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  • 1.
    Ameur, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Wetterbom, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Global and unbiased detection of splice junctions from RNA-seq data2010In: Genome Biology, ISSN 1474-760X, Vol. 11, no 3, p. R34-Article in journal (Refereed)
    Abstract [en]

    We have developed a new strategy for de novo prediction of splice junctions in short-read RNA-seq data, suitable for detection of novel splicing events and chimeric transcripts. When tested on mouse RNA-seq data, > 31,000 splice events were predicted, of which 88% bridged between two regions separated by <= 100 kb, and 74% connected two exons of the same RefSeq gene. Our method also reports genomic rearrangements such as insertions and deletions.

  • 2.
    Berglund, Anna-Karin
    et al.
    Department of Biochemistry and Biophysics, Stockholm University.
    Spånning, Erika
    Department of Biochemistry and Biophysics, Stockholm University.
    Biverståhl, Henrik
    Department of Biochemistry and Biophysics, Stockholm University.
    Maddalo, Gianluca
    Department of Biochemistry and Biophysics, Stockholm University.
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Mäler, Lena
    Department of Biochemistry and Biophysics, Stockholm University.
    Glaser, Elzbieta
    Department of Biochemistry and Biophysics, Stockholm University.
    Dual Targeting to Mitochondria and Chloroplasts: Characterization of Thr–tRNA Synthetase Targeting Peptide2009In: Molecular Plant, ISSN 1674-2052, Vol. 2, no 6, p. 1298-1309Article in journal (Refereed)
    Abstract [en]

    There is a group of proteins that are encoded by a single gene,   expressed as a single precursor protein and dually targeted to both   mitochondria and chloroplasts using an ambiguous targeting peptide.   Sequence analysis of 43 dual targeted proteins in comparison with 385   mitochondrial proteins and 567 chloroplast proteins of Arabidopsis   thaliana revealed an overall significant increase in phenylalanines,   leucines, and serines and a decrease in acidic amino acids and glycine   in dual targeting peptides (dTPs). The N-terminal portion of dTPs has   significantly more serines than mTPs. The number of arginines is   similar to those in mTPs, but almost twice as high as those in cTPs. We   have investigated targeting determinants of the dual targeting peptide   of Thr-tRNA synthetase (ThrRS-dTP) studying organellar import of N- and   C-terminal deletion constructs of ThrRS-dTP coupled to GFP. These   results show that the 23 amino acid long N-terminal portion of   ThrRS-dTP is crucial but not sufficient for the organellar import. The   C-terminal deletions revealed that the shortest peptide that was   capable of conferring dual targeting was 60 amino acids long. We have   purified the ThrRS-dTP(2-60) to homogeneity after its expression as a   fusion construct with GST followed by CNBr cleavage and ion exchange   chromatography. The purified ThrRS-dTP(2-60) inhibited import of   pF(1)beta into mitochondria and of pSSU into chloroplasts at mu M   concentrations showing that dual and organelle-specific proteins use   the same organellar import pathways. Furthermore, the CD spectra of   ThrRS-dTP(2-60) indicated that the peptide has the propensity for   forming alpha-helical structure in membrane mimetic environments;   however, the membrane charge was not important for the amount of   induced helical structure. This is the first study in which a dual   targeting peptide has been purified and investigated by biochemical and   biophysical means.

  • 3.
    Beskow, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rönnholm, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Magnusson, Patrik K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gyllensten, Ulf B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Susceptibility locus for epidermodysplasia verruciformis not linked to cervical cancer in situ2001In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 135, no 1, p. 61-63Article in journal (Refereed)
    Abstract [en]

    Cervical cancer is strongly associated with infection by oncogenic forms of human papillomavirus (HPV), mainly HPV 16 and HPV 18. The aim of this study was to test if a locus previously mapped to a region on chromosome 17 qter in patients with epidermodysplasia verucciformis (EV) and psoriasis and considered to be responsible for an increased susceptibility to HPV 5, also is linked to increased HPV susceptibility in cervical cancer in situ. We also wanted to test whether HPV 16 positivity cluster in families with cervical cancer. DNA was extracted from formalin fixed biopsies of 224 affected from 77 families diagnosed with cervical cancer in situ. Two microsatellite markers (D17S939 and D17S802) containing the locus were genotyped and linkage analysis was performed. No linkage was found to any of the two markers, neither when considering all cancer cases as affected nor when only considering HPV 16 infected cancer cases as affected in the analysis. We conclude that the susceptibility locus for HPV 5 infections associated with EV and psoriasis does not seem to affect susceptibility to HPV 16, frequently detected in cervical cancer. Also, positivity for HPV 16 did not show a significant clustering in families.

