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  • 1.
    Andrade, Pedro
    et al.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Pinho, Catarina
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Perez i de lanuza, Guillem
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Afonso, Sandra
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Brejcha, Jindrich
    Charles Univ Prague, Fac Sci, Dept Philosophy & Hist Sci, Prague 12800 2, Czech Republic;Natl Museum, Dept Zool, Prague 19300, Czech Republic;Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pereira, Paulo
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Sabatino, Stephen J.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Bellati, Adriana
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Pellitteri-Rosa, Daniele
    Univ Pavia, Dept Earth & Environm Sci, I-27100 Pavia, Italy.
    Bosakova, Zuzana
    Charles Univ Prague, Fac Sci, Dept Analyt Chem, Prague 12843 2, Czech Republic.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Carretero, Miguel A.
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal.
    Feiner, Nathalie
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Marsik, Petr
    Czech Univ Life Sci Prague, Fac Agrobiol Food & Nat Resources, Dept Food Sci, Prague 16521 6, Czech Republic.
    Pauperio, Francisco
    Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Salvi, Daniele
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Aquila, Dept Hlth Life & Environm Sci, I-67100 Laquila, Italy.
    Soler, Lucile
    Natl Bioinformat Infrastruct Sweden, Sci Life Lab, S-75123 Uppsala, Sweden.
    While, Geoffrey M.
    Univ Tasmania, Sch ol Biol Sci, Hobart, Tas 7005, Australia;Univ Oxford, Dept Zool, Oxford OX1 3PS, England.
    Uller, Tobias
    Lund Univ, Dept Biol, S-22362 Lund, Sweden.
    Font, Enrique
    Univ Valencia, Cavanilles Inst Biodivers & Evolutionary Biol, Ethol Lab, Paterna 46980, Spain.
    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. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Carneiro, Miguel
    Univ Porto, CIBIO InBIO, Ctr Invest Biodiversidade & Recursos Genet, P-4485661 Vairao, Portugal;Univ Porto, Dept Biol, Fac Ciencias, P-4169007 Porto, Portugal.
    Regulatory changes in pterin and carotenoid genes underlie balanced color polymorphisms in the wall lizard2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 12, p. 5633-5642Article in journal (Refereed)
    Abstract [en]

    Reptiles use pterin and carotenoid pigments to produce yellow, orange, and red colors. These conspicuous colors serve a diversity of signaling functions, but their molecular basis remains unresolved. Here, we show that the genomes of sympatric color morphs of the European common wall lizard (Podarcis muralis), which differ in orange and yellow pigmentation and in their ecology and behavior, are virtually undifferentiated. Genetic differences are restricted to two small regulatory regions near genes associated with pterin [sepiapterin reductase (SPR)] and carotenoid [beta-carotene oxygenase 2 (BCO2)] metabolism, demonstrating that a core gene in the housekeeping pathway of pterin biosynthesis has been coopted for bright coloration in reptiles and indicating that these loci exert pleiotropic effects on other aspects of physiology. Pigmentation differences are explained by extremely divergent alleles, and haplotype analysis revealed abundant transspecific allele sharing with other lacertids exhibiting color polymorphisms. The evolution of these conspicuous color ornaments is the result of ancient genetic variation and cross-species hybridization.

