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  • 51.
    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.

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  • 52.
    Frida, Jonsson
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Underlying genetic mechanisms of hereditary dystrophies in retina and cornea2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Inherited retinal and corneal dystrophies represent a group of disorders with great genetic heterogeneity. Over 250 genes are associated with retinal diseases and 16 genes are causative of corneal dystrophies. This thesis is focused on finding the genetic causes of corneal dystrophy, Leber congenital amaurosis (LCA), Stargardt disease and retinitis pigmentosa in families from northern Sweden.  By whole exome sequencing a novel mutation, c.2816C>T, p.Thr939Ile, in Collagen Type XVII, Alpha 1 chain, COL17A1, gene was identified in several families with epithelial recurrent erosion dystrophy (ERED). We showed that the COL17A1 protein is expressed in the basement membrane of the cornea, explaining the mutation involvement in the corneal symptoms. We could link all the families in this study to a couple born in the late 1700s confirming a founder mutation in northern Sweden. Our finding highlights role of COL17A1 in ERED and suggests screening of this gene in patients with similar phenotype worldwide. Furthermore the genetic causes in several retinal degenerations were identified. In one family with two recessive disorders, LCA and Stargardt disease, a novel stop mutation, c.2557C>T, p.Gln853Stop, was detected in all LCA patients. In the Stargardt patients two intronic variants, the novel c.4773+3A>G and c.5461-10T>C, were detected in the ABCA4 gene. One individual was homozygous for the known variant c.5461-10T>C and the other one was compound heterozygote with both variants present. Both variants, c.4773+3A>G and c.5461-10T>C caused exon skipping in HEK293T cells demonstrated by in vitro splice assay, proving their pathogenicity in Stargardt disease. Finally, in recessive retinitis pigmentosa, Bothnia Dystrophy (BD), we identified a second mutation in the RLBP1 gene, c.677T>A, p.Met226Lys. Thus, BD is caused not only by common c.700C>T variant but also by homozygosity of c.677T>A or compound heterozygosity. Notably, known variant, c.40C>T, p.R14W in the CAIV gene associated with a dominant retinal dystrophy RP17 was detected in one of the compound BD heterozygote and his unaffected mother. This variant appears to be a benign variant in the population of northern Sweden.

    In conclusion, novel genetic causes of retinal dystrophies in northern Sweden were found demonstrating the heterogeneity and complexity of retinal diseases. Identification of the genetic defect in COL17A1 in the corneal dystrophy contributes to understanding ERED pathogenesis and encourages refinement of IC3D classification. Our results provide valuable information for future molecular testing and genetic counselling of the families.

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  • 53.
    Funda, Tomas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Forest Genetics and Plant Physiology, UPSCSwedish University of Agricultural Sciences, Umeå, Sweden.
    Wennström, Ulfstand
    Almqvist, Curt
    Andersson Gull, Bengt
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Mating dynamics of Scots pine in isolation tents2016In: Tree Genetics & Genomes, ISSN 1614-2942, E-ISSN 1614-2950, Vol. 12, no 6, article id 112Article in journal (Refereed)
    Abstract [en]

    Seed orchards are forest tree production populations for supplying the forest industry with consistent and abundant seed crops of superior genetic quality. However, genetic quality can be severely affected by non-random mating among parents and the occurrence of background pollination. This study analyzed mating structure and background pollination in six large isolation tents established in a clonal Scots pine seed orchard in northern Sweden. The isolation tents were intended to form a physical barrier against background pollen and induce earlier flowering relative to the surrounding trees. We scored flowering phenology inside and outside the tents and tracked airborne pollen density inside and outside the seed orchard in three consecutive pollination seasons. We genotyped 5683 offspring collected from the tents and open controls using nine microsatellite loci, and assigned paternity using simple exclusion method. We found that tent trees shed pollen and exhibited maximum female receptivity approximately 1 week earlier than trees in open control. The majority of matings in tents (78.3 %) occurred at distances within two trees apart (about 5 m). Self-fertilization was relatively high (average 21.8 %) in tents without supplemental pollination (SP), but it was substantially reduced in tents with SP (average 7.7 %). Pollen contamination was low in open controls (4.8-7.1 %), and all tents remained entirely free of foreign pollen. Our study demonstrates that tent isolation is effective in blocking pollen immigration and in manipulating flowering phenology. When complimented with supplemental pollination, it could become a useful seed orchard management practice to optimize the gain and diversity of seed orchard crops.

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  • 54.
    Gao, Jie
    et al.
    State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China.
    Wang, Baosheng
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Mao, Ian-Feng
    State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China.
    Ingvarsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Zeng, Qing-Yin
    State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China.
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China.
    Demography and speciation history of the homoploid hybrid pine Pinus densata on the Tibetan Plateau2012In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 21, no 19, p. 4811-4827Article in journal (Refereed)
    Abstract [en]

    Pinus densata is an ecologically successful homoploid hybrid that inhabits vast areas of heterogeneous terrain on the south-eastern Tibetan Plateau as a result of multiple waves of colonization. Its region of origin, route of colonization onto the plateau and the directions of introgression with its parental species have previously been defined, but little is known about the isolation and divergence history of its populations. In this study, we surveyed nucleotide polymorphism over eight nuclear loci in 19 representative populations of P. densata and its parental species. Using this information and coalescence simulations, we assessed the historical changes in its population size, gene flow and divergence in time and space. The results indicate a late Miocene origin for P. densata associated with the recent uplift of south-eastern Tibet. The subsequent differentiation between geographical regions of this species began in the late Pliocene and was induced by regional topographical changes and Pleistocene glaciations. The ancestral P. densata population had a large effective population size but the central and western populations were established by limited founders, suggesting that there were severe bottlenecks during the westward migration out of the ancestral hybrid zone. After separating from their ancestral populations, population expansion occurred in all geographical regions especially in the western range. Gene flow in P. densata was restricted to geographically neighbouring populations, resulting in significant differentiation between regional groups. The new information on the divergence and demographic history of P. densata reported herein enhances our understanding of its speciation process on the Tibetan Plateau.

  • 55.
    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.

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  • 56. Gouzi, Jean Y.
    et al.
    Moressis, Anastasios
    Walker, James A.
    Apostolopoulou, Anthi A.
    Palmer, Ruth H.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bernards, Andre
    Skoulakis, Efthimios M. C.
    The receptor tyrosine kinase alk controls neurofibromin functions in drosophila growth and learning2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 9, p. e1002281-Article in journal (Refereed)
    Abstract [en]

    Anaplastic Lymphoma Kinase (Alk) is a Receptor Tyrosine Kinase (RTK) activated in several cancers, but with largely unknown physiological functions. We report two unexpected roles for the Drosophila ortholog dAlk, in body size determination and associative learning. Remarkably, reducing neuronal dAlk activity increased body size and enhanced associative learning, suggesting that its activation is inhibitory in both processes. Consistently, dAlk activation reduced body size and caused learning deficits resembling phenotypes of null mutations in dNf1, the Ras GTPase Activating Protein-encoding conserved ortholog of the Neurofibromatosis type 1 (NF1) disease gene. We show that dAlk and dNf1 co-localize extensively and interact functionally in the nervous system. Importantly, genetic or pharmacological inhibition of dAlk rescued the reduced body size, adult learning deficits, and Extracellular-Regulated-Kinase (ERK) overactivation dNf1 mutant phenotypes. These results identify dAlk as an upstream activator of dNf1-regulated Ras signaling responsible for several dNf1 defects, and they implicate human Alk as a potential therapeutic target in NF1.

  • 57. Guerra, Lina
    et al.
    Albihn, Ami
    Tronnersjö, Susanna
    Yan, Qinzi
    Guidi, Riccardo
    Stenerlöw, Bo
    Sterzenbach, Torsten
    Josenhans, Christine
    Fox, James G
    Schauer, David B
    Thelestam, Monica
    Larsson, Lars-Gunnar
    Henriksson, Marie
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Myc is required for activation of the ATM-dependent checkpoints in response to DNA damage2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, article id e8924Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The MYC protein controls cellular functions such as differentiation, proliferation, and apoptosis. In response to genotoxic agents, cells overexpressing MYC undergo apoptosis. However, the MYC-regulated effectors acting upstream of the mitochondrial apoptotic pathway are still unknown.

    PRINCIPAL FINDINGS: In this study, we demonstrate that expression of Myc is required to activate the Ataxia telangiectasia mutated (ATM)-dependent DNA damage checkpoint responses in rat cell lines exposed to ionizing radiation (IR) or the bacterial cytolethal distending toxin (CDT). Phosphorylation of the ATM kinase and its downstream effectors, such as histone H2AX, were impaired in the myc null cell line HO15.19, compared to the myc positive TGR-1 and HOmyc3 cells. Nuclear foci formation of the Nijmegen Breakage Syndrome (Nbs) 1 protein, essential for efficient ATM activation, was also reduced in absence of myc. Knock down of the endogenous levels of MYC by siRNA in the human cell line HCT116 resulted in decreased ATM and CHK2 phosphorylation in response to irradiation. Conversely, cell death induced by UV irradiation, known to activate the ATR-dependent checkpoint, was similar in all the cell lines, independently of the myc status.

    CONCLUSION: These data demonstrate that MYC contributes to the activation of the ATM-dependent checkpoint responses, leading to cell death in response to specific genotoxic stimuli.

