edges on paths in trees and is closely connected to tree reconstruction problems involving finite state Markov processes. We show that this space is a contractible finite CW-complex whose face poset can be described via a partial order on semilabelled forests. We then describe some combinatorial properties of this poset, showing that, for example, it is pure, thin and contractible. (C) 2004 Elsevier Inc. All rights reserved.

  • 163.
    Nettelblad, Carl
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Carlborg, Örjan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Pino-Querido, Ania
    University of Santiago de Compostela, Department of Genetics.
    Álvarez-Castro, José M.
    University of Santiago de Compostela, Department of Genetics.
    Coherent estimates of genetic effects with missing information2012In: Open Journal of Genetics, ISSN 2162-4453, E-ISSN 2162-4461, Vol. 2, p. 31-38Article in journal (Refereed)
  • 164.
    Nettelblad, Carl
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Carlborg, Örjan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Álvarez-Castro, José M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Assessing orthogonality and statistical properties of linear regression methods for interval mapping with partial information2010Report (Other academic)
  • 165.
    Nord, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hartmann, Christian
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Piotrowski, Arkadiusz
    Bogdan, Adam
    Kloc, Wojciech
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    von Deimling, Andreas
    Bruder, Carl E. G.
    Southern Research Institute, Birmingham, AL, USA.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    de Ståhl, Teresita Díaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array2009In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 11, no 6, p. 803-818Article in journal (Refereed)
    Abstract [en]

    Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.

  • 166.
    Nord, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    de Ståhl, Teresita Díaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma2010In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 126, no 6, p. 1390-1402Article in journal (Refereed)
    Abstract [en]

    Urinary bladder cancer is a heterogeneous disease with tumors ranging from papillary noninvasive (stage Ta) to solid muscle infiltrating tumors (stage T2+). The risk of progression and death for the most frequent diagnosed type, Ta, is low, but the high incidence of recurrences has a significant effect on the patients' quality of life and poses substantial costs for health care systems. Consequently, the purpose of this study was to search for predictive factors of recurrence on the basis of genetic profiling. A clinically well characterized cohort of Ta bladder carcinomas, selected by the presence or absence of recurrences, was evaluated by an integrated analysis of DNA copy number changes and gene expression (clone-based 32K, respectively, U133Plus2.0 arrays). Only a few chromosomal aberrations have previously been defined in superficial bladder cancer. Surprisingly, the profiling of Ta tumors with a high-resolution array showed that DNA copy alterations are relatively common in this tumor type. Furthermore, we observed an overrepresentation of focal amplifications within high-grade and recurrent cases. Known (FGFR3, CCND1, MYC, MDM2) and novel candidate genes were identified within the loci. For example, MYBL2, a nuclear transcription factor involved in cell-cycle progression; YWHAB, an antiapoptotic protein; and SDC4, an important component of focal adhesions represent interesting candidates detected within two amplicons on chromosome 20, for which DNA amplification correlated with transcript up-regulation. The observed overrepresentation of amplicons within high-grade and recurrent cases may be clinically useful for the identification of patients who will benefit from a more aggressive therapy.

  • 167.
    Novotny, Marian
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Seibert, Marvin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kleywegt, Gerard
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    On the precision of calculated solvent-accessible surface areas2007In: Acta Crystallographica Section D: Biological Crystallography, ISSN 0907-4449, E-ISSN 1399-0047, Vol. 63, no 2, p. 270-274Article in journal (Refereed)
    Abstract [en]

    The fact that protein structures are dynamic by nature and that structure models determined by X-ray crystallography, electron microscopy (EM) and nuclear magnetic resonance (NMR) spectroscopy have limited accuracy limits the precision with which derived properties can be reported. Here, the issue of the precision of calculated solvent-accessible surface areas (ASAs) is addressed. A number of protein structures of different sizes were selected and the effect of random shifts applied to the atomic coordinates on ASA values was investigated. Standard deviations of the ASA calculations were found to range from ∼10 to ∼80  Å2. Similar values are obtained for a handful of cases in the Protein Data Bank (PDB) where `ensembles' of crystal structures were refined against the same data set. The ASA values for 69 hen egg-white lysozyme structures were calculated and a standard deviation of the ASA of 81  Å2 was obtained (the average ASA value was 6571  Å2). The calculated ASA values do not show any correlation with factors such as resolution or overall temperature factors. A molecular-dynamics (MD) trajectory of lysozyme was also analysed. The ASA values during the simulation covered a range of more than 800  Å2. If different programs are used, the ASA values obtained for one small protein show a spread of almost 600  Å2. These results suggest that in most cases reporting ASA values with a precision better than 10  Å2 is probably not realistic and a precision of 50–100  Å2 would seem prudent. The precision of buried surface-area calculations for complexes is also discussed.