  • 4. Heid, Iris M
    et al.
    Jackson, Anne U
    Randall, Joshua C
    Winkler, Thomas W
    Qi, Lu
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Zillikens, M Carola
    Speliotes, Elizabeth K
    Mägi, Reedik
    Workalemahu, Tsegaselassie
    White, Charles C
    Bouatia-Naji, Nabila
    Harris, Tamara B
    Berndt, Sonja I
    Ingelsson, Erik
    Willer, Cristen J
    Weedon, Michael N
    Luan, Jian'an
    Vedantam, Sailaja
    Esko, Tõnu
    Kilpeläinen, Tuomas O
    Kutalik, Zoltán
    Li, Shengxu
    Monda, Keri L
    Dixon, Anna L
    Holmes, Christopher C
    Kaplan, Lee M
    Liang, Liming
    Min, Josine L
    Moffatt, Miriam F
    Molony, Cliona
    Nicholson, George
    Schadt, Eric E
    Zondervan, Krina T
    Feitosa, Mary F
    Ferreira, Teresa
    Allen, Hana Lango
    Weyant, Robert J
    Wheeler, Eleanor
    Wood, Andrew R
    Estrada, Karol
    Goddard, Michael E
    Lettre, Guillaume
    Mangino, Massimo
    Nyholt, Dale R
    Purcell, Shaun
    Smith, Albert Vernon
    Visscher, Peter M
    Yang, Jian
    McCarroll, Steven A
    Nemesh, James
    Voight, Benjamin F
    Absher, Devin
    Amin, Najaf
    Aspelund, Thor
    Coin, Lachlan
    Glazer, Nicole L
    Hayward, Caroline
    Heard-Costa, Nancy L
    Hottenga, Jouke-Jan
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Johnson, Toby
    Kaakinen, Marika
    Kapur, Karen
    Ketkar, Shamika
    Knowles, Joshua W
    Kraft, Peter
    Kraja, Aldi T
    Lamina, Claudia
    Leitzmann, Michael F
    McKnight, Barbara
    Morris, Andrew P
    Ong, Ken K
    Perry, John R B
    Peters, Marjolein J
    Polasek, Ozren
    Prokopenko, Inga
    Rayner, Nigel W
    Ripatti, Samuli
    Rivadeneira, Fernando
    Robertson, Neil R
    Sanna, Serena
    Sovio, Ulla
    Surakka, Ida
    Teumer, Alexander
    van Wingerden, Sophie
    Vitart, Veronique
    Zhao, Jing Hua
    Cavalcanti-Proença, Christine
    Chines, Peter S
    Fisher, Eva
    Kulzer, Jennifer R
    Lecoeur, Cecile
    Narisu, Narisu
    Sandholt, Camilla
    Scott, Laura J
    Silander, Kaisa
    Stark, Klaus
    Tammesoo, Mari-Liis
    Teslovich, Tanya M
    Timpson, Nicholas John
    Watanabe, Richard M
    Welch, Ryan
    Chasman, Daniel I
    Cooper, Matthew N
    Jansson, John-Olov
    Kettunen, Johannes
    Lawrence, Robert W
    Pellikka, Niina
    Perola, Markus
    Vandenput, Liesbeth
    Alavere, Helene
    Almgren, Peter
    Atwood, Larry D
    Bennett, Amanda J
    Biffar, Reiner
    Bonnycastle, Lori L
    Bornstein, Stefan R
    Buchanan, Thomas A
    Campbell, Harry
    Day, Ian N M
    Dei, Mariano
    Dörr, Marcus
    Elliott, Paul
    Erdos, Michael R
    Eriksson, Johan G
    Freimer, Nelson B
    Fu, Mao
    Gaget, Stefan
    Geus, Eco J C
    Gjesing, Anette P
    Grallert, Harald
    Grässler, Jürgen
    Groves, Christopher J
    Guiducci, Candace
    Hartikainen, Anna-Liisa
    Hassanali, Neelam
    Havulinna, Aki S
    Herzig, Karl-Heinz
    Hicks, Andrew A
    Hui, Jennie
    Igl, Wilmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jousilahti, Pekka
    Jula, Antti
    Kajantie, Eero
    Kinnunen, Leena
    Kolcic, Ivana
    Koskinen, Seppo
    Kovacs, Peter
    Kroemer, Heyo K
    Krzelj, Vjekoslav
