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  • 101.
    Bin Kaderi, Mohamed Arifin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Hematology and Immunology.
    Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL.

    In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL.

    In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results.

    In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.

  • 102. Bjorkegren, Johan L. M.
    et al.
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Talukdar, Husain A.
    Asl, Hassan Foroughi
    Jain, Rajeev K.
    Cedergren, Cecilia
    Shang, Ming-Mei
    Rossignoli, Aranzazu
    Takolander, Rabbe
    Melander, Olle
    Hamsten, Anders
    Michoel, Tom
    Skogsberg, Josefin
    Plasma Cholesterol-Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis2014In: PLOS Genetics, ISSN 1553-7404, Vol. 10, no 2, e100420- p.Article in journal (Refereed)
    Abstract [en]

    Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (>= 80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob(100/100)Mttp(flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions. Author Summary The main underlying cause of heart attacks and strokes is atherosclerosis. One strategy to prevent these often deadly clinical events is therefore either to slow atherosclerosis progression or better, induce regression of atherosclerotic plaques making them more stable. Plasma cholesterol lowering (PCL) is the most efficient way to induce atherosclerosis regression but sometimes fails to do so. In our study, we used a mouse model with elevated LDL cholesterol levels, similar to humans who develop early atherosclerosis, and a genetic switch to lower plasma cholesterol at any time during atherosclerosis progression. In this model, we examined atherosclerosis gene expression and regression in response to PCL at three different stages of atherosclerosis progression. PCL led to complete regression in mice with early lesions but was incomplete in mice with mature and advanced lesions, indicating that early prevention with PCL in individuals with increased risk for heart attack or stroke would be particularly useful. In addition, by inferring PCL-responsive gene networks in early, mature and advanced atherosclerotic lesions, we identified key drivers specific for regression of early (PPARG), mature (MLL5) and advanced (SRSF10/XRN2) atherosclerosis. These key drivers should be interesting therapeutic targets to enhance PCL-mediated regression of atherosclerosis.

  • 103. Bjursell, Magnus K.
    et al.
    Blom, Henk J.
    Cayuela, Jordi Asin
    Engvall, Martin L.
    Lesko, Nicole
    Balasubramaniam, Shanti
    Brandberg, Goran
    Halldin, Maria
    Falkenberg, Maria
    Jakobs, Cornelis
    Smith, Desiree
    Struys, Eduard
    von Dobeln, Ulrika
    Gustafsson, Claes M.
    Lundeberg, Joakim
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Biotechnology (BIO), Gene Technology.
    Wedell, Anna
    Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 89, no 4, 507-515 p.Article in journal (Refereed)
    Abstract [en]

    Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (Ado Met), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.

  • 104. Björkesten, Johan
    et al.
    chen, lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Landegren, Ulf
    Rolling Circle Amplification (RCA) Reporters – a new generic tool for the detection of DNA, RNA and proteinsManuscript (preprint) (Other academic)
    Abstract [en]

    Many methods to detect biomolecules with rolling circle amplification (RCA), for example padlock probes and proximity ligation assay (PLA), are tedious and includes several reaction steps combined with long incubation times. The present investigation evaluates a new tool to be included in the toolbox of RCA based detection methods that we refer to as RCA Reporter. The main idea with the RCA Reporter is to use pre-ligated circles protected from RCA initiation by almost entire hybridization to a protector molecule that unlocks through a well characterized and highly specific strand displacement process. The RCA Reporters are a generic tool that can be used to directly detect ssDNA or RNA in a sample, to detect proteins via coupling to proximity recognition using a pair of antibodies or to further amplify ongoing RCA reactions. The latter can be used to allow for efficient digital readout of single molecules via flow cytometry with the potential to develop simple and highly accurate molecular counting assays.

  • 105.
    Blomstergren, Anna
    et al.
    KTH, Superseded Departments, Biotechnology.
    Lundin, A.
    Nilsson, C.
    Engstrand, L.
    Lundeberg, Joakim
    KTH, Superseded Departments, Biotechnology.
    Comparative analysis of the complete cag pathogenicity island sequence in four Helicobacter pylori isolates2004In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 328, 85-93 p.Article in journal (Refereed)
    Abstract [en]

    The cytotoxin-associated gene (cag) pathogenicity island (PAI) is important for the virulence of Helicobacter pylori. In this study, we have compared the complete nucleotide sequence of the cag PAI in four clinical isolates. These isolates were selected from patients matched for age and sex from the same geographical region. The patients suffered from either gastric cancer (Ca52 and Ca73) or duodenal ulcer (Du23:2 and Du52:2). All four strains induced an interleukin (IL)-8 response in AGS cells and translocated CagA into host cells where the protein was tyrosine phosphorylated, and thus harboured a functional type W secretion system encoded by the cag PAL The cagA gene contains a variable region close to its 3' end. Different compositions of this region has been proposed to exert various degrees of morphological changes in cultured gastric epithelial cells, and there are indications that the structure of the repetitive region is connected to the severity of disease. One of the studied strains (Du23:2) possessed five Westem-type repeat regions while the other three strains harboured one Western-type repeat. Strain Du23:2 also contained a major rearrangement or large insertion/ duplication in the intergenic region between HP0546 and HP0547 (cagA). Sequence similar to that of genes HP0510 and HP0509 was found in the 5' end of this region. The 3' end was-similar to the corresponding region of strain ATCC 43504, including a mini IS605 element and a duplication of the 3' end of the cag PAL Finally, a novel gene was identified in the cag PAI in three of the sequenced strains at the position of HP0521. This gene, HP0521B, is present in approximately half of Swedish H. pylori isolates.

  • 106. Bochman, Matthew L
    et al.
    Sabouri, Nasim
    Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA .
    Zakian, Virginia A
    Unwinding the functions of the Pif1 family helicases2010In: DNA Repair, ISSN 1568-7864, E-ISSN 1568-7856, Vol. 9, no 3, 237-249 p.Article in journal (Refereed)
    Abstract [en]

    Helicases are ubiquitous enzymes found in all organisms that are necessary for all (or virtually all) aspects of nucleic acid metabolism. The Pif1 helicase family is a group of 5'-->3' directed, ATP-dependent, super family IB helicases found in nearly all eukaryotes. Here, we review the discovery, evolution, and what is currently known about these enzymes in Saccharomyces cerevisiae (ScPif1 and ScRrm3), Schizosaccharomyces pombe (SpPfh1), Trypanosoma brucei (TbPIF1, 2, 5, and 8), mice (mPif1), and humans (hPif1). Pif1 helicases variously affect telomeric, ribosomal, and mitochondrial DNA replication, as well as Okazaki fragment maturation, and in at least some cases affect these processes by using their helicase activity to disrupt stable nucleoprotein complexes. While the functions of these enzymes vary within and between organisms, it is evident that Pif1 family helicases are crucial for both nuclear and mitochondrial genome maintenance.

  • 107.
    Bodare, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Ravikanth, Gudasalamani
    Ashoka Trust Res Ecol & Environm, Bangalore 560064, Karnataka, India.;Univ Agr Sci, Sch Ecol & Conservat, Bangalore 560065, Karnataka, India..
    Ismail, Sascha A.
    Swiss Fed Inst Technol, Dept Environm Syst Sci, Ecosyst Management, Univ Str 16, CH-8092 Zurich, Switzerland..
    Patel, Mohana Kumara
    Univ Agr Sci, Sch Ecol & Conservat, Bangalore 560065, Karnataka, India..
    Spanu, Ilaria
    CNR, Inst Biosci & Bioresources, Via Madonna del Piano 10, I-50019 Florence, Italy..
    Vasudeva, Ramesh
    Univ Agr Sci, Dept Forest Biol, Coll Forestry, Sirsi 581401, Karnataka, India..
    Shaanker, Ramanan Uma
    Ashoka Trust Res Ecol & Environm, Bangalore 560064, Karnataka, India.;Univ Agr Sci, Sch Ecol & Conservat, Bangalore 560065, Karnataka, India.;Univ Agr Sci, Dept Crop Physiol, Bangalore 560065, Karnataka, India..
    Vendramin, Giovanni Giuseppe
    CNR, Inst Biosci & Bioresources, Via Madonna del Piano 10, I-50019 Florence, Italy..
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Tsuda, Yoshiaki
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Univ Tsukuba, Sugadaira Montane Res Ctr, 1278-294 Sugadairakogen, Ueda, Nagano 3862204, Japan..
    Fine- and local- scale genetic structure of Dysoxylum malabaricum, a late-successional canopy tree species in disturbed forest patches in the Western Ghats, India2017In: Conservation Genetics, ISSN 1566-0621, E-ISSN 1572-9737, Vol. 18, no 1, 1-15 p.Article in journal (Refereed)
    Abstract [en]

    Dysoxylum malabaricum (white cedar) is an economically important tree species, endemic to the Western Ghats, India, which is the world's most densely populated biodiversity hotspot. In this study, we used variation at ten nuclear simple sequence repeat loci to investigate genetic diversity and fine scale spatial genetic structure (FSGS) in seedlings and adults of D. malabaricum from four forest patches in the northern part of the Western Ghats. When genetic variation was compared between seedlings and adults across locations, significant differences were detected in allelic richness, observed heterozygosity, fixation index (F (IS)), and relatedness (P < 0.05). Reduced genetic diversity and increased relatedness at the seedling stage might be due to fragmentation and disturbance. There was no FSGS at the adult stage and FSGS was limited to shorter distance classes at the seedling stage. However, there was clear spatial genetic structure at the landscape level (< 50 km), regardless of age class, due to limited gene flow between forest patches. A comparison of the distributions of size classes in the four locations with published data from a more southern area, showed that large trees (diameter at breast height, DBH, > 130 cm) are present in the southern sacred forests but not in the northern forest reserves. This pattern is likely due to stronger harvesting pressure in the north compared to the south, because in the north there are no cultural taboos regulating the extraction of natural resources. The implications for forest conservation in this biodiversity hotspot are discussed.