  • 58. Guerra, Lina
    et al.
    Cortes-Bratti, Ximena
    Guidi, Riccardo
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
    The biology of the cytolethal distending toxins2011In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 3, no 3, p. 172-190Article, review/survey (Refereed)
    Abstract [en]

    The cytolethal distending toxins (CDTs), produced by a variety of Gram-negative pathogenic bacteria, are the first bacterial genotoxins described, since they cause DNA damage in the target cells. CDT is an A-B(2) toxin, where the CdtA and CdtC subunits are required to mediate the binding on the surface of the target cells, allowing internalization of the active CdtB subunit, which is functionally homologous to the mammalian deoxyribonuclease I. The nature of the surface receptor is still poorly characterized, however binding of CDT requires intact lipid rafts, and its internalization occurs via dynamin-dependent endocytosis. The toxin is retrograde transported through the Golgi complex and the endoplasmic reticulum, and subsequently translocated into the nuclear compartment, where it exerts the toxic activity. Cellular intoxication induces DNA damage and activation of the DNA damage responses, which results in arrest of the target cells in the G1 and/or G2 phases of the cell cycle and activation of DNA repair mechanisms. Cells that fail to repair the damage will senesce or undergo apoptosis. This review will focus on the well-characterized aspects of the CDT biology and discuss the questions that still remain unanswered.

  • 59. Guerra, Lina
    et al.
    Guidi, Riccardo
    Slot, Ilse
    Callegari, Simone
    Sompallae, Ramakrishna
    Pickett, Carol L
    Åström, Stefan
    Eisele, Frederik
    Wolf, Dieter
    Sjögren, Camilla
    Masucci, Maria G
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm.
    Bacterial genotoxin triggers FEN1-dependent RhoA activation, cytoskeleton remodeling and cell survival2011In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 124, no 16, p. 2735-2742Article in journal (Refereed)
    Abstract [en]

    The DNA damage response triggered by bacterial cytolethal distending toxins (CDTs) is associated with activation of the actin-regulating protein RhoA and phosphorylation of the downstream-regulated mitogen-activated protein kinase (MAPK) p38, which promotes the survival of intoxicated (i.e. cells exposed to a bacterial toxin) cells. To identify the effectors of this CDT-induced survival response, we screened a library of 4492 Saccharomyces cerevisiae mutants that carry deletions in nonessential genes for reduced growth following inducible expression of CdtB. We identified 78 genes whose deletion confers hypersensitivity to toxin. Bioinformatics analysis revealed that DNA repair and endocytosis were the two most overrepresented signaling pathways. Among the human orthologs present in our data set, FEN1 and TSG101 regulate DNA repair and endocytosis, respectively, and also share common interacting partners with RhoA. We further demonstrate that FEN1, but not TSG101, regulates cell survival, MAPK p38 phosphorylation, RhoA activation and actin cytoskeleton reorganization in response to DNA damage. Our data reveal a previously unrecognized crosstalk between DNA damage and cytoskeleton dynamics in the regulation of cell survival, and might provide new insights on the role of chronic bacteria infection in carcinogenesis.

  • 60. Guidi, Riccardo
    et al.
    Guerra, Lina
    Levi, Laura
    Stenerlöw, Bo
    Fox, James G
    Josenhans, Christine
    Masucci, Maria G
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Chronic exposure to the cytolethal distending toxins of Gram-negative bacteria promotes genomic instability and altered DNA damage response2013In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 15, no 1, p. 98-113Article in journal (Refereed)
    Abstract [en]

    Epidemiological evidence links chronic bacterial infections to the increased incidence of certain types of cancer but the molecular mechanisms by which bacteria contribute to tumour initiation and progression are still poorly characterized. Here we show that chronic exposure to the genotoxin cytolethal distending toxin (CDT) of Gram-negative bacteria promotes genomic instability and acquisition of phenotypic properties of malignancy in fibroblasts and colon epithelial cells. Cells grown for more than 30 weeks in the presence of sublethal doses of CDT showed increased mutation frequency, and accumulation of chromatin and chromosomal aberrations in the absence of significant alterations of cell cycle distribution, decreased viability or senescence. Cell survival was dependent on sustained activity of the p38 MAP kinase. The ongoing genomic instability was associated with impaired activation of the DNA damage response and failure to efficiently activate cell cycle checkpoints upon exposure to genotoxic stress. Independently selected sublines showed enhanced anchorage-independent growth as assessed by the formation of colonies in semisolid agarose. These findings support the notion that chronic infection by CDT-producing bacteria may promote malignant transformation, and point to the impairment of cellular control mechanisms associated with the detection and repair of DNA damage as critical events in the process.

  • 61.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DNA methylation signatures in precursor lymphoid neoplasms: with focus on clinical implications &  the biology behind2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Precursor lymphoid neoplasms, namely acute lymphoblastic leukemias (ALL) and lymphoblastic lymphomas (LBL), are characterized by an aggressive proliferation of malignant progenitor B- or T-cells. To improve risk classification at diagnosis, better prognostic and treatment stratifying biomarkers are needed. Altered DNA methylation pattern is a hallmark of neoplastic transformation, and has been employed as a molecular prognostic and predictive marker in various cancers, including hematological malignancies. Our research group previously identified a CpG island methylator phenotype (CIMP) panel that classified pediatric T-ALL patients into prognostic subgroups.

    The aim of this thesis was to evaluate distinct DNA methylation signatures in precursor lymphoid neoplasms, and to validate the prognostic value of CIMP classification in separate patient cohorts. Additionally, the biological mechanisms underlying the distinct CIMP methylation signatures in these malignancies were investigated.

    The prognostic relevance of CIMP classification was validated in an independent Nordic cohort of pediatric T-ALL patients. Combination of CIMP status with minimal residual disease (MRD) status, could further dissect the high-risk MRD positive T-ALL patients into two CIMP subgroups with significantly distinct outcomes. Furthermore, CIMP classification at diagnosis was shown to predict overall survival in relapsed BCP-ALL patients. CIMP methylation signatures were also identified in T-LBL patients, indicating a broader relevance of CIMP based classification in lymphoid malignancies. Investigating the biology behind CIMP methylation signatures showed the association of CIMP status with the proliferative history of the leukemic cells. A differential transcriptomic analysis revealed a correlation of CIMP subgroups with known T-ALL drivers, as well as with novel genes in T-ALL biology. Finally, we identified distinct DNA methylation patterns and genetic aberrations in T-ALL and T-LBL that might contribute to the different clinical presentation of these two diseases. In conclusion, we validated the prognostic significance of CIMP methylation signature in precursor lymphoid malignancies and identified transcriptomic profiles that associated with the subgroups. DNA methylation is a strong candidate for further risk classification in lymphoid neoplasms and our findings can contribute to the identification of new potential targets for treatment.

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  • 62.
    Haider, Zahra
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Noren-Nyström, Ulrika
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Epigenetic and genetic distinctions between T-cell acute lymphoblastic leukemia and lymphomaManuscript (preprint) (Other academic)
  • 63.
    Hall, David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå Plant Science Centre, Department of Forest Genetics and Plant PhysiologySwedish University of Agricultural Sciences, Umeå, Sweden.
    Hallingbäck, Henrik R.
    Wu, Harry X.
    Estimation of number and size of QTL effects in forest tree traits2016In: Tree Genetics & Genomes, ISSN 1614-2942, E-ISSN 1614-2950, Vol. 12, no 6, article id 110Article in journal (Refereed)
    Abstract [en]

    Mapping the genetic architecture of forest tree traits is important in order to understand the evolutionary forces that have shaped these traits and to facilitate the development of genomic-based breeding strategies. We examined the number, size, and distribution of allelic effects influencing eight types of traits using 30 published mapping studies (linkage and association mapping) in forest trees. The sizes of allelic effects, measured as the phenotypic variance explained, generally showed a severely right-skewed distribution. We estimated the numbers of underlying causal effects (n(qtl)) for different trait categories by improving a method previously developed by Otto and Jones (Genetics 156: 2093-2107, 2000). Estimates of n(qtl) based on association mapping studies were generally higher (median at 643) than those based on linkage mapping (median at 33). Comparisons with simulated linkage and association mapping data suggested that the lower n(qtl) estimates for the linkage mapping studies could partly be explained by fewer causal loci segregating within the full-sib family populations normally used, but also by the cosegregation of causal loci due to limited recombination. Disease resistance estimates based on linkage mapping studies had the lowest median of four underlying effects, while growth traits based on association mapping had about 580 effects. Theoretically, the capture of 50% of the genetic variation would thus require a population size of about 200 for disease resistance in linkage mapping, while growth traits in association mapping would require about 25,000. The adequacy and reliability of the improved method was successfully verified by applying it to the simulated data.

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  • 64.
    Hall, David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Ma, Xiao-Fei
    Program in Evolutionary Functional Genomics, Evolutionary Biology Center, Uppsala University.
    Ingvarsson, Pär K
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Adaptive evolution of the Populus tremula photoperiod pathway2011In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 20, no 7, p. 1463-1474Article in journal (Refereed)
    Abstract [en]

    Environmental cues entrain the circadian clock, a core component of the photoperiod pathway in plants, to daily and seasonal changes. The circadian clock mediates input signals from light and temperature receptors to downstream target genes through feedback loops. Several studies have shown that a correct timing of the circadian system is a fitness advantage and genes in photoperiod network have been implied to evolve in response to the diversifying selection in heterogeneous environment. In an attempt to quantify the extent of the historical patterns of selection on genes in the photoperiod pathway in the widely distributed tree species European aspen (Populus tremula) we obtained sequences for twenty-five of the genes in the network and these genes were compared to patterns of nucleotide diversity in 77 randomly chosen genes from across the genome of P. tremula. We found a significant reduction in synonymous diversity in photoperiod genes while non-synonymous diversity was in line with data from control genes. A substantial fraction of the genes show signs of selection, with eight genes showing signs of rapid protein evolution. In contrast to our expectations, genes closely associated with the core circadian clock show rapid protein evolution despite their central position in the pathway. Furthermore, selection on non-synonymous mutations is negatively correlated with synonymous diversity across all genes, indicating the action of recurrent selective sweeps.