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Laitinen, Jaana
    Lantieri, Olivier
    Lathrop, G Mark
    Lokki, Marja-Liisa
    Luben, Robert N
    Ludwig, Barbara
    McArdle, Wendy L
    McCarthy, Anne
    Morken, Mario A
    Nelis, Mari
    Neville, Matt J
    Paré, Guillaume
    Parker, Alex N
    Peden, John F
    Pichler, Irene
    Pietiläinen, Kirsi H
    Platou, Carl G P
    Pouta, Anneli
    Ridderstråle, Martin
    Samani, Nilesh J
    Saramies, Jouko
    Sinisalo, Juha
    Smit, Jan H
    Strawbridge, Rona J
    Stringham, Heather M
    Swift, Amy J
    Teder-Laving, Maris
    Thomson, Brian
    Usala, Gianluca
    van Meurs, Joyce B J
    van Ommen, Gert-Jan
    Vatin, Vincent
    Volpato, Claudia B
    Wallaschofski, Henri
    Walters, G Bragi
    Widen, Elisabeth
    Wild, Sarah H
    Willemsen, Gonneke
    Witte, Daniel R
    Zgaga, Lina
    Zitting, Paavo
    Beilby, John P
    James, Alan L
    Kähönen, Mika
    Lehtimäki, Terho
    Nieminen, Markku S
    Ohlsson, Claes
    Palmer, Lyle J
    Raitakari, Olli
    Ridker, Paul M
    Stumvoll, Michael
    Tönjes, Anke
    Viikari, Jorma
    Balkau, Beverley
    Ben-Shlomo, Yoav
    Bergman, Richard N
    Boeing, Heiner
    Smith, George Davey
    Ebrahim, Shah
    Froguel, Philippe
    Hansen, Torben
    Hengstenberg, Christian
    Hveem, Kristian
    Isomaa, Bo
    Jørgensen, Torben
    Karpe, Fredrik
    Khaw, Kay-Tee
    Laakso, Markku
    Lawlor, Debbie A
    Marre, Michel
    Meitinger, Thomas
    Metspalu, Andres
    Midthjell, Kristian
    Pedersen, Oluf
    Salomaa, Veikko
    Schwarz, Peter E H
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Valle, Timo T
    Wareham, Nicholas J
    Arnold, Alice M
    Beckmann, Jacques S
    Bergmann, Sven
    Boerwinkle, Eric
    Boomsma, Dorret I
    Caulfield, Mark J
    Collins, Francis S
    Eiriksdottir, Gudny
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hamsten, Anders
    Hattersley, Andrew T
    Hofman, Albert
    Hu, Frank B
    Illig, Thomas
    Iribarren, Carlos
    Jarvelin, Marjo-Riitta
    Kao, W H Linda
    Kaprio, Jaakko
    Launer, Lenore J
    Munroe, Patricia B
    Oostra, Ben
    Penninx, Brenda W
    Pramstaller, Peter P
    Psaty, Bruce M
    Quertermous, Thomas
    Rissanen, Aila
    Rudan, Igor
    Shuldiner, Alan R
    Soranzo, Nicole
    Spector, Timothy D
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Uda, Manuela
    Uitterlinden, André
    Völzke, Henry
    Vollenweider, Peter
    Wilson, James F
    Witteman, Jacqueline C
    Wright, Alan F
    Abecasis, Gonçalo R
    Boehnke, Michael
    Borecki, Ingrid B
    Deloukas, Panos
    Frayling, Timothy M
    Groop, Leif C
    Haritunians, Talin
    Hunter, David J
    Kaplan, Robert C
    North, Kari E
    O'Connell, Jeffrey R
    Peltonen, Leena
    Schlessinger, David
    Strachan, David P
    Hirschhorn, Joel N
    Assimes, Themistocles L
    Wichmann, H-Erich
    Thorsteinsdottir, Unnur
    van Duijn, Cornelia M
    Stefansson, Kari
    Cupples, L Adrienne
    Loos, Ruth J F
    Barroso, Inês
    McCarthy, Mark I
    Fox, Caroline S
    Mohlke, Karen L
    Lindgren, Cecilia M
    Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 11, p. 949-960Article in journal (Refereed)
    Abstract [en]

    Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

  • 5.
    Ivansson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gustavsson, Inger M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Magnusson, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Steiner, Lori
    Magnusson, Patrik
    Erlich, Henry
    Gyllensten, Ulf B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer2007In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, no 11, p. 2451-2457Article in journal (Refereed)
    Abstract [en]

    Cervical cancer is caused by persistent infection of oncogenichuman papillomavirus (HPV). Most infected women clear the viruswithout developing cervical lesions and it is likely that immunologicalhost factors affect susceptibility to cervical cancer. Theimpact of the human leukocyte antigen (HLA) locus on the risk ofcervical cancer is established and several other genes involved inimmunological pathways have been suggested as biologically plausiblecandidates. The aim of this study was to examine the potentialrole of polymorphisms in 4 candidate genes by analysis of1,306 familial cervical cancer cases and 288 controls. The followinggenes and polymorphisms were studied: Chemokine receptor2 (CCR-2) V64I; Interleukin 4 receptor a (IL-4R) I75V, S503P andQ576R; Interleukin 10 (IL-10) 2592; and Fas ligand (FasL) 2844.The CCR-2 64I variant was associated with decreased risk of cervicalcancer; homozygote carriers of the 64I variant had an oddsratio of 0.31 (0.12–0.77). This association was detected in both carriersand noncarriers of the HLA DQB1*0602 cervical cancer riskallele. The IL-4R 75V variant was associated with increased riskof cervical tumors, cases homozygote for 75V had an odds ratio of1.91 (1.27–2.86) with a tendency that the association was strongerin noncarriers of the DQB1*0602 allele. We did not find any associationfor IL-10 2592, or FasL 2844, previously reported to beassociated with cervical cancer in the Dutch and Chinese populations,respectively.

  • 6.
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Application of Genomic and Expression Arrays for Identification of new Cancer Genes2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Copy number variation (CNV) comprises a recently discovered kind of variation involving deletion and duplication of DNA segments of variable size, ranging from a few hundred basepairs to several million. By altering gene dosage levels or disrupting proximal or distant regulatory elements CNVs create human diversity. They represent also an important factor in human evolution and play a role in many disorders including cancer. Array-based comparative genomic hybridization as well as expression arrays are powerful and suitable methods for determination of copy number variations or gene expression changes in the human genome. In paper I we established a 32K clone-based genomic array, covering 99% of the current assembly of the human genome with high resolution and applied it in the profiling of 71 healthy individuals from three ethnic groups. Novel and previously reported CNVs, involving ~3.5% of the genome, were identified. Interestingly, 87% of the detected CNV regions overlapped with known genes indicating that they probably have phenotypic consequences. In papers II through IV we applied this platform to different tumor types, namely two collections of brain tumors, glioblastoma (paper II) and medulloblastoma (paper III), and a set of bladder carcinoma (paper IV) to identify chromosomal alterations at the level of DNA copy number that could be related to tumor initiation/progression. Tumors of the central nervous system represent a heterogeneous group of both benign and malignant neoplasms that affect both children and adults. Glioblastoma and medulloblastoma are two malignant forms. Glioblastoma often affects adults while the embryonal tumor medulloblastoma is the most common malignant brain tumor among children. The detailed profiling of 78 glioblastomas, allowed us to identify a complex pattern of aberrations including frequent and high copy number amplicons (detected in 79% of samples) as well as a number of homozygously deleted loci. These regions encompassed not only previously reported oncogenes and tumor suppressor genes but also numerous novel genes. In paper III, a subset of 26 medulloblastomas was analyzed using the same genomic array. We observed that alterations involving chromosome 17, especially isochromosome 17q, were the most common genomic aberrations in this tumor type, but copy number alterations involving other chromosomes: 1, 7 and 8 were also frequent. Focal amplifications, on chromosome 1 and 3, not previously described, were also detected. These loci may encompass novel genes involved in medulloblastoma development. In paper IV we examined for the presence of DNA copy number alterations and their effect on gene expression in a subset of 21 well-characterized Ta bladder carcinomas, selected for the presence or absence of recurrences. We identified a number of novel genes as well as a significant association between amplifications and high-grade and recurrent tumors which might be clinically useful.

    The results derived from these studies increase our understanding of the genetic alterations leading to the development of these tumor forms and point out candidate genes that may be used in future as targets for new diagnostic and therapeutic strategies.