  • 2. Birney, Ewan
    et al.
    Stamatoyannopoulos, John A.
    Dutta, Anindya
    Guigó, Roderic
    Gingeras, Thomas R.
    Margulies, Elliott H.
    Weng, Zhiping
    Snyder, Michael
    Dermitzakis, Emmanouil T.
    Thurman, Robert E.
    Kuehn, Michael S.
    Taylor, Christopher M.
    Neph, Shane
    Koch, Christoph M.
    Asthana, Saurabh
    Malhotra, Ankit
    Adzhubei, Ivan
    Greenbaum, Jason A.
    Andrews, Robert M.
    Flicek, Paul
    Boyle, Patrick J.
    Cao, Hua
    Carter, Nigel P.
    Clelland, Gayle K.
    Davis, Sean
    Day, Nathan
    Dhami, Pawandeep
    Dillon, Shane C.
    Dorschner, Michael O.
    Fiegler, Heike
    Giresi, Paul G.
    Goldy, Jeff
    Hawrylycz, Michael
    Haydock, Andrew
    Humbert, Richard
    James, Keith D.
    Johnson, Brett E.
    Johnson, Ericka M.
    Frum, Tristan T.
    Rosenzweig, Elizabeth R.
    Karnani, Neerja
    Lee, Kirsten
    Lefebvre, Gregory C.
    Navas, Patrick A.
    Neri, Fidencio
    Parker, Stephen C.
    Sabo, Peter J.
    Sandstrom, Richard
    Shafer, Anthony
    Vetrie, David
    Weaver, Molly
    Wilcox, Sarah
    Yu, Man
    Collins, Francis S.
    Dekker, Job
    Lieb, Jason D.
    Tullius, Thomas D.
    Crawford, Gregory E.
    Sunyaev, Shamil
    Noble, William S.
    Dunham, Ian
    Denoeud, France
    Reymond, Alexandre
    Kapranov, Philipp
    Rozowsky, Joel
    Zheng, Deyou
    Castelo, Robert
    Frankish, Adam
    Harrow, Jennifer
    Ghosh, Srinka
    Sandelin, Albin
    Hofacker, Ivo L.
    Baertsch, Robert
    Keefe, Damian
    Dike, Sujit
    Cheng, Jill
    Hirsch, Heather A.
    Sekinger, Edward A.
    Lagarde, Julien
    Abril, Josep F.
    Shahab, Atif
    Flamm, Christoph
    Fried, Claudia
    Hackermüller, Jörg
    Hertel, Jana
    Lindemeyer, Manja
    Missal, Kristin
    Tanzer, Andrea
    Washietl, Stefan
    Korbel, Jan
    Emanuelsson, Olof
    Pedersen, Jakob S.
    Holroyd, Nancy
    Taylor, Ruth
    Swarbreck, David
    Matthews, Nicholas
    Dickson, Mark C.
    Thomas, Daryl J.
    Weirauch, Matthew T.
    Gilbert, James
    Drenkow, Jorg
    Bell, Ian
    Zhao, XiaoDong
    Srinivasan, K. G.
    Sung, Wing-Kin
    Ooi, Hong Sain
    Chiu, Kuo Ping
    Foissac, Sylvain
    Alioto, Tyler
    Brent, Michael
    Pachter, Lior
    Tress, Michael L.
    Valencia, Alfonso
    Choo, Siew Woh
    Choo, Chiou Yu
    Ucla, Catherine
    Manzano, Caroline
    Wyss, Carine
    Cheung, Evelyn
    Clark, Taane G.
    Brown, James B.
    Ganesh, Madhavan
    Patel, Sandeep
    Tammana, Hari
    Chrast, Jacqueline
    Henrichsen, Charlotte N.
    Kai, Chikatoshi
    Kawai, Jun
    Nagalakshmi, Ugrappa
    Wu, Jiaqian
    Lian, Zheng
    Lian, Jin
    Newburger, Peter
    Zhang, Xueqing
    Bickel, Peter
    Mattick, John S.
    Carninci, Piero
    Hayashizaki, Yoshihide
    Weissman, Sherman
    Hubbard, Tim
    Myers, Richard M.
    Rogers, Jane
    Stadler, Peter F.
    Lowe, Todd M.
    Wei, Chia-Lin
    Ruan, Yijun
    Struhl, Kevin
    Gerstein, Mark
    Antonarakis, Stylianos E.
    Fu, Yutao
    Green, Eric D.
    Karaöz, U.
    Siepel, Adam
    Taylor, James
    Liefer, Laura A
    Wetterstrand, Kris A.
    Good, Peter J.
    Feingold, Elise A.
    Guyer, Mark S.
    Cooper, Gregory M.
    Asimenos, George
    Dewey, Colin N.
    Hou, Minmei
    Nikolaev, Sergey
    Montoya-Burgos, Juan I.
