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  • 251.
    Eriksson, Jesper
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Structure-Function Studies of Bacteriophage P2 Integrase and Cox protein2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Probably no group of organisms has been as important as bacteriophages when it comes to the understanding of fundamental biological processes like transcriptional control, DNA replication, site-specific recombination, e.t.c.

    The work presented in this thesis is a contribution towards the complete understanding of these organisms. Two proteins, integrase, and Cox, which are important for the choice of the life mode of bacteriophage P2, are investigated. P2 is a temperate phage, i.e. it can either insert its DNA into the host chromosome (by site-specific recombination) and wait (lysogeny), or it can produce new progeny with the help of the host protein machinery and thereafter lyse the cell (lytic cycle). The integrase protein is necessary for the integration and excision of the phage genome. The Cox protein is involved as a directional factor in the site-specific recombination, where it stimulates excision and inhibits integration. It has been shown that the Cox protein also is important for the choice of the lytic cycle. The choice of life mode is regulated on a transcriptional level, where two mutually exclusive promoters direct whether the lytic cycle (Pe) or lysogeny (Pc) is chosen. The Cox pro-tein has been shown to repress the Pc promoter and thereby making tran-scription from the Pe promoter possible, leading to the lytic cycle. Further, the Cox protein can function as a transcriptional activator on the parasite phage, P4. P4 has gained the ability to adopt the P2 protein machinery to its own purposes.

    In this work the importance of the native size for biologically active integrase and Cox proteins has been determined. Further, structure-function analyses of the two proteins have been performed with focus on the protein-protein interfaces. In addition it is shown that P2 Cox and the P2 relative Wphi Cox changes the DNA topology upon specific binding. From the obtained results a mechanism for P2 Cox-DNA interaction is discussed.

    The results from this thesis can be used in the development of a gene delivery system based on the P2 site-specific recombination system.

  • 252.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hellström, Anders
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sayyab, Shumaila
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    David, Gourichon
    INRA, PEAT, Nouzilly, France.
    Bed'hom, Bertrand
    INRA, AgroParisTech, Animal Genetics and Integrative Biology.
    Tixier-Boichard, Michèle
    INRA, AgroParisTech, Animal Genetics and Integrative Biology.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    A frameshift mutation in COMTD1 specifically dilutes pheomelanin pigmentation in chickenManuscript (preprint) (Other academic)
  • 253.
    Eriksson, Mats
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Moseley, Jeffrey L
    Tottey, Stephen
    Del Campo, Jose A
    Quinn, Jeanette
    Kim, Youngbae
    Merchant, Sabeeha
    Genetic dissection of nutritional copper signaling in chlamydomonas distinguishes regulatory and target genes2004In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 168, no 2, 795-807 p.Article in journal (Refereed)
    Abstract [en]

    A genetic screen for Chlamydomonas reinhardtii mutants with copper-dependent growth or nonphotosynthetic phenotypes revealed three loci, COPPER RESPONSE REGULATOR 1 (CRR1), COPPER RESPONSE DEFECT 1 (CRD1), and COPPER RESPONSE DEFECT 2 (CRD2), distinguished as regulatory or target genes on the basis of phenotype. CRR1 was shown previously to be required for transcriptional activation of target genes like CYC6, CPX1, and CRD1, encoding, respectively, cytochrome c(6) (which is a heme-containing substitute for copper-containing plastocyanin), coproporphyrinogen III oxidase, and Mg-protoporphyrin IX monomethylester cyclase. We show here that CRR1 is required also for normal accumulation of copper proteins like plastocyanin and ferroxidase in copper-replete medium and for apoplastocyanin degradation in copper-deficient medium, indicating that a single pathway controls nutritional copper homeostasis at multiple levels. CRR1 is linked to the SUPPRESSOR OF PCY1-AC208 13 (SOP13) locus, which corresponds to a gain-of-function mutation resulting in copper-independent expression of CYC6. CRR1 is required also for hypoxic growth, pointing to a physiologically meaningful regulatory connection between copper deficiency and hypoxia. The growth phenotype of crr1 strains results primarily from secondary iron deficiency owing to reduced ferroxidase abundance, suggesting a role for CRR1 in copper distribution to a multicopper ferroxidase involved in iron assimilation. Mutations at the CRD2 locus also result in copper-conditional iron deficiency, which is consistent with a function for CRD2 in a pathway for copper delivery to the ferroxidase. Taken together, the observations argue for a specialized copper-deficiency adaptation for iron uptake in Chlamydomonas.

  • 254.
    Esberg, Anders
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Moqtaderi, Zarmik
    Fan, Xiaochun
    Lu, Jian
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Struhl, Kevin
    Byström, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Iwr1 protein is important for preinitiation complex formation by all three nuclear RNA polymerases in Saccharomyces cerevisiae2011In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 6, e20829- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Iwr1, a protein conserved throughout eukaryotes, was originally identified by its physical interaction with RNA polymerase (Pol) II.

    PRINCIPAL FINDINGS: Here, we identify Iwr1 in a genetic screen designed to uncover proteins involved in Pol III transcription in S. cerevisiae. Iwr1 is important for Pol III transcription, because an iwr1 mutant strain shows reduced association of TBP and Pol III at Pol III promoters, a decreased rate of Pol III transcription, and lower steady-state levels of Pol III transcripts. Interestingly, an iwr1 mutant strain also displays reduced association of TBP to Pol I-transcribed genes and of both TBP and Pol II to Pol II-transcribed promoters. Despite this, rRNA and mRNA levels are virtually unaffected, suggesting a post-transcriptional mechanism compensating for the occupancy defect.

    CONCLUSIONS: Thus, Iwr1 plays an important role in preinitiation complex formation by all three nuclear RNA polymerases.

  • 255. Falahati-Anbaran, Mohsen
    et al.
    Lundemo, Sverre
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Ansell, Stephen W.
    Stenoien, Hans K.
    Contrasting Patterns of Genetic Structuring in Natural Populations of Arabidopsis lyrata Subsp petraea across Different Regions in Northern Europe2014In: PLoS ONE, ISSN 1932-6203, Vol. 9, no 9, e107479- p.Article in journal (Refereed)
    Abstract [en]

    Level and partitioning of genetic diversity is expected to vary between contrasting habitats, reflecting differences in strength of ecological and evolutionary processes. Therefore, it is necessary to consider processes acting on different time scales when trying to explain diversity patterns in different parts of species' distributions. To explore how historical and contemporary factors jointly may influence patterns of genetic diversity and population differentiation, we compared genetic composition in the perennial herb Arabidopsis lyrata ssp. petraea from the northernmost parts of its distribution range on Iceland to that previously documented in Scandinavia. Leaf tissue and soil were sampled from ten Icelandic populations of A. lyrata. Seedlings were grown from soil samples, and tissue from above-ground and seed bank individuals were genotyped with 21 microsatellite markers. Seed bank density in Icelandic populations was low but not significantly different from that observed in Norwegian populations. While within-population genetic diversity was relatively high on Iceland (H-E = 0.35), among-population differentiation was low (F-ST = 0.10) compared to Norwegian and Swedish populations. Population differentiation was positively associated with geographical distance in both Iceland and Scandinavia, but the strength of this relationship varied between regions. Although topography and a larger distribution range may explain the higher differentiation between mountainous Norwegian relative to lowland populations in Sweden, these factors cannot explain the lower differentiation in Icelandic compared to Swedish populations. We propose that low genetic differentiation among Icelandic populations is not caused by differences in connectivity, but is rather due to large historical effective population sizes. Thus, rather than contemporary processes, historical factors such as survival of Icelandic lineages in northern refugia during the last glacial period may have contributed to the observed pattern.

  • 256.
    Fallahshahroudi, Amir
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Domestication Effects on the Stress Response in Chickens: Genetics, Physiology, and Behaviour2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Animal domestication, the process where animals become adapted to living in proximity to humans, is associated with the alteration of multiple traits, including decreased fearfulness and stress response. With an estimated population of 50 billion, the domesticated chicken is the most populous avian species in the world. Hundreds of chicken breeds have been developed for meat and egg production, hobby or research purposes. Multidirectional selection and the relaxation of natural selection in captivity have created immense phenotypic diversity amongst domesticates in a relatively short evolutionary time. The extensive phenotypic diversity, existence of the wild ancestor, and feasibility of intercrossing various breeds makes the chicken a suitable model animal for deciphering genetic determinants of complex traits such as stress response. We used chicken domestication as a model to gain insights about the mechanisms that regulate stress response in an avian species. We studied behavioural and physiological stress response in the ancestral Red Junglefowl and one of its domesticated progenies, White Leghorn. An advanced intercross between the aforementioned breeds was later used to map genetic loci underlying modification of stress response. The general pattern of the stress response in chickens was comparable with that reported in mammals, however we identified distinctive differences in the stress modulatory pathways in chickens. We showed that changes in the expression levels of several stress modulatory genes in the brain, the pituitary and the adrenal glands underlie the observed modified stress response in domesticated chickens. Using quantitative trait loci (QTL) mapping, several QTL underlying stress induced corticosterone, aldosterone and baseline dehydroepiandrosterone (DHEA) levels were detected. As a next step, we combined QTL mapping with gene expression (eQTL) mapping and narrowed two QTL down to the putative causal genes, SERPINA10 and PDE1C. Both of these genes were differentially expressed in the adrenal glands of White Leghorn and the Red Junglefowl, had overlapping eQTL with hormonal QTL, and their expression levels in the adrenal glands were correlated with plasma levels of corticosterone and al-dosterone. These two genes thus serve as strong candidates for further functional investigation concerning modification of the stress response during domestication. This dissertation increase the knowledge about genetics and physiology of the stress response in an avian species and its modification during domestication. Our findings expand the basic knowledge about the stress response in chicken, which can potentially be used to improve welfare through appropriate genetic selection.