  • 168.
    Näslund, Kalle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Saetre, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    von Salomé, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Bergström, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Jareborg, Niclas
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Genome-wide prediction of human VNTRs2005In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 85, no 1, p. 24-35Article in journal (Refereed)
    Abstract [en]

    Polymorphic minisatellites, also known as variable number of tandem repeats (VNTRs), are tandem repeat regions that show variation in the number of repeat units among chromosomes in a population. Currently, there are no general methods for predicting which minisatellites have a high probability of being polymorphic, given their sequence characteristics. An earlier approach has focused on potentially highly polymorphic and hypervariable minisatellites, which make up only a small fraction of all minisatellites in the human genome. We have developed a model, based on available minisatellite and VNTR sequence data, that predicts the probability that a minisatellite (unit size > or = 6 bp) identified by the computer program Tandem Repeats Finder is polymorphic (VNTR). According to the model, minisatellites with high copy number and high degree of sequence similarity are most likely to be VNTRs. This approach was used to scan the draft sequence of the human genome for VNTRs. A total of 157,549 minisatellite repeats were found, of which 29,224 are predicted to be VNTRs. Contrary to previous results, VNTRs appear to be widespread and abundant throughout the human genome, with an estimated density of 9.1 VNTRs/Mb.

  • 169. Nørsett, Kristin G
    et al.
    Laegreid, Astrid
    Midelfart, Herman
    Yadetie, Fekadu
    Erlandsen, Sten Even
    Falkmer, Sture
    Grønbech, Jon E
    Waldum, Helge L
    Komorowski, Jan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, The Linnaeus Centre for Bioinformatics.
    Sandvik, Arne K
    Gene expression based classification of gastric carcinoma.2004In: Cancer Lett, ISSN 0304-3835, Vol. 210, no 2, p. 227-37Article in journal (Refereed)
  • 170.
    Olsson, Mia
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Meadows, Jennifer R. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Truve, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli Rosengren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Puppo, Francesca
    Mauceli, Evan
    Quilez, Javier
    Tonomura, Noriko
    Zanna, Giordana
    Jose Docampo, Maria
    Bassols, Anna
    Avery, Anne C.
    Karlsson, Elinor K.
    Thomas, Anne
    Kastner, Daniel L.
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sanchez, Armand
    Hedhammar, Åke
    Remmers, Elaine F.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ferrer, Lluis
    Tintle, Linda
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 3, p. e1001332-Article in journal (Refereed)
    Abstract [en]

    Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 x 10(-6), p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p, < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

  • 171.
    Orzechowski Westholm, Jakub
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Genome-wide Studies of Transcriptional Regulation in Yeast2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, nutrient signalling in yeast is used as a model to study several features of gene regulation, such as combinatorial gene regulation, the role of motif context and chromatin modifications. The nutrient signalling system in yeast consists of several pathways that transmit signals about the availability of key nutrients, and regulate the transcription of a large part of the genome. Some of the signalling pathways are also conserved in other eukaryotic species where they are implicated in processes such as aging and in human disease.

     

    Combinatorial gene regulation is examined in papers I and II. In paper I, the role of Mig1, Mig2 and Mig3 is studied. To elucidate how the three proteins contribute to the control of gene expression, we used microarrays to study the expression of all yeast genes in the wild type and in all seven possible combinations of mig1, mig2 and mig3 deletions. In paper II, a similar strategy is used to investigate Gis1 and Rph1, two related transcription factors. Our results reveal that Rph1 is involved in nutrient signalling together with Gis1, and we find that both the activities and the target specificities of Gis1 and Rph1 depend on the growth phase.

     

    Paper III describes ContextFinder, a program for identifying constraints on sequence motif locations and orientations. ContextFinder was used to analyse over 300 cases of motifs that are enriched in experimentally selected groups of yeast promoters. Our results suggest that motif context frequently is important for stable DNA binding and/or regulatory activity of transcription factors.