    Löytynoja, Ari
    Whelan, Simon
    Pardi, Fabio
    Massingham, Tim
    Huang, Haiyan
    Zhang, Nancy R.
    Holmes, Ian
    Mullikin, James C.
    Ureta-Vidal, Abel
    Paten, Benedict
    Seringhaus, Michael
    Church, Deanna
    Rosenbloom, Kate
    Kent, W. James
    Stone, Eric A.
    Batzoglou, Serafim
    Goldman, Nick
    Hardison, Ross C.
    Haussler, David
    Miller, Webb
    Sidow, Arend
    Trinklein, Nathan D.
    Zhang, Zhengdong D.
    Barrera, Leah
    Stuart, Rhona
    King, David C.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bieda, Mark C.
    Kim, Jonghwan
    Bhinge, Akshay A.
    Jiang, Nan
    Liu, Jun
    Yao, Fei
    Vega, Vinsensius B.
    Lee, Charlie W.
    Ng, Patrick
    Shahab, Atif
    Yang, Annie
    Moqtaderi, Zarmik
    Zhu, Zhou
    Xu, Xiaoqin
    Squazzo, Sharon
    Oberley, Matthew J.
    Inman, David
    Singer, Michael A.
    Richmond, Todd A.
    Munn, Kyle J.
    Rada-Iglesias, Alvaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wallerman, Ola
    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.
    Fowler, Joanna C.
    Couttet, Phillippe
    Bruce, Alexander W.
    Dovey, Oliver M.
    Ellis, Peter D.
    Langford, Cordelia F.
    Nix, David A.
    Euskirchen, Ghia
    Hartman, Stephen
    Urban, Alexander E.
    Kraus, Peter
    Van Calcar, Sara
    Heintzman, Nate
    Kim, Tae Hoon
    Wang, Kun
    Qu, Chunxu
    Hon, Gary
    Luna, Rosa
    Glass, Christopher K.
    Rosenfeld, M. Geoff
    Aldred, Shelley Force
    Cooper, Sara J.
    Halees, Anason
    Lin, Jane M.
    Shulha, Hennady P.
    Zhang, Xiaoling
    Xu, Mousheng
    Haidar, Jaafar N.
    Yu, Yong
    Ruan, Yijun
    Iyer, Vishwanath R.
    Green, Roland D.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Farnham, Peggy J.
    Ren, Bing
    Harte, Rachel A.
    Hinrichs, Angie S.
    Trumbower, Heather
    Clawson, Hiram
    Hillman-Jackson, Jennifer
    Zweig, Ann S.
    Smith, Kayla
    Thakkapallayil, Archana
    Barber, Galt
    Kuhn, Robert M.
    Karolchik, Donna
    Armengol, Lluis
    Bird, Christine P.
    de Bakker, Paul I.
    Kern, Andrew D.
    Lopez-Bigas, Nuria
    Martin, Joel D.
    Stranger, Barbara E.
    Woodroffe, Abigail
    Davydov, Eugene
    Dimas, Antigone
    Eyras, Eduardo
    Hallgrí­msdóttir, Ingileif B.
    Huppert, Julian
    Zody, Michael C.
    Abecasis, G. R.
    Estivill, Xavier
    Bouffard, Gerard G.
    Guan, Xiaobin
    Hansen, Nancy F.
    Idol, Jacquelyn R.
    Maduro, Valerie V.
    Maskeri, Baishali
    McDowell, Jennifer C.
    Park, Morgan
    Thomas, Pamela J.
    Young, Alice C.
    Blakesley, Robert W.
    Muzny, Donna M.
    Sodergren, Erica
    Wheeler, David A.
    Worley, Kim C.
    Jiang, Huaiyang
    Weinstock, George M.
    Gibbs, Richard A.
    Graves, Tina
    Fulton, Robert
    Mardis, Elaine R.
    Wilson, Richard K.
    Clamp, Michele
    Cuff, James
    Gnerre, Sante
    Jaffe, David B.
    Chang, Jean L.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lander, Eric S.
    Koriabine, Maxim
    Nefedov, Mikhail
    Osoegawa, Kazutoyo
    Yoshinaga, Yuko
    Zhu, Baoli
    de Jong, Pieter J.
    Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project2007In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 447, no 7146, p. 799-816Article in journal (Refereed)
    Abstract [en]