  • 257.
    Fallahsharoudi, Amir
    et al.
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    de Kock, Neil
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Johnsson, Martin
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    Bektic, Lejla
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Wright, Dominic
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    Jensen, Per
    Linkoping Univ, Dept Phys Chem & Biol, AVIAN Behav Genom & Physiol Grp, S-58183 Linkoping, Sweden..
    Genetic and Targeted eQTL Mapping Reveals Strong Candidate Genes Modulating the Stress Response During Chicken Domestication2017In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 7, no 2, 497-504 p.Article in journal (Refereed)
    Abstract [en]

    The stress response has been largely modified in all domesticated animals, offering a strong tool for genetic mapping. In chickens, ancestral Red Junglefowl react stronger both in terms of physiology and behavior to a brief restraint stress than domesticated White Leghorn, demonstrating modified functions of the hypothalamic-pituitary-adrenal (HPA) axis. We mapped quantitative trait loci (QTL) underlying variations in stress-induced hormone levels using 232 birds from the 12th generation of an advanced intercross between White Leghorn and Red Junglefowl, genotyped for 739 genetic markers. Plasma levels of corticosterone, dehydroepiandrosterone (DHEA), and pregnenolone (PREG) were measured using LC-MS/MS in all genotyped birds. Transcription levels of the candidate genes were measured in the adrenal glands or hypothalamus of 88 out of the 232 birds used for hormone assessment. Genes were targeted for expression analysis when they were located in a hormone QTL region and were differentially expressed in the pure breed birds. One genome-wide significant QTL on chromosome 5 and two suggestive QTL together explained 20% of the variance in corticosterone response. Two significant QTL for aldosterone on chromosome 2 and 5 (explaining 19% of the variance), and one QTL for DHEA on chromosome 4 (explaining 5% of the variance), were detected. Orthologous DNA regions to the significant corticosterone QTL have been previously associated with the physiological stress response in other species but, to our knowledge, the underlying gene(s) have not been identified. SERPINA10 had an expression QTL (eQTL) colocalized with the corticosterone QTL on chromosome 5 and PDE1C had an eQTL colocalized with the aldosterone QTL on chromosome 2. Furthermore, in both cases, the expression levels of the genes were correlated with the plasma levels of the hormones. Hence, both these genes are strong putative candidates for the domestication-induced modifications of the stress response in chickens. Improved understanding of the genes associated with HPA-axis reactivity can provide insights into the pathways and mechanisms causing stress-related pathologies.

  • 258.
    Fallahsharoudi, Amir
    et al.
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    de Kock, Neil
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Johnsson, Martin
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Ubhayasekera, Sarojini J.K.A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Wright, Dominic
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Jensen, Per
    AVIAN Behavioural Genomics and Physiology Group, IFMBiology, Linköping University.
    Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, 15345Article in journal (Refereed)
    Abstract [en]

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal.

  • 259.
    Farisco, Michele
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Petrini, Carlo
    Italian National Institute of Health.
    On the Stand: Another Episode of Neuroscience and Law Discussion From Italy2014In: Neuroethics, ISSN 1874-5490, E-ISSN 1874-5504, Vol. 7, no 2, 243-245 p.Article in journal (Refereed)
    Abstract [en]

    After three proceedings in which neuro-science was a relevant factor for the final verdict inItalian courts, for the first time a recent case puts inquestion the legal relevance of neuroscientific evidence.This decision deserves international attention in itsunderlining that the uncertainty still affecting neuroscien-tific knowledge can have a significant impact on thelaw. It urges the consideration of such uncertainty andthe development of a shared management of it.

  • 260.
    Farkas, Sanja A.
    et al.
    Örebro University, School of Health Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Sorbe, Bengt G.
    Örebro University, School of Health Sciences. Örebro University Hospital. Department of Oncology.
    Nilsson, Torbjörn K.
    Department of Medical Biosciences/Clinical Chemistry, Umeå University, Umeå, Sweden.
    Epigenetic changes as prognostic predictors in endometrial carcinomas2017In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 12, no 1, 19-26 p.Article in journal (Refereed)
    Abstract [en]

    Endometrial carcinoma is one of the most frequent gynecological malignancies of the female. The diagnostic and prognostic markers for the high-risk subgroups with unfavorable prognosis are under intense debate worldwide, and, therefore, the aim of this study was to identify new potential DNA methylation markers for the high-risk groups. We used the Illumina Infinium HumanMethylation450 BeadChip to analyze the DNA methylation pattern and investigated its association with clinicopathological features important for defining the high-risk (FIGO-grade 3) and low-risk (FIGO-grade 1) groups of patients with endometrial cancer (n = 31 and n = 39, respectively). We identified specific DNA methylation signature in high-risk endometrial tumors, and potential molecular biomarker genes (TBX2, CHST11, and NID2) associated with unfavorable clinical predictive and prognostic factors.

  • 261.
    Farnsworth, Bryn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Translational research of the quaking gene: Focusing on the conjunction between development and disease2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Quaking (QKI) is an RNA binding protein involved in the post-transcriptional regulation of gene expression. Originally identified as the cause of hypomyelination in a mouse mutant, it has since been consistently implicated in a wide range of neurological diseases. As a gene exclusively expressed in glial cells of the central nervous system, such associations emphasise the importance of an indirect, or non-neuronal link to aberrant neural function. A role in early neural development has also been suggested from the viable and embryonic lethal mouse mutants, yet detailed and in vivo study has been precluded thus far by the murine uterine gestation, and mutant lethality prior to oligodendrogenesis. This thesis examines the role of QKI in human neurological disease, and explores the use of the zebrafish as a model organism to allow the unimpeded study of neural development.

    We first examined the expression of QKI in human post-mortem brain samples, in separate studies of Alzheimer’s disease (AD) and schizophrenia. In AD we found that QKI and the splice variants QKI5, QKI6, and QKI7 were all significantly upregulated, and were additionally implicated in the regulation of genes related to AD pathogenesis. Within schizophrenic samples, we explored the expression of QKI6B, a newly identified splice variant of QKI, alongside GFAP. We found that both were significantly upregulated, and a previously implicated regulation of GFAP by QKI was supported. In order to advance investigations of the potential of QKI to disturb neural development, we established the suitability of zebrafish for studying qki. This was achieved through phylogenetic and syntenic analysis, coupled with examination of the qki genes expression patterns. We found that qkib and qki2 are orthologues of human QKI, and both have distinct, yet overlapping expression patterns in neural progenitors, and are not found in differentiated neurons. Following from this, we explored the effects of knockdown to qkib and qki2, finding that qkib exclusively led to aberrant motor neuron development, cerebellar abnormalities, and alterations to the progenitor domain. This clearly demonstrated the crucial role of qki in early neural development, and confirms a previously speculated, yet occluded, function prior to oligodendrogenesis.

  • 262.
    Farnsworth, Bryn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Peuckert, Christiane
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Zimmermann, Bettina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Kettunen, Petronella
    University of Gothenburg, The Sahlgrenska Academy, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology.
    Emilsson Sors, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Gene Expression of Quaking in Sporadic Alzheimer’s Disease Patients is Both Upregulated and Related to Expression Levels of Genes Involved in Amyloid Plaque and Neurofibrillary Tangle Formation2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 53, no 1, 209-219 p.Article in journal (Refereed)
    Abstract [en]

    Quaking (QKI) is a gene exclusively expressed within glial cells. QKI has previously been implicated in various neurological disorders and diseases, including Alzheimer’s disease (AD), a condition for which increasing evidence suggests a central role of glia cells. The objective of the present study was to investigate the expression levels of QKI and three QKI isoforms (QKI5, QKI6, and QKI7) in AD. Genes that have previously been related to the ontogeny and progression of AD, specifically APP, PSEN1, PSEN2, and MAPT, were also investigated. A real-time PCR assay of 123 samples from human postmortem sporadic AD patients and control brains was performed. The expression values were analyzed with an analysis of covariance model and subsequent multiple regressions to explore the possibility of related expression values between QKI, QKI isoforms, and AD-related genes. Further, the sequences of AD-related genes were analyzed for the presence of QKI binding domains. QKI and all measured QKI isoforms were found to be significantly upregulated in AD samples, relative to control samples. However, APP, PSEN1, PSEN2, and MAPT were not found to be significantly different. QKI and QKI isoforms were found to be predictive for the variance of APP, PSEN1, PSEN2, and MAPT, and putative QKI binding sites suggests an interaction with QKI. Overall, these results implicate a possible role of QKI in AD, although the exact mechanism by which this occurs remains to be uncovered.

