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  • 1.
    Figueiredo, Margarida L. A.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kim, Maria
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, SE-90187 Umeå, Sweden.
    Allgardsson, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå UniversityUmeå, Sweden; Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Non-coding roX RNAs prevent the binding of the MSL-complex to heterochromatic regions2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, p. e1004865-Article in journal (Refereed)
    Abstract [en]

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

  • 2.
    Figueiredo, Margarida L A
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    HP1a Recruitment to Promoters Is Independent of H3K9 Methylation in Drosophila melanogaster2012In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 11, p. e1003061-Article in journal (Refereed)
    Abstract [en]

    Heterochromatin protein 1 (HP1) proteins, recognized readers of the heterochromatin mark methylation of histone H3 lysine 9 (H3K9me), are important regulators of heterochromatin-mediated gene silencing and chromosome structure. In Drosophila melanogaster three histone lysine methyl transferases (HKMTs) are associated with the methylation of H3K9: Su(var)3-9, Setdb1, and G9a. To probe the dependence of HP1a binding on H3K9me, its dependence on these three HKMTs, and the division of labor between the HKMTs, we have examined correlations between HP1a binding and H3K9me patterns in wild type and null mutants of these HKMTs. We show here that Su(var)3-9 controls H3K9me-dependent binding of HP1a in pericentromeric regions, while Setdb1 controls it in cytological region 2L:31 and (together with POF) in chromosome 4. HP1a binds to the promoters and within bodies of active genes in these three regions. More importantly, however, HP1a binding at promoters of active genes is independent of H3K9me and POF. Rather, it is associated with heterochromatin protein 2 (HP2) and open chromatin. Our results support a hypothesis in which HP1a nucleates with high affinity independently of H3K9me in promoters of active genes and then spreads via H3K9 methylation and transient looping contacts with those H3K9me target sites.

  • 3.
    Forslund, Josefin M. E.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pfeiffer, Annika
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Stojkovič, Gorazd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wanrooij, Pauline H.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The presence of rNTPs decreases the speed of mitochondrial DNA replication2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 3, article id e1007315Article in journal (Refereed)
    Abstract [en]

    Ribonucleotides (rNMPs) are frequently incorporated during replication or repair by DNA polymerases and failure to remove them leads to instability of nuclear DNA (nDNA). Conversely, rNMPs appear to be relatively well-tolerated in mitochondnal DNA (mtDNA), although the mechanisms behind the tolerance remain unclear. We here show that the human mitochondrial DNA polymerase gamma (Pol gamma) bypasses single rNMPs with an unprecedentedly high fidelity and efficiency. In addition, Pol gamma exhibits a strikingly low frequency of rNMP incorporation, a property, which we find is independent of its exonuclease activity. However, the physiological levels of free rNTPs partially inhibit DNA synthesis by Pol gamma and render the polymerase more sensitive to imbalanced dNTP pools. The characteristics of Pol gamma reported here could have implications for forms of rntDNA depletion syndrome (MDS) that are associated with imbalanced cellular dNTP pools. Our results show that at the rNTPidNIP ratios that are expected to prevail in such disease states, Pol gamma enters a polymerasetexonuclease idling mode that leads to mtDNA replication stalling. This could ultimately lead to mtDNA depletion and, consequently, to mitochondrial disease phenotypes such as those observed in MDS.

  • 4.
    Goretti, Daniela
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Department of Biosciences, University of Milan, Via Celoria 26, Milan, Italy.
    Martignago, Damiano
    Landini, Martina
    Brambilla, Vittoria
    Gomez-Ariza, Jorge
    Gnesutta, Nerina
    Galbiati, Francesca
    Collani, Silvio
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Takagi, Hiroki
    Terauchi, Ryohei
    Mantovani, Roberto
    Fornara, Fabio
    Transcriptional and Post-transcriptional Mechanisms Limit Heading Date 1 (Hd1) Function to Adapt Rice to High Latitudes2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 1, article id e1006530Article in journal (Refereed)
    Abstract [en]

    Rice flowering is controlled by changes in the photoperiod that promote the transition to the reproductive phase as days become shorter. Natural genetic variation for flowering time has been largely documented and has been instrumental to define the genetics of the photoperiodic pathway, as well as providing valuable material for artificial selection of varieties better adapted to local environments. We mined genetic variation in a collection of rice varieties highly adapted to European regions and isolated distinct variants of the long day repressor HEADING DATE 1 (Hd1) that perturb its expression or protein function. Specific variants allowed us to define novel features of the photoperiodic flowering pathway. We demonstrate that a histone fold domain scaffold formed by GRAIN YIELD, PLANT HEIGHT AND HEADING DATE 8 (Ghd8) and several NF-YC subunits can accommodate distinct proteins, including Hd1 and PSEUDO RESPONSE REGULATOR 37 (PRR37), and that the resulting OsNF-Y complex containing Hd1 can bind a specific sequence in the promoter of HEADING DATE 3A (Hd3a). Artificial selection has locally favored an Hd1 variant unable to assemble in such heterotrimeric complex. The causal polymorphism was defined as a single conserved lysine in the CCT domain of the Hd1 protein. Our results indicate how genetic variation can be stratified and explored at multiple levels, and how its description can contribute to the molecular understanding of basic developmental processes.