  • 108.
    Boija, Ann
    et al.
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Holmqvist, Per-Henrik
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå, Sweden.
    Zare, Aman
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå, Sweden.
    Meyers, David J.
    Dept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Cole, Philip A.
    Dept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Mannervik, Mattias
    Dept. of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, SwedenDept. Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
    Drosophila CBP cooperates with GAGA factor to induce high levels of Pol II promoter-proximal pausingManuscript (preprint) (Other academic)
  • 109.
    Bolund, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Hayward, Adam
    Pettay, Jenni E.
    Lummaa, Virpi
    Effects of the demographic transition on the genetic variances and covariances of human life-history traits2015In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 69, no 3, 747-755 p.Article in journal (Refereed)
    Abstract [en]

    The recent demographic transitions to lower mortality and fertility rates in most human societies have led to changes and even quick reversals in phenotypic selection pressures. This can only result in evolutionary change if the affected traits are heritable, but changes in environmental conditions may also lead to subsequent changes in the genetic variance and covariance (the G matrix) of traits. It currently remains unclear if there have been concomitant changes in the G matrix of life-history traits following the demographic transition. Using 300 years of genealogical data from Finland, we found that four key life-history traits were heritable both before and after the demographic transition. The estimated heritabilities allow a quantifiable genetic response to selection during both time periods, thus facilitating continued evolutionary change. Further, the G matrices remained largely stable but revealed a trend for an increased additive genetic variance and thus evolutionary potential of the population after the transition. Our results demonstrate the validity of predictions of evolutionary change in human populations even after the recent dramatic environmental change, and facilitate predictions of how our biology interacts with changing environments, with implications for global public health and demography.

  • 110.
    Bolund, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Lummaa, V.
    Univ Turku, Dept Biol, Turku, Finland..
    The effects of resource availability and the demographic transition on the genetic correlation between number of children and grandchildren in humans2017In: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 118, no 2, 186-192 p.Article in journal (Refereed)
    Abstract [en]

    Studies of evolutionary change require an estimate of fitness, and lifetime reproductive success is widely used for this purpose. However, many species face a trade-off between the number and quality of offspring and in such cases number of grandoffspring may better represent the genetic contribution to future generations. Here, we apply quantitative genetic methods to a genealogical data set on humans from Finland to address how the genetic correlation between number of children and grandchildren is influenced by the severity of the trade-off between offspring quality and quantity, as estimated by different levels of resource access among individuals in the population. Further, we compare the genetic correlation before and after the demographic transition to low mortality and fertility rates. The genetic correlation was consistently high (0.79-0.92) with the strongest correlations occurring in individuals with higher access to resources and before the demographic transition, and a tendency for lower correlations in resource poor individuals and after the transition. These results indicate that number of grandoffspring is a slightly better predictor of long-term genetic fitness than number of offspring in a human population across a range of environmental conditions, and more generally, that patterns of resource availability need to be taken into account when estimating genetic covariances with fitness.

  • 111. Bond, Brian C
    et al.
    Virley, David J
    Cairns, Nigel J
    Hunter, A Jackie
    Moore, Gary B T
    Moss, Stephen J
    Mudge, Anne W
    Walsh, Frank S
    Jazin, Elena
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Preece, Paul
    The quantification of gene expression in an animal model of brain ischaemia using TaqMan real-time RT-PCR.2002In: Brain Res Mol Brain Res, ISSN 0169-328X, Vol. 106, no 1-2, 101-16 p.Article in journal (Other scientific)
  • 112.
    Borg, Malin
    Södertörn University, School of Life Sciences.
    Does eutrophication cause directional genetic selection in three-spined stickleback (Gasterosteus aculeatus)?: A study of multiple Baltic Sea populations.2011Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Human-induced eutrophication is indirectly affecting aquatic organisms by altering their environment. This brings on altered selective pressures and could thereby cause changes in the genetic composition of exposed populations. Since anthropogenic environmental changes are usually occurring at a much higher rate than naturally occurring changes, they force populations to adapt to the new conditions faster than normal. Here, I have studied populations of three-spined sticklebacks (Gasterosteus aculeatus) from four eutrophicated and four adjacent reference sites, along the coast of Finland, to investigate if this species has responded genetically to the human-induced eutrophication of the Baltic Sea. For this purpose I used amplified fragment length polymorphism (AFLP) and found distinctions in genetic composition between the two habitats, as well as similarities between populations from eutrophicated sites. This suggests a similar genetic response to eutrophicated conditions by stickleback populations from different geographical areas. Moreover I found a distinct geographic structure among three-spined sticklebacks in the Baltic Sea.

  • 113.
    Borg, Malin
    Södertörn University, School of Life Sciences.
    Does eutrophication cause directional genetic selection in three-spined sticklebacks (Gasterosteus aculeatus)?: A study of multiple Baltic Sea populations2011Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Human-induced eutrophication is indirectly affecting aquatic organisms by altering their environment. This brings on altered selective pressures and could thereby cause changes in the genetic composition of exposed populations. Since anthropogenic environmental changes are usually occurring at a much higher rate than naturally occurring changes, they force populations to adapt to the new conditions faster than normal. Here, I have studied populations of three-spined sticklebacks (Gasterosteus aculeatus) from four eutrophicated and four adjacent reference sites, along the coast of Finland, to investigate if this species has responded genetically to the human-induced eutrophication of the Baltic Sea. For this purpose I used amplified fragment length polymorphism (AFLP) and found distinctions in genetic composition between the two habitats, as well as similarities between populations from eutrophicated sites. This suggests a similar genetic response to eutrophicated conditions by stickleback populations from different geographical areas. Moreover I found a distinct geographic structure among three-spined sticklebacks in the Baltic Sea.

  • 114.
    Bornelöv, Susanne
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England..
    Seroussi, Eyal
    Agr Res Org, Volcani Ctr, Rishon Leziyyon, Israel..
    Yosefi, Sara
    Agr Res Org, Volcani Ctr, Rishon Leziyyon, Israel..
    Pendavis, Ken
    Univ Arizona, Coll Agr & Life Sci, Tucson, AZ 85721 USA..
    Burgess, Shane C.
    Univ Arizona, Coll Agr & Life Sci, Tucson, AZ 85721 USA..
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Friedman-Einat, Miriam
    Agr Res Org, Volcani Ctr, Rishon Leziyyon, Israel..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    Correspondence on Lovell et al.: identification of chicken genes previously assumed to be evolutionarily lost2017In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 18, 112Article in journal (Refereed)
    Abstract [en]

    Through RNA-Seq analyses, we identified 137 genes that are missing in chicken, including the long-sought-after nephrin and tumor necrosis factor genes. These genes tended to cluster in GC-rich regions that have poor coverage in genome sequence databases. Hence, the occurrence of syntenic groups of vertebrate genes that have not been observed in Aves does not prove the evolutionary loss of such genes.

  • 115. Bosley, Katrine S
    et al.
    Botchan, Michael
    Bredenoord, Annelien L
    Carroll, Dana
    Charo, R Alta
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Cohen, Ron
    Corn, Jacob
    Doudna, Jennifer
    Feng, Guoping
    Greely, Henry T
    Isasi, Rosario
    Ji, Weihzi
    Kim, Jin-Soo
    Knoppers, Bartha
    Lanphier, Edward
    Li, Jinsong
    Lovell-Badge, Robin
    Martin, G Steven
    Moreno, Jonathan
    Naldini, Luigi
    Pera, Martin
    Perry, Anthony C F
    Venter, J Craig
    Zhang, Feng
    Zhou, Qi
    CRISPR germline engineering--the community speaks.2015In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 33, no 5, 478-486 p.Article in journal (Refereed)
  • 116.
    Boughman, Janette W.
    et al.
    Michigan State Univ, Dept Integrat Biol, E Lansing, MI 48824 USA..
    Svanbäck, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Synergistic selection between ecological niche and mate preference primes diversification2017In: Evolution, ISSN 0014-3820, E-ISSN 1558-5646, Vol. 71, no 1, 6-22 p.Article in journal (Refereed)
    Abstract [en]

    The ecological niche and mate preferences have independently been shown to be important for the process of speciation. Here, we articulate a novel mechanism by which ecological niche use and mate preference can be linked to promote speciation. The degree to which individual niches are narrow and clustered affects the strength of divergent natural selection and population splitting. Similarly, the degree to which individual mate preferences are narrow and clustered affects the strength of divergent sexual selection and assortative mating between diverging forms. This novel perspective is inspired by the literature on ecological niches; it also explores mate preferences and how they may contribute to speciation. Unlike much comparative work, we do not search for evolutionary patterns using proxies for adaptation and sexual selection, but rather we elucidate how ideas from niche theory relate to mate preference, and how this relationship can foster speciation. Recognizing that individual and population niches are conceptually and ecologically linked to individual and population mate preference functions will significantly increase our understanding of rapid evolutionary diversification in nature. It has potential to help solve the difficult challenge of testing the role of sexual selection in the speciation process. We also identify ecological factors that are likely to affect individual niche and individual mate preference in synergistic ways and as a consequence to promote speciation. The ecological niche an individual occupies can directly affect its mate preference. Clusters of individuals with narrow, differentiated niches are likely to have narrow, differentiated mate preference functions. Our approach integrates ecological and sexual selection research to further our understanding of diversification processes. Such integration may be necessary for progress because these processes seem inextricably linked in the natural world.