  • 263.
    Farnsworth, Bryn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Radomska, Kataryzna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology. Institut de Biologie de l'École Normale Supérieure, Department of Biology .
    Zimmermann, Bettina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Kettunen, Petronella
    University of Gothenburg, The Sahlgrenska Academy, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    QKI6B is upregulated in schizophrenic brains and predicts GFAP expressionIn: Schizophrenia Research, ISSN 0920-9964, E-ISSN 1573-2509Article in journal (Other academic)
    Abstract [en]

    Schizophrenia is a highly heritable disorder with a heterogeneous symptomatology. Research increasingly indicates the importance of the crucial and often overlooked glial perturbations within schizophrenic brains. Within this study, we examined an isoform of quaking (gene encoding an RNA-binding protein that is exclusively expressed in glial cells), known as QKI6B, and an astrocyte marker glial fibrillary acidic protein (GFAP), postulated to be under the regulation of QKI. The expression levels of these genes were quantified across post-mortem samples from the prefrontal cortex of 55 schizophrenic brains, and 55 healthy control brains, using real-time PCR. We report, through an analysis of covariance (ANCOVA) model, an upregulation of both QKI6B, and GFAP in the prefrontal cortex of schizophrenic brains. Previous research has suggested that the QKI protein directly regulates the expression of several genes through interaction with a motif in the target’s sequence, termed the Quaking Response Element (QRE). We therefore examined if QKI6B expression can predict the outcome of GFAP, and several oligodendrocyte-related genes, using a multiple linear regression approach. We found that QKI6B significantly predicts, and possibly regulates the expression of GFAP, but does not predict oligodendrocyte-related gene outcome, as previously seen with other QKI isoforms. 

  • 264.
    Farnsworth, Bryn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Radomska, Katarzyna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Sager, Jonathan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Kettunen, Petronella
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
    Morpholino knockdown of qkib leads to disturbed neural development in the larval zebrafish.Manuscript (preprint) (Other academic)
    Abstract [en]

    Quaking (QKI) is a member of the Signal Transduction and Activation of RNA (STAR) protein family and has been found to regulate the splicing, quantity, and translation of mRNA. Several studies have also found an association of QKI with a variety of human neurological disorders, such as schizophrenia, ataxia, and Alzheimer’s disease, amongst others. Mouse mutants show clear developmental defects in myelin formation. Critical periods for the investigation of myelin aberration have been precluded by the embryonic lethality of Qk null mice mutants. We have previously shown that the zebrafish is a suitable tool in which to interrogate qki function. Within this study we employ a gene-knockdown approach with the use of morpholinos and the Tg(olig2:DsRed2), and Tg(-4.9sox10:eGFP) transgenic zebrafish lines, and confocal imaging. We find a reduction in the number of oligodendrocytes, critical for the formation of myelin. We also find aberrations in the development and arborization of motor neurons across the spinal cord, and a complete absence of eurydendroid cells within the cerebellum. These findings have parallels to both neuroanatomical evidence from viable Qk mutant mice, and to aspects of related human neurological disease.

  • 265.
    Faucillion, Marie-Line
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Increased expression of X-linked genes in mammals is associated with a higher stability of transcripts and an increased ribosome density2015In: Genome Biology and Evolution, ISSN 1759-6653, Vol. 7, no 4, 1039-1052 p.Article in journal (Refereed)
    Abstract [en]

    Mammalian sex chromosomes evolved from the degeneration of one homolog of a pair of ancestral autosomes, the proto-Y. This resulted in a gene dose imbalance that is believed to be restored (partially or fully) through up-regulation of gene expression from the single active X-chromosome in both sexes by a dosage compensatory mechanism. We analyzed multiple genome-wide RNA stability datasets and found significantly longer average half-lives for X-chromosome transcripts than for autosomal transcripts in various human cell lines, both male and female, and in mice. Analysis of ribosome profiling data shows that ribosome density is higher on X-chromosome transcripts than on autosomal transcripts in both humans and mice, suggesting that the higher stability is causally linked to a higher translation rate. Our results and observations are in accordance with a dosage compensatory upregulation of expressed X-linked genes. We therefore propose that differential mRNA stability and translation rates of the autosomes and sex chromosomes contribute to an evolutionarily conserved dosage compensation mechanism in mammals.

  • 266.
    Fegraeus, Kim Jaderkvist
    et al.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Johansson, Lisa
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Maenpaa, Minna
    Suomen Hipposry, Espoo, Finland..
    Mykkanen, Anna
    Univ Helsinki, Dept Equine & Small Anim Med, Helsinki, Finland..
    Andersson, Lisa S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Velie, Brandon D.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Andersson, Leif
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Arnason, Thorvaldur
    IHBC AB, Knubbo, Morgongava, Sweden..
    Lindgren, Gabriella
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Different DMRT3 Genotypes Are Best Adapted for Harness Racing and Riding in Finnhorses2015In: Journal of Heredity, ISSN 0022-1503, E-ISSN 1465-7333, Vol. 106, no 6, 734-740 p.Article in journal (Refereed)
    Abstract [en]

    Previous studies showed a positive effect of the DMRT3 "gait keeper" mutation on harness racing performance in Standardbreds, French-, and Nordic trotters. The mutation has also been shown to influence riding traits in multiple breeds. This study investigated the effect of the DMRT3 mutation on harness racing performance and riding traits in Finnhorses. Finnhorses used for harness racing (n = 180) and for riding (n = 59) were genotyped for the DMRT3 mutation. For the trotters the genotypes were evaluated for association with racing performance (number of starts, victories, placings, earnings, and race times). At 3-6 years of age the AA genotype was superior compared with the CA and CC genotypes. The AA horses had a significantly higher proportion of victories (P = 1.4 x 10(-6)) and placings (P = 4.1 x 10(-7)), better race times (P = 0.01), and earned more money (P = 0.009) compared with C-horses. For the Finnhorses used for riding the owners answered a questionnaire to score how well the horse performed the gaits walk, trot, and canter on a scale from 1 to 6. These scores were tested for association with the DMRT3 genotypes. Although AA horses were more successful as racehorses, the CC and CA horses appear more adapted for classical riding disciplines. The AA horses received significantly lower gait scores compared with C-horses for the majority of gaits. Except for rhythm in extended canter (P = 0.05), there were no significant differences between CA and CC horses. This study shows that there are different optimal genotypes for different disciplines and the DMRT3 mutation clearly influences gaits and performance in Finnhorses.

  • 267. Fermer, C
    et al.
    Nilsson, P
    Larhed, M
    Microwave-assisted high-speed PCR2003In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 18, no 2, 129-132 p.Article in journal (Refereed)
    Abstract [en]

    PCR amplification has emerged as a very important tool in biological research. The utility of the PCR is, however, hampered by the fact that it is a slow technique. Faster heating cycles are therefore needed, both to enhance the activity of the enzyme, and to enable shortening of the reaction times. In this paper, polymerase chain reactions with focused microwave irradiation as the source of heat were demonstrated for the first time. Thus, it was established that continuous microwave heating does not terminate the enzymatic function of the polymerase. The results indicate the possibility to shorten the total reaction time. In addition, the technique may give the possibility to perform PCR reactions in millilitre scale. (C) 2002 Elsevier Science B.V. All rights reserved.

  • 268.
    Figueiredo, Margarida L. A.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kim, Maria
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå University, SE-90187 Umeå, Sweden.
    Allgardsson, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Computational Life Science Cluster (CLiC), Umeå UniversityUmeå, Sweden; Division of CBRN Defence and Security, FOI, Swedish Defence Research Agency, Sweden.
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Non-coding roX RNAs prevent the binding of the MSL-complex to heterochromatic regions2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 12, e1004865- p.Article in journal (Refereed)
    Abstract [en]

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

  • 269.
    Figueiredo, Margarida L A
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    HP1a Recruitment to Promoters Is Independent of H3K9 Methylation in Drosophila melanogaster2012In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 8, no 11, e1003061- p.Article in journal (Refereed)
    Abstract [en]

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

  • 270.
    Figueroa-Martinez, Francisco
    et al.
    Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico.
    Funes, Soledad
    Institut für Physiologische Chemie, Ludwig-Maximilians-Universität München, Germany .
    Franzén, Lars-Gunnar
    Halmstad University, School of Business and Engineering (SET), Biological and Environmental Systems (BLESS), Plant Cell Biology: Energy transduction in plant cells.
    González-Halphen, Diego
    Departamento de Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico.
    Reconstructing the mitochondrial protein import machinery of Chlamydomonas reinhardtii2008In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 179, no 1, 149-155 p.Article in journal (Refereed)
    Abstract [en]

    In Chlamydomonas reinhardtii several nucleus-encoded proteins that participate in the mitochondrial oxidative phosphorylation are targeted to the organelle by unusually long mitochondrial targeting sequences. Here, we explored the components of the mitochondrial import machinery of the green alga. We mined the algal genome, searching for yeast and plant homologs, and reconstructed the mitochondrial import machinery. All the main translocation components were identified in Chlamydomonas as well as in Arabidopsis thaliana and in the recently sequenced moss Physcomitrella patens. Some of these components appear to be duplicated, as is the case of Tim22. In contrast, several yeast components that have relatively large hydrophilic regions exposed to the cytosol or to the intermembrane space seem to be absent in land plants and green algae. If present at all, these components of plants and algae may differ significantly from their yeast counterparts. We propose that long mitochondrial targeting sequences in some Chlamydomonas mitochondrial protein precursors are involved in preventing the aggregation of the hydrophobic proteins they carry.