    We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

  • 3.
    Bysani, Madhu Sudhan Reddy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bornelöv, Susanne
    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.
    Zatloukal, Kurt
    Komorowski, Jan
    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.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer2013In: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 6, p. 50-Article in journal (Refereed)
    Abstract [en]

    Background: Steatohepatitis occurs in alcoholic liver disease and may progress to liver cirrhosis and hepatocellular carcinoma. Its molecular pathogenesis is to a large degree unknown. Histone modifications play a key role in transcriptional regulations as marks for silencing and activation of gene expression and as marks for functional elements. Many transcription factors (TFs) are crucial for the control of the genes involved in metabolism, and abnormality in their function may lead to disease. Methods: We performed ChIP-seq of the histone modifications H3K4me1, H3K4me3 and H3K27ac and a candidate transcription factor (USF1) in liver tissue from patients with steatohepatitis and normal livers and correlated results to mRNA-expression and genotypes. Results: We found several regions that are differentially enriched for histone modifications between disease and normal tissue, and qRT-PCR results indicated that the expression of the tested genes strongly correlated with differential enrichment of histone modifications but is independent of USF1 enrichment. By gene ontology analysis of differentially modified genes we found many disease associated genes, some of which had previously been implicated in the etiology of steatohepatitis. Importantly, the genes associated to the strongest histone peaks in the patient were over-represented in cancer specific pathways suggesting that the tissue was on a path to develop to cancer, a common complication to the disease. We also found several novel SNPs and GWAS catalogue SNPs that are candidates to be functional and therefore needs further study. Conclusion: In summary we find that analysis of chromatin features in tissue samples provides insight into disease mechanisms.

  • 4.
    Bysani, Madhusudhan Reddy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bornelöv, Susanne
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Zatloukal, Kurt
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancerManuscript (preprint) (Other academic)
  • 5.
    Cavalli, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baltzer, Nicholas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Umer, Husen Muhammad
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Grau, Jan
    Martin Luther Univ Halle Wittenberg, Inst Comp Sci, Halle, Germany.
    Lemnian, Ioana
    Martin Luther Univ Halle Wittenberg, Inst Comp Sci, Halle, Germany.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Spalinskas, Rapolas
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden.
    Sahlen, Pelin
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden.
    Grosse, Ivo
    Martin Luther Univ Halle Wittenberg, Inst Comp Sci, Halle, Germany;German Ctr Integrat Biodivers Res iDiv, Leipzig, Germany.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 2695Article in journal (Refereed)
    Abstract [en]

    Several Genome Wide Association Studies (GWAS) have reported variants associated to immune diseases. However, the identified variants are rarely the drivers of the associations and the molecular mechanisms behind the genetic contributions remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs showing significant allele specific signals (AS-SNPs). AS-SNPs can change a TF binding site resulting in altered gene regulation and are primary candidates to explain associations observed in GWAS and expression studies. We identified 17,293 unique AS-SNPs across 7 lymphoblastoid cell lines. In this set of cell lines we interrogated 85% of common genetic variants in the population for potential regulatory effect and we identified 237 AS-SNPs associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatory mechanisms we integrated long-range 3D interactions data to identify putative target genes and motif predictions to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPs associated to gene expression and 60 to B cell related traits. We present a systems strategy to find functional gene regulatory variants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.