    List of papers
    1. Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BAC-clone-based array
    Open this publication in new window or tab >>Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BAC-clone-based array
    Show others...
    2008 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 29, no 3, p. 398-408Article in journal (Refereed) Published
    Abstract [en]

    To further explore the extent of structural large-scale variation in the human genome, we assessed copy number variations (CNVs) in a series of 71 healthy subjects from three ethnic groups. CNVs were analyzed using comparative genomic hybridization (CGH) to a BAC array covering the human genome, using DNA extracted from peripheral blood, thus avoiding any culture-induced rearrangements. By applying a newly developed computational algorithm based on Hidden Markov modeling, we identified 1,078 autosomal CNVs, including at least two neighboring/overlapping BACs, which represent 315 distinct regions. The average size of the sequence polymorphisms was approximately 350 kb and involved in total approximately 117 Mb or approximately 3.5% of the genome. Gains were about four times more common than deletions, and segmental duplications (SDs) were overrepresented, especially in larger deletion variants. This strengthens the notion that SDs often define hotspots of chromosomal rearrangements. Over 60% of the identified autosomal rearrangements match previously reported CNVs, recognized with various platforms. However, results from chromosome X do not agree well with the previously annotated CNVs. Furthermore, data from single BACs deviating in copy number suggest that our above estimate of total variation is conservative. This report contributes to the establishment of the common baseline for CNV, which is an important resource in human genetics.

    Keywords
    genetic variation, array-CGH, genetics, population, polymorphism, human genome, gene dosage
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102483 (URN)10.1002/humu.20659 (DOI)000253837300009 ()18058796 (PubMedID)
    Note

    De två (2) sista författarna delar sistaförfattarskapet.

    Available from: 2009-05-07 Created: 2009-05-07 Last updated: 2017-12-13Bibliographically approved
    2. Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array
    Open this publication in new window or tab >>Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array
    Show others...
    2009 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 11, no 6, p. 803-818Article in journal (Refereed) Published
    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.

    Keywords
    amplification, array-CGH, cancer, deletion, glioblastoma
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-113074 (URN)10.1215/15228517-2009-013 (DOI)000272974100010 ()19304958 (PubMedID)
    Available from: 2010-01-25 Created: 2010-01-25 Last updated: 2017-12-12Bibliographically approved
    3. Novel amplicons in pediatric medulloblastoma identified by high-resolution genomic analysis: Genetic aberrations in medulloblastoma
    Open this publication in new window or tab >>Novel amplicons in pediatric medulloblastoma identified by high-resolution genomic analysis: Genetic aberrations in medulloblastoma
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Medulloblastoma (MB) is an aggressive and invasive embryonal CNS tumor that mainly affects children. Despite treatment, ~30% of the patients die within 2 years from diagnosis. MB patients are currently categorized into high- or standard-risk based on the clinical criteria, with high-risk group including patients <3 years, with incomplete tumor resection or with concomitant metastatic disease at presentation. However, these clinical parameters do not always predict patient outcome and additional biomarkers are desirable. In this study we have profiled a series of 25 MB samples with a high-resolution 32K BAC-array covering 99% of the current assembly of the human genome for the identification of genetic copy number alterations. The most frequent observed alteration was the combination of 17p loss and 17q gain, indicative of an isochromosome 17q, which was identified in 40% of the patients. This aberration was detected in both high- and standard-risk groups and was not associated with worse outcome. We also defined minimal overlapping regions of aberrations, including 16 regions of gains and 18 regions of loss in different chromosomes. Noteworthy, are a few very narrow amplified loci identified on autosomes 1, 3 and 8, aberrations that were verified with an alternative platform (Illumina 610Q chips). Several genes as CYR61, LMO4, EOMES, and MLH1 encompassed within these loci were also found to present with transcript up-regulation. These genes represent novel candidate genes most probably involved in MB development.

     

    Keywords
    Medulloblastoma
    Research subject
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-121954 (URN)
    Available from: 2010-03-31 Created: 2010-03-31 Last updated: 2010-03-31
    4. Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma
    Open this publication in new window or tab >>Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma
    Show others...
    2010 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 126, no 6, p. 1390-1402Article in journal (Refereed) Published
    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.