  • 271.
    Fitzsimmons, Carolyn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Exploring the Realm of Gene Expression Differences Between White Leghorn and Red Junglefowl Chickens2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis we attempted to elicit patterns of gene expression that influence phenotype, and that may also have been altered by thousands of years of domestication and selection, between red junglefowl and White Leghorn chickens. Red junglefowl are the wild ancestor to all domesticated chickens, and poultry in general are highly valued as a research animal and food resource. The project was also begun in order to complement an earlier study of an intercross between White Leghorn and red junglefowl, which identified several regions that were linked with phenotypic differences between the two birds.

    We began by creating our own cDNA microarray via generating four cDNA libraries from red junglefowl/White Leghorn brain and testis. We generated 12,549 unique transcripts. This included 400 new putative transcripts specific to chickens, and 180 transcripts that were not found in any other database. When investigating polymorphisms between White Leghorn and red junglefowl we found a SNP rate of 1.9/kb coding region, and a synonymous and non-synonymous percentage for these SNPs of 80 and 20% respectively.

    In the last two studies we used the cDNA microarray to measure gene expression differences between White Leghorn and red junglefowl in both hypothalamus/thalamus and liver. We found that there appears to be a significant number of genes down-regulated in White Leghorn hypothalamus/thalamus, plus an over-representation of up-regulated genes from well-known pathways, as compared with red junglefowl. We hypothesize that domestication/selection may be connected with this characteristic. We also found that the p-arm of chicken chromosome 4, which is an ancestral microchromosome, was over represented with differentially expressed genes in hypothalamus/thalamus. A number of differentially expressed genes are shared between the two tissues, and these genes are expressed in same manner between red junglefowl and White Leghorn.

  • 272.
    Flagstad, Ö.
    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.
    Hedmark, E.
    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.
    Landa, A.
    Bröseth, H.
    Persson, J.
    Andersen, R.
    Segerström, P.
    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.
    Colonization history and non-invasive monitoring of a re-established wolverine (Gulo gulo) population.2004In: Conservation Biology, no 18, 676-688 p.Article in journal (Refereed)
  • 273.
    Foerster, Daniel W.
    et al.
    Univ York, Dept Biol, Wentworth Way, York YO10 5DD, N Yorkshire, England.;Leibniz Inst Zoo & Wildlife Res, Dept Evolutionary Genet, Alfred Kowalke Str 17, D-10315 Berlin, Germany..
    Jones, Eleanor P.
    Univ York, Dept Biol, Wentworth Way, York YO10 5DD, N Yorkshire, England.;Fera Sci, York YO41 1LZ, N Yorkshire, England..
    Johannesdottir, Frioa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics. Univ York, Dept Biol, Wentworth Way, York YO10 5DD, N Yorkshire, England.;Cornell Univ, Dept Ecol & Evolut, Corson Hall, Ithaca, NY 14853 USA..
    Gabriel, Sofia I.
    Univ York, Dept Biol, Wentworth Way, York YO10 5DD, N Yorkshire, England.;Univ Lisbon, Fac Ciencias, Dept Biol Anim, CESAM Ctr Environm & Marine Studies, P-1749016 Lisbon, Portugal..
    Gimenez, Mabel D.
    Univ York, Dept Biol, Wentworth Way, York YO10 5DD, N Yorkshire, England.;Univ Nacl Misiones, Fac Ciencias Exactas Quim & Nat, Inst Biol Subtrop, Felix Azara 1552,N3300LQH, Posadas, Misiones, Argentina..
    Panithanarak, Thadsin
    Burapha Univ, Inst Marine Sci, Chon Buri, Thailand..
    Hauffe, Heidi C.
    Univ York, Dept Biol, Wentworth Way, York YO10 5DD, N Yorkshire, England.;Fdn Edmund Mach, Res & Innovat Ctr, Dept Biodivers & Mol Ecol, Via E Mach 1, I-38010 Michele Alladige S, TN, Italy..
    Searle, Jeremy B.
    Univ York, Dept Biol, Wentworth Way, York YO10 5DD, N Yorkshire, England.;Cornell Univ, Dept Ecol & Evolut, Corson Hall, Ithaca, NY 14853 USA..
    Genetic differentiation within and away from the chromosomal rearrangements characterising hybridising chromosomal races of the western house mouse (Mus musculus domesticus)2016In: Chromosome Research, ISSN 0967-3849, E-ISSN 1573-6849, Vol. 24, no 2, 271-280 p.Article in journal (Refereed)
    Abstract [en]

    The importance of chromosomal rearrangements for speciation can be inferred from studies of genetic exchange between hybridising chromosomal races within species. Reduced fertility or recombination suppression in karyotypic hybrids has the potential to maintain or promote genetic differentiation in genomic regions near rearrangement breakpoints. We studied genetic exchange between two hybridising groups of chromosomal races of house mouse in Upper Valtellina (Lombardy, Italy), using microsatellites. These groups differ by Robertsonian fusions and/or whole-arm reciprocal translocations such that F-1 hybrids have a chain-of-five meiotic configuration. Previous studies showed genetic differentiation in two chromosomes in the chain-of-five (10 and 12) close to their centromeres (i.e. the rearrangement breakpoints); we have shown here that the centromeric regions of the other two chromosomes in the chain (2 and 8) are similarly differentiated. The internal chromosomes of the chain (8 and 12) show the greatest differentiation, which may reflect pairing and recombination properties of internal and external elements in a meiotic chain. Importantly, we found that centromeric regions of some non-rearranged chromosomes also showed genetic differentiation between the hybridising groups, indicating a complex interplay between chromosomal rearrangements and other parts of the genome in maintaining or promoting differentiation and potentially driving speciation between chromosomal races.

  • 274.
    Foote, Andrew D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Liu, Yue
    Thomas, Gregg W. C.
    Vinar, Tomas
    Alfoeldi, Jessica
    Deng, Jixin
    Dugan, Shannon
    van Elk, Cornelis E.
    Hunter, Margaret E.
    Joshi, Vandita
    Khan, Ziad
    Kovar, Christie
    Lee, Sandra L.
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mancia, Annalaura
    Nielsen, Rasmus
    Qin, Xiang
    Qu, Jiaxin
    Raney, Brian J.
    Vijay, Nagarjun
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Wolf, Jochen B. W.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Hahn, Matthew W.
    Muzny, Donna M.
    Worley, Kim C.
    Gilbert, M. Thomas P.
    Gibbs, Richard A.
    Convergent evolution of the genomes of marine mammals2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 3, 272-275 p.Article in journal (Refereed)
    Abstract [en]

    Marine mammals from different mammalian orders share several phenotypic traits adapted to the aquatic environment and therefore represent a classic example of convergent evolution. To investigate convergent evolution at the genomic level, we sequenced and performed de novo assembly of the genomes of three species of marine mammals (the killer whale, walrus and manatee) from three mammalian orders that share independently evolved phenotypic adaptations to a marine existence. Our comparative genomic analyses found that convergent amino acid substitutions were widespread throughout the genome and that a subset of these substitutions were in genes evolving under positive selection and putatively associated with a marine phenotype. However, we found higher levels of convergent amino acid substitutions in a control set of terrestrial sister taxa to the marine mammals. Our results suggest that, whereas convergent molecular evolution is relatively common, adaptive molecular convergence linked to phenotypic convergence is comparatively rare.

  • 275.
    Foreberg, Christina
    et al.
    Swedish National Forensic Centre, Linköping, Sweden.
    Jansson, Linda
    Applied Microbiology, Department of Chemistry, Lund University, Lund, Sweden.
    Ansell, Ricky
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering. Swedish National Forensic Centre, Linköping, Sweden.
    Hedman, Johannes
    Swedish National Forensic Centre, Linköping, Sweden, Applied Microbiology, Department of Chemistry, Lund University, Lund, Sweden.
    High-throughput DNA extraction of forensic adhesive tapes2016In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 24, 158-163 p.Article in journal (Refereed)
    Abstract [en]

    Tape-lifting has since its introduction in the early 2000's become a well-established sampling method in forensic DNA analysis. Sampling is quick and straightforward while the following DNA extraction is more challenging due to the "stickiness", rigidity and size of the tape. We have developed, validated and implemented a simple and efficient direct lysis DNA extraction protocol for adhesive tapes that requires limited manual labour. The method uses Chelex beads and is applied with SceneSafe FAST tape. This direct lysis protocol provided higher mean DNA yields than PrepFiler Express BTA on Automate Express, although the differences were not significant when using clothes worn in a controlled fashion as reference material (p=0.13 and p=0.34 for T-shirts and button-down shirts, respectively). Through in-house validation we show that the method is fit-for-purpose for application in casework, as it provides high DNA yields and amplifiability, as well as good reproducibility and DNA extract stability. After implementation in casework, the proportion of extracts with DNA concentrations above 0.01ng/μL increased from 71% to 76%. Apart from providing higher DNA yields compared with the previous method, the introduction of the developed direct lysis protocol also reduced the amount of manual labour by half and doubled the potential throughput for tapes at the laboratory. Generally, simplified manual protocols can serve as a cost-effective alternative to sophisticated automation solutions when the aim is to enable high-throughput DNA extraction of complex crime scene samples.

  • 276.
    Forsberg, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Complex Trait Genetics: Beyond Additivity2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The link between the genotype and the phenotype of an organism is immensely complex. Despite this it can, to a great extent, be captured using models that assume that gene variants combine their effects in an additive manner. This thesis explores aspects of genetics that cannot be fully captured using such additive models. Using experimental data from three different model organisms, I study two phenomena that fall outside of the additive paradigm: genetic interactions and genetic variance heterogeneity.