  • 117. Brace, Selina
    et al.
    Thomas, Jessica A.
    Dalén, Love
    Swedish Museum of Natural History, Department of Bioinformatics and Genetics.
    Burger, Joachim
    MacPhee, Ross D. E.
    Barnes, Ian
    Turvey, Samuel T.
    Evolutionary History of the Nesophontidae, the Last Unplaced Recent Mammal Family2016In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 33, no 12, 3095-3103 p.Article in journal (Refereed)
    Abstract [en]

    The mammalian evolutionary tree has lost several major clades through recent human-caused extinctions. This process of historical biodiversity loss has particularly affected tropical island regions such as the Caribbean, an area of great evolutionary diversification but poor molecular preservation. The most enigmatic of the recently extinct endemic Caribbean mammals are the Nesophontidae, a family of morphologically plesiomorphic lipotyphlan insectivores with no consensus on their evolutionary affinities, and which constitute the only major recent mammal clade to lack any molecular information on their phylogenetic placement. Here, we use a palaeogenomic approach to place Nesophontidae within the phylogeny of recent Lipotyphla. We recovered the near-complete mitochondrial genome and sequences for 17 nuclear genes from a similar to 750-year-old Hispaniolan Nesophontes specimen, and identify a divergence from their closest living relatives, the Solenodontidae, more than 40 million years ago. Nesophontidae is thus an older distinct lineage than many extant mammalian orders, highlighting not only the role of island systems as "museums" of diversity that preserve ancient lineages, but also the major human-caused loss of evolutionary history.

  • 118.
    Brandis, Gerrit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The Selective Advantage of Synonymous Codon Usage Bias in Salmonella2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 3, e1005926Article in journal (Refereed)
    Abstract [en]

    The genetic code in mRNA is redundant, with 61 sense codons translated into 20 different amino acids. Individual amino acids are encoded by up to six different codons but within codon families some are used more frequently than others. This phenomenon is referred to as synonymous codon usage bias. The genomes of free-living unicellular organisms such as bacteria have an extreme codon usage bias and the degree of bias differs between genes within the same genome. The strong positive correlation between codon usage bias and gene expression levels in many microorganisms is attributed to selection for translational efficiency. However, this putative selective advantage has never been measured in bacteria and theoretical estimates vary widely. By systematically exchanging optimal codons for synonymous codons in the tuf genes we quantified the selective advantage of biased codon usage in highly expressed genes to be in the range 0.2–4.2 x 10−4 per codon per generation. These data quantify for the first time the potential for selection on synonymous codon choice to drive genome-wide sequence evolution in bacteria, and in particular to optimize the sequences of highly expressed genes. This quantification may have predictive applications in the design of synthetic genes and for heterologous gene expression in biotechnology.

  • 119. Brattås, Per Ludvik
    et al.
    Jönsson, Marie E.
    Fasching, Liana
    Nelander Wahlestedt, Jenny
    Shahsavani, Mansoureh
    Falk, Ronny
    Falk, Anna
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Parmar, Malin
    Jakobsson, Johan
    TRIM28 Controls a Gene Regulatory Network Based on Endogenous Retroviruses in Human Neural Progenitor Cells2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 1, 1-11 p.Article in journal (Refereed)
    Abstract [en]

    Endogenous retroviruses (ERVs), which make up 8% of the human genome, have been proposed to participate in the control of gene regulatory networks. In this study, we find a region- and developmental stage-specific expression pattern of ERVs in the developing human brain, which is linked to a transcriptional network based on ERVs. We demonstrate that almost 10,000, primarily primate-specific, ERVs act as docking platforms for the co-repressor protein TRIM28 in human neural progenitor cells, which results in the establishment of local heterochromatin. Thereby, TRIM28 represses ERVs and consequently regulates the expression of neighboring genes. These results uncover a gene regulatory network based on ERVs that participates in control of gene expression of protein-coding transcripts important for brain development.

  • 120.
    Breed, Martin
    et al.
    Australian Centre for Evolutionary Biology and Biodiversity (ACEBB) and School of Earth and Environmental Sciences, University of Adelaide.
    Gardner, Michael G.
    Ottewell, Kym M.
    Navarro, Carlos M.
    Lowe, Andrew J.
    Shifts in reproductive assurance strategies and inbreeding costs associated with habitat fragmentation in Central American mahogany2012In: Ecology Letters, ISSN 1461-023X, E-ISSN 1461-0248, Vol. 15, no 5, 444-452 p.Article in journal (Refereed)
    Abstract [en]

    The influence of habitat fragmentation on mating patterns and progeny fitness in trees is critical for understanding the long-term impact of contemporary landscape change on the sustainability of biodiversity. We examined the relationship between mating patterns, using microsatellites, and fitness of progeny, in a common garden trial, for the insect-pollinated big-leaf mahogany, Swietenia macrophylla King, sourced from forests and isolated trees in 16 populations across Central America. As expected, isolated trees had disrupted mating patterns and reduced fitness. However, for dry provenances, fitness was negatively related to correlated paternity, while for mesic provenances, fitness was correlated positively with outcrossing rate and negatively with correlated paternity. Poorer performance of mesic provenances is likely because of reduced effective pollen donor density due to poorer environmental suitability and greater disturbance history. Our results demonstrate a differential shift in reproductive assurance and inbreeding costs in mahogany, driven by exploitation history and contemporary landscape context.

  • 121.
    Brehwens, Karl
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bajinskis, Ainars
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Staaf, Elina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cederwall, Bo
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    A NEW DEVICE TO EXPOSE CELLS TO CHANGING DOSE RATES OF IONISING RADIATION2012In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 148, no 3, 366-371 p.Article in journal (Refereed)
    Abstract [en]

    In many exposure scenarios to ionising radiation, the dose rate is not constant. Despite this, most in vitro studies aimed at investigating the effects of ionising radiation are carried out exposing samples at constant dose rates. Consequently, very little data exist on the biological effects of exposures to changing dose rates. This may be due to technical limitations of standard irradiation facilities, but also to the fact that the importance of research in this area has not been appreciated. We have recently shown that cells exposed to a decreasing dose rate suffer higher levels of cytogenetic damage than do cells exposed to an increasing or a constant dose rate. To further study the effects of changing dose rates, a new device was constructed that permits the exposure of cell samples in tubes, flasks or Petri dishes to changing dose rates of X-rays. This report presents the technical data, performance and dosimetry of this novel device.

  • 122.
    Brikell, Isabell
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Heritability of attention-deficit hyperactivity disorder in adults2015In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 168, no 6, 406-413 p.Article, review/survey (Refereed)
    Abstract [en]

    Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Symptoms often persist into adulthood, with a prevalence of 2.5-5% in adult populations. Twin studies in childhood consistently report high heritabilities of 70-80%, while studies in adult samples show only moderate heritability of 30-40% when estimated from self-ratings. This review summarizes the available research on the heritability of ADHD in adults. Three key findings are outlined: (i) self-ratings lead to relatively low heritability estimates of ADHD, independent of age and whether ratings refer to current or retrospective symptoms; (ii) studies relying on different informants to rate each twin within a pair (i.e., self-ratings and different parents/teachers rating each twin in a pair) consistently yield lower heritability estimates than studies relying on ratings from a single informant; (iii) studies using cross-informant data via either combined parent and self-ratings or clinical diagnoses information suggest that the heritability of ADHD in adults could be as high as 70-80%. Together, the reviewed studies suggest that the previously reported low heritability of ADHD in adults is unlikely to reflect a true developmental change. Instead, the drop in heritability is better explained by rater effects related to a switch from using one rater for both twins in a pair (parent/teacher) in childhood, to relying on self-ratings (where each twin rates themselves) of ADHD symptoms in adulthood. When rater effects are addressed using cross-informant approaches, the heritability of ADHD in adults appears to be comparable to the heritability of ADHD in childhood.