     

    In paper IV, we investigated how gene expression changes resulting from nitrogen starvation are accompanied by chromatin modifications. Activation of gene expression is concentrated to specific genomic regions. It is associated with nucleosome depletion (in both promoters and coding regions) and increased levels of H3K9ac (but not H4K5ac).

    List of papers
    1. Combinatorial control of gene expression by the three yeast repressors Mig1, Mig2 and Mig3
    Open this publication in new window or tab >>Combinatorial control of gene expression by the three yeast repressors Mig1, Mig2 and Mig3
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    2008 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, p. 601-Article in journal (Refereed) Published
    Abstract [en]

    Background: Expression of a large number of yeast genes is repressed by glucose. The zinc finger protein Mig1 is the main effector in glucose repression, but yeast also has two related proteins: Mig2 and Mig3. We have used microarrays to study global gene expression in all possible combinations of mig1, mig2 and mig3 deletion mutants. Results: Mig1 and Mig2 repress a largely overlapping set of genes on 2% glucose. Genes that are upregulated in a mig1 mig2 double mutant were grouped according to the contribution of Mig2. Most of them show partially redundant repression, with Mig1 being the major repressor, but some genes show complete redundancy, and some are repressed only by Mig1. Several redundantly repressed genes are involved in phosphate metabolism. The promoters of these genes are enriched for Pho4 sites, a novel GGGAGG motif, and a variant Mig1 site which is absent from genes repressed only by Mig1. Genes repressed only by Mig1 on 2% glucose include the hexose transporter gene HXT4, but Mig2 contributes to HXT4 repression on 10% glucose. HXT6 is one of the few genes that are more strongly repressed by Mig2. Mig3 does not seem to overlap in function with Mig1 and Mig2. Instead, Mig3 downregulates the SIR2 gene encoding a histone deacetylase involved in gene silencing and the control of aging. Conclusions: Mig2 fine-tunes glucose repression by targeting a subset of the Mig1-repressed genes, and by responding to higher glucose concentrations. Mig3 does not target the same genes as Mig1 and Mig2, but instead downregulates the SIR2 gene.

    National Category
    Natural Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-87130 (URN)10.1186/1471-2164-9-601 (DOI)000263109200001 ()19087243 (PubMedID)
    Available from: 2008-12-17 Created: 2008-12-17 Last updated: 2017-12-14Bibliographically approved
    2. Yeast JmjC domain proteins Gis1 and Rph1 have dual roles in growth phase-dependent gene expression
    Open this publication in new window or tab >>Yeast JmjC domain proteins Gis1 and Rph1 have dual roles in growth phase-dependent gene expression
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    (English)Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-99198 (URN)
    Available from: 2009-03-10 Created: 2009-03-10 Last updated: 2010-01-14
    3.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    4. Genome-wide chromatin profiling of the response to nitrogen starvation in the fission yeast Schizosaccharomyces pombe
    Open this publication in new window or tab >>Genome-wide chromatin profiling of the response to nitrogen starvation in the fission yeast Schizosaccharomyces pombe
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    (English)Manuscript (Other (popular science, discussion, etc.))
    Identifiers
    urn:nbn:se:uu:diva-99201 (URN)
    Available from: 2009-03-10 Created: 2009-03-10 Last updated: 2011-06-28
  • 172.
    Orzechowski Westholm, Jakub
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Nordberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Ronne, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Combinatorial control of gene expression by the three yeast repressors Mig1, Mig2 and Mig32008In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, p. 601-Article in journal (Refereed)
    Abstract [en]

    Background: Expression of a large number of yeast genes is repressed by glucose. The zinc finger protein Mig1 is the main effector in glucose repression, but yeast also has two related proteins: Mig2 and Mig3. We have used microarrays to study global gene expression in all possible combinations of mig1, mig2 and mig3 deletion mutants. Results: Mig1 and Mig2 repress a largely overlapping set of genes on 2% glucose. Genes that are upregulated in a mig1 mig2 double mutant were grouped according to the contribution of Mig2. Most of them show partially redundant repression, with Mig1 being the major repressor, but some genes show complete redundancy, and some are repressed only by Mig1. Several redundantly repressed genes are involved in phosphate metabolism. The promoters of these genes are enriched for Pho4 sites, a novel GGGAGG motif, and a variant Mig1 site which is absent from genes repressed only by Mig1. Genes repressed only by Mig1 on 2% glucose include the hexose transporter gene HXT4, but Mig2 contributes to HXT4 repression on 10% glucose. HXT6 is one of the few genes that are more strongly repressed by Mig2. Mig3 does not seem to overlap in function with Mig1 and Mig2. Instead, Mig3 downregulates the SIR2 gene encoding a histone deacetylase involved in gene silencing and the control of aging. Conclusions: Mig2 fine-tunes glucose repression by targeting a subset of the Mig1-repressed genes, and by responding to higher glucose concentrations. Mig3 does not target the same genes as Mig1 and Mig2, but instead downregulates the SIR2 gene.