    Using the model plant Arabidopsis thaliana, we show how important biological insights can be reached by exploring loci that display genetic variance heterogeneity. In the first study, this approach identified alleles in the gene CMT2 associated with the climate at sampling locations, suggesting a role in climate adaption. These alleles affected the genome wide methylation pattern, and a complete knock down of this gene increased the plants heat tolerance. In the second study, we demonstrate how the observed genetic variance heterogeneity was the result of the partial linkage of many functional alleles near the gene MOT1, all contributing to Molybdenum levels in the leaves.

    Further, we explore genetic interactions using data from dogs and budding yeast (Saccharomyces cerevisiae). In the dog population, two interacting loci were associated with fructosamine levels, a biomarker used to monitor blood glucose. One of the loci displayed the pattern of a selective sweep in some of the studied breeds, suggesting that the interaction is important for the phenotypic breed-differences.

    In a cross between two strains of yeast, with the advantage of large population size and nearly equal allele frequencies, we identified large epistatic networks. The networks were largely centered on a number of hub-loci and altogether involved hundreds of genetic interactions. Most network hubs had the ability to either suppress or uncover the phenotypic effects of other loci. Many multi-locus allele combinations resulted in phenotypes that deviated significantly from the expectations, had the loci acted in an additive manner.

    Critically, this thesis demonstrates that non-additive genetic mechanisms often need to be considered in order to fully understand the genetics of complex traits. 

  • 277.
    Forsberg, Simon K G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeastManuscript (preprint) (Other academic)
    Abstract [en]

    Experiments in model organisms report abundant genetic interactions underlying biologically important traits, whereas quantitative genetics theory predicts, and data support, that most genetic variance in populations is additive. Here we describe networks of capacitating genetic interactions that contribute to quantitative trait variation in a large yeast intercross population. The additive variance explained by individual loci in a network is highly dependent on the allele frequencies of the interacting loci. Modeling of phenotypes for multi-locus genotype classes in the epistatic networks is often improved by accounting for the interactions. We discuss the implications of these results for attempts to dissect genetic architectures and to predict individual phenotypes and long-term responses to selection.

  • 278. Forsell, M. N. E.
    et al.
    Kvastad, Linda
    KTH, School of Biotechnology (BIO), Gene Technology.
    Sedimbi, S. K.
    Andersson, J.
    Karlsson, M. C. I.
    Regulation of subunit-specific germinal center B cell responses to the HIV-1 envelope glycoproteins by antibody-mediated feedback2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, no JUN, 738Article in journal (Refereed)
    Abstract [en]

    The regulation of germinal center (GC) B cell responses to single epitopes is well investigated. How monoclonal B cells are regulated within the polyclonal B cell response to protein antigens is less so. Here, we investigate the primary GC B cell response after injection of mice with HIV-1 envelope glycoproteins. We demonstrate that single GCs are seeded by a diverse number of B cell clones shortly after a single immunization and that the presence of Env-specific antibodies can inhibit the development of early GC B cells. Importantly, the suppression was dependent on the GC B cells and the infused antibodies to target the same subunit of the injected HIV-1 envelope glycoproteins. An affinity-dependent antibody feedback has previously been shown to regulate GC B cell development. Here, we propose that this antibody-based feedback acts on GC B cells only if they target the same or overlapping epitopes. This study provides important basic information of GC B cell regulation, and for future vaccine designs with aim to elicit neutralizing antibodies against HIV-1.

  • 279.
    Fotouhi, Asal
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cornella, Nicola
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ramezani, Mehrafarin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Investigation of micronucleus induction in MTH1 knockdown cells exposed to UVA, UVB or UVC2015In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 793, no SI, 161-165 p.Article in journal (Refereed)
    Abstract [en]

    The longer wave parts of UVR can increase the production of reactive oxygen species (ROS) which can oxidize nucleotides in the DNA or in the nucleotide pool leading to mutations. Oxidized bases in the DNA are repaired mainly by the DNA base excision repair system and incorporation of oxidized nucleotides into newly synthesized DNA can be prevented by the enzyme MTH1. Here we hypothesize that the formation of several oxidized base damages (from pool and DNA) in close proximity, would cause a high number of base excision repair events, leading to DNA double strand breaks (DSB) and therefore giving rise to cytogenetic damage. If this hypothesis is true, cells with low levels of MTH1 will show higher cytogenetic damage after the longer wave parts of UVR. We analyzed micronuclei induction (MN) as an endpoint for cytogenetic damage in the human lymphoblastoid cell line, TK6, with a normal and a reduced level of MTH1 exposed to UVR. The results indicate a higher level of micronuclei at all incubation times after exposure to the longer wave parts of UVR. There is no significant difference between wildtype and MTH1-knockdown TK6 cells, indicating that MTH1 has no protective role in UVR-induced cytogenetic damage. This indicates that DSBs induced by UV arise from damage forms by direct interaction of UV or ROS with the DNA rather than through oxidation of dNTP.

  • 280.
    Fountain, Toby
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Univ Helsinki, Dept Biosci, Helsinki, Finland.;Univ Sheffield, Dept Anim & Plant Sci, Sheffield, S Yorkshire, England..
    Ravinet, Mark
    Natl Inst Genet, Ecol Genet Div, Mishima, Shizuoka, Japan..
    Naylor, Richard
    Univ Sheffield, Dept Anim & Plant Sci, Sheffield S10 2TN, S Yorkshire, England..
    Reinhardt, Klaus
    Tech Univ Dresden, Appl Zool, Dept Biol, D-01069 Dresden, Germany..
    Butlin, Roger K.
    Univ Gothenburg, Dept Marine Sci, Gothenburg, Sweden.;Univ Sheffield, Dept Anim & Plant Sci, Sheffield S10 2TN, S Yorkshire, England..
    A Linkage Map and QTL Analysis for Pyrethroid Resistance in the Bed Bug Cimex lectularius2016In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 6, no 12, 4059-4066 p.Article in journal (Refereed)
    Abstract [en]

    The rapid evolution of insecticide resistance remains one of the biggest challenges in the control of medically and economically important pests. Insects have evolved a diverse range of mechanisms to reduce the efficacy of the commonly used classes of insecticides, and finding the genetic basis of resistance is a major aid to management. In a previously unstudied population, we performed an F-2 resistance mapping cross for the common bed bug, Cimex lectularius, for which insecticide resistance is increasingly widespread. Using 334 SNP markers obtained through RAD-sequencing, we constructed the first linkage map for the species, consisting of 14 putative linkage groups (LG), with a length of 407 cM and an average marker spacing of 1.3 cM. The linkage map was used to reassemble the recently published reference genome, facilitating refinement and validation of the current genome assembly. We detected a major QTL on LG12 associated with insecticide resistance, occurring in close proximity (1.2 Mb) to a carboxylesterase encoding candidate gene for pyrethroid resistance. This provides another example of this candidate gene playing a major role in determining survival in a bed bug population following pesticide resistance evolution. The recent availability of the bed bug genome, complete with a full list of potential candidate genes related to insecticide resistance, in addition to the linkage map generated here, provides an excellent resource for future research on the development and spread of insecticide resistance in this resurging pest species.

  • 281.
    Fowlkes, Charless C.
    et al.
    Department of Computer Science, University of California Irvine.
    Eckenrode, Kelly B.
    Department of Systems Biology, Harvard Medical School.
    Bragdon, Meghan D.
    Department of Systems Biology, Harvard Medical School.
    Meyer, Miriah
    School of Engineering and Applied Sciences, Harvard University.
    Wunderlich, Zeba
    Department of Systems Biology, Harvard Medical School.
    Simirenko, Lisa
    California Institute for Quantitative Biosciences, University of California Berkeley.
    Luengo Hendriks, Cris L.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Keränen, Soile V. E.
    Genomics and Life Sciences Division, Lawrence Berkeley National Laboratory.
    Henriquez, Clara
    Genomics and Life Sciences Division, Lawrence Berkeley National Laboratory.
    Knowles, David W.
    Genomics and Life Sciences Division, Lawrence Berkeley National Laboratory.
    Biggin, Mark D.
    Genomics and Life Sciences Division, Lawrence Berkeley National Laboratory.
    Eisen, Michael B.
    California Institute for Quantitative Biosciences, University of California Berkeley.
    DePace, Angela H.
    Department of Systems Biology, Harvard Medical School.
    A Conserved Developmental Patterning Network Produces Quantitatively Different Output in Multiple Species of Drosophila2011In: PLoS Genetics, ISSN 1553-7390, Vol. 7, no 10, e1002346- p.Article in journal (Refereed)
  • 282.
    Francois, Liesbeth
    et al.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden.;Katholieke Univ Leuven, Dept Biosyst, Livestock Genet, B-3001 Leuven, Belgium..
    Fegraeus, Kim Jaderkvist
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Eriksson, Susanne
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Andersson, Lisa S.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Tesfayonas, Yohannes G.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Viluma, Agnese
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Imsland, Freyja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Buys, Nadine
    Katholieke Univ Leuven, Dept Biosyst, Livestock Genet, B-3001 Leuven, Belgium..
    Mikko, Sofia
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Lindgren, Gabriella
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Velie, Brandon D.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
    Conformation Traits and Gaits in the Icelandic Horse are Associated with Genetic Variants in Myostatin (MSTN)2016In: Journal of Heredity, ISSN 0022-1503, E-ISSN 1465-7333, Vol. 107, no 5, 431-437 p.Article in journal (Refereed)
    Abstract [en]