  • 5. Graff, Mariaelisa
    et al.
    Scott, Robert A.
    Justice, Anne E.
    Young, Kristin L.
    Feitosa, Mary F.
    Barata, Llilda
    Winkler, Thomas W.
    Chu, Audrey Y.
    Mahajan, Anubha
    Hadley, David
    Xue, Luting
    Workalemahu, Tsegaselassie
    Heard-Costa, Nancy L.
    den Hoed, Marcel
    Ahluwalia, Tarunveer S.
    Qi, Qibin
    Ngwa, Julius S.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden.
    Quaye, Lydia
    Eicher, John D.
    Hayes, James E.
    Cornelis, Marilyn
    Kutalik, Zoltan
    Lim, Elise
    Luan, Jian'an
    Huffman, Jennifer E.
    Zhang, Weihua
    Zhao, Wei
    Griffin, Paula J.
    Haller, Toomas
    Ahmad, Shafqat
    Marques-Vidal, Pedro M.
    Bien, Stephanie
    Yengo, Loic
    Teumer, Alexander
    Smith, Albert Vernon
    Kumari, Meena
    Harder, Marie Neergaard
    Justesen, Johanne Marie
    Kleber, Marcus E.
    Hollensted, Mette
    Lohman, Kurt
    Rivera, Natalia V.
    Whitfield, John B.
    Zhao, Jing Hua
    Stringham, Heather M.
    Lyytikainen, Leo-Pekka
    Huppertz, Charlotte
    Willemsen, Gonneke
    Peyrot, Wouter J.
    Wu, Ying
    Kristiansson, Kati
    Demirkan, Ayse
    Fornage, Myriam
    Hassinen, Maija
    Bielak, Lawrence F.
    Cadby, Gemma
    Tanaka, Toshiko
    Magl, Reedlk
    Van der Most, Peter J.
    Jackson, Anne U.
    Bragg-Gresham, Jennifer L.
    Vitart, Veronique
    Marten, Jonathan
    Navarro, Pau
    Bellis, Claire
    Pasko, Dorota
    Johansson, Asa
    Snitker, Soren
    Cheng, Yu-Ching
    Eriksson, Joel
    Lim, Unhee
    Aadahl, Mette
    Adair, Linda S.
    Amin, Najaf
    Balkau, Beverley
    Auvinen, Juha
    Beilby, John
    Bergman, Richard N.
    Bergmann, Sven
    Bertoni, Alain G.
    Blangero, John
    Bonnefond, Amelle
    Bonnycastle, Lori L.
    Borja, Judith B.
    Brage, Soren
    Busonero, Fabio
    Buyske, Steve
    Campbell, Harry
    Chines, Peter S.
    Collins, Francis S.
    Corre, Tanguy
    Smith, George Davey
    Delgado, Graciela E.
    Dueker, Nicole
    Doerr, Marcus
    Ebeling, Tapani
    Eiriksdottir, Gudny
    Esko, Tonu
    Faul, Jessica D.
    Fu, Mao
    Faerch, Kristine
    Gieger, Christian
    Glaeser, Sven
    Gong, Jian
    Gordon-Larsen, Penny
    Grallert, Harald
    Grammer, Tanja B.
    Grarup, Niels
    van Grootheest, Gerard
    Harald, Kennet
    Hastie, Nicholas D.
    Havulinna, Aki S.
    Hernandez, Dena
    Hindorff, Lucia
    Hocking, Lynne J.
    Holmens, Oddgeir L.
    Holzapfel, Christina
    Hottenga, Jouke Jan
    Huang, Jie
    Huang, Tao
    Hui, Jennie
    Huth, Cornelia
    Hutri-Kahonen, Nina
    James, Alan L.
    Jansson, John-Olov
    Jhun, Min A.
    Juonala, Markus
    Kinnunen, Leena
    Koistinen, Heikki A.
    Kolcic, Ivana
    Komulainen, Pirjo
    Kuusisto, Johanna
    Kvaloy, Kirsti
    Kahonen, Mika
    Lakka, Timo A.
    Launer, Lenore J.
    Lehne, Benjamin
    Lindgren, Cecilia M.
    Lorentzon, Mattias
    Luben, Robert
    Marre, Michel
    Milaneschi, Yuri
    Monda, Keri L.
    Montgomery, Grant W.
    De Moor, Marleen H. M.
    Mulas, Antonella
    Mueller-Nurasyid, Martina
    Musk, A. W.
    Mannikko, Reija
    Mannisto, Satu
    Narisu, Narisu
    Nauck, Matthias
    Nettleton, Jennifer A.
    Nolte, Ilja M.
    Oldehinkel, Albertine J.
    Olden, Matthias
    Ong, Ken K.
    Padmanabhan, Sandosh
    Paternoster, Lavinia
    Perez, Jeremiah
    Perola, Markus
    Peters, Annette
    Peters, Ulrike
    Peyser, Patricia A.
    Prokopenko, Inga
    Puolijoki, Hannu
    Raitakari, Olli T.
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J.
    Rawal, Rajesh
    Ridker, Paul M.
    Rose, Lynda M.
    Rudan, Igor
    Sarti, Cinzia
    Sarzynski, Mark A.
    Savonen, Kai
    Scott, William R.
    Sanna, Serena
    Shuldiner, Alan R.
    Sidney, Steve
    Silbernagel, Guenther
    Smith, Blair H.
    Smith, Jennifer A.
    Snieder, Harold
    Stancakova, Alena
    Sternfeld, Barbara
    Swift, Amy J.
    Tammelin, Tuija
    Tan, Sian-Tsung
    Thorand, Barbara
    Thuillier, Dorothee
    Vandenput, Liesbeth
    Vestergaard, Henrik
    van Vliet-Ostaptchouk, Jana V.
    Vohl, Marie-Claude
    Voelker, Uwe
    Waeber, Gerard
    Walker, Mark
    Wild, Sarah
    Wong, Andrew
    Wright, Alan F.
    Zillikens, M. Carola
    Zubair, Niha
    Haiman, Christopher A.
    Lemarchand, Loic
    Gyllensten, Ulf
    Ohlsson, Claes
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, Andre G.
    Perusse, Louis
    Wilson, James F.
    Hayward, Caroline
    Polasek, Ozren
    Cucca, Francesco
    Hveem, Kristian
    Hartman, Catharina A.
    Toenjes, Anke
    Bandinelli, Stefania
    Palmer, Lyle J.
    Kardia, Sharon L. R.
    Rauramaa, Rainer
    Sorensen, Thorkild I. A.
    Tuomilehto, Jaakko
    Salomaa, Veikko
    Penninx, Brenda W. J. H.
    de Geus, Eco J. C.
    Boomsma, Dorret I.
    Lehtimaki, Terho
    Mangino, Massimo
    Laakso, Markku
    Bouchard, Claude
    Martin, Nicholas G.
    Kuh, Diana
    Liu, Yongmei
    Linneberg, Allan
    Maerz, Winfried
    Strauch, Konstantin
    Kivimaki, Mika
    Harris, Tamara B.
    Gudnason, Vilmundur
    Voelzke, Henry
    Qi, Lu
    Jarvelin, Marjo-Riitta
    Chambers, John C.
    Kooner, Jaspal S.
    Froguel, Philippe
    Kooperberg, Charles
    Vollenweider, Peter
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hansen, Torben
    Pedersen, Oluf
    Metspalu, Andres
    Wareham, Nicholas J.
    Langenberg, Claudia
    Weir, David R.
    Porteous, David J.
    Boerwinkle, Eric
    Chasman, Daniel I.
    Abecasis, Goncalo R.
    Barroso, Ines
    McCarthy, Mark I.
    Frayling, Timothy M.
    O'Connell, Jeffrey R.
    van Duijn, Cornelia M.
    Boehnke, Michael
    Heid, Iris M.
    Mohlke, Karen L.
    Strachan, David P.
    Fox, Caroline S.
    Liu, Ching-Ti
    Hirschhorn, Joel N.
    Klein, Robert J.
    Johnson, Andrew D.
    Borecki, Ingrid B.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA ; Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden.
    North, Kari E.
    Cupples, L. Adrienne
    Loos, Ruth J. F.
    Kilpelainen, Tuomas O.
    Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006528Article in journal (Refereed)
    Abstract [en]

    Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

  • 6. Haag, Daniel
    et al.
    Zipper, Petra
    Westrich, Viola
    Karra, Daniela
    Pfleger, Karin
    Toedt, Grischa
    Blond, Frederik
    Delhomme, Nicolas
    Hahn, Meinhard
    Reifenberger, Julia
    Reifenberger, Guido
    Lichter, Peter
    Nos2 inactivation promotes the development of medulloblastoma in Ptch1(+/-) mice by deregulation of Gap43-dependent granule cell precursor migration.2012In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 3Article in journal (Refereed)
    Abstract [en]

    Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/-) mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/-) mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/-) Nos2(-/-) mice compared to Ptch1(+/-) Nos2(+/+) mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+) Nos2(-/-) mice but not from Ptch1(+/-) Nos2(-/-) mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+) Nos2(-/-) mice but increased in Ptch1(+/-) Nos2(-/) (-) mice relative to Ptch1(+/-) Nos2(+/+) mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/-) mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression.

  • 7.
    Holmqvist, Per-Henrik
    et al.
    The Wenner-Gren Institute, Developmental Biology, Stockholm University, Stockholm.
    Boija, Ann
    The Wenner-Gren Institute, Developmental Biology, Stockholm University, Stockholm.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Crona, Filip
    The Wenner-Gren Institute, Developmental Biology, Stockholm University, Stockholm.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Mannervik, Mattias
    The Wenner-Gren Institute, Developmental Biology, Stockholm University, Stockholm.
    Preferential Genome Targeting of the CBP Co-Activator by Rel and Smad Proteins in Early Drosophila melanogaster Embryos2012In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 6, p. e1002769-Article in journal (Refereed)
    Abstract [en]

    CBP and the related p300 protein are widely used transcriptional co-activators in metazoans that interact with multiple transcription factors. Whether CBP/p300 occupies the genome equally with all factors or preferentially binds together with some factors is not known. We therefore compared Drosophila melanogaster CBP (nejire) ChIP-seq peaks with regions bound by 40 different transcription factors in early embryos, and we found high co-occupancy with the Rel-family protein Dorsal. Dorsal is required for CBP occupancy in the embryo, but only at regions where few other factors are present. CBP peaks in mutant embryos lacking nuclear Dorsal are best correlated with TGF-ß/Dpp-signaling and Smad-protein binding. Differences in CBP occupancy in mutant embryos reflect gene expression changes genome-wide, but CBP also occupies some non-expressed genes. The presence of CBP at silent genes does not result in histone acetylation. We find that Polycomb-repressed H3K27me3 chromatin does not preclude CBP binding, but restricts histone acetylation at CBP-bound genomic sites. We conclude that CBP occupancy in Drosophila embryos preferentially overlaps factors controlling dorso-ventral patterning and that CBP binds silent genes without causing histone hyperacetylation.

  • 8.
    Jafari, Shadi
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    Cis-Regulatory Mechanisms for Robust Olfactory Sensory Neuron Class-restricted Odorant Receptor Gene Expression in Drosophila2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 3, article id e1005051Article in journal (Refereed)
    Abstract [en]

    Odor perception requires that each olfactory sensory neuron (OSN) class continuously express a single odorant receptor (OR) regardless of changes in the environment. However, little is known about the control of the robust, class-specific OR expression involved. Here, we investigate the cis-regulatory mechanisms and components that generate robust and OSN class-specific OR expression in Drosophila. Our results demonstrate that the spatial restriction of expression to a single OSN class is directed by clusters of transcription-factor DNA binding motifs. Our dissection of motif clusters of differing complexity demonstrates that structural components such as motif overlap and motif order integrate transcription factor combinations and chromatin status to form a spatially restricted pattern. We further demonstrate that changes in metabolism or temperature perturb the function of complex clusters. We show that the cooperative regulation between motifs around and within the cluster generates robust, class-specific OR expression.