  • 123.
    Brohede, J.
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Arnheim, N.
    Ellegren, H.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Single molecule analysis of the hypermutable tetranucleotide rpeat locus D21S1245 through sperm genotyping:: A heterogeneous pattern of mutation but no clear male age effect.2004In: Molecular Biology and Evolution, no 21, 58-64 p.Article in journal (Refereed)
  • 124. Broushaki, Farnaz
    et al.
    Thomas, Mark G
    Link, Vivian
    López, Saioa
    van Dorp, Lucy
    Kirsanow, Karola
    Hofmanová, Zuzana
    Diekmann, Yoan
    Cassidy, Lara M
    Díez-del-Molino, David
    Kousathanas, Athanasios
    Sell, Christian
    Robson, Harry K
    Martiniano, Rui
    Blöcher, Jens
    Scheu, Amelie
    Kreutzer, Susanne
    Bollongino, Ruth
    Bobo, Dean
    Davoudi, Hossein
    Munoz, Olivia
    Currat, Mathias
    Abdi, Kamyar
    Biglari, Fereidoun
    Craig, Oliver E
    Bradley, Daniel G
    Shennan, Stephen
    Veeramah, Krishna R
    Mashkour, Marjan
    Wegmann, Daniel
    Hellenthal, Garrett
    Burger, Joachim
    Early Neolithic genomes from the eastern Fertile Crescent.2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 353, no 6298Article in journal (Refereed)
    Abstract [en]

    We sequenced Early Neolithic genomes from the Zagros region of Iran (eastern Fertile Crescent), where some of the earliest evidence for farming is found, and identify a previously uncharacterized population that is neither ancestral to the first European farmers nor has contributed substantially to the ancestry of modern Europeans. These people are estimated to have separated from Early Neolithic farmers in Anatolia some 46,000 to 77,000 years ago and show affinities to modern-day Pakistani and Afghan populations, but particularly to Iranian Zoroastrians. We conclude that multiple, genetically differentiated hunter-gatherer populations adopted farming in southwestern Asia, that components of pre-Neolithic population structure were preserved as farming spread into neighboring regions, and that the Zagros region was the cradle of eastward expansion.

  • 125. Brown, Keith S., Jr.
    et al.
    von Schoultz, Barbara
    Saura, Anja O.
    Saura, Anssi
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Chromosomal evolution in the South American Riodinidae (Lepidoptera Papilionoidea)2012In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 149, no 4, 128-138 p.Article in journal (Refereed)
    Abstract [en]

    We give the haploid chromosome numbers of 173 species or subspecies of Riodinidae as well as of 17 species or subspecies of neotropical Lycaenidae for comparison. The chromosome numbers of riodinids have thus far been very poorly known. We find that their range of variation extends from n =?9 to n =?110 but numbers above n =?31 are rare. While lepidopterans in general have stable chromosome numbers, or variation is limited at most a subfamily or genus, the entire family Riodinidae shows variation within genera, tribes and subfamilies with no single modal number. In particular, a stepwise pattern with chromosome numbers that are about even multiples is seen in several unrelated genera. We propose that this variation is attributable to the small population sizes, fragmented populations with little migration, and the behavior of these butterflies. Small and isolated riodinid populations would allow for inbreeding to take place. Newly arisen chromosomal variants could become fixed and contribute to reproductive isolation and speciation. In contrast to the riodinids, the neotropical Lycaenidae (Theclinae and Polyommatinae) conform to the modal n =?24 that characterizes the family.

  • 126.
    Buckland, Philip I.
    et al.
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies, Environmental Archaeology Lab.
    Hammarlund, Dan
    Lund University.
    Hjärthner-Holdar, Eva
    Swedish National Historical Museums.
    Lidén, Kerstin
    Stockholm University.
    Lindahl, Anders
    Lund University.
    Palm, Fredrik
    Umeå University, Faculty of Arts, Humlab.
    Possnert, Göran
    Uppsala University.
    The Strategic Environmental Archaeology Database: a resource for international, multiproxy and transdisciplinary studies of environmental and climatic change2015Conference paper (Refereed)
    Abstract [en]

    Climate and environmental change are global challenges which require global data and infrastructure to investigate. These challenges also require a multi-proxy approach, integrating evidence from Quaternary science and archaeology with information from studies on modern ecology and physical processes among other disciplines. The Strategic Environmental Archaeology Database (SEAD http://www.sead.se) is a Swedish based international research e-infrastructure for storing, managing, analysing and disseminating palaeoenvironmental data from an almost unlimited number of analysis methods. The system currently makes available raw data from over 1500 sites (>5300 datasets) and the analysis of Quaternary fossil insects, plant macrofossils, pollen, geochemistry and sediment physical properties, dendrochronology and wood anatomy, ceramic geochemistry and bones, along with numerous dating methods. This capacity will be expanded in the near future to include isotopes, multi-spectral and archaeo-metalurgical data. SEAD also includes expandable climate and environment calibration datasets, a complete bibliography and extensive metadata and services for linking these data to other resources. All data is available as Open Access through http://qsead.sead.se and downloadable software.

     

    SEAD is maintained and managed at the Environmental Archaeology Lab and HUMlab at Umea University, Sweden. Development and data ingestion is progressing in cooperation with The Laboratory for Ceramic Research and the National Laboratory for Wood Anatomy and Dendrochronology at Lund University, Sweden, the Archaeological Research Laboratory, Stockholm University, the Geoarchaeological Laboratory, Swedish National Historical Museums Agency and several international partners and research projects. Current plans include expanding its capacity to serve as a data source for any system and integration with the Swedish National Heritage Board's information systems.

     

    SEAD is partnered with the Neotoma palaeoecology database (http://www.neotomadb.org) and a new initiative for building cyberinfrastructure for transdisciplinary research and visualization of the long-term human ecodynamics of the North Atlantic funded by the National Science Foundation (NSF).

  • 127.
    Budnjo, Almir
    University of Skövde, School of Bioscience.
    Gene expression of MAP2K1 and Cyclin D1 in BDII rat model of Endometrial cancer2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Endometrial adenocarcinoma (EAC) is the most frequently diagnosed gynecological cancer of the female genital tract in the Western world. Research studies in EC is difficult to conduct on human tumor samples due to the complex nature of tumor arousal and genetic heterogeneousness in the human population. Therefore, inbred animal models can be promising tools to use in EC research due to similar histopathology and pathogenesis as humans. Studies performed on MAP2K1 and CCND1 has shown that their altered expression play a crucial role in carcinogenesis. CCND1 has been demonstrated to have oncogenic properties when overexpressed in human neoplasias.

    The aim of this study is to investigate gene expression levels of MAP2K1 and CCND1 in BDII rat model of endometrial adenocarcinoma cells. Quantitative real-time PCR was used to analyze expression levels of MAP2K1 and CCND1 genes in BDII/Han rat model of endometrial cancer cells using TaqMan approach. The differences in gene expression levels of MAP2K1 and CCND1 between pathologically EAC malignant and nonmalignant cells showed an upregulation of MAP2K1 and CCND1 in EAC malignant cells. The analyzed data presented observable mean differences between MAP2K1 and CCND1 in several endometrial cell lines that were examined.

    Although no statistical significance was reached, an alteration in gene expression levels in malignant and nonmalignant endometrial cells could be observed. Furthermore, this present study shows observable upregulation of MAP2K1 and CCND1 in endometrial carcinoma cells vs. nonmalignant endometrium cells and encourages further investigation of the role of CCND1 and MAP2K genes in endometrial carcinogenesis.

  • 128.
    Burt, S. Alexandra
    et al.
    Department of Psychology, Michigan State University, 107D Psychology Building, East Lansing, United States .
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Klump, Kelly L
    Department of Psychology, Michigan State University, 107D Psychology Building, East Lansing, United States.
    Additional evidence against shared environmental contributions to attention-deficit/hyperactivity problems2012In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 42, no 5, 711-721 p.Article in journal (Refereed)
    Abstract [en]

    A recent meta-analysis "Burt (Psychol Bull 135:608-637, 2009)" indicated that shared environmental influences (C) do not contribute to Attention-Deficit/Hyperactivity Disorder (ADHD). Unfortunately, the meta-analysis relied almost exclusively on classical twin studies. Although useful in many ways, some of the assumptions of the classical twin model (e.g., dominant genetic and shared environmental influences do not simultaneously influence the phenotype) can artifactually decrease estimates of C. There is thus a need to confirm that dominant genetic influences are not suppressing estimates of C on ADHD. The current study sought to do just this via the use of a nuclear twin family model, which allows researchers to simultaneously model and estimate dominant genetic and shared environmental influences. We examined two independent samples of child twins: 312 pairs from the Michigan State University Twin Registry and 854 pairs from the PrE School Twin Study in Sweden. Shared environmental influences were found to be statistically indistinguishable from zero and to account for less than 5 % of the variance. We conclude that the presence of dominant genetic influences does not account for the absence of C on ADHD.