    Many genes are known to have an influence on conformation and performance traits; however, the role of one gene, Myostatin (MSTN), has been highlighted in recent studies on horses. Myostatin acts as a repressor in the development and regulation of differentiation and proliferative growth of skeletal muscle. Several studies have examined the link between MSTN, conformation, and performance in racing breeds, but no studies have investigated the relationship in Icelandic horses. Icelandic horses, a highly unique breed, are known both for their robust and compact conformation as well as their additional gaits tolt and pace. Three SNPs (g.65868604G>T [PR8604], g.66493737C>T [PR3737], and g.66495826A>G [PR5826]) flanking or within equine MSTN were genotyped in 195 Icelandic horses. The SNPs and haplotypes were analyzed for association with official estimated breeding values (EBV) for conformation traits (n = 11) and gaits (n = 5). The EBV for neck, withers, and shoulders was significantly associated with both PR8604 and PR3737 (P < 0.05). PR8604 was also associated with EBV for total conformation (P = 0.05). These associations were all supported by the haplotype analysis. However, while SNP PR5826 showed a significant association with EBVs for leg stance and hooves (P < 0.05), haplotype analyses for these traits failed to fully support these associations. This study demonstrates the possible role of MSTN on both the form and function of horses from non-racing breeds. Further analysis of Icelandic horses as well as other non-racing breeds would be beneficial and likely help to completely understand the influence of MSTN on conformation and performance in horses.

  • 283.
    Francuski, Ljubinka
    et al.
    Univ Novi Sad, Fac Sci, Dept Biol & Ecol, Trg Dositeja Obradovica 2, Novi Sad 21000, Serbia..
    Milankov, Vesna
    Univ Novi Sad, Fac Sci, Dept Biol & Ecol, Trg Dositeja Obradovica 2, Novi Sad 21000, Serbia..
    Ludoski, Jasmina
    Univ Novi Sad, Fac Sci, Dept Biol & Ecol, Trg Dositeja Obradovica 2, Novi Sad 21000, Serbia..
    Krtinic, Bosiljka
    Ciklonizacija, Primorska 76, Novi Sad 21000, Serbia..
    Lundström, Jan O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kemenesi, Gabor
    Univ Pecs, Szentagothai Res Ctr, Virol Res Grp, Pecs, Hungary..
    Ferenc, Jakab
    Univ Pecs, Szentagothai Res Ctr, Virol Res Grp, Pecs, Hungary..
    Genetic and phenotypic variation in central and northern European populations of Aedes (Aedimorphus) vexans (Meigen, 1830) (Diptera, Culicidae)2016In: Journal of Vector Ecology, ISSN 1081-1710, E-ISSN 1948-7134, Vol. 41, no 1, 160-171 p.Article in journal (Refereed)
    Abstract [en]

    The floodwater mosquito Aedes vexans can be a massive nuisance in the flood plain areas of mainland Europe, and is the vector of Tahyna virus and a potential vector of Dirofilaria immitis. This epidemiologically important species forms three subspecies worldwide, of which Aedes vexans arabiensis has a wide distribution in Europe and Africa. We quantified the genetic and phenotypic variation in Ae. vexans arabiensis in populations from Sweden (northern Europe), Hungary, and Serbia (central Europe). A landscape genetics approach (F-ST, STRUCTURE, BAPS, GENELAND) revealed significant differentiation between northern and southern populations. Similar to genetic data, wing geometric morphometrics revealed two different clusters, one made by Swedish populations, while another included Hungarian and Serbian populations. Moreover, integrated genetic and morphometric data from the spatial analysis suggested groupings of populations into three clusters, one of which was from Swedish and Hungarian populations. Data on spatial analysis regarding an intermediate status of the Hungarian population was supported by observed Isolation-by-Distance patterns. Furthermore, a low proportion of interpopulation vs intrapopulation variance revealed by AMOVA and low-to-moderate F-ST values on a broader geographical scale indicate a continuous between-population exchange of individuals, including considerable gene flow on the regional scale, are likely to be responsible for the maintenance of the observed population similarity in A.. vexans. We discussed data considering population structure in the light of vector control strategies of the mosquito from public health importance.

  • 284.
    Fraser, Magdalena
    et al.
    Gotland University, School of Culture, Energy and Environment.
    Sten, Sabine
    Gotland University, School of Culture, Energy and Environment.
    Götherström, Anders
    Department of Ecology and Genetics, Evolutionary Biology Centre, Uppsala University, Norbyvägen 18D, 752 36 Uppsala, Sweden.
    Neolithic Hedgehogs (Erinaceus europaeus) from the Island of Gotland show early contacts with the Swedish mainland2012In: Journal of Archaeological Science, ISSN 0305-4403, E-ISSN 1095-9238, Vol. 39, no 2, 229-233 p.Article in journal (Refereed)
    Abstract [en]

    Previous research probing early migrations and contacts in the Baltic Sea area is characterized by the analysis of different chronologies and subsistent strategies on all sides of the Sea. Several studies performed on artifact typology, ceramics, grave rituals and physical anthropology ended with varying results. Although the question of human origins remains inconclusive, in this study, we rely on the phylogeography of an animal associated with humans to elucidate findings regarding prehistoric human migration and contacts.

    Hedgehogs, along with other fauna on Gotland, were brought over to the island by humans. We examined hedgehog mitochondrial DNA from the Pitted Ware Culture (Middle Neolithic). The genetic signatures of the animals on the island were investigated to determine the animals origin.

    From the 23 bones originally examined, twelve bones from all five locations studied yielded reliable results and resembled published extant Erinaceus europaeus sequences from Sweden, Norway and Denmark. We postulate that a western heritage for the Neolithic hedgehogs on Gotland indicates early human contact with the Swedish mainland.

  • 285.
    Fredlund, Elisabeth
    et al.
    Department of Microbiology, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Beerlage, Christiane
    Department of Microbiology, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Melin, Petter
    Department of Microbiology, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Schnürer, Johan
    Department of Microbiology, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Passoth, Volkmar
    Department of Microbiology, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
    Oxygen and carbon source-regulated expression of PDC and ADH genes in the respiratory yeast Pichia anomala2006In: Yeast, ISSN 0749-503X, E-ISSN 1097-0061, Vol. 23, no 16, 1137-1149 p.Article in journal (Refereed)
    Abstract [en]

    We amplified, sequenced and studied the transcriptional regulation of genes of the alcoholic fermentation pathway in the biocontrol and non-Saccharomyces wine yeast, Pichia anomala. Two ADH isogenes, PaADH1 and PaADH2, and one PDC gene, PaPDC1, were amplified from genomic P. anomala DNA by a two-step PCR approach, using degenerated primers against conserved regions of the respective genes for cloning core regions, and PCR-based gene walking for cloning the respective 5' and 3'-ends. According to sequence analysis, ADHI and PDC1 are most likely cytoplasmatic proteins, while ADH2 is most probably localized in the mitochondria. PaADH1 was expressed during aerobic growth on glucose, ethanol and succinate, but was ninefold upregulated in response to oxygen limitation when grown on glucose. The gene seems to be involved in both production and consumption of ethanol. Only low expression of PaADH2 was detected during growth on glucose and ethanol, but it was highly expressed during growth on the non-fermentable carbon source succinate and repressed by the addition of glucose. PaPDC1 was expressed during aerobic growth on glucose and was upregulated four-fold in response to oxygen limitation. PaPDC1 expression was lower in cells grown on ethanol and succinate than on glucose and was up- regulated two- and four-fold, respectively, after glucose addition. Our results demonstrate that transcription of genes of the fermentative pathway is regulated by hypoxia and carbon source but posttranscriptional regulation may play a major role in regulating the metabolic flux.

  • 286. Freimann, Krista
    et al.
    Kurrikoff, Kaido
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Galanin receptors as a potential target for neurological disease2015In: Expert opinion on therapeutic targets, ISSN 1472-8222, E-ISSN 1744-7631, Vol. 19, no 12, 1665-1676 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Galanin is a 29/30 amino acid long neuropeptide that is widely expressed in the brains of many mammals. Galanin exerts its biological activities through three different G protein-coupled receptors, GalR1, GalR2 and GalR3. The widespread distribution of galanin and its receptors in the CNS and the various physiological and pharmacological effects of galanin make the galanin receptors attractive drug targets.

    AREAS COVERED: This review provides an overview of the role of galanin and its receptors in the CNS, the involvement of the galaninergic system in various neurological diseases and the development of new galanin receptor-specific ligands.

    EXPERT OPINION: Recent advances and novel approaches in migrating the directions of subtype-selective ligand development and chemical modifications of the peptide backbone highlight the importance of the galanin neurochemical system as a potential target for drug development.