  • 9. Jakobsdottir, Johanna
    et al.
    van der Lee, Sven J.
    Bis, Joshua C.
    Chouraki, Vincent
    Li-Kroeger, David
    Yamamoto, Shinya
    Grove, Megan L.
    Naj, Adam
    Vronskaya, Maria
    Salazar, Jose L.
    DeStefano, Anita L.
    Brody, Jennifer A.
    Smith, Albert V.
    Amin, Najaf
    Sims, Rebecca
    Ibrahim-Verbaas, Carla A.
    Choi, Seung-Hoan
    Satizabal, Claudia L.
    Lopez, Oscar L.
    Beiser, Alexa
    Ikram, M. Arfan
    Garcia, Melissa E.
    Hayward, Caroline
    Varga, Tibor V.
    Ripatti, Samuli
    Franks, Paul W.
    Department of Public Health & Clinical Medicine, Umeå University Hospital, Umeå, Sweden; .
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Jansson, Jan-Hakon
    Porteous, David J.
    Salomaa, Veikko
    Eiriksdottir, Gudny
    Rice, Kenneth M.
    Bellen, Hugo J.
    Levy, Daniel
    Uitterlinden, Andre G.
    Emilsson, Valur
    Rotter, Jerome I.
    Aspelund, Thor
    O'Donnell, Christopher J.
    Fitzpatrick, Annette L.
    Launer, Lenore J.
    Hofman, Albert
    Wang, Li-San
    Williams, Julie
    Schellenberg, Gerard D.
    Boerwinkle, Eric
    Psaty, Bruce M.
    Seshadri, Sudha
    Shulman, Joshua M.
    Gudnason, Vilmundur
    Van Duijn, Cornelia M.
    Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 10, article id e1006327Article in journal (Refereed)
    Abstract [en]

    We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (similar to 0.5% versus < 0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES substudy, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10(-9)]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade.

  • 10. Kasparek, Petr
    et al.
    Ileninova, Zuzana
    Zbodakova, Olga
    Kanchev, Ivan
    Benada, Oldrich
    Chalupsky, Karel
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Beck, Inken M.
    Sedlacek, Radislav
    KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 1, article id e1006566Article in journal (Refereed)
    Abstract [en]

    Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy.

  • 11.
    Kim, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Faucillion, Marie-Line
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    RNA-on-X 1 and 2 in Drosophila melanogaster fulfill separate functions in dosage compensation2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 12, article id e1007842Article in journal (Refereed)
    Abstract [en]

    In Drosophila melanogaster, the male-specific lethal (MSL) complex plays a key role in dosage compensation by stimulating expression of male X-chromosome genes. It consists of MSL proteins and two long noncoding RNAs, roX1 and roX2, that are required for spreading of the complex on the chromosome and are redundant in the sense that loss of either does not affect male viability. However, despite rapid evolution, both roX species are present in diverse Drosophilidae species, raising doubts about their full functional redundancy. Thus, we have investigated consequences of deleting roX1 and/or roX2 to probe their specific roles and redundancies in Dmelanogaster. We have created a new mutant allele of roX2 and show that roX1 and roX2 have partly separable functions in dosage compensation. In larvae, roX1 is the most abundant variant and the only variant present in the MSL complex when the complex is transmitted (physically associated with the X-chromosome) in mitosis. Loss of roX1 results in reduced expression of the genes on the X-chromosome, while loss of roX2 leads to MSL-independent upregulation of genes with male-biased testis-specific transcription. In roX1 roX2mutant, gene expression is strongly reduced in a manner that is not related to proximity to high-affinity sites. Our results suggest that high tolerance of mis-expression of the X-chromosome has evolved. We propose that this may be a common property of sex-chromosomes, that dosage compensation is a stochastic process and its precision for each individual gene is regulated by the density of high-affinity sites in the locus.

  • 12. Kumar, Anmol
    et al.
    Kopra, Jaakko
    Varendi, Kart
    Porokuokka, Lauriina L.
    Panhelainen, Anne
    Kuure, Satu
    Marshall, Pepin
    Karalija, Nina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Harma, Mari-Anne
    Vilenius, Carolina
    Lillevaeli, Kersti
    Tekko, Triin
    Mijatovic, Jelena
    Pulkkinen, Nita
    Jakobson, Madis
    Jakobson, Maili
    Ola, Roxana
    Palm, Erik
    Lindahl, Maria
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Voikar, Vootele
    Piepponen, T. Petteri
    Saarma, Mart
    Andressoo, Jaan-Olle
    GDNF Overexpression from the Native Locus Reveals its Role in the Nigrostriatal Dopaminergic System Function2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 12, article id e1005710Article in journal (Refereed)
    Abstract [en]

    Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3'UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3'UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial expression of GDNF. Furthermore, our results suggest that 3'UTR targeting may constitute a useful tool in analyzing gene function.

  • 13. Lempe, J.
    et al.
    Balasubramanian, S.
    Sureshkumar, S.
    Singh, A.
    Schmid, M.
    Department of Molecular Biology, Max Planck Institute for Developmental Biology, Tübingen, Germany .
    Weigel, D.
    Diversity of flowering responses in wild Arabidopsis thaliana strains2005In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 1, no 1, p. 109-118Article in journal (Refereed)
  • 14. Leo, Paul J
    et al.
    Madeleine, Margaret M
    Wang, Sophia
    Schwartz, Stephen M
    Newell, Felicity
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, Kari
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Tiews, Sven
    Steinberg, Winfried
    Rader, Janet S
    Castro, Felipe
    Safaeian, Mahboobeh
    Franco, Eduardo L
    Coutlée, François
    Ohlsson, Claes
    Cortes, Adrian
    Marshall, Mhairi
    Mukhopadhyay, Pamela
    Cremin, Katie
    Johnson, Lisa G
    Garland, Suzanne
    Tabrizi, Sepehr N
    Wentzensen, Nicolas
    Sitas, Freddy
    Little, Julian
    Cruickshank, Maggie
    Frazer, Ian H
    Hildesheim, Allan
    Brown, Matthew A
    Defining the genetic susceptibility to cervical neoplasia: A genome-wide association study2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 8, article id e1006866Article in journal (Refereed)
    Abstract [en]

    A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

  • 15. Li, Xiaoli
    et al.
    Jin, Xuejiao
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Xiaojing
    Zhang, Jiaxin
    Niu, Yanling
    Li, Jiani
    Li, Zhen
    Zhang, Jingjing
    Cao, Qinhong
    Hou, Wenya
    Du, Li-Lin
    Liu, Beidong
    Lou, Huiqiang
    Mck1 defines a key S-phase checkpoint effector in response to various degrees of replication threats2019In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 8, article id e1008136Article in journal (Refereed)
    Abstract [en]

    The S-phase checkpoint plays an essential role in regulation of the ribonucleotide reductase (RNR) activity to maintain the dNTP pools. How eukaryotic cells respond appropriately to different levels of replication threats remains elusive. Here, we have identified that a conserved GSK-3 kinase Mck1 cooperates with Dun1 in regulating this process. Deleting MCK1 sensitizes dun1 Delta to hydroxyurea (HU) reminiscent of mec1 Delta or rad53 Delta. While Mck1 is downstream of Rad53, it does not participate in the post-translational regulation of RNR as Dun1 does. Mck1 phosphorylates and releases the Crt1 repressor from the promoters of DNA damage-inducible genes as RNR2-4 and HUG1. Hug1, an Rnr2 inhibitor normally silenced, is induced as a counterweight to excessive RNR. When cells suffer a more severe threat, Mck1 inhibits HUG1 transcription. Consistently, only a combined deletion of HUG1 and CRT1, confers a dramatic boost of dNTP levels and the survival of mck1 Delta dun1 Delta or mec1 Delta cells assaulted by a lethal dose of HU. These findings reveal the division-of-labor between Mck1 and Dun1 at the S-phase checkpoint pathway to fine-tune dNTP homeostasis. Author summary The appropriate amount and balance of four dNTPs are crucial for all cells correctly copying and passing on their genetic material generation by generation. Eukaryotes have developed an alert and response system to deal with the disturbance. Here, we uncovered a second-level effector branch. It is activated by the upstream surveillance kinase cascade, which can induce the expression of dNTP-producing enzymes. It can also reduce the inhibitor of these enzymes to further boost their activity according to the degrees of threats. These findings suggest a multi-level response system to guarantee the appropriate dNTP supply, which is essential to maintain genetic stability under various environmental challenges.