  • 129. Burwinkel, Barbara
    et al.
    Scott, John W.
    Bührer, Christoph
    van Landeghem, Frank K. H.
    Cox, Gerald F.
    Wilson, Callum J.
    Hardie, D. Grahame
    Kilimann, Manfred W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the γ2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency2005In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 76, no 6, 1034-1049 p.Article in journal (Refereed)
  • 130. Bykova, Natalia V.
    et al.
    Møller, Ian M.
    Gardeström, Per
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Igamberdiev, Abir U.
    The function of glycine decarboxylase complex is optimized to maintain high photorespiratory flux via buffering of its reaction products2014In: Mitochondrion (Amsterdam. Print), ISSN 1567-7249, E-ISSN 1872-8278, Vol. 19, 357-364 p.Article in journal (Refereed)
    Abstract [en]

    Oxidation of glycine in photorespiratory pathway is the major flux through mitochondria of C3 plants in the light. It sustains increased intramitochondrial concentrations of NADH and NADPH, which are required to engage the internal rotenone-insensitive NAD(P)H dehydrogenases and the alternative oxidase. We discuss here possible mechanisms of high photorespiratory flux maintenance in mitochondria and suggest that it is fulfilled under conditions where the concentrations of glycine decarboxylase reaction products NADH and CO2 achieve an equilibrium provided by malate dehydrogenase and carbonic anhydrase, respectively. This results in the removal of these products from the glycine decarboxylase multienzyme active sites and in the maintenance of their concentrations at levels sufficiently low to prevent substrate inhibition of the reaction. 

  • 131.
    Bærholm Schnell, Ida
    et al.
    Centre for GeoGenetics, Natural History Museum of Denmark,.
    Fraser, Magdalena
    Gotland University, School of Culture, Energy and Environment.
    Willerslev, Eske
    Centre for GeoGenetics, Natural History Museum of Denmark,.
    Gilbert, M. Thomas P.
    Centre for GeoGenetics, Natural History Museum of Denmark,.
    Characterisation of insect and plant origins using DNA extracted from small volumes of bee honey2010In: Arthropod-Plant Interactions, ISSN 1872-8855, Vol. 4, no 2, 107-116 p.Article in journal (Refereed)
    Abstract [en]

    A DNA-based tool was validated that potentially enables the characterisation of both plant and insect of origin of small (approximately 1 ml) samples of bee honey. Using this method, mitochondrial, nuclear and chloroplast DNA (mtDNA, nuDNA, cpDNA) markers were successfully extracted, PCR amplified, and sequenced from a range of honeys, and the relative amount of plant nuDNA and cpDNA, and bee mtDNA in the samples was quantified using quantitative real-time PCR.

    Short, but taxonomically informative lengths of insect and plant organelle DNA could be routinely recovered from all honey samples tested, and longer organelle, and nuclear DNA sequences can be recovered from many. The data also enabled preliminary characterisation of the quality of these different DNA sources in honey. Although the absolute quantity of the different genetic markers varied considerably between sample, a general trend was observed of insect mtDNA dominating over plant organelle DNA, and with plant nuclear DNA at the lowest levels. Furthermore there was a clear correlation between the plant DNA content and the success of the PCR assays. To maximise successful characterisation of samples, future studies are recommended to focus on the use of organelle markers, and limit the size of PCR amplicons targeted, although with appropriate sample selection and assay optimisation, other approaches may be possible.

  • 132.
    Bélteky, Johan
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Chicken domestication: Effects of tameness on brain gene expression and DNA methylation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Domestication greatly increases phenotypic variation in a short time span, with selection for a single phenotype and a plethora of associated phenotypic changes as an outcome of the process. The domestication process influences the underlying genomic architecture of a species, and the success and speed of the process is likely influenced by it. The main aims of my thesis was to study how domestication affects the brain of chickens: specifically changes in morphology, gene expression, and DNA methylation. Differences in gene expression and DNA methylation between White Leghorn and Red Junglefowl chickens were mapped, and inheritance of these patterns were quantified, indicating a faithful transmission of breed-specific epigenetic markers. Selection on the behavioral trait fearfulness, generated high and low fearful lines of Red Junglefowl. Both the parental population and the fifth selected generation were used for the analyses in this thesis. One experiment studied morphological changes in the brain and other vital organs, and found that relative total brain size increased in high fearful birds, as a consequence of an increase in cerebral hemisphere size in high fearful birds and not in low fearful birds. Also, the relative heart, liver, spleen and testis size increased in high fearful birds, indicating correlated morphological changes with selection for fearfulness. Two additional experiments examined differential gene expression in the hypothalamus and the anterior cerebral hemisphere. The hypothalamus differed in expression of genes with reproductive and immunological functions, whilst the cerebral hemisphere differed in expression of genes related to social behaviors and neurological functions especially those upregulated in low fearful birds.  These results indicate the occurrence of tissue- and species-specific changes in gene expression as overlap with other domestication events were nearly nonexistent. A fourth experiment sought to associate the change in fear levels and gene expression differences with DNA methylation. Chromosomal regions with differential DNA methylation between high and low fearful birds were identified, and genes in these regions had annotated functions relevant to phenotypic differences between the selection lines. This thesis is the first to study the genetic alterations of domestication using the wild ancestor of an already domesticated species to repeat the domestication process selecting against fear of humans. The findings corroborate results from previous comparisons of wild and domestic animals, and further support the theory that rigorous selection for a behavioral trait can cause a cascade of genetic and epigenetic changes facilitating the domestication of a population.

  • 133.
    Bürglin, Thomas R.
    Södertörn University, School of Life Sciences.
    Evolution of hedgehog and hedgehog-related genes, their origin from Hog proteins in ancestral eukaryotes and discovery of a novel Hint motif2008In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, 127- p.Article in journal (Refereed)
    Abstract [en]

    Background: The Hedgehog (Hh) signaling pathway plays important roles in human and animal development as well as in carcinogenesis. Hh molecules have been found in both protostomes and deuterostomes, but curiously the nematode Caenorhabditis elegans lacks a bona-fide Hh. Instead a series of Hh-related proteins are found, which share the Hint/Hog domain with Hh, but have distinct N-termini. Results: We performed extensive genome searches such as the cnidarian Nematostella vectensis and several nematodes to gain further insights into Hh evolution. We found six genes in N. vectensis with a relationship to Hh: two Hh genes, one gene with a Hh N-terminal domain fused to a Willebrand factor type A domain (VWA), and three genes containing Hint/Hog domains with distinct novel N-termini. In the nematode Brugia malayi we find the same types of hh-related genes as in C. elegans. In the more distantly related Enoplea nematodes Xiphinema and Trichinella spiralis we find a bona-fide Hh. In addition, T. spiralis also has a quahog gene like C. elegans, and there are several additional hh-related genes, some of which have secreted N-terminal domains of only 15 to 25 residues. Examination of other Hh pathway components revealed that T. spiralis - like C. elegans - lacks some of these components. Extending our search to all eukaryotes, we recovered genes containing a Hog domain similar to Hh from many different groups of protists. In addition, we identified a novel Hint gene family present in many eukaryote groups that encodes a VWA domain fused to a distinct Hint domain we call Vint. Further members of a poorly characterized Hint family were also retrieved from bacteria. Conclusion: In Cnidaria and nematodes the evolution of hh genes occurred in parallel to the evolution of other genes that contain a Hog domain but have different N-termini. The fact that Hog genes comprising a secreted N-terminus and a Hog domain are found in many protists indicates that this gene family must have arisen in very early eukaryotic evolution, and gave rise eventually to hh and hh-related genes in animals. The results indicate a hitherto unsuspected ability of Hog domain encoding genes to evolve new N-termini. In one instance in Cnidaria, the Hh N-terminal signaling domain is associated with a VWA domain and lacks a Hog domain, suggesting a modular mode of evolution also for the N-terminal domain. The Hog domain proteins, the inteins and VWA-Vint proteins are three families of Hint domain proteins that evolved in parallel in eukaryotes.

  • 134.
    Camus, M. Florencia
    et al.
    Monash Univ, Sch Biol Sci, Clayton, Vic 3800, Australia..
    Wolf, Jochen B. W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Morrow, Edward H.
    Univ Sussex, Sch Life Sci, Brighton BN1 9QG, E Sussex, England..
    Dowling, Damian K.
    Monash Univ, Sch Biol Sci, Clayton, Vic 3800, Australia..
    Single Nucleotides in the mtDNA Sequence Modify Mitochondrial Molecular Function and Are Associated with Sex-Specific Effects on Fertility and Aging2015In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 25, no 20, 2717-2722 p.Article in journal (Refereed)
    Abstract [en]

    Mitochondria underpin energy conversion in eukaryotes. Their small genomes have been the subject of increasing attention, and there is evidence that mitochondrial genetic variation can affect evolutionary trajectories and shape the expression of life-history traits considered to be key human health indicators [1, 2]. However, it is not understood how genetic variation across a diminutive genome, which in most species harbors only about a dozen protein-coding genes, can exert broad-scale effects on the organisnnal phenotype [2, 3]. Such effects are particularly puzzling given that the mitochondrial genes involved are under strong evolutionary constraint and that mitochondrial gene expression is highly conserved across diverse taxa [4]. We used replicated genetic lines in the fruit fly, Drosophila melanogaster, each characterized by a distinct and naturally occurring mitochondrial haplotype placed alongside an isogenic nuclear background. We demonstrate that sequence variation within the mitochondria! DNA (mtDNA) affects both the copy number of mitochondrial genomes and patterns of gene expression across key mitochondrial protein-coding genes. In several cases, haplotype-mediated patterns of gene expression were gene-specific, even for genes from within the same transcriptional units. This invokes post-transcriptional processing of RNA in the regulation of mitochondrial genetic effects on organismal phenotypes. Notably, the haplotype-mediated effects on gene expression could be traced backward to the level of individual nucleotides and forward to sex-specific effects on fertility and longevity. Our study thus elucidates how small-scale sequence changes in the mitochondrial genome can achieve broad-scale regulation of health-related phenotypes and even contribute to sex-related differences in longevity.