  • 287.
    Friberg, Urban
    Department of Ecology and Environmental Science, Section of Animal Ecology, Umeå University, Umeå , Sweden.
    Genetic variation in male and female reproductive characters associated with sexual conflict in Drosophila melanogaster2005In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 35, no 4, 455-462 p.Article in journal (Refereed)
    Abstract [en]

    Recent studies have shown that elevated mating, courtship and seminal substances affect female fitness negatively in Drosophila melanogaster. It has also been shown that males vary with respect to these characters and that male harm to females correlates positively with components of male fitness. These results suggest that there is sexual conflict over the effect of such male characters. An important component of this scenario is that females have evolved counteradaptations to male harm, but so far there is limited evidence for this. Here I define female resistance as the ability to withstand an increased exposure to males. Across 10 genetically differentiated lines of D. melanogaster, I found genetic variation among females in the reduction of lifespan that followed from exposure to males of different durations. There was also genetic variation among males with regards to the degree to which they decrease the lifespan of their mates. These results suggest that genetic variation for female ability to endure male sexually antagonistic adaptations exists and may play an important role in male–female coevolution.

  • 288.
    Friberg, Urban
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Två kön och många organ: men bara en arvsmassa2016In: Tidskriften för svensk psykiatri, ISSN 1653-8579, no 4, 28-29 p.Article in journal (Other academic)
    Abstract [sv]

    Hos många arter uppvisar könen en rad skillnader.Dessa omfattar vanligtvis deras utseende så väl som beteende. Vad är det egentligen som orsakar evolution av könsskillnader, hur är den möjlig då könen har i princip samma gener, och kan detta tänkas ha konsekvenser för hur vi människor fungerar?

  • 289.
    Friberg, Urban
    et al.
    Department of Ecology, Evolution, and Marine Biology, University of California Santa Barbara, Santa Barbara, California, USA.
    Rice, Willliam R.
    Department of Ecology and Evolutionary Biology, University of Tennessee, Knoxville, Tennessee, USA / Department of Mathematics, University of Tennessee, Knoxville, Tennessee, USA.
    Gavrilets, Sergey
    Department of Ecology, Evolution, and Marine Biology, University of California Santa Barbara, Santa Barbara, California, USA.
    Sexually Antagonistic “Zygotic Drive” of the Sex Chromosomes2008In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 4, no 12, 1000313Article in journal (Refereed)
    Abstract [en]

    Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic “zygotic drive”, because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic “arms race” between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans.

  • 290.
    Friberg, Urban
    et al.
    Department of Ecology, Evolution and Marine Biology, University of California Santa Barbara, Santa Barbara, California, United States of America / Department of Evolutionary Biology, Uppsala University, Uppsala, Sweden .
    Stewart, Andrew D.
    Department of Ecology, Evolution and Marine Biology, University of California Santa Barbara, Santa Barbara, California, USA.
    Rice, William R.
    Department of Ecology, Evolution and Marine Biology, University of California Santa Barbara, Santa Barbara, California, USA.
    Empirical Evidence for Son-Killing X Chromosomes and the Operation of SA-Zygotic Drive2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, e23508Article in journal (Refereed)
    Abstract [en]

    Background: Diploid organisms have two copies of all genes, but only one is carried by each haploid gamete and diploid offspring. This causes a fundamental genetic conflict over transmission rate between alternative alleles. Single genes, or gene clusters, only rarely code for the complex phenotypes needed to give them a transmission advantage (drive phenotype). However, all genes on a male's X and Y chromosomes co-segregate, allowing different sex-linked genes to code for different parts of the drive phenotype. Correspondingly, the well-characterized phenomenon of male gametic drive, occurring during haploid gametogenesis, is especially common on sex chromosomes. The new theory of sexually antagonistic zygotic drive of the sex chromosomes (SA-zygotic drive) extends the logic of gametic drive into the diploid phase of the lifecycle, whenever there is competition among siblings or harmful sib-sib mating. The X and Y are predicted to gain a transmission advantage by harming offspring of the sex that does not carry them. Results: Here we analyzed a mutant X-chromosome in Drosophila simulans that produced an excess of daughters when transmitted from males. We developed a series of tests to differentiate between gametic and SA-zygotic drive, and provide multiple lines of evidence that SA-zygotic drive is responsible for the sex ratio bias. Driving sires produce about 50% more surviving daughters than sons. Conclusion: Sex-ratio distortion due to genetic conflict has evolved via gametic drive and maternally transmitted endosymbionts. Our data indicate that sex chromosomes can also drive by harming the non-carrier sex of offspring.

  • 291.
    Frida, Jonsson
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Underlying genetic mechanisms of hereditary dystrophies in retina and cornea2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

  • 292. Friedlaender, Jonathan S
    et al.
    Hunley, Keith
    University of New Mexico.
    Dunn, Michael
    Radboud University; Max Planck Institute for Psycholinguistics.
    Terrill, Angela
    Radboud University.
    Lindström, Eva
    Stockholm University, Faculty of Humanities, Department of Linguistics, General Linguistics.
    Friedlaender, Françoise
    Linguistics More Robust Than Genetics: (Letter to the editors)2009Other (Refereed)
  • 293.
    Funda, Tomas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Forest Genetics and Plant Physiology, UPSCSwedish University of Agricultural Sciences, Umeå, Sweden.
    Wennström, Ulfstand
    Almqvist, Curt
    Andersson Gull, Bengt
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Mating dynamics of Scots pine in isolation tents2016In: Tree Genetics & Genomes, ISSN 1614-2942, E-ISSN 1614-2950, Vol. 12, no 6, 112Article in journal (Refereed)
    Abstract [en]

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

  • 294.
    Gabriel Antonio, Ascue Avalos
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Analysis of the response of Lactococcus lactis towards sublethal alcohol concentrations2013Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    In this study, I analyzed the Lactococcus lactis subspecies cremoris MG1363 stress response at sub-lethal alcohol levels during exponential growth phase at transcriptomics, proteomics, metabolomics levels. Ethanol, 1-butanol, 1-hexanol were the selected alcohols. Manganese- transporter- and arginine catabolic pathway genes were up-regulated by all alcohols suggesting they evoked oxidative and acidic stress. ATP manganese transporter genes, histidine- and galactose genes were also up-regulated. Purine- and pyrimidine synthesis genes were down-regulated. HPLC analysis displayed decreased biomass yield and glycolytic flux, suggesting increased glycolytic energy production and slowed down overall enzymatic rate. Proteomics analysis displayed differential expressed proteins associated with heat and oxidative stress.

  • 295.
    Gajardo Gunnarsson, Tania
    Mälardalen University, Department of Biology and Chemical Engineering.
    identifiering av genetisk markör för könsbestämning av Gasterousteus aculeatus2008Independent thesis Advanced level (degree of Magister), 20 points / 30 hpStudent thesis
    Abstract [sv]

    Arbetets uppgift var att identifiera en DNA-sekvens som skulle kunna finnas hos storspiggens könsbestämningsregion. Avsikten med detta arbete är att utveckla en enkel PCR-baserad metod för att kunna könsbestämma storspiggar genetiskt. Tidigare genetiska studier har visat en skillnad mellan honor och hanar vid jämförelse av deras RAPD-3 PCR produkter. Skillnaden består i att endast hanarna har ett fragment som är runt 250 bp stort. Detta fragment ska isoleras, renas, klonas och sekvenseras med hjälp av olika metoder. Sekvensen ska användas för att beställa designerade primer som testades för att vara specifika för hanar.

    I detta arbete kunde endast en sekvens användas för detta syfte och två egendesignerade primers beställdes, dessa visade sig dock icke vara specifika för hanar.

  • 296. Gallus, S.
    et al.
    Hallström, Björn M.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Senckenberg Gesellschaft für Naturforschung, Germany .
    Kumar, V.
    Dodt, W. G.
    Janke, A.
    Schumann, G. G.
    Nilsson, M. A.
    Evolutionary histories of transposable elements in the genome of the largest living marsupial carnivore, the tasmanian devil2015In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 32, no 5, 1268-1283 p.Article in journal (Refereed)
    Abstract [en]

    The largest living carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii), is the sole survivor of a lineage originating about 12 Ma. We set out to investigate the spectrum of transposable elements found in the Tasmanian devil genome, the first high-coverage genome of an Australian marsupial. Marsupial genomes have been shown to have the highest amount of transposable elements among vertebrates. We analyzed the horizontally transmitted DNA transposons OC1 and hAT-1-MEu in the Tasmanian devil genome. OC1 is present in all carnivorous marsupials, while having a very limited distribution among the remaining Australian marsupial orders. In contrast, hAT-1-MEu is present in all Australian marsupial orders, and has so far only been identified in a few placental mammals. We screened 158 introns for phylogenetically informative retrotransposons in the order Dasyuromorphia, and found that the youngest SINE (Short INterspersed Element), WSINE1, is no longer active in the subfamily Dasyuridae. The lack of detectable WSINE1 activity in this group may be due to a retrotransposon inactivation event approximately 30 Ma. We found that the Tasmanian devil genome contains a relatively low number of continuous full-length LINE-1 (Long INterspersed Element 1, L1) retrotransposons compared with the opossum genome. Furthermore, all L1 elements in the Tasmanian devil appeared to be nonfunctional. Hidden Markov Model approaches suggested that other potential sources of functional reverse transcriptase are absent from the genome. We discuss the issues associated with assembling long, highly similar L1 copies from short read Illumina data and describe how assembly artifacts can potentially lead to erroneous conclusions.