  • 16. Macagno, Juan Pablo
    et al.
    Vera, Jesica Diaz
    Yu, Yachuan
    MacPherson, Iain
    Sandilands, Emma
    Palmer, Ruth
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Norman, Jim C.
    Frame, Margaret
    Vidal, Marcos
    FAK Acts as a Suppressor of RTK-MAP Kinase Signalling in Drosophila melanogaster Epithelia and Human Cancer Cells2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 3, p. e1004262-Article in journal (Refereed)
    Abstract [en]

    Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours.

  • 17.
    Maicher, André
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gazy, Inbal
    Sharma, Sushma
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Grinberg, Gilad
    Shemesh, Keren
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Kupiec, Martin
    Rnr1, but not Rnr3, facilitates the sustained telomerase-dependent elongation of telomeres2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 10, article id e1007082Article in journal (Refereed)
    Abstract [en]

    Ribonucleotide reductase (RNR) provides the precursors for the generation of dNTPs, which are required for DNA synthesis and repair. Here, we investigated the function of the major RNR subunits Rnr1 and Rnr3 in telomere elongation in budding yeast. We show that Rnr1 is essential for the sustained elongation of short telomeres by telomerase. In the absence of Rnr1, cells harbor very short, but functional, telomeres, which cannot become elongated by increased telomerase activity or by tethering of telomerase to telomeres. Furthermore, we demonstrate that Rnr1 function is critical to prevent an early onset of replicative senescence and premature survivor formation in telomerase-negative cells but dispensable for telomere elongation by Homology-Directed-Repair. Our results suggest that telomerase has a "basal activity" mode that is sufficient to compensate for the "end-replication-problem" and does not require the presence of Rnr1 and a different "sustained activity" mode necessary for the elongation of short telomeres, which requires an upregulation of dNTP levels and dGTP ratios specifically through Rnr1 function. By analyzing telomere length and dNTP levels in different mutants showing changes in RNR complex composition and activity we provide evidence that the Mec1ATR checkpoint protein promotes telomere elongation by increasing both dNTP levels and dGTP ratios through Rnr1 upregulation in a mechanism that cannot be replaced by its homolog Rnr3.

  • 18. McDonald, Karin R.
    et al.
    Guise, Amanda J.
    Pourbozorgi-Langroudi, Parham
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Cristea, Ileana M.
    Zakian, Virginia A.
    Capra, John A.
    Sabouri, Nasim
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 9, article id e1006238Article in journal (Refereed)
    Abstract [en]

    Replicative DNA helicases expose the two strands of the double helix to the replication apparatus, but accessory helicases are often needed to help forks move past naturally occurring hard-to-replicate sites, such as tightly bound proteins, RNA/DNA hybrids, and DNA secondary structures. Although the Schizosaccharomyces pombe 5'-to-3' DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry. Of the 621 high confidence Pfh1-binding sites in wild type cells, about 40% were sites of fork slowing (as marked by high DNA polymerase occupancy) and/or DNA damage (as marked by high levels of phosphorylated H2A). The replication and integrity of tRNA and 5S rRNA genes, highly transcribed RNA polymerase II genes, and nucleosome depleted regions were particularly Pfh1-dependent. The association of Pfh1 with genomic integrity at highly transcribed genes was S phase dependent, and thus unlikely to be an artifact of high transcription rates. Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase. Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner. Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites. These data provide insight into mechanisms by which this evolutionarily conserved helicase helps preserve genome integrity.

  • 19.
    Mendoza-Garcia, Patricia
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hugosson, Fredrik
    Fallah, Mahsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Higgins, Michael L.
    Iwasaki, Yasuno
    Pfeifer, Kathrin
    Wolfstetter, Georg
    Varshney, Gaurav
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Popichenko, Dmitry
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gergen, J. Peter
    Hens, Korneel
    Deplancke, Bart
    Palmer, Ruth H.
    The Zic family homologue Odd-paired regulates Alk expression in Drosophila2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006617Article in journal (Refereed)
    Abstract [en]

    The Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) plays a critical role in the specification of founder cells (FCs) in the Drosophila visceral mesoderm (VM) during embryogenesis. Reporter gene and CRISPR/Cas9 deletion analysis reveals enhancer regions in and upstream of the Alk locus that influence tissue-specific expression in the amnioserosa (AS), the VM and the epidermis. By performing high throughput yeast one-hybrid screens (Y1H) with a library of Drosophila transcription factors (TFs) we identify Odd-paired (Opa), the Drosophila homologue of the vertebrate Zic family of TFs, as a novel regulator of embryonic Alk expression. Further characterization identifies evolutionarily conserved Opa-binding cis-regulatory motifs in one of the Alk associated enhancer elements. Employing Alk reporter lines as well as CRISPR/Cas9-mediated removal of regulatory elements in the Alk locus, we show modulation of Alk expression by Opa in the embryonic AS, epidermis and VM. In addition, we identify enhancer elements that integrate input from additional TFs, such as Binou (Bin) and Bagpipe (Bap), to regulate VM expression of Alk in a combinatorial manner. Taken together, our data show that the Opa zinc finger TF is a novel regulator of embryonic Alk expression.

  • 20.
    Mähler, Niklas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Norwegian Univ Life Sci, Dept Chem Biotechnol & Food Sci, Norway.
    Wang, Jing
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Centre for Integrative Genetics, Faculty of Biosciences, Norwegian University of Life Sciences, Norway.
    Terebieniec, Barbara K.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Ingvarsson, Pär K.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Swedish Univ Agr Sci, Dept Plant Biol, Uppsala, Sweden.
    Street, Nathaniel R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Norwegian Univ Life Sci, Dept Chem Biotechnol & Food Sci, As, Norway.
    Gene co-expression network connectivity is an important determinant of selective constraint2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006402Article in journal (Refereed)
    Abstract [en]

    While several studies have investigated general properties of the genetic architecture of natural variation in gene expression, few of these have considered natural, outbreeding populations. In parallel, systems biology has established that a general feature of biological networks is that they are scale-free, rendering them buffered against random mutations. To date, few studies have attempted to examine the relationship between the selective processes acting to maintain natural variation of gene expression and the associated co-expression network structure. Here we utilised RNA-Sequencing to assay gene expression in winter buds undergoing bud flush in a natural population of Populus tremula, an outbreeding forest tree species. We performed expression Quantitative Trait Locus (eQTL) mapping and identified 164,290 significant eQTLs associating 6,241 unique genes (eGenes) with 147,419 unique SNPs (eSNPs). We found approximately four times as many local as distant eQTLs, with local eQTLs having significantly higher effect sizes. eQTLs were primarily located in regulatory regions of genes (UTRs or flanking regions), regardless of whether they were local or distant. We used the gene expression data to infer a co-expression network and investigated the relationship between network topology, the genetic architecture of gene expression and signatures of selection. Within the co-expression network, eGenes were underrepresented in network module cores (hubs) and overrepresented in the periphery of the network, with a negative correlation between eQTL effect size and network connectivity. We additionally found that module core genes have experienced stronger selective constraint on coding and non-coding sequence, with connectivity associated with signatures of selection. Our integrated genetics and genomics results suggest that purifying selection is the primary mechanism underlying the genetic architecture of natural variation in gene expression assayed in flushing leaf buds of P. tremula and that connectivity within the co-expression network is linked to the strength of purifying selection.