    Keywords
    Amplification, Array-CGH, Cancer, Deletion, Expression arrays, Metabolism of xenobiotics, Oncogenes, Ta bladder cancer, Tumor suppressor genes
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-121019 (URN)10.1002/ijc.24954 (DOI)000275434100010 ()19821490 (PubMedID)
    Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2017-12-12Bibliographically approved
  • 7.
    Nord, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nilsson, Pelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nistér, Monica
    Alafuzoff, Irina
    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, Genomics.
    Díaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Novel amplicons in pediatric medulloblastoma identified by high-resolution genomic analysis: Genetic aberrations in medulloblastomaManuscript (preprint) (Other academic)
    Abstract [en]

    Medulloblastoma (MB) is an aggressive and invasive embryonal CNS tumor that mainly affects children. Despite treatment, ~30% of the patients die within 2 years from diagnosis. MB patients are currently categorized into high- or standard-risk based on the clinical criteria, with high-risk group including patients <3 years, with incomplete tumor resection or with concomitant metastatic disease at presentation. However, these clinical parameters do not always predict patient outcome and additional biomarkers are desirable. In this study we have profiled a series of 25 MB samples with a high-resolution 32K BAC-array covering 99% of the current assembly of the human genome for the identification of genetic copy number alterations. The most frequent observed alteration was the combination of 17p loss and 17q gain, indicative of an isochromosome 17q, which was identified in 40% of the patients. This aberration was detected in both high- and standard-risk groups and was not associated with worse outcome. We also defined minimal overlapping regions of aberrations, including 16 regions of gains and 18 regions of loss in different chromosomes. Noteworthy, are a few very narrow amplified loci identified on autosomes 1, 3 and 8, aberrations that were verified with an alternative platform (Illumina 610Q chips). Several genes as CYR61, LMO4, EOMES, and MLH1 encompassed within these loci were also found to present with transcript up-regulation. These genes represent novel candidate genes most probably involved in MB development.

     

  • 8.
    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.

  • 9.
    Wetterbom, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Genome and Transcriptome Comparisons between Human and Chimpanzee2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The chimpanzee is humankind’s closest living relative and the two species diverged ~6 million years ago. Comparative studies of the human and chimpanzee genomes and transcriptomes are of great interest to understand the molecular mechanisms of speciation and the development of species-specific traits.

    The aim of this thesis is to characterize differences between the two species with regard to their genome sequences and the resulting transcript profiles. The first two papers focus on indel divergence and in particular, indels causing premature termination codons (PTCs) in 8% of the chimpanzee genes. The density of PTC genes is correlated with both the distance to the telomere and the indel divergence. Many PTC genes have several associated transcripts and since not all are affected by the PTC we propose that PTCs may affect the pattern of expressed isoforms. In the third paper, we investigate the transcriptome divergence in cerebellum, heart and liver, using high-density exon arrays. The results show that gene expression differs more between tissues than between species. Approximately 15% of the genes are differentially expressed between species, and half of the genes show different splicing patterns. We identify 28 cassette exons which are only included in one of the species, often in a tissue-specific manner. In the fourth paper, we use massive parallel sequencing to study the chimpanzee transcriptome in frontal cortex and liver. We estimate gene expression and search for novel transcribed regions (TRs). The majority of TRs are located close to genes and possibly extend the annotations. A subset of TRs are not found in the human genome. The brain transcriptome differs substantially from that of the liver and we identify a subset of genes enriched with TRs in frontal cortex.

    In conclusion, this thesis provides evidence of extensive genomic and transcriptomic variability between human and chimpanzee. The findings provide a basis for further studies of the underlying differences affecting phenotypic divergence between human and chimpanzee.

     

     

     

    List of papers
    1. Comparative genomic analysis of human and chimpanzee indicates a key role for indels in primate evolution
    Open this publication in new window or tab >>Comparative genomic analysis of human and chimpanzee indicates a key role for indels in primate evolution
    2006 (English)In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 63, no 5, p. 682-690Article in journal (Refereed) Published
    Abstract [en]

    Sequence comparison of humans and chimpanzees is of interest to understand the mechanisms behind primate evolution. Here we present an independent analysis of human chromosome 21 and the high-quality BAC clone sequences of the homologous chimpanzee chromosome 22. In contrast to previous studies, we have used global alignment methods and Ensembl predictions of protein coding genes (n = 224) for the analysis. Divergence due to insertions and deletions (indels) along with substitutions was examined separately for different genomic features (coding, noncoding genic, and intergenic sequence). The major part of the genomic divergence could be attributed to indels (5.07%), while the nucleotide divergence was estimated as 1.52%. Thus the total divergence was estimated as 6.58%. When excluding repeats and low-complexity DNA the total divergence decreased to 2.37%. The chromosomal distribution of nucleotide substitutions and indel events was significantly correlated. To further examine the role of indels in primate evolution we focused on coding sequences. Indels were found within the coding sequence of 13% of the genes and approximately half of the indels have not been reported previously. In 5% of the chimpanzee genes, indels or substitutions caused premature stop codons that rendered the affected transcripts nonfunctional. Taken together, our findings demonstrate that indels comprise the majority of the genomic divergence. Furthermore, indels occur frequently in coding sequences. Our results thereby support the hypothesis that indels may have a key role in primate evolution.