  • 135.
    Cardemil, Carina
    Department of Biomaterials, Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
    Effects of antiresorptive agents on inflammation and bone regeneration in different osseous sites - experimental and clinical studies2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The biological mechanisms involved in bone regeneration in osteoporotic bone and the effect of antiresorptive drugs in relation to surgically inserted biomaterials are not fully understood. Improved osseointegration of titanium implants but also adverse effects of antiresorptive therapies, such as osteonecrotic jaw have been described in the literature. The aims of this research project were, firstly, to investigate and to understand the biological events determining bone regeneration and implant integration, after administration of antiresorptive agents; secondly, to determine the cellular and molecular patterns of bone regeneration at implants and synthetic bone substitutes under osteoporotic conditions and, thirdly, to determine how different skeletal sites are affected. The present research included a study of jawbone morphology and gene expression in patients treated with systemic bisphosphonates. When compared to controls, higher gene expression levels of IL-1β was observed in bisphosphonate treated patients with osteonecrosis while bisphosphonate treated patients without necrosis showed lower expression levels of caspase 8, an apoptosis marker involved in the immune response. In ovariectomised rats, zoledronic acid resulted in site-specific differences in the rate of osseointegration and also of gene expression involved in bone healing and regeneration. Strontium-doped calcium phosphate inserted in the rat femur induced lower expression of osteoclastic markers compared to hydroxyapatite and higher bone formation in the periphery of the defects. Whereas major structural changes were demonstrated in the long bones of the ovariectomised rat, less structural alterations were shown in the mandible. However, ovariectomy resulted in lower expression of genes coding for bone formation and angiogenesis in the mandible. In conclusion, the present study shows that the mandible is differently affected by experimentally induced estrogen deficiency than the long bones. Bisphosphonates, administered systemically to estrogen deficient animals, impair osseointegration in the mandible, at least partly related to a downregulation of genes important for the osteogenic process. These observations may have implications for understanding the mechanisms involved in the deranged bone healing observed in the jawbone of bisphosphonate treated patients.

  • 136.
    Cardoso Palacios, Carlos
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Site-specific recombination in P2-like coliphages2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The scope of these studies has been to investigate the site-specific recombination systems of P2-like coliphages, both in an evolutionary perspective by a comparative analysis of related phages as well as in a functional perspective.

    Surveys of P2-like phages in Escherichia coli isolated from nature reveal the existence of seven discrete immunity classes and three integration sites, one of them previously unknown. Phylogenetic analysis of the repressor proteins and other analyses show that homologous recombination plays a role in the appearance of new immunities. Other studies of P2-like prophages from sequenced genomes from public databases show that the P2-like phages grow in different γ-proteobacteria. Based on the type of immunity and site-specific recombination system they can be roughly subdivided in two distinct subgroups and some new host integration sites could be identified. Some of the host attachment sites have a high identity to the sequences in the human genome, making them interesting as potential tools for targeted gene insertions into unmodified human cells.

    The functional studies have been focused on the identification of the determinants for site specificity, which is important for the use of the enzyme for targeted gene insertions into unmodified genomes. Two approaches have been used. In one, we have performed a structure-function analysis of P2 Int that has identified several presumptive residues involved in specific binding to the core sequence, all of them located in the same alpha-helix. This knowledge could be a base for an in vitro evolution of the integrase to enable it to accept new DNA targets with a high affinity. With respect to the excisionases from P2-like coliphages integrating in different sites, we found that they share some common features when they bind and bend to their DNA targets, but there are also significant differences, especially those related to the number of binding sites and the distribution of these and the IHF binding sites in the attP regions. In the other approach we have started to characterize the site-specific recombination system of another P2-like phage, ΦD145, that has a host target with a high identity to a site in the human genome. This looks promising since the human sequence can be used in vivo in E. coli with a rather high efficiency.

  • 137.
    Cardoso-Palacios, Carlos
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sylwan, Lina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mandali, Sridhar
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Frumerie, Clara
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    A structure-function analysis of P2 integraseManuscript (preprint) (Other academic)
    Abstract [en]

    Bacteriophage P2 integrase catalyzes site-specific recombination between the phage DNA and the host chromosome thereby promoting integration or excision of the phage genome. P2 integrase belongs to the large tyrosine family of integrases that shows little sequence identity besides some conserved boxes and patches in the catalytic domain. However, the overall structure of the tyrosine family of integrases seems to be similar. Phage integrases have the potential as tools for site-specific gene insertions into eukaryotic genomes provided that target sequences are available. To elucidate the possibility of evolving the P2 integrase to accept new targets, we have in this work initiated a structure-function analysis of the P2 integrase using two approaches based on a comparison of the predicted secondary structure of P2 integrase with that determined for the lambda integrase. First, we have made hybrids between P2 integrase and the related WΦ integrase that has a different host DNA target, to locate the region promoting specificity between the integrases. This, however, has not been possible, the N-terminal domains can be exchanged without losing biological activity and this will not affect the specificity. All other hybrids made were biological inactive. Next we have made an alanine scanning of the alpha helices believed to be involved in specific interactions with the target, and four amino acids have been identified as candidates for sequence-specific interactions with the core.

  • 138.
    Caren, Helena
    et al.
    University of Gothenburg, Sweden.
    Erichsen, Jennie
    University of Gothenburg, Sweden.
    Olsson, Linda
    University of Gothenburg, Sweden.
    Enerbäck, Charlotta
    University of Gothenburg, Sweden.
    Sjoberg, Rose-Marie
    University of Gothenburg, Sweden.
    Abrahamsson, Jonas
    University of Gothenburg, Sweden.
    Kogner, Per
    Childhood Canc Res Unit, SE-17176 Stockholm, Sweden .
    Martinsson, Tommy
    University of Gothenburg, Sweden.
    High-resolution array copy number analyses for detection of deletion, gain, amplification and copy-neutral LOH in primary neuroblastoma tumors: Four cases of homozygous deletions of the CDKN2A gene2008In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, no 353Article in journal (Refereed)
    Abstract [en]

    Background: Neuroblastoma is a very heterogeneous pediatric tumor of the sympathetic nervous system showing clinically significant patterns of genetic alterations. Favorable tumors usually have near-triploid karyotypes with few structural rearrangements. Aggressive stage 4 tumors often have near-diploid or near-tetraploid karyotypes and structural rearrangements. Whole genome approaches for analysis of genome-wide copy number have been used to analyze chromosomal abnormalities in tumor samples. We have used array-based copy number analysis using oligonucleotide single nucleotide polymorphisms (SNP) arrays to analyze the chromosomal structure of a large number of neuroblastoma tumors of different clinical and biological subsets. Results: Ninety-two neuroblastoma tumors were analyzed with 50 K and/or 250 K SNP arrays from Affymetrix, using CNAG3.0 software. Thirty percent of the tumors harbored 1p deletion, 22% deletion of 11q, 26% had MYCN amplification and 45% 17q gain. Most of the tumors with 1p deletion were found among those with MYCN amplification. Loss of 11q was most commonly seen in tumors without MYCN amplification. In the case of MYCN amplification, two types were identified. One type displayed simple continuous amplicons; the other type harbored more complex rearrangements. MYCN was the only common gene in all cases with amplification. Complex amplification on chromosome 12 was detected in two tumors and three different overlapping regions of amplification were identified. Two regions with homozygous deletions, four cases with CDKN2A deletions in 9p and one case with deletion on 3p (the gene RBMS3) were also detected in the tumors. Conclusion: SNP arrays provide useful tools for high-resolution characterization of significant chromosomal rearrangements in neuroblastoma tumors. The mapping arrays from Affymetrix provide both copy number and allele-specific information at a resolution of 10-12 kb. Chromosome 9p, especially the gene CDKN2A, is subject to homozygous (four cases) and heterozygous deletions (five cases) in neuroblastoma tumors.