  • 6.
    Cavalli, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75108 Uppsala, Sweden.;Galderma, Dept Preclin Dev, Uppsala, Sweden..
    Arzt, Emelie Wallén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Karolinska Inst, Ctr Biosci, Dept Biosci & Nutr, Huddinge, Sweden..
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Allele-specific transcription factor binding in liver and cervix cells unveils many likely drivers of GWAS signals2016In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 107, no 6, p. 248-254Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) point to regions with associated genetic variants but rarely to a specific gene and therefore detailed knowledge regarding the genes contributing to complex traits and diseases remains elusive. The functional role of GWAS-SNPs is also affected by linkage disequilibrium with many variants on the same haplotype and sometimes in the same regulatory element almost equally likely to mediate the effect. Using ChIP-seq data on many transcription factors, we pinpointed genetic variants in HepG2 and HeLa-S3 cell lines which show a genome-wide significant difference in binding between alleles. We identified a collection of 3713 candidate functional regulatory variants many of which are likely drivers of GWAS signals or genetic difference in expression. A recent study investigated many variants before finding the functional ones at the GALNT2 locus, which we found in our genome-wide screen in HepG2. This illustrates the efficiency of our approach.

  • 7.
    Cavalli, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Arzt, Emelie Wallén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci, Huddinge, Sweden..
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Toh, Kerstin Lindblad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression2016In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 135, no 5, p. 485-497Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.

  • 8.
    Cavalli, Marco
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pan, Gang
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallén Arzt, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Biosciences and Nutrition, Center for Biosciences, Karolinska Institute, Sweden.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic prevention of hepatitis C virus-induced liver fibrosis by allele-specific downregulation of MERTK2017In: Hepatology Research, ISSN 1386-6346, E-ISSN 1872-034X, Vol. 47, no 8, p. 826-830Article in journal (Refereed)
    Abstract [en]

    AIM: Infection by hepatitis C virus (HCV) can result in the development of liver fibrosis and may eventually progress into cirrhosis and hepatocellular carcinoma. However, the molecular mechanisms for this process are not fully known. Several genome-wide association studies have been carried out to pinpoint causative variants in HCV-infected patient cohorts, but these variants are usually not the functional ones. The aim of this study was to identify the regulatory single nucleotide polymorphism associated with the risk of HCV-induced liver fibrosis and elucidate its molecular mechanism.

    METHODS: We utilized a bioinformatics approach to identify a non-coding regulatory variant, located in an intron of the MERTK gene, based on differential transcription factor binding between the alleles. We validated the results using expression reporter assays and electrophoresis mobility shift assays.

    RESULTS: Chromatin immunoprecipitation sequencing indicated that transcription factor(s) bind stronger to the A allele of rs6726639. Electrophoresis mobility shift assays supported these findings and suggested that the transcription factor is interferon regulatory factor 1 (IRF1). Luciferase report assays showed lower enhancer activity from the A allele and that IRF1 may act as a repressor.

    CONCLUSIONS: Treatment of hepatitis C with interferon-α results in increased IRF1 levels and our data suggest that this leads to an allele-specific downregulation of MERTK mediated by an allelic effect on the regulatory element containing the functional rs6726639. This variant also shows the hallmarks for being the driver of the genome-wide association studies for reduced risk of liver fibrosis and non-alcoholic fatty liver disease at MERTK.

  • 9.
    Christmas, Matthew J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallberg, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Olsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    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.
    Chromosomal inversions associated with environmental adaptation in honeybees2019In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 28, no 6, p. 1358-1374Article in journal (Refereed)
    Abstract [en]

    Chromosomal inversions can facilitate local adaptation in the presence of gene flow by suppressing recombination between well-adapted native haplotypes and poorly adapted migrant haplotypes. East African mountain populations of the honeybee Apis mellifera are highly divergent from neighbouring lowland populations at two extended regions in the genome, despite high similarity in the rest of the genome, suggesting that these genomic regions harbour inversions governing local adaptation. Here, we utilize a new highly contiguous assembly of the honeybee genome to characterize these regions. Using whole-genome sequencing data from 55 highland and lowland bees, we find that the highland haplotypes at both regions are present at high frequencies in three independent highland populations but extremely rare elsewhere. The boundaries of both divergent regions are characterized by regions of high homology with each other positioned in opposite orientations and contain highly repetitive, long inverted repeats with homology to transposable elements. These regions are likely to represent inversion breakpoints that participate in nonallelic homologous recombination. Using long-read data, we confirm that the lowland samples are contiguous across breakpoint regions. We do not find evidence for disruption of functional sequence by these breakpoints, which suggests that the inversions are likely maintained due to their allelic content conferring local adaptation in highland environments. Finally, we identify a third divergent genomic region, which contains highly divergent segregating haplotypes that also may contain inversion variants under selection. The results add to a growing body of evidence indicating the importance of chromosomal inversions in local adaptation.