  • 65.
    Hall, David
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Zhao, Wei
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Advanced Innovation Center for Tree Breeding by MolecularDesign; College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China.
    Wennström, Ulfstand
    Andersson Gull, Bengt
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Parentage and relatedness reconstruction in Pinus sylvestris using genotyping-by-sequencing2020In: Heredity, ISSN 0018-067X, E-ISSN 1365-2540Article in journal (Refereed)
    Abstract [en]

    Estimating kinship is fundamental for studies of evolution, conservation, and breeding. Genotyping-by-sequencing (GBS) and other restriction based genotyping methods have become widely applied in these applications in non-model organisms. However, sequencing errors, depth, and reproducibility between library preps could potentially hinder accurate genetic inferences. In this study, we tested different sets of parameters in data filtering, different reference populations and eight estimation methods to obtain a robust procedure for relatedness estimation in Scots pine (Pinus sylvestris L.). We used a seed orchard as our study system, where candidate parents are known and pedigree reconstruction can be compared with theoretical expectations. We found that relatedness estimates were lower than expected for all categories of kinship estimated if the proportion of shared SNPs was low. However, estimates reached expected values if loci showing an excess of heterozygotes were removed and genotyping error rates were considered. The genetic variance-covariance matrix (G-matrix) estimation, however, performed poorly in kinship estimation. The reduced relatedness estimates are likely due to false heterozygosity calls. We analyzed the mating structure in the seed orchard and identified a selfing rate of 3% (including crosses between clone mates) and external pollen contamination of 33.6%. Little genetic structure was observed in the sampled Scots pine natural populations, and the degree of inbreeding in the orchard seed crop is comparable to natural stands. We illustrate that under our optimized data processing procedure, relatedness, and genetic composition, including level of pollen contamination within a seed orchard crop, can be established consistently by different estimators.

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  • 66.
    Hannuksela, Matias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Klar, Joakim
    Ameur, Adam
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Sorensen, Karen
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Carlberg, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A novel variant in MYLK causes thoracic aortic dissections: genotypic and phenotypic description2016In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 17, article id 61Article in journal (Refereed)
    Abstract [en]

    Background: Mutations in MYLK cause non- syndromic familial thoracic aortic aneurysms and dissections (FTAAD). Very little is known about the phenotype of affected families. We sought to characterize the aortic disease and the presence of other vascular abnormalities in FTAAD caused by a deletion in MYLK and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers.

    Methods: We studied FTAAD in a 5-generation family that included 19 living members. Exome sequencing was performed to identify the underlying gene defect. Aortic elastic properties measured by TTE, MRI and pulse wave velocity were then compared between mutation carriers and non-carriers.

    Results: Exome sequencing led to the identification of a 2-bp deletion in MYLK (c3272_ 3273del, p. Ser1091*) that led to a premature stop codon and nonsense-mediated decay. Eleven people were mutation carriers and eight people were non-carriers. Five aortic ruptures or dissections occurred in this family, with two survivors. There were no differences in aortic diameter or stiffness between carriers and non-carriers of the mutation.

    Conclusions: Individuals carrying this deletion in MYLK have a high risk of presenting with an acute aortic dissection or rupture. Aortic events occur over a wide range of ages and are not always preceded by obvious aortic dilatation. Aortic elastic properties do not differ between carriers and non-carriers of this mutation, rendering it uncertain whether and when carriers should undergo elective prophylactic surgery.

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  • 67.
    Hed, Helen
    Umeå University.
    Opportunity for selection during the 17th-19thcenturies in the diocese of Linkoping as estimated with Crow's Index in a population of clergymen's wives1984In: Human Heredity, ISSN 0001-5652, E-ISSN 1423-0062, Vol. 34, no 6, p. 378-387Article in journal (Refereed)
  • 68.
    Hed, Helen
    Umeå University.
    Opportunity for selection in the parish of Tuna, Sweden.1987In: Human Heredity, ISSN 0001-5652, Vol. 37, no 1, p. 30-35Article in journal (Refereed)
  • 69.
    Hed, Helen
    Umeå University.
    Selection opportunities in 7 swedish 19TH-century populations1986In: Human Biology, ISSN 0018-7143, E-ISSN 1534-6617, Vol. 58, no 6, p. 919-931Article in journal (Refereed)
  • 70.
    Hed, Helen
    Umeå University.
    Trends in opportunity for natural selection in the Swedish population during the period 1650-19801987In: Human biology, ISSN 0018-7143, Vol. 59, no 5, p. 785-797Article in journal (Refereed)
  • 71.
    Hed, Helen M. E.
    Umeå University, Faculty of Science and Technology.
    Opportunity for natural selection in Sweden: a study of childhood mortality and differential reproductivity1986Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Opportunity for natural selection in human populations has so far mainly been studied on anthropological data for tribal populations or on census data for nations. The present study is mainly based on data on individual lifehistories but also, for part of the longitudinal study, on census data. Six of the populations, Nedertorneå, Tuna, Svinnegarn, Trosa, Locknevi and Fleninge are parishes. These sets of data covers the period 1800-1850 as defined by the birthyears of the women. The data for the longitudinal study are derived from two sour­ces, a biography over all clergymen in the diocese of Linköping, cove­ring the period 1600-1845, and material published by the National Swe­dish Central Bureau of Statistics (SCB) that covers the period 1750-1980. For each subpopulation data on childhood mortality and female fertility has been collected and from these data Crow's index of opportunity for natural selection has been calculated. The original index has also been modified in order to estimate the importance of childlessness in relation to the total index.

    The study shows that for the periods and the populations studied, there is a considerable opportunity for natural selection both through mortality and through differential fertility and that, during our cen­tury, differential fertility has become the main asset for natural se­lection, as mortality has been reduced to very low levels. It is also obvious that childlessness is an important factor as regards natural selection in human populations. The cross-sectional study shows signi­ficant differences between the populations for all components of the index. The longitudinal study covers when, the two sets of data are combined, a period of over 350 years, 1600-1980. Over this period changes in index of opportunity for natural selection have occured but these changes are not very drastic as compared to other longitudinal studies. However, within a separate region there can be drastic chang­es in index between decades and there are large differences between regions.

    Mortality and fertility patterns have been studied from different angles. With the exception for the census data, each woman in the stu­dy has be followed from 16 to 40 years of age and each of her children (if any) has be followed from birth to 16 years of age or death, if prior. Therefore it was possible to obtain distributions for age at first childbirth, sibship size, succesful sibship size, childhood mor­tality by age at death, female mortality, and childlessness, total and marital. In some cases a study of sex ratio at birth and at 16 years of age, and birth intervals, have been made. Statistical analysis of the results shows significant differences between populations for all tests that have been applied. The Linköping data was analysed for dif­ferences between periods. Significant differences were found for all of the parameters with the exception of female mortality.

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  • 72.
    Hed, Helen
    et al.
    Umeå University.
    Rasmuson, Marianne
    Umeå University.
    Cohort study of Opportunity for selection on 2 Swedish 19th-century parishes with a survey of other estimates1981In: Human Heredity, ISSN 0001-5652, E-ISSN 1423-0062, Vol. 31, no 2, p. 78-83Article in journal (Refereed)
  • 73.
    Hjältén, Joakim
    et al.
    SLU, Umeå.
    Axelsson, E Petter
    SLU, Umeå.
    Whitham, Thomas G
    Arizona, United States of America.
    LeRoy, Carri J
    Washington, United States of America.
    Julkunen-Tiitto, Riitta
    Joensuu, Finland.
    Wennström, Anders
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Pilate, Gilles
    Orle´ans, France.
    Increased Resistance of Bt Aspens to Phratora vitellinae (Coleoptera) Leads to Increased Plant Growth under Experimental Conditions2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 1, article id e30640Article in journal (Refereed)
    Abstract [en]

    One main aim with genetic modification (GM) of trees is to produce plants that are resistant to various types of pests. The effectiveness of GM-introduced toxins against specific pest species on trees has been shown in the laboratory. However, few attempts have been made to determine if the production of these toxins and reduced herbivory will translate into increased tree productivity. We established an experiment with two lines of potted aspens (Populus tremulaxPopulus tremuloides) which express Bt (Bacillus thuringiensis) toxins and the isogenic wildtype (Wt) in the lab. The goal was to explore how experimentally controlled levels of a targeted leaf beetle Phratora vitellinae (Coleoptera; Chrysomelidae) influenced leaf damage severity, leaf beetle performance and the growth of aspen. Four patterns emerged. Firstly, we found clear evidence that Bt toxins reduce leaf damage. The damage on the Bt lines was significantly lower than for the Wt line in high and low herbivory treatment, respectively. Secondly, Bt toxins had a significant negative effect on leaf beetle survival. Thirdly, the significant decrease in height of the Wt line with increasing herbivory and the relative increase in height of one of the Bt lines compared with the Wt line in the presence of herbivores suggest that this also might translate into increased biomass production of Bt trees. This realized benefit was context-dependent and is likely to be manifested only if herbivore pressure is sufficiently high. However, these herbivore induced patterns did not translate into significant affect on biomass, instead one Bt line overall produced less biomass than the Wt. Fourthly, compiled results suggest that the growth reduction in one Bt line as indicated here is likely due to events in the transformation process and that a hypothesized cost of producing Bt toxins is of subordinate significance.