  • 21. Navarro-Gonzalez, Carmen
    et al.
    Moukadiri, Ismail
    Villarroya, Magda
    Lopez-Pascual, Ernesto
    Tuck, Simon
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eugenia Armengod, M.
    Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 7, article id e1006921Article in journal (Refereed)
    Abstract [en]

    Several oxidative phosphorylation (OXPHOS) diseases are caused by defects in the post-transcriptional modification of mitochondrial tRNAs (mt-tRNAs). Mutations in MTO1 or GTPBP3 impair the modification of the wobble uridine at position 5 of the pyrimidine ring and cause heart failure. Mutations in TRMU affect modification at position 2 and cause liver disease. Presently, the molecular basis of the diseases and why mutations in the different genes lead to such different clinical symptoms is poorly understood. Here we use Caenorhabditis elegans as a model organism to investigate how defects in the TRMU, GTPBP3 and MTO1 orthologues (designated as mttu-1, mtcu-1, and mtcu-2, respectively) exert their effects. We found that whereas the inactivation of each C. elegans gene is associated with a mild OXPHOS dysfunction, mutations in mtcu-1 or mtcu-2 cause changes in the expression of metabolic and mitochondrial stress response genes that are quite different from those caused by mttu-1 mutations. Our data suggest that retrograde signaling promotes defect-specific metabolic reprogramming, which is able to rescue the OXPHOS dysfunction in the single mutants by stimulating the oxidative tricarboxylic acid cycle flux through complex II. This adaptive response, however, appears to be associated with a biological cost since the single mutant worms exhibit thermosensitivity and decreased fertility and, in the case of mttu-1, longer reproductive cycle. Notably, mttu-1 worms also exhibit increased lifespan. We further show that mtcu-1; mttu-1 and mtcu-2; mttu-1 double mutants display severe growth defects and sterility. The animal models presented here support the idea that the pathological states in humans may initially develop not as a direct consequence of a bioenergetic defect, but from the cell's maladaptive response to the hypomodification status of mt-tRNAs. Our work highlights the important association of the defect-specific metabolic rewiring with the pathological phenotype, which must be taken into consideration in exploring specific therapeutic interventions.

  • 22. Nishant, K T
    et al.
    Wei, Wu
    Mancera, Eugenio
    Argueso, Juan Lucas
    Schlattl, Andreas
    Delhomme, Nicolas
    Ma, Xin
    Bustamante, Carlos D
    Korbel, Jan O
    Gu, Zhenglong
    Steinmetz, Lars M
    Alani, Eric
    The baker's yeast diploid genome is remarkably stable in vegetative growth and meiosis.2010In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 6, no 9Article in journal (Refereed)
    Abstract [en]

    Accurate estimates of mutation rates provide critical information to analyze genome evolution and organism fitness. We used whole-genome DNA sequencing, pulse-field gel electrophoresis, and comparative genome hybridization to determine mutation rates in diploid vegetative and meiotic mutation accumulation lines of Saccharomyces cerevisiae. The vegetative lines underwent only mitotic divisions while the meiotic lines underwent a meiotic cycle every ∼20 vegetative divisions. Similar base substitution rates were estimated for both lines. Given our experimental design, these measures indicated that the meiotic mutation rate is within the range of being equal to zero to being 55-fold higher than the vegetative rate. Mutations detected in vegetative lines were all heterozygous while those in meiotic lines were homozygous. A quantitative analysis of intra-tetrad mating events in the meiotic lines showed that inter-spore mating is primarily responsible for rapidly fixing mutations to homozygosity as well as for removing mutations. We did not observe 1-2 nt insertion/deletion (in-del) mutations in any of the sequenced lines and only one structural variant in a non-telomeric location was found. However, a large number of structural variations in subtelomeric sequences were seen in both vegetative and meiotic lines that did not affect viability. Our results indicate that the diploid yeast nuclear genome is remarkably stable during the vegetative and meiotic cell cycles and support the hypothesis that peripheral regions of chromosomes are more dynamic than gene-rich central sections where structural rearrangements could be deleterious. This work also provides an improved estimate for the mutational load carried by diploid organisms.

  • 23. Peng, Xiao P.
    et al.
    Lim, Shelly
    Li, Shibai
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zhao, Xiaolan
    Acute Smc5/6 depletion reveals its primary role in rDNA replication by restraining recombination at fork pausing sites2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 1, article id e1007129Article in journal (Refereed)
    Abstract [en]

    Smc5/6, a member of the conserved SMC family of complexes, is essential for growth in most organisms. Its exact functions in a mitotic cell cycle are controversial, as chronic Smc5/6 loss-of-function alleles produce varying phenotypes. To circumvent this issue, we acutely depleted Smc5/6 in budding yeast and determined the first cell cycle consequences of Smc5/6 removal. We found a striking primary defect in replication of the ribosomal DNA (rDNA) array. Each rDNA repeat contains a programmed replication fork barrier (RFB) established by the Fob1 protein. Fob1 removal improves rDNA replication in Smc5/6 depleted cells, implicating Smc5/6 in the management of programmed fork pausing. A similar improvement is achieved by removing the DNA helicase Mph1 whose recombinogenic activity can be inhibited by Smc5/6 under DNA damage conditions. DNA 2D gel analyses further show that Smc5/6 loss increases recombination structures at RFB regions; moreover, mph1 Delta and fob1 Delta similarly reduce this accumulation. These findings point to an important mitotic role for Smc5/6 in restraining recombination events when protein barriers in rDNA stall replication forks. As rDNA maintenance influences multiple essential cellular processes, Smc5/6 likely links rDNA stability to overall mitotic growth.

  • 24. Prát, Tomáš
    et al.
    Hajný, Jakub
    Grunewald, Wim
    Vasileva, Mina
    Molnár, Gergely
    Tejos, Ricardo
    Schmid, Markus
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Sauer, Michael
    Friml, Jiří
    WRKY23 is a component of the transcriptional network mediating auxin feedback on PIN polarity2018In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 14, no 1, article id e1007177Article in journal (Refereed)
    Abstract [en]

    Auxin is unique among plant hormones due to its directional transport that is mediated by the polarly distributed PIN auxin transporters at the plasma membrane. The canalization hypothesis proposes that the auxin feedback on its polar flow is a crucial, plant-specific mechanism mediating multiple self-organizing developmental processes. Here, we used the auxin effect on the PIN polar localization in Arabidopsis thaliana roots as a proxy for the auxin feedback on the PIN polarity during canalization. We performed microarray experiments to find regulators of this process that act downstream of auxin. We identified genes that were transcriptionally regulated by auxin in an AXR3/IAA17-and ARF7/ARF19-dependent manner. Besides the known components of the PIN polarity, such as PID and PIP5K kinases, a number of potential new regulators were detected, among which the WRKY23 transcription factor, which was characterized in more detail. Gain-and loss-of-function mutants confirmed a role for WRKY23 in mediating the auxin effect on the PIN polarity. Accordingly, processes requiring auxin-mediated PIN polarity rearrangements, such as vascular tissue development during leaf venation, showed a higher WRKY23 expression and required the WRKY23 activity. Our results provide initial insights into the auxin transcriptional network acting upstream of PIN polarization and, potentially, canalization-mediated plant development.