  • 297. Gambelunghe, G.
    et al.
    Ghaderi, M.
    Gharizadeh, Baback
    KTH, Superseded Departments, Biotechnology.
    Brozzetti, A.
    Tortoioli, C.
    Del Sindaco, P.
    Sanjeevi, C. B.
    Hjelmstrom, P.
    Sirsjo, A.
    Nyrén, Pål
    KTH, Superseded Departments, Biochemistry and Biotechnology.
    Santeusanio, F.
    Falorni, A.
    Lack of association of human chemokine receptor gene polymorphisms CCR2-64I and CCR5-Delta 32 with autoimmune Addison's disease2004In: European journal of immunogenetics, ISSN 0960-7420, E-ISSN 1365-2370, Vol. 31, no 2, 73-76 p.Article in journal (Refereed)
    Abstract [en]

    The attraction of leukocytes to tissues is essential for inflammation and the initiation of the autoimmune reaction. The process is controlled by chemokines, which are chemotactic cytokines. We investigated whether human chemokine receptor gene polymorphisms, namely CCR5-Delta32 and CCR2-64I, are associated with susceptibility to autoimmune Addison's disease. Genotyping was performed in 56 patients and 127 healthy controls by a new method using pyrosequencing for CCR2-64I and by polymerase chain reaction and detecting gel for CCR5-Delta32. None of the CCR2 or CCR5 alleles was found to be associated, either positively or negatively, with disease risk. Our results indicate that the CCR2-64I and CCR5-Delta32 gene polymorphisms do not play a major role in conferring genetic risk for, and/or protection against, autoimmune Addison's disease.

  • 298.
    Gao, Jie
    et al.
    State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China.
    Wang, Baosheng
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Mao, Ian-Feng
    State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China.
    Ingvarsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Zeng, Qing-Yin
    State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China.
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing 100093, China.
    Demography and speciation history of the homoploid hybrid pine Pinus densata on the Tibetan Plateau2012In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 21, no 19, 4811-4827 p.Article in journal (Refereed)
    Abstract [en]

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

  • 299.
    Gattepaille, Lucie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Günther, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Jakobsson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Inferring Past Effective Population Size from Distributions of Coalescent Times2016In: Genetics, ISSN 0016-6731, E-ISSN 1943-2631, Vol. 204, no 3, 1191-1206 p.Article in journal (Refereed)
    Abstract [en]

    Inferring and understanding changes in effective population size over time is a major challenge for population genetics. Here we investigate some theoretical properties of random-mating populations with varying size over time. In particular, we present an exact solution to compute the population size as a function of time, N-e(t), based on distributions of coalescent times of samples of any size. This result reduces the problem of population size inference to a problem of estimating coalescent time distributions. To illustrate the analytic results, we design a heuristic method using a tree-inference algorithm and investigate simulated and empirical population-genetic data. We investigate the effects of a range of conditions associated with empirical data, for instance number of loci, sample size, mutation rate, and cryptic recombination. We show that our approach performs well with genomic data ( 10,000 loci) and that increasing the sample size from 2 to 10 greatly improves the inference of Ne(t) whereas further increase in sample size results in modest improvements, even under a scenario of exponential growth. We also investigate the impact of recombination and characterize the potential biases in inference of Ne(t). The approach can handle large sample sizes and the computations are fast. We apply our method to human genomes from four populations and reconstruct population size profiles that are coherent with previous finds, including the Out-of-Africa bottleneck. Additionally, we uncover a potential difference in population size between African and non-African populations as early as 400 KYA. In summary, we provide an analytic relationship between distributions of coalescent times and Ne(t), which can be incorporated into powerful approaches for inferring past population sizes from population-genomic data.

  • 300. Gaulton, Kyle J.
    et al.
    Ferreira, Teresa
    Lee, Yeji
    Raimondo, Anne
    Maegi, Reedik
    Reschen, Michael E.
    Mahajan, Anubha
    Locke, Adam
    Rayner, N. William
    Robertson, Neil
    Scott, Robert A.
    Prokopenko, Inga
    Scott, Laura J.
    Green, Todd
    Sparso, Thomas
    Thuillier, Dorothee
    Yengo, Loic
    Grallert, Harald
    Wahl, Simone
    Frånberg, Mattias
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden.
    Strawbridge, Rona J.
    Kestler, Hans
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Karssen, Lennart C.
    van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Li, Man
    Chen, Han
    Fuchsberger, Christian
    Kwan, Phoenix
    Ma, Clement
    Linderman, Michael
    Lu, Yingchang
    Thomsen, Soren K.
    Rundle, Jana K.
    Beer, Nicola L.
    van de Bunt, Martijn
    Chalisey, Anil
    Kang, Hyun Min
    Voight, Benjamin F.
    Abecasis, Goncalo R.
    Almgren, Peter
    Baldassarre, Damiano
    Balkau, Beverley
    Benediktsson, Rafn
    Blueher, Matthias
    Boeing, Heiner
    Bonnycastle, Lori L.
    Bottinger, Erwin P.
    Burtt, Noel P.
    Carey, Jason
    Charpentier, Guillaume
    Chines, Peter S.
    Cornelis, Marilyn C.
    Couper, David J.
    Crenshaw, Andrew T.
    van Dam, Rob M.
    Doney, Alex S. F.
    Dorkhan, Mozhgan
    Edkins, Sarah
    Eriksson, Johan G.
    Esko, Tonu
    Eury, Elodie
    Fadista, Joao
    Flannick, Jason
    Fontanillas, Pierre
    Fox, Caroline
    Franks, Paul W.
    Gertow, Karl
    Gieger, Christian
    Gigante, Bruna
    Gottesman, Omri
    Grant, George B.
    Grarup, Niels
    Groves, Christopher J.
    Hassinen, Maija
    Have, Christian T.
    Herder, Christian
    Holmen, Oddgeir L.
    Hreidarsson, Astradur B.
    Humphries, Steve E.
    Hunter, David J.
    Jackson, Anne U.
    Jonsson, Anna
    Jorgensen, Marit E.
    Jorgensen, Torben
    Kao, Wen-Hong L.
    Kerrison, Nicola D.
    Kinnunen, Leena
    Klopp, Norman
    Kong, Augustine
    Kovacs, Peter
    Kraft, Peter
    Kravic, Jasmina
    Langford, Cordelia
    Leander, Karin
    Liang, Liming
    Lichtner, Peter
    Lindgren, Cecilia M.
    Lindholm, Eero
    Linneberg, Allan
    Liu, Ching-Ti
    Lobbens, Stephane
    Luan, Jian'an
    Lyssenko, Valeriya
    Mannisto, Satu
    McLeod, Olga
    Meyer, Julia
    Mihailov, Evelin
    Mirza, Ghazala
    Muehleisen, Thomas W.
    Mueller-Nurasyid, Martina
    Navarro, Carmen
    Noethen, Markus M.
    Oskolkov, Nikolay N.
    Owen, Katharine R.
    Palli, Domenico
    Pechlivanis, Sonali
    Peltonen, Leena
    Perry, John R. B.
    Platou, Carl G. P.
    Roden, Michael
    Ruderfer, Douglas
    Rybin, Denis
    van der Schouw, Yvonne T.
    Sennblad, Bengt
    Sigurdsson, Gunnar
    Stancakova, Alena
    Steinbach, Gerald
    Storm, Petter
    Strauch, Konstantin
    Stringham, Heather M.
    Sun, Qi
    Thorand, Barbara
    Tikkanen, Emmi
    Tonjes, Anke
    Trakalo, Joseph
    Tremoli, Elena
    Tuomi, Tiinamaija
    Wennauer, Roman
    Wiltshire, Steven
    Wood, Andrew R.
    Zeggini, Eleftheria
    Dunham, Ian
    Birney, Ewan
    Pasquali, Lorenzo
    Ferrer, Jorge
    Loos, Ruth J. F.
    Dupuis, Josee
    Florez, Jose C.
    Boerwinkle, Eric
    Pankow, James S.
    van Duijn, Cornelia
    Sijbrands, Eric
    Meigs, James B.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Lakka, Timo A.
    Rauramaa, Rainer
    Stumvoll, Michael
    Pedersen, Nancy L.
    Lind, Lars
    Keinanen-Kiukaanniemi, Sirkka M.
    Korpi-Hyovalti, Eeva
    Saaristo, Timo E.
    Saltevo, Juha
    Kuusisto, Johanna
    Laakso, Markku
    Metspalu, Andres
    Erbel, Raimund
    Joecke, Karl-Heinz
    Moebus, Susanne
    Ripatti, Samuli
    Salomaa, Veikko
    Ingelsson, Erik
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Koistinen, Heikki
    Tuomilehto, Jaakko
    Hveem, Kristian
    Njolstad, Inger
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    de Faire, Ulf
    Hamsten, Anders
    Illig, Thomas
    Peters, Annette
    Cauchi, Stephane
    Sladek, Rob
    Froguel, Philippe
    Hansen, Torben
    Pedersen, Oluf
    Morris, Andrew D.
    Palmer, Collin N. A.
    Kathiresan, Sekar
    Melander, Olle
    Nilsson, Peter M.
    Groop, Leif C.
    Barroso, Ines
    Langenberg, Claudia
    Wareham, Nicholas J.
    O'Callaghan, Christopher A.
    Gloyn, Anna L.
    Altshuler, David
    Boehnke, Michael
    Teslovich, Tanya M.
    McCarthy, Mark I.
    Morris, Andrew P.
    Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 12, 1415-+ p.Article in journal (Refereed)
    Abstract [en]

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

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