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  • 74.
    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.

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  • 75. Huckins, Laura M.
    et al.
    Dobbyn, Amanda
    Ruderfer, Douglas M.
    Hoffman, Gabriel
    Wang, Weiqing
    Pardinas, Antonio F.
    Rajagopal, Veera M.
    Als, Thomas D.
    Nguyen, Hoang T.
    Girdhar, Kiran
    Boocock, James
    Roussos, Panos
    Fromer, Menachem
    Kramer, Robin
    Domenici, Enrico
    Gamazon, Eric R.
    Purcell, Shaun
    Demontis, Ditte
    Borglum, Anders D.
    Walters, James T. R.
    O'Donovan, Michael C.
    Sullivan, Patrick
    Owen, Michael J.
    Devlin, Bernie
    Sieberts, Solveig K.
    Cox, Nancy J.
    Im, Hae Kyung
    Sklar, Pamela
    Stahl, Eli A.
    Johnson, Jessica S.
    Shah, Hardik R.
    Klein, Lambertus L.
    Dang, Kristen K.
    Logsdon, Benjamin A.
    Mahajan, Milind C.
    Mangravite, Lara M.
    Toyoshiba, Hiroyoshi
    Gur, Raquel E.
    Hahn, Chang-Gyu
    Schadt, Eric
    Lewis, David A.
    Haroutunian, Vahram
    Peters, Mette A.
    Lipska, Barbara K.
    Buxbaum, Joseph D.
    Hirai, Keisuke
    Perumal, Thanneer M.
    Essioux, Laurent
    Rajagopal, Veera Manikandan
    Mattheisen, Manuel
    Grove, Jakob
    Werge, Thomas
    Mortensen, Preben Bo
    Pedersen, Carsten Bocker
    Agerbo, Esben
    Pedersen, Marianne Giortz
    Mors, Ole
    Nordentoft, Merete
    Hougaard, David M.
    Bybjerg-Grauholm, Jonas
    Baekvad-Hansen, Marie
    Hansen, Christine Soholm
    Ripke, Stephan
    Neale, Benjamin M.
    Corvin, Aiden
    Farh, Kai-How
    Holmans, Peter A.
    Lee, Phil
    Bulik-Sullivan, Brendan
    Collier, David A.
    Huang, Hailiang
    Pers, Tune H.
    Agartz, Ingrid
    Albus, Margot
    Alexander, Madeline
    Amin, Farooq
    Bacanu, Silviu A.
    Begemann, Martin
    Belliveau, Richard A., Jr.
    Bene, Judit
    Bergen, Sarah E.
    Bevilacqua, Elizabeth
    Bigdeli, Tim B.
    Black, Donald W.
    Bruggeman, Richard
    Buccola, Nancy G.
    Buckner, Randy L.
    Byerley, William
    Cahn, Wiepke
    Cai, Guiqing
    Campion, Dominique
    Cantor, Rita M.
    Carr, Vaughan J.
    Carrera, Noa
    Catts, Stanley, V
    Chambert, Kimberly D.
    Chan, Raymond C. K.
    Chen, Ronald Y. L.
    Chen, Eric Y. H.
    Cheng, Wei
    Cheung, Eric F. C.
    Chong, Siow Ann
    Cloninger, C. Robert
    Cohen, David
    Cohen, Nadine
    Cormican, Paul
    Craddock, Nick
    Crowley, James J.
    Curtis, David
    Davidson, Michael
    Davis, Kenneth L.
    Degenhardt, Franziska
    Del Favero, Jurgen
    Dikeos, Dimitris
    Dinan, Timothy
    Djurovic, Srdjan
    Donohoe, Gary
    Drapeau, Elodie
    Duan, Jubao
    Dudbridge, Frank
    Durmishi, Naser
    Eichhammer, Peter
    Eriksson, Johan
    Escott-Price, Valentina
    Fanous, Ayman H.
    Farrell, Martilias S.
    Frank, Josef
    Franke, Lude
    Freedman, Robert
    Freimer, Nelson B.
    Friedl, Marion
    Friedman, Joseph, I
    Genovese, Giulio
    Georgieva, Lyudmila
    Giegling, Ina
    Giusti-Rodriguez, Paola
    Godard, Stephanie
    Goldstein, Jacqueline, I
    Golimbet, Vera
    Gopal, Srihari
    Gratten, Jacob
    de Haan, Lieuwe
    Hammer, Christian
    Hamshere, Marian L.
    Hansen, Mark
    Hansen, Thomas
    Hartmann, Annette M.
    Henskens, Frans A.
    Herms, Stefan
    Hirschhorn, Joel N.
    Hoffmann, Per
    Hofman, Andrea
    Hollegaard, Mads, V
    Ikeda, Masashi
    Joa, Inge
    Julia, Antonio
    Kahn, Rene S.
    Kalaydjieva, Luba
    Karachanak-Yankova, Sena
    Karjalainen, Juha
    Kavanagh, David
    Keller, Matthew C.
    Kennedy, James L.
    Khrunin, Andrey
    Kim, Yunjung
    Klovins, Janis
    Knowles, James A.
    Konte, Bettina
    Kucinskas, Vaidutis
    Kucinskiene, Zita Ausrele
    Kuzelova-Ptackova, Hana
    Kahler, Anna K.
    Laurent, Claudine
    Keong, Jimmy Lee Chee
    Lee, S. Hong
    Legge, Sophie E.
    Lerer, Bernard
    Li, Miaoxin
    Li, Tao
    Liang, Kung-Yee
    Lieberman, Jeffrey
    Limborska, Svetlana
    Loughland, Carmel M.
    Lubinski, Jan
    Lonnqvist, Jouko
    Macek, Milan, Jr.
    Magnusson, Patrik K. E.
    Maher, Brion S.
    Maier, Wolfgang
    Mallet, Jacques
    Marsal, Sara
    Mattingsdal, Morten
    McCarley, Robert W.
    McDonald, Colm
    McIntosh, Andrew M.
    Meier, Sandra
    Meijer, Carin J.
    Melegh, Bela
    Melle, Ingrid
    Mesholam-Gately, Raquelle, I
    Metspalu, Andres
    Michie, Patricia T.
    Milani, Lili
    Milanova, Vihra
    Mokrab, Younes
    Morris, Derek W.
    Murphy, Kieran C.
    Murray, Robin M.
    Myin-Germeys, Inez
    Muller-Myhsok, Bertram
    Nelis, Mari
    Nenadic, Igor
    Nertney, Deborah A.
    Nestadt, Gerald
    Nicodemus, Kristin K.
    Nikitina-Zake, Liene
    Nisenbaum, Laura
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    O'Callaghan, Eadbhard
    O'Dushlaine, Colm
    O'Neill, F. Anthony
    Oh, Sang-Yun
    Olincy, Ann
    Olsen, Line
    Van Os, Jim
    Pantelis, Christos
    Papadimitriou, George N.
    Papiol, Sergi
    Parkhomenko, Elena
    Pato, Michele T.
    Paunio, Tiina
    Pejovic-Milovancevic, Milica
    Perkins, Diana O.
    Pietilainen, Olli
    Pimm, Jonathan
    Pocklington, Andrew J.
    Powell, John
    Price, Alkes
    Pulver, Ann E.
    Purcell, Shaun M.
    Quested, Digby
    Rasmussen, Henrik B.
    Reichenberg, Abraham
    Reimers, Mark A.
    Richards, Alexander L.
    Roffman, Joshua L.
    Salomaa, Veikko
    Sanders, Alan R.
    Schall, Ulrich
    Schubert, Christian R.
    Schulze, Thomas G.
    Schwab, Sibylle G.
    Scolnick, Edward M.
    Scott, Rodney J.
    Seidman, Larry J.
    Shi, Jianxin
    Sigurdsson, Engilbert
    Silagadze, Teimuraz
    Silverman, Jeremy M.
    Sim, Kang
    Slominsky, Petr
    Smoller, Jordan W.
    So, Hon-Cheong
    Spencer, Chris C. A.
    Stefansson, Hreinn
    Steinberg, Stacy
    Stogmann, Elisabeth
    Straub, Richard E.
    Strengman, Eric
    Strohmaier, Jana
    Stroup, T. Scott
    Subramaniam, Mythily
    Suvisaari, Jaana
    Svrakic, Dragan M.
    Szatkiewicz, Jin P.
    Soderman, Erik
    Thirumalai, Srinivas
    Toncheva, Draga
    Tosato, Sarah
    Veijola, Juha
    Waddington, John
    Walsh, Dermot
    Wang, Dai
    Wang, Qiang
    Webb, Bradley T.
    Weiser, Mark
    Wildenauer, Dieter B.
    Williams, Nigel M.
    Williams, Stephanie
    Witt, Stephanie H.
    Wolen, Aaron R.
    Wong, Emily H. M.
    Wormley, Brandon K.
    Xi, Hualin Simon
    Zai, Clement C.
    Zheng, Xuebin
    Zimprich, Fritz
    Wray, Naomi R.
    Stefansson, Kari
    Visscher, Peter M.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Andreassen, Ole A.
    Blackwood, Douglas H. R.
    Bramon, Elvira
    Cichon, Sven
    Darvasi, Ariel
    Ehrenreich, Hannelore
    Esko, Tonu
    Gejman, Pablo, V
    Gill, Michael
    Gurling, Hugh
    Hultman, Christina M.
    Iwata, Nakao
    Jablensky, Assen, V
    Jonsson, Erik G.
    Kendler, Kenneth S.
    Kirov, George
    Knight, Jo
    Lencz, Todd
    Levinson, Douglas F.
    Li, Qingqin S.
    Liu, Jianjun
    Malhotra, Anil K.
    McCarroll, Steven A.
    McQuillin, Andrew
    Moran, Jennifer L.
    Mortensen, Preben B.
    Mowry, Bryan J.
    Nothen, Markus M.
    Ophoff, Roel A.
    Palotie, Aarno
    Pato, Carlos N.
    Petryshen, Tracey L.
    Posthuma, Danielle
    Rietschel, Marcella
    Riley, Brien P.
    Rujescu, Dan
    Sham, Pak C.
    St Clair, David
    Weinberger, Daniel R.
    Wendland, Jens R.
    Daly, Mark J.
    Sullivan, Patrick F.
    Gene expression imputation across multiple brain regions provides insights into schizophrenia risk2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 4, p. 659-+Article in journal (Refereed)
    Abstract [en]

    Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

  • 76. Igamberdiev, Abir U.
    et al.
    Lernmark, Ulrika
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Gardeström, Per
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Activity of the mitochondrial pyruvate dehydrogenase complex in plants is stimulated in the presence of malate2014In: Mitochondrion (Amsterdam. Print), ISSN 1567-7249, E-ISSN 1872-8278, Vol. 19, no Part B, p. 184-190Article in journal (Refereed)
    Abstract [en]

    The effect of malate on the steady-state activity of the pea (Pisum sativum L.) and barley (Hordeum vulgare L) leaf pyruvate dehydrogenase complex (PDC) has been studied in isolated mitochondria. The addition of malate was found to be stimulatory for the mitochondrial PDC, however there was no stimulation of chloroplast PDC. The stimulation was saturated below 1 mM malate and was apparently related to a partially activated complex, which activity increased in the presence of malate by about twofold. Malate also reversed the reduction of PDC activity in the presence of glycine. Based on the obtained kinetic data, we suggest that the effect of malate is rather not a direct activation of PDC but involves the establishment of NAD-malate dehydrogenase equilibrium, decreasing concentration of NADH and relieving its inhibitory effect of PDC. 

  • 77.
    Ingvarsson, Pär K
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Molecular population genetics of herbivore-induced protease inhibitor genes in European aspen (Populus tremula, L., Salicaceae)2005In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 22, no 9, p. 1802-1812Article in journal (Refereed)
    Abstract [en]

    Plants defend themselves against the attack of natural enemies by using an array of both constitutively expressed and induced defenses. Long-lived woody perennials are overrepresented among plant species that show strong induced defense responses, whereas annual plants and crop species are underrepresented. However, most studies of plant defense genes have been performed on annual or short-lived perennial weeds or crop species. Here I use molecular population genetic methods to survey six wound-inducible protease inhibitors (PIs) in a long-lived woody, perennial plant species, the European aspen (Populus tremula), to evaluate the likelihood of either recurrent selective sweeps or balancing selection maintaining amino acid polymorphisms in these genes. The results show that none of the six PI genes have reduced diversities at synonymous sites, as would be expected in the presence of recurrent selective sweeps. However, several genes show some evidence of nonneutral evolution such as enhanced linkage disequilibrium and a large number of high-frequency-derived mutations. A group of at least four Kunitz trypsin inhibitor genes appear to have experienced elevated levels of nonsynonymous substitutions, indicating allelic turnover on an evolutionary timescale. One gene, T11, has enhanced levels of intraspecific polymorphism at nonsynonymous sites and also has an unusual haplotype structure characterized by two divergent haplotypes occurring at roughly equal frequencies in the sample. One haplotype has very low levels of intraallelic nucleotide diversity, whereas the other haplotype has levels of diversity comparable to other genes in P. tremula. Patterns of sequence diversity at T11 do not fit a simple model of either balancing selection or recurrent selective sweeps. This suggests that selection at T11 is more complex, possibly involving allelic cycling.

  • 78.
    Ingvarsson, Pär K.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, 1432,As, Norway.
    Street, Nathaniel R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Towards integration of population and comparative genomics in forest trees2016In: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 212, no 2, p. 338-344Article, review/survey (Refereed)
    Abstract [en]

    The past decade saw the initiation of an ongoing revolution in sequencing technologies that is transforming all fields of biology. This has been driven by the advent and widespread availability of high-throughput, massively parallel short-read sequencing (MPS) platforms. These technologies have enabled previously unimaginable studies, including draft assemblies of the massive genomes of coniferous species and population-scale resequencing. Transcriptomics studies have likewise been transformed, with RNA-sequencing enabling studies in nonmodel organisms, the discovery of previously unannotated genes (novel transcripts), entirely new classes of RNAs and previously unknown regulatory mechanisms. Here we touch upon current developments in the areas of genome assembly, comparative regulomics and population genetics as they relate to studies of forest tree species.

  • 79. Isabel, Nathalie
    et al.
    Lamothe, Manuel
    Thompson, Stacey Lee
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Laurentian Forestry Centre, Canadian Forest Service, Natural Resources Canada, Québec, Canada.
    A second-generation diagnostic single nucleotide polymorphism (SNP)-based assay, optimized to distinguish among eight poplar (Populus L.) species and their early hybrids2013In: Tree Genetics & Genomes, ISSN 1614-2942, E-ISSN 1614-2950, Vol. 9, no 2, p. 621-626Article in journal (Refereed)
    Abstract [en]

    Rapid identification of Populus L. species and hybrids can be achieved with relatively little effort through the use of primer extension-based single nucleotide polymorphism (SNP) genotyping assays. We present an optimized set of 36 SNP markers from 28 gene regions that diagnose eight poplar species (Populus angustifolia James, Populus balsamifera L., Populus deltoides Bartram, Populus fremontii Watson, Populus laurifolia Ledeb., Populus maximowiczii Henry, Populus nigra L., and Populus trichocarpa Torr. & Gray). A total of 700 DNA sequences from six Populus species (1–15 individuals per species) were used to construct the array. A set of flanking and probe oligonucleotides was developed and tested. The accuracy of the SNP assay was validated by genotyping 448 putatively "pure" individuals from 14 species of Populus. Overall, the SNP assay had a high success rate (97.6 %) and will prove useful for the identification of all Aigeiros Duby and Tacamahaca Spach. species and their early-generation hybrids within natural populations and breeding programs. Null alleles and intraspecific polymorphisms were detected for a few locus/species combinations in the Aigeiros and Tacamahaca sections. When we attempted to genotype aspens of the section Populus (Populus alba L., Populus grandidentata Michx., Populus tremula L., and Populus tremuloides Michx.), the success rate of the SNP array decreased by 13 %, demonstrating moderate cross-sectional transferability.

  • 80. Jin, Yuqing
    et al.
    Ma, Yongpeng
    Wang, Shun
    Hu, Xian-Ge
    Huang, Li-Sha
    Li, Yue
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). 1National Engineering Laboratory for Tree Breeding, Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants, Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China.
    Mao, Jian-Feng
    Genetic evaluation of the breeding population of a valuable reforestation conifer Platycladus orientalis (Cupressaceae)2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 34821Article in journal (Refereed)
    Abstract [en]

    Platycladus orientalis, a widespread conifer with long lifespan and significant adaptability. It is much used in reforestation in north China and commonly planted in central Asia. With the increasing demand for plantation forest in central to north China, breeding programs are progressively established for this species. Efficient use of breeding resources requires good understanding of the genetic value of the founder breeding materials. This study investigated the distribution of genetic variation in 192 elite trees collected for the breeding program for the central range of the species. We developed first set of 27 polymorphic EST-derived SSR loci for the species from transcriptome/genome data. After examination of amplification quality, 10 loci were used to evaluate the genetic variation in the breeding population. We found moderate genetic diversity (average H-e = 0.348) and low population differentiation (Fst = 0.011). Extensive admixture and no significant geographic population structure characterized this set of collections. Our analyses of the diversity and population structure are important steps toward a long-term sustainable deployment of the species and provide valuable genetic information for conservation and breeding applications.