  • 173.
    Orzechowski Westholm, Jakub
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Tronnersjö, Susanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nordberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Ronne, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yeast JmjC domain proteins Gis1 and Rph1 have dual roles in growth phase-dependent gene expressionManuscript (Other academic)
  • 174.
    Orzechowski Westholm, Jakub
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Tronnersjö, Susanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nordberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsson, Ida
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ronne, Hans
    Gis1 and Rph1 Regulate Glycerol and Acetate Metabolism in Glucose Depleted Yeast Cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, p. e31577-Article in journal (Refereed)
    Abstract [en]

    Aging in organisms as diverse as yeast, nematodes, and mammals is delayed by caloric restriction, an effect mediated by the nutrient sensing TOR, RAS/cAMP, and AKT/Sch9 pathways. The transcription factor Gis1 functions downstream of these pathways in extending the lifespan of nutrient restricted yeast cells, but the mechanisms involved are still poorly understood. We have used gene expression microarrays to study the targets of Gis1 and the related protein Rph1 in different growth phases. Our results show that Gis1 and Rph1 act both as repressors and activators, on overlapping sets of genes as well as on distinct targets. Interestingly, both the activities and the target specificities of Gis1 and Rph1 depend on the growth phase. Thus, both proteins are associated with repression during exponential growth, targeting genes with STRE or PDS motifs in their promoters. After the diauxic shift, both become involved in activation, with Gis1 acting primarily on genes with PDS motifs, and Rph1 on genes with STRE motifs. Significantly, Gis1 and Rph1 control a number of genes involved in acetate and glycerol formation, metabolites that have been implicated in aging. Furthermore, several genes involved in acetyl CoA metabolism are downregulated by Gis1.

  • 175. Ottervald, Jan
    et al.
    Franzén, Bo
    Nilsson, Kerstin
    Andersson, Lars I.
    Khademi, Mohsen
    Eriksson, Bodil
    Kjellstrom, Sven
    Marko-Varga, Gyorgy
    Vegvari, Akos
    Harris, Robert A.
    Laurell, Thomas
    Miliotis, Tasso
    Matusevicius, Darius
    Salter, Hugh
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Ferm, Mats
    Olsson, Tomas
    Multiple sclerosis: Identification and clinical evaluation of novel CSF biomarkers2010In: Journal of Proteomics, ISSN 1876-7737, Vol. 73, no 6, p. 1117-1132Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that results in damage to myelin sheaths and axons in the central nervous system and which preferentially affects young adults. We performed a proteomics-based biomarker discovery study in which cerebrospinal fluid (CSF) from MS and control individuals was analyzed (n=112). Ten candidate biomarkers were selected for evaluation by quantitative immunoassay using an independent cohort of MS and control subjects (n=209). In relapsing remitting MS (ARMS) patients there were significant increases in the CSF levels of alpha-1 antichymotrypsin (A1AC), alpha-1 macroglobulin (A2MG) and fibulin 1 as compared to control subjects. In secondary progressive MS (SPMS) four additional proteins (contactin 1, fetuin A, vitamin D binding protein and angiotensinogen (ANGT)) were increased as compared to control subjects. In particular, ANGT was increased 3-fold in SPMS, indicating a potential as biomarker of disease progression in MS. In PPMS, A1AC and A2MG exhibit significantly higher CSF levels than controls, with a trend of increase for ANGT. Classification models based on the biomarker panel could identify 70% of the RRMS and 80% of the SPMS patients correctly. Further evaluation was conducted in a pilot study of CSF from RRMS patients (n=36), before and after treatment with natalizumab.