  • 10.
    Enroth, Stefan
    et al.
    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.
    Bysani, Madhusudhan Reddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Tuch, Brian
    De la Vega, Fransisco
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Nucleosome regulatory dynamics in response to TGF-beta treatment in HepG2 cells2014In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, no 11, p. 6921-6934Article in journal (Refereed)
  • 11.
    Enroth, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. 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.
    Bysani, Madhusudhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Termén, Stefan
    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.
    Tuch, Brian B
    Applied Biosystems, part of Life Technologies, Foster City, CA 94404, USA.
    De La Vega, Francisco M
    Applied Biosystems, part of Life Technologies, Foster City, CA 94404, USA.
    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.
    Moustakas, Aristidis
    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.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Institute of Computer Science, Polish Academy of Sciences, ul. Jana Kazimierza 5, 01-248 Warszawa, Poland.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nucleosome regulatory dynamics in response to TGF beta2014In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, no 11, p. 6921-6934Article in journal (Refereed)
    Abstract [en]

    Nucleosomes play important roles in a cell beyond their basal functionality in chromatin compaction. Their placement affects all steps in transcriptional regulation, from transcription factor (TF) binding to messenger ribonucleic acid (mRNA) synthesis. Careful profiling of their locations and dynamics in response to stimuli is important to further our understanding of transcriptional regulation by the state of chromatin. We measured nucleosome occupancy in human hepatic cells before and after treatment with transforming growth factor beta 1 (TGFβ1), using massively parallel sequencing. With a newly developed method, SuMMIt, for precise positioning of nucleosomes we inferred dynamics of the nucleosomal landscape. Distinct nucleosome positioning has previously been described at transcription start site and flanking TF binding sites. We found that the average pattern is present at very few sites and, in case of TF binding, the double peak surrounding the sites is just an artifact of averaging over many loci. We systematically searched for depleted nucleosomes in stimulated cells compared to unstimulated cells and identified 24 318 loci. Depending on genomic annotation, 44-78% of them were over-represented in binding motifs for TFs. Changes in binding affinity were verified for HNF4α by qPCR. Strikingly many of these loci were associated with expression changes, as measured by RNA sequencing.

  • 12.
    Enroth, Stefan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Rada-Iglesisas, Alvaro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. 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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pahlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa2011In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 11, p. 450-Article in journal (Refereed)
    Abstract [en]

    Background: Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples. Methods: Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29. Results: By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors. Conclusions: Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers.

  • 13.
    Hiltunen, Markus
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Grudzinska-Sterno, Magdalena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ryberg, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Johannesson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Maintenance of High Genome Integrity over Vegetative Growth in the Fairy-Ring Mushroom Marasmius oreades2019In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 29, no 16, p. 2758-2765Article in journal (Refereed)
    Abstract [en]

    Most mutations in coding regions of the genome are deleterious, causing selection to favor mechanisms that minimize the mutational load over time [1-5]. DNA replication during cell division is a major source of new mutations. It is therefore important to limit the number of cell divisions between generations, particularly for large and long-lived organisms [6-9]. The germline cells of animals and the slowly dividing cells in plant meristems are adaptations to control the number of mutations that accumulate over generations [9-11]. Fungi lack a separated germline while harboring species with very large and long-lived individuals that appear to maintain highly stable genomes within their mycelia [8, 12, 13]. Here, we studied genomic mutation accumulation in the fairy-ring mushroom Marasmius oreades. We generated a chromosome-level genome assembly using a combination of cutting-edge DNA sequencing technologies and resequenced 40 samples originating from six individuals of this fungus. The low number of mutations recovered in the sequencing data suggests the presence of an unknown mechanism that works to maintain extraordinary genome integrity over vegetative growth in M. oreades. The highly structured growth pattern of M. oreades allowed us to estimate the number of cell divisions leading up to each sample [14, 15], and from this data, we infer an incredibly low per mitosis mutation rate (3.8 x 10(-12) mutations per site and cell division) as one of several possible explanations for the low number of identified mutations.