  • 25. Randall, Joshua C
    et al.
    Winkler, Thomas W
    Kutalik, Zoltán
    Berndt, Sonja I
    Jackson, Anne U
    Monda, Keri L
    Kilpeläinen, Tuomas O
    Esko, Tõnu
    Mägi, Reedik
    Li, Shengxu
    Workalemahu, Tsegaselassie
    Feitosa, Mary F
    Croteau-Chonka, Damien C
    Day, Felix R
    Fall, Tove
    Ferreira, Teresa
    Gustafsson, Stefan
    Locke, Adam E
    Mathieson, Iain
    Scherag, Andre
    Vedantam, Sailaja
    Wood, Andrew R
    Liang, Liming
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Dermitzakis, Emmanouil T
    Dimas, Antigone S
    Karpe, Fredrik
    Min, Josine L
    Nicholson, George
    Clegg, Deborah J
    Person, Thomas
    Krohn, Jon P
    Bauer, Sabrina
    Buechler, Christa
    Eisinger, Kristina
    Bonnefond, Amélie
    Froguel, Philippe
    Hottenga, Jouke-Jan
    Prokopenko, Inga
    Waite, Lindsay L
    Harris, Tamara B
    Smith, Albert Vernon
    Shuldiner, Alan R
    McArdle, Wendy L
    Caulfield, Mark J
    Munroe, Patricia B
    Grönberg, Henrik
    Chen, Yii-Der Ida
    Li, Guo
    Beckmann, Jacques S
    Johnson, Toby
    Thorsteinsdottir, Unnur
    Teder-Laving, Maris
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Zhao, Jing Hua
    Amin, Najaf
    Oostra, Ben A
    Kraja, Aldi T
    Province, Michael A
    Cupples, L Adrienne
    Heard-Costa, Nancy L
    Kaprio, Jaakko
    Ripatti, Samuli
    Surakka, Ida
    Collins, Francis S
    Saramies, Jouko
    Tuomilehto, Jaakko
    Jula, Antti
    Salomaa, Veikko
    Erdmann, Jeanette
    Hengstenberg, Christian
    Loley, Christina
    Schunkert, Heribert
    Lamina, Claudia
    Wichmann, H Erich
    Albrecht, Eva
    Gieger, Christian
    Hicks, Andrew A
    Johansson, Asa
    Pramstaller, Peter P
    Kathiresan, Sekar
    Speliotes, Elizabeth K
    Penninx, Brenda
    Hartikainen, Anna-Liisa
    Jarvelin, Marjo-Riitta
    Gyllensten, Ulf
    Boomsma, Dorret I
    Campbell, Harry
    Wilson, James F
    Chanock, Stephen J
    Farrall, Martin
    Goel, Anuj
    Medina-Gomez, Carolina
    Rivadeneira, Fernando
    Estrada, Karol
    Uitterlinden, André G
    Hofman, Albert
    Zillikens, M Carola
    den Heijer, Martin
    Kiemeney, Lambertus A
    Maschio, Andrea
    Hall, Per
    Tyrer, Jonathan
    Teumer, Alexander
    Völzke, Henry
    Kovacs, Peter
    Tönjes, Anke
    Mangino, Massimo
    Spector, Tim D
    Hayward, Caroline
    Rudan, Igor
    Hall, Alistair S
    Samani, Nilesh J
    Attwood, Antony Paul
    Sambrook, Jennifer G
    Hung, Joseph
    Palmer, Lyle J
    Lokki, Marja-Liisa
    Sinisalo, Juha
    Boucher, Gabrielle
    Huikuri, Heikki
    Lorentzon, Mattias
    Ohlsson, Claes
    Eklund, Niina
    Eriksson, Johan G
    Barlassina, Cristina
    Rivolta, Carlo
    Nolte, Ilja M
    Snieder, Harold
    Van der Klauw, Melanie M
    Van Vliet-Ostaptchouk, Jana V
    Gejman, Pablo V
    Shi, Jianxin
    Jacobs, Kevin B
    Wang, Zhaoming
    Bakker, Stephan J L
    Mateo Leach, Irene
    Navis, Gerjan
    van der Harst, Pim
    Martin, Nicholas G
    Medland, Sarah E
    Montgomery, Grant W
    Yang, Jian
    Chasman, Daniel I
    Ridker, Paul M
    Rose, Lynda M
    Lehtimäki, Terho
    Raitakari, Olli
    Absher, Devin
    Iribarren, Carlos
    Basart, Hanneke
    Hovingh, Kees G
    Hyppönen, Elina
    Power, Chris
    Anderson, Denise
    Beilby, John P
    Hui, Jennie
    Jolley, Jennifer
    Sager, Hendrik
    Bornstein, Stefan R
    Schwarz, Peter E H
    Kristiansson, Kati
    Perola, Markus
    Lindström, Jaana
    Swift, Amy J
    Uusitupa, Matti
    Atalay, Mustafa
    Lakka, Timo A
    Rauramaa, Rainer
    Bolton, Jennifer L
    Fowkes, Gerry
    Fraser, Ross M
    Price, Jackie F
    Fischer, Krista
    Krjutå Kov, Kaarel
    Metspalu, Andres
    Mihailov, Evelin
    Langenberg, Claudia
    Luan, Jian'an
    Ong, Ken K
    Chines, Peter S
    Keinanen-Kiukaanniemi, Sirkka M
    Saaristo, Timo E
    Edkins, Sarah
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Morris, Andrew David
    Palmer, Colin N A
    Erbel, Raimund
    Moebus, Susanne
    Nöthen, Markus M
    Pechlivanis, Sonali
    Hveem, Kristian
    Narisu, Narisu
    Hamsten, Anders
    Humphries, Steve E
    Strawbridge, Rona J
    Tremoli, Elena
    Grallert, Harald
    Thorand, Barbara
    Illig, Thomas
    Koenig, Wolfgang
    Müller-Nurasyid, Martina
    Peters, Annette
    Boehm, Bernhard O
    Kleber, Marcus E
    März, Winfried
    Winkelmann, Bernhard R
    Kuusisto, Johanna
    Laakso, Markku
    Arveiler, Dominique
    Cesana, Giancarlo
    Kuulasmaa, Kari
    Virtamo, Jarmo
    Yarnell, John W G
    Kuh, Diana
    Wong, Andrew
    Lind, Lars
    de Faire, Ulf
    Gigante, Bruna
    Magnusson, Patrik K E
    Pedersen, Nancy L
    Dedoussis, George
    Dimitriou, Maria
    Kolovou, Genovefa
    Kanoni, Stavroula
    Stirrups, Kathleen
    Bonnycastle, Lori L
    Njølstad, Inger
    Wilsgaard, Tom
    Ganna, Andrea
    Rehnberg, Emil
    Hingorani, Aroon
    Kivimaki, Mika
    Kumari, Meena
    Assimes, Themistocles L
    Barroso, Inês
    Boehnke, Michael
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Frayling, Timothy
    Groop, Leif C
    Haritunians, Talin
    Hunter, David
    Ingelsson, Erik
    Kaplan, Robert
    Mohlke, Karen L
    O'Connell, Jeffrey R
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    McCarthy, Mark I
    Hirschhorn, Joel N
    Qi, Lu
    Loos, Ruth J F
    Lindgren, Cecilia M
    North, Kari E
    Heid, Iris M
    Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits2013In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 6, p. e1003500-Article in journal (Refereed)
    Abstract [en]

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

  • 26.
    Shungin, Dmitry
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.
    Deng, Wei Q.
    Varga, Tibor V.
    Luan, Jian'an
    Mihailov, Evelin
    Metspalu, Andres
    Morris, Andrew P.
    Forouhi, Nita G.
    Lindgren, Cecilia
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Chu, Audrey Y.
    Justice, Anne E.
    Graff, Mariaelisa
    Winkler, Thomas W.
    Rose, Lynda M.
    Langenberg, Claudia
    Cupples, L. Adrienne
    Ridker, Paul M.
    Wareham, Nicholas J.
    Ong, Ken K.
    Loos, Ruth J. F.
    Chasman, Daniel I.
    Ingelsson, Erik
    Kilpeläinen, Tuomas O.
    Scott, Robert A.
    Mägi, Reedik
    Paré, Guillaume
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
    Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006812Article in journal (Refereed)
    Abstract [en]

    Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (GxE) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P-v), GxE interaction effects (with smoking and physical activity), and marginal genetic effects (P-m). Correlations between P-v and P-m were stronger for SNPs with established marginal effects (Spearman's rho = 0.401 for triglycerides, and rho = 0.236 for BMI) compared to all SNPs. When P-v and P-m were compared for all pruned SNPs, only BMI was statistically significant (Spearman's rho = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P-v distribution (P-binomial < 0.05). SNPs from the top 1% of the P-m distribution for BMI had more significant P-v values (Pmann-Whitney = 1.46x10(-5)), and the odds ratio of SNPs with nominally significant (< 0.05) P-m and P-v was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant GxE interaction P-values (Pint < 0.05) were enriched with nominally significant P-v values (P-binomial = 8.63x10(-9) and 8.52x10(-7) for SNP x smoking and SNP x physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for GxE, and variance-based prioritization can be used to identify them.

  • 27.
    Stenberg, Per
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lundberg, Lina E.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Anna-Mia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Social Sciences, Department of Statistics.
    Svensson, Malin J.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster2009In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 5, no 5Article in journal (Refereed)
    Abstract [en]

    Chromosomal instability, which involves the deletion and duplication of chromosomes or chromosome parts, is a common feature of cancers, and deficiency screens are commonly used to detect genes involved in various biological pathways. However, despite their importance, the effects of deficiencies, duplications, and chromosome losses on the regulation of whole chromosomes and large chromosome domains are largely unknown. Therefore, to explore these effects, we examined expression patterns of genes in several Drosophila deficiency hemizygotes and a duplication hemizygote using microarrays. The results indicate that genes expressed in deficiency hemizygotes are significantly buffered, and that the buffering effect is general rather than being mainly mediated by feedback regulation of individual genes. In addition, differentially expressed genes in haploid condition appear to be generally more strongly buffered than ubiquitously expressed genes in haploid condition, but, among genes present in triploid condition, ubiquitously expressed genes are generally more strongly buffered than differentially expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest general mechanisms have evolved that stimulate or repress gene expression of aneuploid regions as appropriate, and on the 4th chromosome of Drosophila this compensation is mediated by Painting of Fourth (POF).