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  • 81. Jin, Yuqing
    et al.
    Zhao, Wei
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, National Engineering Laboratory for Tree Breeding, Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants of Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, 100083, China; .
    Nie, Shuai
    Liu, Si-Si
    El-Kassaby, Yousry A.
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, National Engineering Laboratory for Tree Breeding, Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants of Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, 100083, China.
    Mao, Jian-Feng
    Genome-Wide Variant Identification and High-Density Genetic Map Construction Using RADseq for Platycladus orientalis (Cupressaceae)2019In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 9, no 11, p. 3663-3672Article in journal (Refereed)
    Abstract [en]

    Platycladus orientalis is an ecologically important native conifer in Northern China and exotic species in many parts of the world; however, knowledge about the species' genetics and genome are very limited. The availability of well-developed battery of genetic markers, with large genome coverage, is a prerequisite for the species genetic dissection of adaptive attributes and efficient selective breeding. Here, we present a genome-wide genotyping method with double-digestion restriction site associated DNA sequencing (ddRAD-seq) that is effective in generating large number of Mendelian markers for genome mapping and other genetic applications. Using 139 megagametophytes collected from a single mother tree, we assembled 397,226 loci, of which 108,683 (27.4%) were polymorphic. After stringent filtering for 1:1 segregation ratio and missing rate of <20%, the remaining 23,926 loci (22% of the polymorphic loci) were ordered into 11 linkage groups (LGs) and distributed across 7,559 unique positions, with a total map length of 1,443 cM and an average spacing of 0.2 cM between adjacent unique positions. The 11 LGs correspond to the species' 11 haploid genome chromosome number. This genetic map is among few high-density maps available for conifers to date, and represents the first genetic map for P. orientalis. The information generated serves as a solid foundation not only for marker-assisted breeding efforts, but also for comparative conifer genomic studies.

  • 82.
    Johansson, Anna-Mia
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Chromosome-wide gene regulatory mechanisms in Drosophila melanogaster2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In Drosophila there are two different chromosome-wide targeting systems, the dosage compensation system that equalizes the transcriptional output from X-linked genes between males and females, and the regulation of the 4th chromosome mediated by the POF protein.

     

    The best studied of these two mechanisms is the dosage compensation system. To attain dosage compensation in Drosophila at least five different proteins, encoded by the male-specific lethal genes msl1, msl2, msl3, mle and mof, are required. These proteins together with two non-coding RNAs (roX1 and roX2) form a dosage compensation complex (MSL complex), which binds exclusively to the X chromosome in Drosophila males and up-regulates the transcription approximately two times.

     

    In this thesis I show that roX1 and roX2 are most likely the only non-coding RNAs within the MSL complex. As expected, the roX transcripts were enriched within the MSL complex. Interestingly, one additional transcript was identified within the MSL complex. This transcript did not associate with the X chromosome and is therefore not believed to be involved in up-regulation of the X-linked genes. This transcript encodes for the rate limiting component in the MSL complex, the MSL2 protein. A model is proposed in which free, partial or complete, MSL complex feed-back regulates the amount of msl2 transcript, and thereby limits the MSL complex production.

     

    The second chromosome-wide regulatory system in flies acts on an autosome, the heterochromatic 4th chromosome. This regulation is a balancing mechanism between at least two different proteins, the chromosome 4 specific protein painting of fourth (POF) and heterochromatin protein 1 (HP1). POF binds to nascent RNAs transcribed from the 4th chromosome and HP1 target the same set of genes at the chromatin level. POF stimulates the transcribed genes, while HP1 represses them; together they create the most optimal condition for these genes. This type of balancing mechanism may be a more general way to fine-tune transcription at a chromosome-wide level and raises the question about autosomal gene regulation as a general mechanism.

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  • 83.
    Johansson, Anna-Mia
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Allgardsson, Anders
    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).
    msl2 mRNA is bound by free nuclear MSL complex in Drosophila melanogaster2011In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no 15, p. 6428-6439Article in journal (Refereed)
    Abstract [en]

    In Drosophila, the global increase in transcription from the male X chromosome to compensate for its monosomy is mediated by the male-specific lethal (MSL) complex consisting of five proteins and two non-coding RNAs, roX1 and roX2. After an initial sequence-dependent recognition by the MSL complex of 150-300 high affinity sites, the spread to the majority of the X-linked genes depends on local MSL-complex concentration and active transcription. We have explored whether any additional RNA species are associated with the MSL complex. No additional roX RNA species were found, but a strong association was found between a spliced and poly-adenylated msl2 RNA and the MSL complex. Based on our results, we propose a model in which a non-chromatin-associated partial or complete MSL-complex titrates newly transcribed msl2 mRNA and thus regulates the amount of available MSL complex by feedback. This represents a novel mechanism in chromatin structure regulation.

  • 84.
    Johansson, Anna-Mia
    et al.
    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).
    Genome-wide mapping of Painting of fourth on Drosophila melanogaster salivary gland polytene chromosomes2014In: Genomics Data, ISSN 1025-6059, E-ISSN 2213-5960, Vol. 2, p. 63-65Article in journal (Refereed)
    Abstract [en]

    The protein Painting of fourth (POF) in Drosophila melanogaster specifically targets and stimulates expression output from the heterochromatic 4th chromosome, thereby representing an autosome specific protein [1,2]. Despite the high specificity for chromosome 4 genes, POF is occasionally observed binding to the cytological region 2L:31 in males and females [3] and two loci on the X-chromosome, PoX1 and PoX2 only in females [4]. Here we provide a detailed description of the experimental design and analysis of the tiling array data presented by Lundberg and colleagues in G3: Genes, Genomes, Genetics 2013 [4], where the female specific POF binding to PoX1 and PoX2 loci on the X chromosome was reported. We show the genome-wide high resolution binding profile of the POF protein where these different POF binding sites are detected. The complete data set is available at http://www.ncbi.nlm.nih.gov/geo/ (accession: GSE45402).

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  • 85.
    Johansson, Anna-Mia
    et al.
    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).
    Allgardsson, Anders
    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).
    POF Regulates the Expression of Genes on the Fourth Chromosome in Drosophila melanogaster by Binding to Nascent RNA2012In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 32, no 11, p. 2121-2134Article in journal (Other academic)
    Abstract [en]

    In Drosophila, two chromosome-wide compensatory systems have been characterized: the dosage compensation system that acts on the male X chromosome and the chromosome-specific regulation of genes located on the heterochromatic fourth chromosome. Dosage compensation in Drosophila is accomplished by hypertranscription of the single male X chromosome mediated by the male-specific lethal (MSL) complex. The mechanism of this compensation is suggested to involve enhanced transcriptional elongation mediated by the MSL complex, while the mechanism of compensation mediated by the painting of fourth (POF) protein on the fourth chromosome has remained elusive. Here, we show that POF binds to nascent RNA, and this binding is associated with increased transcription output from chromosome 4. We also show that genes located in heterochromatic regions spend less time in transition from the site of transcription to the nuclear envelope. These results provide useful insights into the means by which genes in heterochromatic regions can overcome the repressive influence of their hostile environment.

  • 86. Johansson, Helena
    et al.
    Ingvarsson, Pär K
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Johansson, Frank
    Cross-species amplification and development of microsatellites for six species of European Coenagrionid damselflies2012In: Conservation Genetics Resources, ISSN 1877-7252, E-ISSN 1877-7260, Vol. 4, no 1, p. 191-196Article in journal (Refereed)
    Abstract [en]

    We describe the cross-amplification and development of new loci for six species of closely related European damselflies. First, twenty-nine published microsatellites for the damselflies Coenagrion puella and C. mercuriale were multiplexed using M13-tagged primers, tested on 23 individuals, and then cross-species amplified on 21-26 individuals of C. armatum, C. johanssoni, C. pulchellum and C. scitulum. Second, sixteen new primers were developed for use in C. armatum, C. johanssoni and C. scitulum, and screened on 21 individuals. Values for observed heterozygosities and number of alleles ranged between 0.00-0.87 and 2-19 respectively (over all loci and species). For all species the tested loci provide a minimum of 1-8 usable markers for population genetic studies.

  • 87.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Boström, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Burstedt, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Holmberg, Monica
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    ATP-binding cassette subfamily A, member 4 intronic variants c.4773+3A > G and c.5461-10T > C cause Stargardt disease due to defective splicing2018In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 96, no 7, p. 737-743Article in journal (Refereed)
    Abstract [en]

    Purpose

    Inherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP‐binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated. In this study, we aimed to reveal how intronic variants present in patients with Stargardt from the same Swedish family affect splicing.

    Methods

    The splicing of the ABCA4 gene was studied in human embryonic kidney cells, HEK293T, and in human retinal pigment epithelium cells, ARPE‐19, using a minigene system containing variants c.4773+3A>G and c.5461‐10T>C.

    Results

    We showed that both ABCA4 variants, c.4773+3A>G and c.5461‐10T>C, cause aberrant splicing of the ABCA4 minigene resulting in exon skipping. We also demonstrated that splicing of ABCA4 has different outcomes depending on transfected cell type.

    Conclusion

    Two intronic variants c.4773+3A>G and c.5461‐10T>C, both predicted to affect splicing, are indeed disease‐causing mutations due to skipping of exons 33, 34, 39 and 40 of ABCA4 gene. The experimental proof that ABCA4 mutations in STGD patients affect protein function is crucial for their inclusion to future clinical trials; therefore, functional testing of all ABCA4 intronic variants associated with Stargardt disease by minigene technology is desirable.

  • 88.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Westin, IM
    Österman, L
    Burstedt, MS
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    ABCA4 intronic variants c.4773+3A and c.5461-10T>C cause Stargardt disease due to defective splicing.: Intronic ABCA4 variants cause splice defects in Stargardt diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Inherited retinal dystrophies (IRD) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRD and to-date more than 250 genes are associated with autosomal dominant, autosomal recessive and X-linked IRD. Stargardt disease (#248200) or macular degeneration with flecks, type 1, STGD1 is associated with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in ABCA4 gene. In this study, two intronic variants potentially causing the Stargardt disease were functionally tested in HEK293T and ARPE-19 cells using in vitro splice minigene assay. The two variants, c.4773+3A>G and c.5461-10T>C in the ABCA4 gene encoding ATP binding cassette sub-family A, member 4 protein, responsible for transport of a vitamin A precursor in the photoreceptors of the retina, were present in two Stargardt patients, members of the same Swedish family. It was suggested that the disease in one of the patients was caused by homozygous variant c.5461-10T>C and by both variants, in the other patient. The c.5461–10T>C, the third most common variant in STGD1 patients always segregating with the disease was proposed to be a polymorphism, a risk allele and finally, a disease-associated mutation, though its functional impact remained unknown for a long time. Functional analysis of the ABCA4 variants are complicated due to predominant expression of the ABCA4  in photoreceptors, which means no affected tissue can be easily obtained from the patients.