  • 14.
    Jiang, Lin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gilbert, Elizabeth
    Virginia Polytechnic Institute and State University, Department of Animal and Poultry Sciences.
    Sundström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ghazal, Awaisa
    Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics.
    Zhang, Xiaolan
    Broad Institute.
    Wang, Li
    Broad Institute.
    Mikkelsen, Tarjei
    Harvard University, Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology.
    Andersson, Göran
    Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The role of ZBED6 in transcriptional regulation studied by transcriptome  analysis after RNAi in mouse myoblastsArticle, review/survey (Other academic)
    Abstract [en]

    ZBED6 is a recently discovered transcription factor that has evolved from a domesticated DNA transposon and is unique to placental mammals. Here we further characterize the functional significance of ZBED6 based on transcriptome analysis of mouse myoblasts after Zbed6-silencing. ZBED6 appears as an important transcriptional regulator since differential expression of more than 700 genes was observed after Zbed6-silencing. The most significantly enriched GO term was muscle protein and contractile fiber, which is consistent with increased myotube formation. Twenty small nucleolar RNAs showed differential expression and all increased in expression after Zbed6-silencing. This is particularly interesting because ZBED6 localization is strongly enriched in the nucleolus. There was an overrepresentation of genes with ZBED6 binding sites among the differentially expressed genes after silencing, suggesting that ZBED6 acts as a transcriptional regulator at many loci. Many genes showed significant down-regulation after Zbed6-silencing, which begs the question of whether ZBED6 acts as an activator at some of these loci or if the decreased mRNA levels of these genes all represent secondary effects. The co-localization of histone marks and ZBED6 binding sites and the effect of ZBED6-silencing on distribution of histone marks was evaluated by ChIP-seq. There was a strong association between ZBED6 binding sites and the H3K4me3, H3K4me2 and H3K27ac modifications, which are usually found at active promoters, but no association with the repressive marks H3K27me3. We propose that ZBED6 preferentially binds to active promoters and modulates transcriptional activity by a novel mechanism rather than by recruiting repressive histone modifications.  

  • 15.
    Jiang, Lin
    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.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rubin, Carl-Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gilbert, Elizabeth R.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundström, Elisabeth
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ghazal, Awaisa
    Zhang, Xiaolan
    Wang, Li
    Mikkelsen, Tarjei S.
    Andersson, Goran
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    ZBED6 Modulates the Transcription of Myogenic Genes in Mouse Myoblast Cells2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e94187-Article in journal (Refereed)
    Abstract [en]

    ZBED6 is a recently discovered transcription factor, unique to placental mammals, that has evolved from a domesticated DNA transposon. It acts as a repressor at the IGF2 locus. Here we show that ZBED6 acts as a transcriptional modulator in mouse myoblast cells, where more than 700 genes were differentially expressed after Zbed6-silencing. The most significantly enriched GO term was muscle protein and contractile fiber, which was consistent with increased myotube formation. Twenty small nucleolar RNAs all showed increased expression after Zbed6-silencing. The co-localization of histone marks and ZBED6 binding sites and the effect of Zbed6-silencing on distribution of histone marks was evaluated by ChIP-seq analysis. There was a strong association between ZBED6 binding sites and the H3K4me3, H3K4me2 and H3K27ac modifications, which are usually found at active promoters, but no association with the repressive mark H3K27me3. Zbed6-silencing led to increased enrichment of active marks at myogenic genes, in agreement with the RNA-seq findings. We propose that ZBED6 preferentially binds to active promoters and modulates transcriptional activity without recruiting repressive histone modifications.

  • 16.
    Kruczyk, Marcin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Przanowski, Piotr
    Dabrowski, Michal
    Swiatek-Machado, Karolina
    Mieczkowski, Jakub
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ronowicz, Anna
    Piotrowski, Arkadiusz <