  • 28. von Salomé, Jenny
    et al.
    Boonstra, Philip S.
    Karimi, Masoud
    Silander, Gustav
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Stenmark-Askmalm, Marie
    Gebre-Medhin, Samuel
    Aravidis, Christos
    Nilbert, Mef
    Lindblom, Annika
    Lagerstedt-Robinson, Kristina
    Genetic anticipation in Swedish Lynch syndrome families2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 10, article id e1007012Article in journal (Refereed)
    Abstract [en]

    Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a large cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linkoping, Uppsala and Umea between the years 1990-2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM-MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller.

  • 29. Weiste, Christoph
    et al.
    Pedrotti, Lorenzo
    Selvanayagam, Jebasingh
    Muralidhara, Prathibha
    Fröschel, Christian
    Novák, Ondřej
    Ljung, Karin
    Hanson, Johannes
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Dröge-Laser, Wolfgang
    The Arabidopsis bZIP11 transcription factor links low-energy signalling to auxin-mediated control of primary root growth2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 2Article in journal (Refereed)
    Abstract [en]

    Plants have to tightly control their energy homeostasis to ensure survival and fitness under constantly changing environmental conditions. Thus, it is stringently required that energy-consuming stress-adaptation and growth-related processes are dynamically tuned according to the prevailing energy availability. The evolutionary conserved SUCROSE NON-FERMENTING1 RELATED KINASES1 (SnRK1) and the downstream group C/S1 basic leucine zipper (bZIP) transcription factors (TFs) are well-characterised central players in plants' low-energy management. Nevertheless, mechanistic insights into plant growth control under energy deprived conditions remains largely elusive. In this work, we disclose the novel function of the low-energy activated group S1 bZIP11-related TFs as regulators of auxin-mediated primary root growth. Whereas transgenic gain-of-function approaches of these bZIPs interfere with the activity of the root apical meristem and result in root growth repression, root growth of loss-of-function plants show a pronounced insensitivity to low-energy conditions. Based on ensuing molecular and biochemical analyses, we propose a mechanistic model, in which bZIP11-related TFs gain control over the root meristem by directly activating IAA3/SHY2 transcription. IAA3/SHY2 is a pivotal negative regulator of root growth, which has been demonstrated to efficiently repress transcription of major auxin transport facilitators of the PIN-FORMED (PIN) gene family, thereby restricting polar auxin transport to the root tip and in consequence auxin-driven primary root growth. Taken together, our results disclose the central low-energy activated SnRK1-C/S1-bZIP signalling module as gateway to integrate information on the plant's energy status into root meristem control, thereby balancing plant growth and cellular energy resources.