    Keywords
    indels, comparative genomics, chimpanzee, primate evolution
    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-10256 (URN)10.1007/s00239-006-0045-7 (DOI)000242014800010 ()17075697 (PubMedID)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-11Bibliographically approved
    2. Genome-wide analysis of chimpanzee genes with premature termination codons
    Open this publication in new window or tab >>Genome-wide analysis of chimpanzee genes with premature termination codons
    2009 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 10, p. 56-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Premature termination codons (PTCs) cause mRNA degradation or a truncated protein and thereby contribute to the transcriptome and proteome divergence between species. Here we present the first genome-wide study of PTCs in the chimpanzee. By comparing the human and chimpanzee genome sequences we identify and characterize genes with PTCs, in order to understand the contribution of these mutations to the transcriptome diversity between the species. RESULTS: We have studied a total of 13,487 human-chimpanzee gene pairs and found that ~8% were affected by PTCs in the chimpanzee. A majority (764/1,109) of PTCs were caused by insertions or deletions and the remaining part was caused by substitutions. The distribution of PTC genes varied between chromosomes, with Y having the highest proportion. Furthermore, the density of PTC genes varied on a megabasepair scale within chromosomes and we found the density to be correlated both with indel divergence and proximity to the telomere. Within genes, PTCs were more common close to the 5' and 3' ends of the amino acid sequence. Gene Ontology classification revealed that olfactory receptor genes were over represented among the PTC genes. CONCLUSION: Our results showed that the density of PTC genes fluctuated across the genome depending on the local genomic context. PTCs were preferentially located in the terminal parts of the transcript, which generally have a lower frequency of functional domains, indicating that selection was operating against PTCs at sites central to protein function. The enrichment of GO terms associated with olfaction suggests that PTCs may have influenced the difference in the repertoire of olfactory genes between humans and chimpanzees. In summary, 8% of the chimpanzee genes were affected by PTCs and this type of variation is likely to have an important effect on the transcript and proteomic divergence between humans and chimpanzees.

    Keywords
    cervical carcinoma, HLA, HPV 16 E6
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-102555 (URN)10.1186/1471-2164-10-56 (DOI)000264122500002 ()19178713 (PubMedID)
    Available from: 2009-05-08 Created: 2009-05-08 Last updated: 2017-12-13Bibliographically approved
    3. Global comparison of the human and chimpanzee transcriptomes using Affymetrix exon arrays
    Open this publication in new window or tab >>Global comparison of the human and chimpanzee transcriptomes using Affymetrix exon arrays
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We have used high-density exon arrays to study the human and chimpanzee transcriptome in cerebellum, heart and liver excluding probesets with mismatches to the chimpanzee. A total of 6281 RefSeq genes were expressed in our samples, the majority being expressed in two or more tissues, while ~ 6 % lacked expression in one of the species. A total of 923 RefSeq genes showed differences in expression between human and chimpanzes. More genes were differentially expressed in cerebellum (8.4 %) than in liver (6.9 %) and heart (4.5 %). Genes showing differential expression between species to a large extent also showed strong tissue-specific expression within species. Of the differentially expressed genes, more were upregulated in human versus chimpanzee, than the other way around. Liver had the highest proportion of genes with spliced genes (50 %), followed by cerebellum (40 %) and heart (30 %). Differentially expressed genes were often detected also as spliced (66-78 %). As one type of splice variation, we identified 26 genes with cassette exons, i.e. the exon is only included in one species. Cassette exon usage was tissue specific to a large extent and for the majority of cassette exons we observed expression in both human and chimpanzee in the other tissues. Taken together, our results indicate that splicing differences represents an extensive and important source of variation between species.

    Keywords
    chimpanzee human transcriptome comparison
    National Category
    Medical Genetics
    Research subject
    Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-113576 (URN)
    Available from: 2010-01-30 Created: 2010-01-30 Last updated: 2018-01-12
    4. Deep sequencing of the chimpanzee transcriptome identifies numerous novel transcribed regions in frontal cortex and liver
    Open this publication in new window or tab >>Deep sequencing of the chimpanzee transcriptome identifies numerous novel transcribed regions in frontal cortex and liver
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We have performed the first global profiling of the chimpanzee transcriptome by using deep sequencing of cDNA from brain and liver. This enabled us to quantify expression of RefSeq transcripts, identify novel transcribed regions with no previous annotations in databases and additionally search for transcribed regions with no support in the human genome.