  • 176.
    Pandey, Radha Raman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mondal, Tanmoy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mohammad, Faizaan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Redrup, Lisa
    Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Nagano, Takashi
    Laboratory of Chromatin and Gene Expression, The Babraham Institute, Cambridge.
    Mancini-Dinardo, Debora
    Myriad Genetics.
    Kanduri, Chandrasekhar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation2008In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 32, no 2, p. 232-46Article in journal (Refereed)
    Abstract [en]

    Recent investigations have implicated long antisense noncoding RNAs in the epigenetic regulation of chromosomal domains. Here we show that Kcnq1ot1 is an RNA polymerase II-encoded, 91 kb-long, moderately stable nuclear transcript and that its stability is important for bidirectional silencing of genes in the Kcnq1 domain. Kcnq1ot1 interacts with chromatin and with the H3K9- and H3K27-specific histone methyltransferases G9a and the PRC2 complex in a lineage-specific manner. This interaction correlates with the presence of extended regions of chromatin enriched with H3K9me3 and H3K27me3 in the Kcnq1 domain in placenta, whereas fetal liver lacks both chromatin interactions and heterochromatin structures. In addition, the Kcnq1 domain is more often found in contact with the nucleolar compartment in placenta than in liver. Taken together, our data describe a mechanism whereby Kcnq1ot1 establishes lineage-specific transcriptional silencing patterns through recruitment of chromatin remodeling complexes and maintenance of these patterns through subsequent cell divisions occurs via targeting the associated regions to the perinucleolar compartment.

  • 177.
    Papoutsoglou, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tsubakihara, Yutaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pallis, Paris
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The TGFB2-AS1 lncRNA regulates TGFβ signaling by modulating corepressor activity2018Article in journal (Refereed)
    Abstract [en]

    LncRNAs regulate cell function through many physiological processes. We have identified lncRNAs whose expression is regulated by transforming growth factor β (TGFβ), by a transcriptomic screen. We focused on TGFB2-antisense RNA1 (TGFB2-AS1), which was induced by TGFβ through Smad and protein kinase pathways, and exhibited predominantly nuclear localization. Depleting TGFB2-AS1 enhanced TGFβ/Smad-mediated transcription and expression of the TGFβ-target genes FN1 and SERPINE1. Overexpression of TGFB2-AS1 reduced expression of these genes, attenuated TGFβ-induced cell growth arrest, and altered BMP and Wnt pathway gene profiles. Mechanistically, TGFB2-AS1 mainly via its 3’ terminal region, bound to EED, an adaptor of the Polycomb repressor complex 2 (PRC2), promoting repressive histone H3K27me3 modifications at TGFβ-target gene promoters. Silencing EED or inhibiting PRC2 methylation activity, partially rescued TGFB2-AS1 mediated gene repression. Our observations support the notion that TGFB2-AS1 is a TGFβ-induced lncRNA with inhibitory functions on TGFβ and BMP pathways output, constituting an auto-regulatory negative feedback mechanism that balances TGFβ- and BMP-mediated responses.

  • 178.
    Pettersson, Fredrik B M
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Mikrobiologi.
    Ardell, David H
    The Linnaeus Centre for Bioinformatics.
    Kirsebom, Leif A
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Mikrobiologi.
    The length of the 5' leader of Escherichia coli tRNA precursors influences2005In: J Mol Biol, ISSN 0022-2836, Vol. 351, no 1, p. 9-15Article in journal (Refereed)
  • 179. Pettifer, Steve
    et al.
    Ison, Jon
    Kalas, Matus
    Thorne, Dave
    McDermott, Philip
    Jonassen, Inge
    Liaquat, Ali
    Fernandez, Jose M.
    Rodriguez, Jose M.
    Pisano, David G.
    Blanchet, Christophe
    Uludag, Mahmut
    Rice, Peter
    Bartaseviciute, Edita
    Rapacki, Kristoffer
    Hekkelman, Maarten
    Sand, Olivier
    Stockinger, Heinz
    Clegg, Andrew B.
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Salzemann, Jean
    Breton, Vincent
    Attwood, Teresa K.
    Cameron, Graham
    Vriend, Gert
    The EMBRACE web service collection2010In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 38, p. W683-W688Article in journal (Refereed)
    Abstract [en]

    The EMBRACE ( European Model for Bioinformatics Research and Community Education) web service collection is the culmination of a 5-year project that set out to investigate issues involved in developing and deploying web services for use in the life sciences. The project concluded that in order for web services to achieve widespread adoption, standards must be defined for the choice of web service technology, for semantically annotating both service function and the data exchanged, and a mechanism for discovering services must be provided. Building on this, the project developed: EDAM, an ontology for describing life science web services; BioXSD, a schema for exchanging data between services; and a centralized registry (http://www.embraceregistry.net) that collects together around 1000 services developed by the consortium partners. This article presents the current status of the collection and its associated recommendations and standards definitions.