    This study provides the evidence that c.4773+3A>G and c.5461-10T>C cause aberrant splicing and are indeed disease-causative variants.

  • 89.
    Kahn, Tatyana G.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dorafshan, Eshagh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schultheis, Dorothea
    Zare, Aman
    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). Division of CBRN Defense and Security, Swedish Defense Research Agency, FOI, Umea, 906 21, Sweden.
    Reim, Ingolf
    Pirrotta, Vincenzo
    Schwartz, Yuri B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Interdependence of PRC1 and PRC2 for recruitment to Polycomb Response Elements2016In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, no 21, p. 10132-10149Article in journal (Refereed)
    Abstract [en]

    Polycomb Group (PcG) proteins are epigenetic repressors essential for control of development and cell differentiation. They form multiple complexes of which PRC1 and PRC2 are evolutionary conserved and obligatory for repression. The targeting of PRC1 and PRC2 is poorly understood and was proposed to be hierarchical and involve tri-methylation of histone H3 (H3K27me3) and/or monoubiquitylation of histone H2A (H2AK118ub). Here, we present a strict test of this hypothesis using the Drosophila model. We discover that neither H3K27me3 nor H2AK118ub is required for targeting PRC complexes to Polycomb Response Elements (PREs). We find that PRC1 can bind PREs in the absence of PRC2 but at many PREs PRC2 requires PRC1 to be targeted. We show that one role of H3K27me3 is to allow PcG complexes anchored at PREs to interact with surrounding chromatin. In contrast, the bulk of H2AK118ub is unrelated to PcG repression. These findings radically change our view of how PcG repression is targeted and suggest that PRC1 and PRC2 can communicate independently of histone modifications.

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  • 90.
    Karah, Nabil
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Jolley, Keith A.
    Hall, Ruth M.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Database for the ampC alleles in Acinetobacter baumannii2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176695Article in journal (Refereed)
    Abstract [en]

    Acinetobacter baumannii is a troublesome opportunistic pathogen with a high capacity for clonal dissemination. We announce the establishment of a database for the ampC locus in A. baumannii, in which novel ampC alleles are differentiated based on the occurrence of >= 1 nucleotide change, regardless of whether it is silent or missense. The database is openly accessible at the pubmlst platform for A. baumannii (http://pubmlst.org/abaumannii/). Forty-eight distinctive alleles of the ampC locus have so far been identified and deposited in the database. Isolates from clonal complex 1 (CC1), according to the Pasteur multilocus sequence typing scheme, had a variety of the ampC locus alleles, including alleles 1, 3, 4, 5, 6, 7, 8, 13, 14, 17, and 18. On the other hand, isolates from CC2 had the ampC alleles 2, 3, 19, 20, 21, 22, 23, 24, 26, 27, 28, and 46. Allele 3 was characteristic for sequence types ST3 or ST32. The ampC alleles 10, 16, and 25 were characteristic for CC10, ST16, and CC25, respectively. Our study points out that novel gene databases, in which alleles are numbered based on differences in their nucleotide identities, should replace traditional records that use amino acid substitutions to define new alleles.

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  • 91. Karlberg, Anna
    et al.
    Bako, Laszlo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Bhalerao, Rishikesh P
    Short Day-Mediated Cessation of Growth Requires the Downregulation of AINTEGUMENTALIKE1 Transcription Factor in Hybrid Aspen.2011In: PLoS genetics, ISSN 1553-7404, Vol. 7, no 11, p. e1002361-Article in journal (Refereed)
    Abstract [en]

    Day length is a key environmental cue regulating the timing of major developmental transitions in plants. For example, in perennial plants such as the long-lived trees of the boreal forest, exposure to short days (SD) leads to the termination of meristem activity and bud set (referred to as growth cessation). The mechanism underlying SD-mediated induction of growth cessation is poorly understood. Here we show that the AIL1-AIL4 (AINTEGUMENTALIKE) transcription factors of the AP2 family are the downstream targets of the SD signal in the regulation of growth cessation response in hybrid aspen trees. AIL1 is expressed in the shoot apical meristem and leaf primordia, and exposure to SD signal downregulates AIL1 expression. Downregulation of AIL gene expression by SDs is altered in transgenic hybrid aspen plants that are defective in SD perception and/or response, e.g. PHYA or FT overexpressors. Importantly, SD-mediated regulation of growth cessation response is also affected by overexpression or downregulation of AIL gene expression. AIL1 protein can interact with the promoter of the key cell cycle genes, e.g. CYCD3.2, and downregulation of the expression of D-type cyclins after SD treatment is prevented by AIL1 overexpression. These data reveal that execution of SD-mediated growth cessation response requires the downregulation of AIL gene expression. Thus, while early acting components like PHYA and the CO/FT regulon are conserved in day-length regulation of flowering time and growth cessation between annual and perennial plants, signaling pathways downstream of SD perception diverge, with AIL transcription factors being novel targets of the CO/FT regulon connecting the perception of SD signal to the regulation of meristem activity.

  • 92. Katti, Christiana
    et al.
    Stacey-Solis, Micaela
    Anahí Coronel-Rojas, Nicole
    Davies, Wayne I. L.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Oceans Graduate School, University of Western Australia, Crawley, Australia; Oceans Institute, University of Western Australia, Crawley, Australia; School of Biological Sciences, University of Western Australia, Perth, Australia; Center for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.
    The Diversity and Adaptive Evolution of Visual Photopigments in Reptiles2019In: Frontiers in Ecology and Evolution, E-ISSN 2296-701X, Vol. 7, article id 352Article in journal (Refereed)
    Abstract [en]

    Reptiles are a highly diverse class that consists of snakes, geckos, iguanid lizards, and chameleons among others. Given their unique phylogenetic position in relation to both birds and mammals, reptiles are interesting animal models with which to decipher the evolution of vertebrate photopigments (opsin protein plus a light-sensitive retinal chromophore) and their contribution to vision. Reptiles possess different types of retinae that are defined primarily by variations in photoreceptor morphology, which range from pure-cone to rod-dominated retinae with many species possessing duplex (rods and cones) retinae. In most cases, the type of retina is thought to reflect both the lifestyle and the behavior of the animal, which can vary between diurnal, nocturnal, or crepuscular behavioral activities. Reptiles, and in particular geckos and snakes, have been used as prime examples for the “transmutation” hypothesis proposed by Walls in the 1930s-1940s, which postulates that some reptilian species have migrated from diurnality to nocturnality, before subsequently returning to diurnal activities once again. This theory further states that these behavioral changes are reflected in subsequent changes in photoreceptor morphology and function from cones to rods, with a return to cone-like photoreceptors once again. Modern sequencing techniques have further investigated the “transmutation” hypothesis by using molecular biology to study the phototransduction cascades of rod- and cone-like photoreceptors in the reptilian retina. This review will discuss what is currently known about the evolution of opsin-based photopigments in reptiles, relating habitat to photoreceptor morphology, as well as opsin and phototransduction cascade gene expression.

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  • 93.
    Kim, Maria
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ekhteraei-Tousi, Samaneh
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lewerentz, Jacob
    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).
    The X-linked 1.688 satellite in Drosophila melanogaster promotes specific targeting by Painting of Fourth2018In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 208, no 2, p. 623-632Article in journal (Refereed)
    Abstract [en]

    Repetitive DNA, represented by transposons and satellite DNA, constitutes a large portion of eukaryotic genomes, being the major component of constitutive heterochromatin. There is a growing body of evidence that it regulates several nuclear functions including chromatin state and the proper functioning of centromeres and telomeres. The 1.688 satellite is one of the most abundant repetitive sequences in Drosophila melanogaster, with the longest array being located in the pericentromeric region of the X-chromosome. Short arrays of 1.688 repeats are widespread within the euchromatic part of the X-chromosome, and these arrays were recently suggested to assist in recognition of the X-chromosome by the dosage compensation male-specific lethal complex. We discovered that a short array of 1.688 satellite repeats is essential for recruitment of the protein POF to a previously described site on the X-chromosome (PoX2) and to various transgenic constructs. On an isolated target, i.e., an autosomic transgene consisting of a gene upstream of 1.688 satellite repeats, POF is recruited to the transgene in both males and females. The sequence of the satellite, as well as its length and position within the recruitment element, are the major determinants of targeting. Moreover, the 1.688 array promotes POF targeting to the roX1-proximal PoX1 site in trans Finally, binding of POF to the 1.688-related satellite-enriched sequences is conserved in evolution. We hypothesize that the 1.688 satellite functioned in an ancient dosage compensation system involving POF targeting to the X-chromosome.

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  • 94.
    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.