    Using stringent criteria for transcription, we identified 9,061 expressed RefSeq transcripts and 5,532 novel transcribed regions., of which the vast majority were found intronically in RefSeq transcripts and ~ 15 % mapped intergenically. In addition,  a little less than 150 novel transcribed regions in the chimpanzee appeared to be absent from the human reference sequence. Novel transcribed regions may represent new coding regions, untranslated regions unspliced mRNAs or diferent types of non-coding transcripts. The transcriptional profile of the brain stands out in several ways: a higher number of RefSeq transcripts were expressed in brain than in liver and novel transcribed regions were also more abundant in brain. Furthermore, we identified an interesting subset of RefSeq genes with a high density of novel transcribed regions scattered across the introns. These genes clustered in central pathways of the nervous system, with an overrepresentation of genes acting in the synapse and many of which have been associated to cognitive disorders in the human.

    Our results support the prevailing view of wide-spread transcription in mammalian genomes and further highlight the vast, mostly uncharacterized, transcript variability in the primate brain.

     

    Keywords
    chimpanzee, transcriptome profiling, deep sequencing
    National Category
    Medical Genetics
    Research subject
    Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-113577 (URN)
    Available from: 2010-01-30 Created: 2010-01-30 Last updated: 2018-01-12
  • 10.
    Wetterbom, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Bergström, Tomas
    Department of Animal breeding and genetics, SLU.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Global comparison of the human and chimpanzee transcriptomes using Affymetrix exon arraysManuscript (preprint) (Other academic)
    Abstract [en]

    We have used high-density exon arrays to study the human and chimpanzee transcriptome in cerebellum, heart and liver excluding probesets with mismatches to the chimpanzee. A total of 6281 RefSeq genes were expressed in our samples, the majority being expressed in two or more tissues, while ~ 6 % lacked expression in one of the species. A total of 923 RefSeq genes showed differences in expression between human and chimpanzes. More genes were differentially expressed in cerebellum (8.4 %) than in liver (6.9 %) and heart (4.5 %). Genes showing differential expression between species to a large extent also showed strong tissue-specific expression within species. Of the differentially expressed genes, more were upregulated in human versus chimpanzee, than the other way around. Liver had the highest proportion of genes with spliced genes (50 %), followed by cerebellum (40 %) and heart (30 %). Differentially expressed genes were often detected also as spliced (66-78 %). As one type of splice variation, we identified 26 genes with cassette exons, i.e. the exon is only included in one species. Cassette exon usage was tissue specific to a large extent and for the majority of cassette exons we observed expression in both human and chimpanzee in the other tissues. Taken together, our results indicate that splicing differences represents an extensive and important source of variation between species.

  • 11.
    Wetterbom, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics.
    Deep sequencing of the chimpanzee transcriptome identifies numerous novel transcribed regions in frontal cortex and liverManuscript (preprint) (Other academic)
    Abstract [en]

    We have performed the first global profiling of the chimpanzee transcriptome by using deep sequencing of cDNA from brain and liver. This enabled us to quantify expression of RefSeq transcripts, identify novel transcribed regions with no previous annotations in databases and additionally search for transcribed regions with no support in the human genome.

    Using stringent criteria for transcription, we identified 9,061 expressed RefSeq transcripts and 5,532 novel transcribed regions., of which the vast majority were found intronically in RefSeq transcripts and ~ 15 % mapped intergenically. In addition,  a little less than 150 novel transcribed regions in the chimpanzee appeared to be absent from the human reference sequence. Novel transcribed regions may represent new coding regions, untranslated regions unspliced mRNAs or diferent types of non-coding transcripts. The transcriptional profile of the brain stands out in several ways: a higher number of RefSeq transcripts were expressed in brain than in liver and novel transcribed regions were also more abundant in brain. Furthermore, we identified an interesting subset of RefSeq genes with a high density of novel transcribed regions scattered across the introns. These genes clustered in central pathways of the nervous system, with an overrepresentation of genes acting in the synapse and many of which have been associated to cognitive disorders in the human.

    Our results support the prevailing view of wide-spread transcription in mammalian genomes and further highlight the vast, mostly uncharacterized, transcript variability in the primate brain.

     

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