  • 180. Piotrowski, Arkadiusz
    et al.
    Bruder, Carl E G
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    de Ståhl, Teresita Diaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Poplawski, Andrzej
    von Tell, Desiree
    Crasto, Chiquito
    Bogdan, Adam
    Bartoszewski, Rafal
    Bebok, Zsuzsa
    Krzyzanowski, Maciej
    Jankowski, Zbigniew
    Partridge, E Christopher
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Somatic mosaicism for copy number variation in differentiated human tissues2008In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 29, no 9, p. 1118-24Article in journal (Refereed)
    Abstract [en]

    Two major types of genetic variation are known: single nucleotide polymorphisms (SNPs), and a more recently discovered structural variation, involving changes in copy number (CNVs) of kilobase- to megabase-sized chromosomal segments. It is unknown whether CNVs arise in somatic cells, but it is, however, generally assumed that normal cells are genetically identical. We tested 34 tissue samples from three subjects and, having analyzed for each tissue < or =10(-6) of all cells expected in an adult human, we observed at least six CNVs, affecting a single organ or one or more tissues of the same subject. The CNVs ranged from 82 to 176 kb, often encompassing known genes, potentially affecting gene function. Our results indicate that humans are commonly affected by somatic mosaicism for stochastic CNVs, which occur in a substantial fraction of cells. The majority of described CNVs were previously shown to be polymorphic between unrelated subjects, suggesting that some CNVs previously reported as germline might represent somatic events, since in most studies of this kind, only one tissue is typically examined and analysis of parents for the studied subjects is not routinely performed. A considerable number of human phenotypes are a consequence of a somatic process. Thus, our conclusions will be important for the delineation of genetic factors behind these phenotypes. Consequently, biobanks should consider sampling multiple tissues to better address mosaicism in the studies of somatic disorders.

  • 181. Poplawski, Andrzej B.
    et al.
    Jankowski, Michal
    Erickson, Stephen W.
    de Ståhl, Teresita Díaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Partridge, E. Christopher
    Crasto, Chiquito
    Guo, Jingyu
    Gibson, John
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bruder, Carl E. G.
    Kaczmarczyk, Aneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Benetkiewicz, Magdalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Zegarska, Barbara
    Bala, Dariusz
    Srutek, Ewa
    Allison, David B.
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Zegarski, Wojciech
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Frequent genetic differences between matched primary and metastatic breast cancer provide an approach to identification of biomarkers for disease progression2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, no 5, p. 560-568Article in journal (Refereed)
    Abstract [en]

    Breast cancer is a major cause of morbidity and mortality in women and its metastatic spread is the principal reason behind the fatal outcome. Metastasis-related research of breast cancer is however underdeveloped when compared with the abundant literature on primary tumors. We applied an unexplored approach comparing at high resolution the genomic profiles of primary tumors and synchronous axillary lymph node metastases from 13 patients with breast cancer. Overall, primary tumors displayed 20% higher number of aberrations than metastases. In all but two patients, we detected in total 157 statistically significant differences between primary lesions and matched metastases. We further observed differences that can be linked to metastatic disease and there was also an overlapping pattern of changes between different patients. Many of the differences described here have been previously linked to poor patient survival, suggesting that this is a viable approach toward finding biomarkers for disease progression and definition of new targets useful for development of anticancer drugs. Frequent genetic differences between primary tumors and metastases in breast cancer also question, at least to some extent, the role of primary tumors as a surrogate subject of study for the systemic disease. European Journal of Human Genetics (2010) 18, 560-568; doi:10.1038/ejhg.2009.230; published online 6 January 2010

  • 182.
    Rada-Iglesias, Alvaro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Kapranov, Philipp
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Gingeras, Thomas
    Wadelius, Claes