  • 30. Winkler, Thomas W
    et al.
    Justice, Anne E
    Graff, Mariaelisa
    Barata, Llilda
    Feitosa, Mary F
    Chu, Su
    Czajkowski, Jacek
    Esko, Tõnu
    Fall, Tove
    Kilpeläinen, Tuomas O
    Lu, Yingchang
    Mägi, Reedik
    Mihailov, Evelin
    Pers, Tune H
    Rüeger, Sina
    Teumer, Alexander
    Ehret, Georg B
    Ferreira, Teresa
    Heard-Costa, Nancy L
    Karjalainen, Juha
    Lagou, Vasiliki
    Mahajan, Anubha
    Neinast, Michael D
    Prokopenko, Inga
    Simino, Jeannette
    Teslovich, Tanya M
    Jansen, Rick
    Westra, Harm-Jan
    White, Charles C
    Absher, Devin
    Ahluwalia, Tarunveer S
    Ahmad, Shafqat
    Albrecht, Eva
    Alves, Alexessander Couto
    Bragg-Gresham, Jennifer L
    de Craen, Anton J M
    Bis, Joshua C
    Bonnefond, Amélie
    Boucher, Gabrielle
    Cadby, Gemma
    Cheng, Yu-Ching
    Chiang, Charleston W K
    Delgado, Graciela
    Demirkan, Ayse
    Dueker, Nicole
    Eklund, Niina
    Eiriksdottir, Gudny
    Eriksson, Joel
    Feenstra, Bjarke
    Fischer, Krista
    Frau, Francesca
    Galesloot, Tessel E
    Geller, Frank
    Goel, Anuj
    Gorski, Mathias
    Grammer, Tanja B
    Gustafsson, Stefan
    Haitjema, Saskia
    Hottenga, Jouke-Jan
    Huffman, Jennifer E
    Jackson, Anne U
    Jacobs, Kevin B
    Johansson, Åsa
    Kaakinen, Marika
    Kleber, Marcus E
    Lahti, Jari
    Mateo Leach, Irene
    Lehne, Benjamin
    Liu, Youfang
    Lo, Ken Sin
    Lorentzon, Mattias
    Luan, Jian'an
    Madden, Pamela A F
    Mangino, Massimo
    McKnight, Barbara
    Medina-Gomez, Carolina
    Monda, Keri L
    Montasser, May E
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Nolte, Ilja M
    Panoutsopoulou, Kalliope
    Pascoe, Laura
    Paternoster, Lavinia
    Rayner, Nigel W
    Renström, Frida
    Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.
    Rizzi, Federica
    Rose, Lynda M
    Ryan, Kathy A
    Salo, Perttu
    Sanna, Serena
    Scharnagl, Hubert
    Shi, Jianxin
    Smith, Albert Vernon
    Southam, Lorraine
    Stančáková, Alena
    Steinthorsdottir, Valgerdur
    Strawbridge, Rona J
    Sung, Yun Ju
    Tachmazidou, Ioanna
    Tanaka, Toshiko
    Thorleifsson, Gudmar
    Trompet, Stella
    Pervjakova, Natalia
    Tyrer, Jonathan P
    Vandenput, Liesbeth
    van der Laan, Sander W
    van der Velde, Nathalie
    van Setten, Jessica
    van Vliet-Ostaptchouk, Jana V
    Verweij, Niek
    Vlachopoulou, Efthymia
    Waite, Lindsay L
    Wang, Sophie R
    Wang, Zhaoming
    Wild, Sarah H
    Willenborg, Christina
    Wilson, James F
    Wong, Andrew
    Yang, Jian
    Yengo, Loïc
    Yerges-Armstrong, Laura M
    Yu, Lei
    Zhang, Weihua
    Zhao, Jing Hua
    Andersson, Ehm A
    Bakker, Stephan J L
    Baldassarre, Damiano
    Banasik, Karina
    Barcella, Matteo
    Barlassina, Cristina
    Bellis, Claire
    Benaglio, Paola
    Blangero, John
    Blüher, Matthias
    Bonnet, Fabrice
    Bonnycastle, Lori L
    Boyd, Heather A
    Bruinenberg, Marcel
    Buchman, Aron S
    Campbell, Harry
    Chen, Yii-Der Ida
    Chines, Peter S
    Claudi-Boehm, Simone
    Cole, John
    Collins, Francis S
    de Geus, Eco J C
    de Groot, Lisette C P G M
    Dimitriou, Maria
    Duan, Jubao
    Enroth, Stefan
    Eury, Elodie
    Farmaki, Aliki-Eleni
    Forouhi, Nita G
    Friedrich, Nele
    Gejman, Pablo V
    Gigante, Bruna
    Glorioso, Nicola
    Go, Alan S
    Gottesman, Omri
    Gräßler, Jürgen
    Grallert, Harald
    Grarup, Niels
    Gu, Yu-Mei
    Broer, Linda
    Ham, Annelies C
    Hansen, Torben
    Harris, Tamara B
    Hartman, Catharina A
    Hassinen, Maija
    Hastie, Nicholas
    Hattersley, Andrew T
    Heath, Andrew C
    Henders, Anjali K
    Hernandez, Dena
    Hillege, Hans
    Holmen, Oddgeir
    Hovingh, Kees G
    Hui, Jennie
    Husemoen, Lise L
    Hutri-Kähönen, Nina
    Hysi, Pirro G
    Illig, Thomas
    De Jager, Philip L
    Jalilzadeh, Shapour
    Jørgensen, Torben
    Jukema, J Wouter
    Juonala, Markus
    Kanoni, Stavroula
    Karaleftheri, Maria
    Khaw, Kay Tee
    Kinnunen, Leena
    Kittner, Steven J
    Koenig, Wolfgang
    Kolcic, Ivana
    Kovacs, Peter
    Krarup, Nikolaj T
    Kratzer, Wolfgang
    Krüger, Janine
    Kuh, Diana
    Kumari, Meena
    Kyriakou, Theodosios
    Langenberg, Claudia
    Lannfelt, Lars
    Lanzani, Chiara
    Lotay, Vaneet
    Launer, Lenore J
    Leander, Karin
    Lindström, Jaana
    Linneberg, Allan
    Liu, Yan-Ping
    Lobbens, Stéphane
    Luben, Robert
    Lyssenko, Valeriya
    Männistö, Satu
    Magnusson, Patrik K
    McArdle, Wendy L
    Menni, Cristina
    Merger, Sigrun
    Milani, Lili
    Montgomery, Grant W
    Morris, Andrew P
    Narisu, Narisu
    Nelis, Mari
    Ong, Ken K
    Palotie, Aarno
    Pérusse, Louis
    Pichler, Irene
    Pilia, Maria G
    Pouta, Anneli
    Rheinberger, Myriam
    Ribel-Madsen, Rasmus
    Richards, Marcus
    Rice, Kenneth M
    Rice, Treva K
    Rivolta, Carlo
    Salomaa, Veikko
    Sanders, Alan R
    Sarzynski, Mark A
    Scholtens, Salome
    Scott, Robert A
    Scott, William R
    Sebert, Sylvain
    Sengupta, Sebanti
    Sennblad, Bengt
    Seufferlein, Thomas
    Silveira, Angela
    Slagboom, P Eline
    Smit, Jan H
    Sparsø, Thomas H
    Stirrups, Kathleen
    Stolk, Ronald P
    Stringham, Heather M
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Tan, Sian-Tsung
    Thorand, Barbara
    Tönjes, Anke
    Tremblay, Angelo
    Tsafantakis, Emmanouil
    van der Most, Peter J
    Völker, Uwe
    Vohl, Marie-Claude
    Vonk, Judith M
    Waldenberger, Melanie
    Walker, Ryan W
    Wennauer, Roman
    Widén, Elisabeth
    Willemsen, Gonneke
    Wilsgaard, Tom
    Wright, Alan F
    Zillikens, M Carola
    van Dijk, Suzanne C
    van Schoor, Natasja M
    Asselbergs, Folkert W
    de Bakker, Paul I W
    Beckmann, Jacques S
    Beilby, John
    Bennett, David A
    Bergman, Richard N
    Bergmann, Sven
    Böger, Carsten A
    Boehm, Bernhard O
    Boerwinkle, Eric
    Boomsma, Dorret I
    Bornstein, Stefan R
    Bottinger, Erwin P
    Bouchard, Claude
    Chambers, John C
    Chanock, Stephen J
    Chasman, Daniel I
    Cucca, Francesco
    Cusi, Daniele
    Dedoussis, George
    Erdmann, Jeanette
    Eriksson, Johan G
    Evans, Denis A
    de Faire, Ulf
    Farrall, Martin
    Ferrucci, Luigi
    Ford, Ian
    Franke, Lude
    Franks, Paul W
    Umeå University Hospital; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America .
    Froguel, Philippe
    Gansevoort, Ron T
    Gieger, Christian
    Grönberg, Henrik
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Hall, Per
    Hamsten, Anders
    van der Harst, Pim
    Hayward, Caroline
    Heliövaara, Markku
    Hengstenberg, Christian
    Hicks, Andrew A
    Hingorani, Aroon
    Hofman, Albert
    Hu, Frank
    Huikuri, Heikki V
    Hveem, Kristian
    James, Alan L
    Jordan, Joanne M
    Jula, Antti
    Kähönen, Mika
    Kajantie, Eero
    Kathiresan, Sekar
    Kiemeney, Lambertus A L M
    Kivimaki, Mika
    Knekt, Paul B
    Koistinen, Heikki A
    Kooner, Jaspal S
    Koskinen, Seppo
    Kuusisto, Johanna
    Maerz, Winfried
    Martin, Nicholas G
    Laakso, Markku
    Lakka, Timo A
    Lehtimäki, Terho
    Lettre, Guillaume
    Levinson, Douglas F
    Lind, Lars
    Lokki, Marja-Liisa
    Mäntyselkä, Pekka
    Melbye, Mads
    Metspalu, Andres
    Mitchell, Braxton D
    Moll, Frans L
    Murray, Jeffrey C
    Musk, Arthur W
    Nieminen, Markku S
    Njølstad, Inger
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Oostra, Ben A
    Palmer, Lyle J
    Pankow, James S
    Pasterkamp, Gerard
    Pedersen, Nancy L
    Pedersen, Oluf
    Penninx, Brenda W
    Perola, Markus
    Peters, Annette
    Polašek, Ozren
    Pramstaller, Peter P
    Psaty, Bruce M
    Qi, Lu
    Quertermous, Thomas
    Raitakari, Olli T
    Rankinen, Tuomo
    Rauramaa, Rainer
    Ridker, Paul M
    Rioux, John D
    Rivadeneira, Fernando
    Rotter, Jerome I
    Rudan, Igor
    den Ruijter, Hester M
    Saltevo, Juha
    Sattar, Naveed
    Schunkert, Heribert
    Schwarz, Peter E H
    Shuldiner, Alan R
    Sinisalo, Juha
    Snieder, Harold
    Sørensen, Thorkild I A
    Spector, Tim D
    Staessen, Jan A
    Stefania, Bandinelli
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tardif, Jean-Claude
    Tremoli, Elena
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    Verbeek, André L M
    Vermeulen, Sita H
    Viikari, Jorma S
    Vitart, Veronique
    Völzke, Henry
    Vollenweider, Peter
    Waeber, Gérard
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J
    Watkins, Hugh
    Zeggini, Eleftheria
    Chakravarti, Aravinda
    Clegg, Deborah J
    Cupples, L Adrienne
    Gordon-Larsen, Penny
    Jaquish, Cashell E
    Rao, D C
    Abecasis, Goncalo R
    Assimes, Themistocles L
    Barroso, Inês
    Berndt, Sonja I
    Boehnke, Michael
    Deloukas, Panos
    Fox, Caroline S
    Groop, Leif C
    Hunter, David J
    Ingelsson, Erik
    Kaplan, Robert C
    McCarthy, Mark I
    Mohlke, Karen L
    O'Connell, Jeffrey R
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Hirschhorn, Joel N
    Lindgren, Cecilia M
    Heid, Iris M
    North, Kari E
    Borecki, Ingrid B
    Kutalik, Zoltán
    Loos, Ruth J F
    The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study2015In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 10, article id e1005378Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

  • 31.
    Xu, Fu
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Byström, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Marcus J. O.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    SSD1 suppresses phenotypes induced by the lack of Elongator-dependent tRNA modifications2019In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 8, article id e1008117Article in journal (Refereed)
    Abstract [en]

    The Elongator complex promotes formation of 5-methoxycarbonylmethyl (mcm5 ) and 5-carbamoylmethyl (ncm5 ) side-chains on uridines at the wobble position of cytosolic eukaryotic tRNAs. In all eukaryotic organisms tested to date, the inactivation of Elongator not only leads to the lack of mcm5 /ncm5 groups in tRNAs, but also a wide variety of additional phenotypes. Although the phenotypes are most likely caused by a translational defect induced by reduced functionality of the hypomodified tRNAs, the mechanism(s) underlying individual phenotypes are poorly understood. In this study, we show that the genetic background modulates the phenotypes induced by the lack of mcm5 /ncm5 groups in Saccharomyces cerevisiae. We show that the stress-induced growth defects of Elongator mutants are stronger in the W303 than in the closely related S288C genetic background and that the phenotypic differences are caused by the known polymorphism at the locus for the mRNA binding protein Ssd1. Moreover, the mutant ssd1 allele found in W303 cells is required for the reported histone H3 acetylation and telomeric gene silencing defects of Elongator mutants. The difference at the SSD1 locus also partially explains why the simultaneous lack of mcm5 and 2- thio groups at wobble uridines is lethal in the W303 but not in the S288C background. Collectively, our results demonstrate that the SSD1 locus modulates phenotypes induced by the lack of Elongator-dependent tRNA modifications.

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