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  • 95.
    Kindgren, Peter
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Dubreuil, Carole
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Strand, Åsa
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    The Recovery of Plastid Function Is Required for Optimal Response to Low Temperatures in Arabidopsis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0138010Article in journal (Refereed)
    Abstract [en]

    Cold acclimation is an essential response in higher plants to survive freezing temperatures. Here, we report that two independent mutant alleles of the H-subunit of Mg-chelatase, CHLH, gun5-1 and cch in Arabidopsis are sensitive to low temperatures. Plants were grown in photoperiodic conditions and exposed to low temperatures for short-and long-term periods. Tetrapyrrole biosynthesis was initially significantly inhibited in response to low temperature but recovered in wild type (Col-0), although the tetrapyrrole levels were lower in cold compared to control conditions. The gun5-1 and cch alleles showed an inability to recover chlorophyll biosynthesis in addition to a significant decrease in freezing tolerance. We found that the impaired plastid function in the CHLH mutant plants resulted in compromised de novo protein synthesis at low temperatures. The expression of the transcription factors CBF1-3 was super-induced in gun5-1 and cch mutant alleles but expression levels of their target genes, COR15a, COR47 and COR78 were similar or even lower compared to Col-0. In addition, the protein levels of COR15a were lower in gun5-1 and cch and a general defect in protein synthesis could be seen in the gun5-1 mutant following a 35S labelling experiment performed at low temperature. Taken together, our results demonstrate the importance of a functional chloroplast for the cold acclimation process and further suggest that impaired plastid function could result in inhibition of protein synthesis at low temperature.

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  • 96.
    Kotova, Irina
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Purification of general RNA polymerase II transcription factors from mouse for studies of proliferation-specific transcription2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Accurate initiation of transcription by RNA polymerase II depends on general transcription factors (GTFs), which include the TATA-binding protein (TBP) and the transcription factors (TF) IIB, IIF, IIE and IIH. In order to reconstitute mouse transcription in vitro, we cloned the genes encoding mouse TFIIB, and both subunits of TFIIE and TFIIF from a mouse cDNA library. TBP and TFIIB were expressed in E.coli, while both subunits of TFIIE and the two subunits of TFIIF were expressed in a baculovirus system. All these factors were purified to > 90% homogeneity. The more complex transcription factors, TFIIH and RNA polymerase II, were purified more than 1000-fold and to near homogeneity, respectively, from tissue cultured mouse ascites cells. We have shown that the purified mouse transcription factors are active in a reconstituted RNA polymerase II in vitro transcription assay. The transcription reaction was inhibited by α-amanitine, and dependent on the addition of all the GTFs.

    Ribonucleotide reductase is a key enzyme in deoxyribonucleotide synthesis. It consists of two subunits, R1 and R2, which are both required for the enzyme activity. Transcription of the R1 and R2 genes is restiricted to the S-phase of the cell cycle, but the mechanisms that control this coordinated expression remain to be identified. We have studied initiation of transcription from the mouse R2 gene using a combination of in vivo reporter gene assays and in vitro transcription assays with crude nuclear extracts or with purified transcription factors. This promoter has an atypical TATA-box and a CCAAT-box that binds the transcription factor NF-Y.

    We found that a mutation in the R2 CCAAT-box had no effect on the transcription level in in vitro transcription assays reconstituted with pure transcription factors. However, it significantly decreased the level of transcription in similar experiments using crude nuclear extract. We also found that the sequence downstream from the R2 transcription start site (5´-UTR) (from +1 to +17 base pairs relative to transcription start site) is essential for initiation of transcription from this promoter. The presence of the wild type 5´-UTR made the R2 TATA-box redundant. On the other hand, the R2 5´-UTR had a repressing effect on transcription from the mouse R2 promoter. This region contains a palindrome sequence that covers 10 base pairs, and it is partially conserved in the human R2 promoter. Gel shift assays and in vitro transcription experiments using antibodies against mouse TAF4 (=TAF135) demonstrate that TAF4 is a component of the protein complex that interacts with this palindrome region, and suggest involvement of this component of the TFIID complex in negative regulation of the R2 promoter.

    The Adenovirus Major Late (AdML) promoter is commonly used as a model for studies of transcription initiation and regulation. It is a TATA-box dependent promoter, which also contains an initiator (Inr) element, a CCAAT-box interacting with transcription factor NF-Y, and an E-box binding the upstream stimulatory factor (USF). Using gel shift assays with recombinant NF-Y, USF, and immunopurified human TFIID, we show that binding of USF1 and NF-Y to DNA is not cooperative and that both factors independently facilitate binding of TFIID to the core promoter. The activation domains of NF-Y are expendable for this effect. Negative cofactor (NC2) comprises two subunits, which have a histone-fold structure similar to NF-Y, and represses transcription through formation of an inhibitory complex with TBP. Using an in vitro transcription system based on crude nuclear extracts, we show that NC2 has a negative effect on transcription in the presence of NF-Y or USF1, indicating that the two activators do not act as antirepressors. In vitro transcription using highly purified transcription factors efficiently reproduces repression of transcription by NC2. However, USF1 was inactive and NF-Y had a repressing effect in this system, which suggests that the activator functions of USF and NF-Y depend on cofactors.

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  • 97. Kravchuk, O. I.
    et al.
    Mikhailov, V. S.
    Savitsky, Mikhail
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    A simple and efficient method of inducing targeted deletions in the drosophila genome2015In: Russian journal of genetics, ISSN 1022-7954, E-ISSN 1608-3369, Vol. 51, no 11, p. 1144-1148Article in journal (Refereed)
    Abstract [en]

    Deletion mutagenesis is one of the most efficient approaches to studying gene function. However, conventional methods of inducing targeted mutations in the drosophila genome are timeand labor-consuming. This work proposes a new, simple, and effective method of producing drosophila mutants with gene deletions. The method involves the insertion of I-SceI and I-CreI recognition sites and a fragment homologous to the target sequence into the chromosome region of interest by means of an attB-containing construct, the induction of double-strand DNA breaks by the appropriate meganuclease, and their repair by homologous recombination. The procedure results in a deletion extending from the attP-site to the target locus. A cassette was designed to enable single-step construct production for the deletion of any given genomic region. A set of markers facilitates the selection of recombination events. The efficacy of the proposed technique was confirmed by the induction of a 47-kb deletion containing the qtc gene.

  • 98.
    Kronhamn, Jesper
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Genetic analysis of genes found on the 4th chromosome of Drosophila - emphasizing the developmental context of Pax62004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The small size and the lack of recombination set the fourth chromosome of Drosophila melanogaster apart from the other chromosomes. I have shown that the Minute gene on chromosome 4, earlier named Minute-4, encodes the ribosomal protein RpS3A. Two Pax6 genes, eyeless (ey) and twin of eyeless (toy) are also located on chromosome 4.

    Pax6 genes are important in head and eye development in both mammals and Drosophila. I have focused much of the study on ey and toy. The first mutant of toy that was characterized showed a headless phenotype. This indicates that Toy is important for the development of both the eye and antennal discs. The phenotype of the null mutation in toy is temperature sensitive due to that transcription of ey is temperature dependent in the eye-antennal primordium in absence of Toy. This temperature dependence was used to find out that the phenocritical period for ey in the adult head development is during embryonic stage 12-16 when ey first is expressed in the eye-antennal primordium. I also conclude that ey is activated by Toy in the eye-antennal primordium.

    The strong eyD mutation was molecularly characterized and it was finally settled that it is an allele in the ey locus. I also show that eyD homozygotes have a headless phenotype, much stronger than the earlier ey mutations.

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  • 99.
    Kunz, Sabine
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Pesquet, Edouard
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Kleczkowski, Leszek A.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Functional Dissection of Sugar Signals Affecting Gene Expression in Arabidopsis thaliana2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e100312-Article in journal (Refereed)
    Abstract [en]

    Background: Sugars modulate expression of hundreds of genes in plants. Previous studies on sugar signaling, using intact plants or plant tissues, were hampered by tissue heterogeneity, uneven sugar transport and/or inter-conversions of the applied sugars. This, in turn, could obscure the identity of a specific sugar that acts as a signal affecting expression of given gene in a given tissue or cell-type. Methodology/Principal Findings: To bypass those biases, we have developed a novel biological system, based on stem-cell-like Arabidopsis suspension culture. The cells were grown in a hormone-free medium and were sustained on xylose as the only carbon source. Using functional genomics we have identified 290 sugar responsive genes, responding rapidly (within 1 h) and specifically to low concentration (1 mM) of glucose, fructose and/or sucrose. For selected genes, the true nature of the signaling sugar molecules and sites of sugar perception were further clarified using non-metabolizable sugar analogues. Using both transgenic and wild-type A. thaliana seedlings, it was shown that the expression of selected sugar-responsive genes was not restricted to a specific tissue or cell type and responded to photoperiod-related changes in sugar availability. This suggested that sugar-responsiveness of genes identified in the cell culture system was not biased toward heterotrophic background and resembled that in whole plants. Conclusions: Altogether, our research strategy, using a combination of cell culture and whole plants, has provided an unequivocal evidence for the identity of sugar-responsive genes and the identity of the sugar signaling molecules, independently from their inter-conversions or use for energy metabolism.

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  • 100.
    Kuzhandaivel, Anujaianthi
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Schultz, Sebastian W.
    Linköpings universitet, Avdelningen för cellbiologi.
    Alkhori, Liza
    Linköpings universitet, Avdelningen för cellbiologi.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    Cilia-Mediated Hedgehog Signaling in Drosophila2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 7, no 3, p. 672-680Article in journal (Refereed)
    Abstract [en]

    Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates.

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