  • 139.
    Carlborg, Örjan
    et al.
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Schutz, K
    Jacobsson, L
    Jensen, P
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A global search reveals epistatic interaction between QTL for early growthin the chicken2003In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 13, 413-421 p.Article in journal (Refereed)
  • 140.
    Carlsson, Fredrik
    et al.
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Natural Sciences.
    Koch, Christin
    Edman, Mattias
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Natural Sciences.
    Holm, Svante
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Natural Sciences.
    Testing the probability of finding major decomposing basidiomycetes in logs with T-RFLP - implications for field samplingManuscript (preprint) (Other academic)
    Abstract [en]

    In this article we examine the limitations and potential of T-RFLP for the accurate detection of fungal species in dead wood. We collected cross-sections of decayed logs to evaluate the number of fungal species domains that are likely to be hit when drilling a sawdust sample from a log. We used these estimates to simulate the number of species that would be found using a certain number of samples. We found that in 99% of the simulations, 4 or fewer species would be contained in a sample. Based on these results we tested the probability of detecting two species of wood-decaying basidiomycetes at three different DNA concentration ratios: 1:1, 1:5 and 1:20. An additional experiment was done with 3-5 species. It was possible to detect all species at ratios higher than 1:20 but lower than 1:5; in this range all peaks were easily detected. We were able to detect all species in the mixtures of 3-5 species, with extracts from both pure cultures and wood.

  • 141.
    Carlsson, Fredrik
    et al.
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Natural Sciences.
    Olsson, Jörgen
    Holm, Svante
    Mid Sweden University, Faculty of Science, Technology and Media, Department of Natural Sciences.
    Strong clustering in a SNP study of Phlebiopsis gigantea in swedenManuscript (preprint) (Other academic)
    Abstract [en]

    The population structures of wood decaying basidomycetes depend on several factors; one is dispersal pattern of spores, another is age structure including lifespan and also environmental impacts like forest fires. Phlebiopsis gigantea has been shown to be in the group of basidomycetes that have a well developed tolerance to heat, is long-distance wind dispersed and whose fruit body show up early in succession on fallen logs. In a study of 132 individuals from 3 pairs of locations, 350 km apart, in middle to northern Sweden we used 26 SNP-markers in 6 loci to make a genetic clustering study using STRUCTURE (v. 2.3.4.). The hypothesis; first, clustering should follow the geographic sampling locations with more gene flow between geographically close locations, second; that genetic distance between different clusters should be low due to the long distance dispersal of spores, third; as markers are random we don’t expect to find a correlation between locations affected by forest fires and locations not affected by forest fires. In the study we found 5 clusters (Pr[K= 1]) with moderate to high Fst values (0,0697-03939). Clusters had a poor geographical correlation to sampled populations indicating a complicated population structure. Out of 132 individuals 119 had a private genotype showing a large genetic variation over the total area and a low level of clones in the field.         

  • 142.
    Carneiro, Miguel
    et al.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.;Univ Porto, Fac Ciencias, Dept Biol, P-4169007 Oporto, Portugal..
    Hu, Dou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Archer, John
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal..
    Feng, Chungang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Afonso, Sandra
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal..
    Chen, Congying
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Jiangxi Agr Univ, State Key Lab Pig Genet Improvement & Prod Techno, Nanchang 330045, Jiangxi, Peoples R China..
    Blanco-Aguiar, Jose A.
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.;Inst Invest Recursos Cineget IREC CSIC UCLM JCCM, Ciudad Real 13071, Spain..
    Garreau, Herve
    Univ Toulouse, INRA, Genet Physiol & Syst Elevage UMR1388, F-31326 Castanet Tolosan, France..
    Boucher, Samuel
    FFC, F-75009 Paris, France..
    Ferreira, Paula G.
    Univ Porto, ICBAS, Dept Anat, P-4050343 Oporto, Portugal.;Univ Porto, UMIB, P-4050343 Oporto, Portugal..
    Ferrand, Nuno
    Univ Porto, Ctr Invest Biodiversidade & Recursos Genet, CIBIO InBIO, Campus Agr Vairao, P-4485661 Vairao, Portugal.;Univ Porto, Fac Ciencias, Dept Biol, P-4169007 Oporto, Portugal.;Univ Johannesburg, Fac Sci, Dept Zool, ZA-2006 Auckland Pk, South Africa..
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden.;Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. ETH, Inst Anim Sci, CH-8092 Zurich, Switzerland..
    Dwarfism and Altered Craniofacial Development in Rabbits Is Caused by a 12.1 kb Deletion at the HMGA2 Locus2017In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 205, no 2, 955-965 p.Article in journal (Refereed)
    Abstract [en]

    The dwarf phenotype characterizes the smallest of rabbit breeds and is governed largely by the effects of a single dwarfing allele with an incompletely dominant effect on growth. Dwarf rabbits typically weigh under 1 kg and have altered craniofacial morphology. The dwarf allele is recessive lethal and dwarf homozygotes die within a few days of birth. The dwarf phenotype is expressed in heterozygous individuals and rabbits from dwarf breeds homozygous for the wild-type allele are normal, although smaller when compared to other breeds. Here, we show that the dwarf allele constitutes a similar to 12.1 kb deletion overlapping the promoter region and first three exons of the HMGA2 gene leading to inactivation of this gene. HMGA2 has been frequently associated with variation in body size across species. Homozygotes for null alleles are viable in mice but not in rabbits and probably not in humans. RNA-sequencing analysis of rabbit embryos showed that very few genes (4-29 genes) were differentially expressed among the three HMGA2/dwarf genotypes, suggesting that dwarfism and inviability in rabbits are caused by modest changes in gene expression. Our results show that HMGA2 is critical for normal expression of IGF2BP2, which encodes an RNA-binding protein. Finally, we report a catalog of regions of elevated genetic differentiation between dwarf and normal-size rabbits, including LCORL-NCAPG, STC2, HOXD cluster, and IGF2BP2. Levels and patterns of genetic diversity at the LCORL-NCAPG locus further suggest that small size in dwarf breeds was enhanced by crosses with wild rabbits. Overall, our results imply that small size in dwarf rabbits results from a large effect, loss-of-function (LOF) mutation in HMGA2 combined with polygenic selection.

  • 143. Carneiro, Miguel
    et al.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Di Palma, Federica
    Albert, Frank W.
    Alfoeldi, Jessica
    Barrio, Alvaro Martinez
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rafati, Nima
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sayyab, Shumaila
    Turner-Maier, Jason
    Younis, Shady
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Afonso, Sandra
    Aken, Bronwen
    Alves, Joel M.
    Barrell, Daniel
    Bolet, Gerard
    Boucher, Samuel
    Burbano, Hernan A.
    Campos, Rita
    Chang, Jean L.
    Duranthon, Veronique
    Fontanesi, Luca
    Garreau, Herve
    Heiman, David
    Johnson, Jeremy
    Mage, Rose G.
    Peng, Ze
    Queney, Guillaume
    Rogel-Gaillard, Claire
    Ruffier, Magali
    Searle, Steve
    Villafuerte, Rafael
    Xiong, Anqi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Sarah
    Forsberg-Nilsson, Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Good, Jeffrey M.
    Lander, Eric S.
    Ferrand, Nuno
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rabbit genome analysis reveals a polygenic basis for phenotypic change during domestication2014In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 345, no 6200, 1074-1079 p.Article in journal (Refereed)
    Abstract [en]

    The genetic changes underlying the initial steps of animal domestication are still poorly understood. We generated a high-quality reference genome for the rabbit and compared it to resequencing data from populations of wild and domestic rabbits. We identified more than 100 selective sweeps specific to domestic rabbits but only a relatively small number of fixed (or nearly fixed) single-nucleotide polymorphisms (SNPs) for derived alleles. SNPs with marked allele frequency differences between wild and domestic rabbits were enriched for conserved noncoding sites. Enrichment analyses suggest that genes affecting brain and neuronal development have often been targeted during domestication. We propose that because of a truly complex genetic background, tame behavior in rabbits and other domestic animals evolved by shifts in allele frequencies at many loci, rather than by critical changes at only a few domestication loci.

  • 144. Castelain, Mathieu
    et al.
    Le Hir, Rozenn
    Bellini, Catherine
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    The non-DNA-binding bHLH transcription factor PRE3/bHLH135/ATBS1/TMO7 is involved in the regulation of light signaling pathway in Arabidopsis2012In: Physiologia Plantarum: An International Journal for Plant Biology, ISSN 0031-9317, E-ISSN 1399-3054, Vol. 145, no 3, 450-460 p.Article in journal (Refereed)
    Abstract [en]

    Plant basic Helix-loop-helix (bHLH) proteins are transcription factors that are involved in many developmental mechanisms, including light signaling and hormone homeostasis. Some of them are non-DNA-binding proteins and could act as dominant negative regulators of other bHLH proteins by forming heterodimers, in a similar way to animal inhibitor of DNA-binding proteins. It has been recently reported that several non-DNA-binding bHLHs are involved in light signaling (KDR/PRE6), gibberellic acid signaling (PRE1/BNQ1/bHLH136) or brassinosteroid signaling (ATBS1). Here we report that Arabidopsis lines overexpressing the PRE3/bHLH135/ATBS1/TMO7 gene are less responsive to red, far-red and blue light than wild-type which is likely to explain the light hyposensitive phenotype displayed when grown under white light conditions. Using quantitative polymerase chain reaction, we show that the expression of PRE3 and KDR/PRE6 genes is regulated by light and that light-related genes are deregulated in the PRE3-ox lines. We show that PRE3 is expressed in the shoot and root meristems and that PRE3-ox lines also have a defect in lateral root development. Our results not only suggest that PRE3 is involved in the regulation of light signaling, but also support the hypothesis that non-DNA-binding bHLH genes are promiscuous genes regulating a wide range of both overlapping and specific regulatory pathways.

  • 145.
    Castensson, Anja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Preece, Paul
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    High-resolution quantification of specific mRNA levels in human brain autopsies and biopsies2000In: Genome Research, ISSN 1088-9051, Vol. 10, no 8, 1219-29 p.Article in journal (Refereed)
    Abstract [en]

    Quantification of mRNA levels in human cortical brain biopsies and autopsies was performed using a fluorogenic 5' nuclease assay. The reproducibility of the assay using replica plates was 97%-99%. Relative quantities of mRNA from 16 different genes were evaluated using a statistical approach based on ANCOVA analysis. Comparison of the relative mRNA levels between two groups of samples with different time postmortem revealed unchanged relative expression levels for most genes. Only CYP26A1 mRNA levels showed a significant decrease with prolonged time postmortem (p = 0.00004). Also, there was a general decrease in measured mRNA levels for all genes in autopsies compared to biopsies; however, on comparing mRNA levels after adjusting with reference genes, no significant differences were found between mRNA levels in autopsies and biopsies. This observation indicates that studies of postmortem material can be performed to reveal the relative in vivo mRNA levels of genes. Power calculations were done to determine the number of individuals necessary to detect differences in mRNA levels of 1.5-fold to tenfold using the strategy described here. This analysis showed that samples from at least 50 individuals per group, patients and controls, are required for high-resolution ( approximately twofold changes) differential expression screenings in the human brain. Experiments done on ten individuals per group will result in a resolution of approximately fivefold changes in expression levels. In general, the sensitivity and resolution of any differential expression study will depend on the sample size used and the between-individual variability of the genes analyzed.

  • 146.
    Castensson, Anja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Sundberg, Rolf
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis2003In: Biological Psychiatry, ISSN 0006-3223, Vol. 54, no 11, 1212-1221 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: RNA expression profiling can provide hints for the selection of candidate susceptibility genes, for formulation of hypotheses about the development of a disease, and/or for selection of candidate gene targets for novel drug development. We measured messenger RNA expression levels of 16 candidate genes in brain samples from 55 schizophrenia patients and 55 controls. This is the largest sample so far used to identify genes differentially expressed in schizophrenia brains. METHODS: We used a sensitive real-time polymerase chain reaction methodology and a novel statistical approach, including the development of a linear model of analysis of covariance type. RESULTS: We found two genes differentially expressed: monoamine oxidase B was significantly increased in schizophrenia brain (p =.001), whereas one of the serotonin receptor genes, serotonin receptor 2C, was significantly decreased (p =.001). Other genes, previously proposed to be differentially expressed in schizophrenia brain, were invariant in our analysis. CONCLUSIONS:The differential expression of serotonin receptor 2C is particularly relevant for the development of new atypical antipsychotic drugs. The strategy presented here is useful to evaluate hypothesizes for the development of the disease proposed by other investigators.

  • 147.
    Castensson, Anja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Åberg, Karolina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    McCarthy, Shane
    Saetre, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Andersson, Björn
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Serotonin Receptor 2C (HTR2C) and Schizophrenia: Examination of Possible Medication and Genetic Influences on Expression Levels2005In: American Journal of Medical Genetics, ISSN 0148-7299, Vol. 134B, 84-89 p.Article in journal (Refereed)
    Abstract [en]

    The serotonin receptor 2C (HTR2C) gene is of interest in schizophrenia due to its involvement in regulation of dopamine activity in the prefrontal cortex. We have previously reported a decreased expression of HTR2C mRNA levels in the prefrontal cortex of schizophrenia patients. The variability in mRNA expression levels is evaluated here more closely in relation to promoter haplotypes and neuroleptic treatment received by the patients. The decrease in HTR2C mRNA was present in neuroleptic treated individuals and in patients untreated at death, indicating that the lower expression is not a short-term medication effect. Three promoter polymorphisms were used to construct haplotypes. No SNP displayed genotypic or haplotypic association with the disease. Gene expression of HTR2C was not affected by haplotype and the expression decrease in schizophrenia patients was similar in all haplotype combinations (diplotypes). We conclude that the decrease in HTR2C expression in schizophrenia may be related to the disease mechanism rather than to drug treatment. The disease related changes in HTR2C expression are not related to the promoter variants typed in our sample, but could be due to other regulatory variants or trans-acting factors.

  • 148.
    Castroviejo-Fisher, Santiago
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Skoglund, Pontus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Valadez, Raul
    Laboratorio de Paleozoología, Instituto de Investigaciones Antropológicas, Universidad Nacional Autónoma de México.
    Vilá, Carles
    Conservation and Evolutionary Genetics Group, Estación Biológica de Doñana (EBD-CSIC).
    Leonard, Jennifer A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Vanishing Native American dog lineages2011In: BMC Evolutionary Biology, ISSN 1471-2148, Vol. 11, 73- p.Article in journal (Refereed)
    Abstract [en]

    Background: Dogs were an important element in many native American cultures at the time Europeans arrived. Although previous ancient DNA studies revealed the existence of unique native American mitochondrial sequences, these have not been found in modern dogs, mainly purebred, studied so far.

    Results: We identified many previously undescribed mitochondrial control region sequences in 400 dogs from rural and isolated areas as well as street dogs from across the Americas. However, sequences of native American origin proved to be exceedingly rare, and we estimate that the native population contributed only a minor fraction of the gene pool that constitutes the modern population.

    Conclusions: The high number of previously unidentified haplotypes in our sample suggests that a lot of unsampled genetic variation exists in non-breed dogs. Our results also suggest that the arrival of European colonists to the Americas may have led to an extensive replacement of the native American dog population by the dogs of the invaders.

  • 149. Catania, Francesco
    et al.
    Gao, Xiang
    Scofield, Douglas
    Endogenous Mechanisms for the Origins of Spliceosomal Introns2009In: Journal of Heredity, ISSN 0022-1503, E-ISSN 1465-7333, Vol. 100, no 5, 591-596 p.Article in journal (Refereed)
    Abstract [en]

    Over 30 years since their discovery, the origin of spliceosomal introns remains uncertain. One nearly universally accepted hypothesis maintains that spliceosomal introns originated from self-splicing group-II introns that invaded the uninterrupted genes of the last eukaryotic common ancestor (LECA) and proliferated by “insertion” events. Although this is a possible explanation for the original presence of introns and splicing machinery, the emphasis on a high number of insertion events in the genome of the LECA neglects a considerable body of empirical evidence showing that spliceosomal introns can simply arise from coding or, more generally, nonintronic sequences within genes. After presenting a concise overview of some of the most common hypotheses and mechanisms for intron origin, we propose two further hypotheses that are broadly based on central cellular processes: 1) internal gene duplication and 2) the response to aberrant and fortuitously spliced transcripts. These two nonmutually exclusive hypotheses provide a powerful way to explain the establishment of spliceosomal introns in eukaryotes without invoking an exogenous source.

  • 150. Cavelier, L
    et al.
    Erikson, I
    Tammi, M
    Jalonen, P
    Lindholm, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Smith, P
    Luthman, H
    Gyllensten, U
    MtDNA mutations in maternally inherited diabetes: presence of the 3397 ND1 mutation previously associated with Alzheimer's and Parkinson's disease2001In: Hereditas, ISSN 0018-0661, Vol. 135, no 1, 65-70 p.Article in journal (Refereed)
    Abstract [en]

    Mutations in the mitochondrial tRNA(leu) (UUR) gene have been associated with diabetes mellitus and deafness. We screened for the presence of mtDNA mutations in the tRNA(leu) (UUR) gene and adjacent ND1 sequences in 12 diabetes mellitus pedigrees with a possible maternal inheritance of the disease. One patient carried a G to A substitution at nt 3243 (tRNA(leu) (UUR) gene) in heteroplasmic state. In a second pedigree a patient had an A to G substitution at nt 3397 in the ND1 gene. All maternal relatives of the proband had the 3397 substitution in homoplasmic state. This substitution was not present in 246 nonsymptomatic Caucasian controls. The 3397 substitution changes a highly conserved methionine to a valine at aa 31 and has previously been found in Alzheimer's (AD) and Parkinson's (PD) disease patients. Substitutions in the mitochondrial ND1 gene at aa 30 and 31 have associated with a number of different diseases (e.g. AD/PD, MELAS, cardiomyopathy and diabetes mellitus, LHON, Wolfram-syndrome and maternal inherited diabetes) suggesting that changes at these two codons may be associated with very diverse pathogenic processes. In a further attempt to search for mtDNA mutations outside the tRNAleu gene associated with diabetes, the whole mtDNA genome sequence was determined for two patients with maternally inherited diabetes and deafness. Except for substitutions previously reported as polymorphisms, none of the two patients showed any non-synonymous substitutions either in homoplasmic or heteroplasmic state. These results imply that the maternal inherited diabetes and deafness in these patients must result from alterations of nuclear genes and/or environmental factors.

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