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  • 251.
    Berg, Florian
    et al.
    University of Bergen, Department of Biology, Bergen; Institute of Marine Research (IMR), Nordnes, Bergen.
    Almeland, Oda W.
    University of Bergen, Department of Biology, Bergen.
    Skadal, Julie
    University of Bergen, Department of Biology, Bergen.
    Slotte, Aril
    Institute of Marine Research (IMR), Nordnes, Bergen.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics, Uppsala; Texas A&M University, Department of Veterinary Integrative Biosciences, College Station, Texas.
    Folkvord, Arild
    University of Bergen, Department of Biology, Bergen; Institute of Marine Research (IMR), Nordnes, Bergen.
    Genetic factors have a major effect on growth, number of vertebrae and otolith shape in Atlantic herring (Clupea harengus)2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0190995Article in journal (Refereed)
    Abstract [en]

    Atlantic herring, Clupea harengus, have complex population structures. Mixing of populations is known, but the extent of connectivity is still unclear. Phenotypic plasticity results in divergent phenotypes in response to environmental factors. A marked salinity gradient occurs from Atlantic Ocean (salinity 35) into the Baltic Sea (salinity range 2–12). Herring from both habitats display phenotypic and genetic variability. To explore how genetic factors and salinity influence phenotypic traits like growth, number of vertebrae and otolith shape an experimental population consisting of Atlantic purebreds and Atlantic/Baltic F1 hybrids were incubated and co-reared at two different salinities, 16 and 35, for three years. The F1-generation was repeatedly sampled to evaluate temporal variation. A von Bertalanffy growth model indicated that reared Atlantic purebreds had a higher maximum length (26.2 cm) than Atlantic/Baltic hybrids (24.8 cm) at salinity 35, but not at salinity 16 (25.0 and 24.8 cm, respectively). In contrast, Atlantic/Baltic hybrids achieved larger size-at-age than the wild caught Baltic parental group. Mean vertebral counts and otolith aspect ratios were higher for reared Atlantic purebreds than Atlantic/Baltic hybrids, consistent with the differences between parental groups. There were no significant differences in vertebral counts and otolith aspect ratios between herring with the same genotype but raised in different salinities. A Canonical Analysis of Principal Coordinates was applied to analyze the variation in wavelet coefficients that described otolith shape. The first discriminating axis identified the differences between Atlantic purebreds and Atlantic/Baltic hybrids, while the second axis represented salinity differences. Assigning otoliths based on genetic groups (Atlantic purebreds vs. Atlantic/Baltic hybrids) yielded higher classification success (~90%) than based on salinities (16 vs. 35; ~60%). Our results demonstrate that otolith shape and vertebral counts have a significant genetic component and are therefore useful for studies on population dynamics and connectivity.

  • 252.
    Berg, Florian
    et al.
    Univ Bergen, Dept Biol Sci, Post Box 7803, N-5020 Bergen, Norway;IMR, Post Box 1870 Nordnes, N-5018 Bergen, Norway.
    Slotte, Aril
    IMR, Post Box 1870 Nordnes, N-5018 Bergen, Norway.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Folkvord, Arild
    Univ Bergen, Dept Biol Sci, Post Box 7803, N-5020 Bergen, Norway;IMR, Post Box 1870 Nordnes, N-5018 Bergen, Norway.
    Genetic origin and salinity history influence the reproductive success of Atlantic herring2019In: Marine Ecology Progress Series, ISSN 0171-8630, E-ISSN 1616-1599, Vol. 617, p. 81-94Article in journal (Refereed)
    Abstract [en]

    Atlantic herring populations inhabit environments ranging in salinity from fully marine to nearly freshwater, but their relative reproductive success in these respective environments remains unclear. We conducted factorial crossing experiments using parents from 3 wild populations associated with different salinity environments: the Baltic Sea (similar to 6 psu), an inland brackish lake in Norway (Landvikvannet, similar to 16 psu), and the Atlantic (similar to 30 to 35 psu). Further experiments used crosses within and between Atlantic purebreds and Atlantic/Baltic hybrids reared until first maturity at 3 yr of age. Crossing experiments were conducted at 6, 16 and 35 psu. Fertilization and hatching rates were estimated, and egg sizes were measured. Fertilization rates were highest at 16 psu for all combinations. The paternal genetic and salinity origin influenced fertilization rates at 6 and 35 psu, indicating a genetic adaptation to their original environment. Fertilization rates for males originating from 16 psu were low at 35 psu. Atlantic/Baltic hybrids had lower fertilization rates than Atlantic purebreds at 35 psu. Hatching rates were not influenced by any parental factors or salinity. Maternal effects and salinity influenced egg size. Atlantic females had significantly larger eggs than the Atlantic/Baltic hybrid females. For all genetic groups, egg size decreased with increasing salinity at incubation mainly due to osmotic effects. The observed lower fertilization success at salinities other than those of the parental fish habitat would have evolutionary consequences when herring colonize new habitats with different salinities or if interbreeding occurred between populations originating from different salinity habitats.

  • 253.
    Berg, Frida
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Genetic Analysis of Fat Metabolism in Domestic Pigs and their Wild Ancestor2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The domestication of the pig began about 9 000 years ago and many of the existing domestic breeds have been selected for phenotypic traits like lean meat and fast growth. Domestic pigs are phenotypically very different from the ancestral wild boar that has adapted to survive in their natural environment. Because of their divergence, crosses between domestic pigs and wild boars are suitable for constructing genetic maps and Quantitative trait locus (QTL) analyses. A cross between the Large White and the European wild boar was thus initiated in the late 1980s. A major QTL for fat deposition and growth, denoted FAT1, was found on chromosome 4. The aim of this thesis was to further characterise the FAT1 locus and to identify the causative gene(s) and mutation(s). We have identified new markers and constructed a high-resolution linkage and RH map of the FAT1 QTL interval. We also performed comparative mapping to the human genome and showed that the pig chromosome 4 is homologous to human chromosomes 1 and 8. The gene order is very well conserved between the two species. In parallel we have narrowed down the FAT1 QTL interval by repeated backcrossing to the domestic Large White breed for six generations. The QTL could be confirmed for fatness but not for growth. Furthermore, the data strongly suggested that there might be more than one gene underlying the FAT1 QTL. Depending on which hypothesis to consider, the one- or two-loci model, the FAT1 interval can be reduced to 3,3 or 20 centiMorgan (cM), respectively, based on the backcross experiments. In the last study we confirm the two-loci model with one locus primarily effecting abdominal fat and another locus primarily effecting subcutaneous fat. We have identified a missense mutation in the RXRG gene which is in strong association with the abdominal fat QTL and the mutation is a potential candidate for that locus.

    Brown adipose tissue (BAT) is a specific type of fat essential for non-shivering thermogenesis in mammals. Piglets appear to lack BAT and rely on shivering as the main mechanism for thermoregulation. Uncoupling protein 1 (UCP1) gene is exclusively expressed in BAT and its physiological role is to generate heat by uncoupling oxidative phosphorylation. We show that the UCP1 gene has been disrupted in the pig lineage about 20 years ago. The inactivation of UCP1 provides a genetic explanation for the poor thermoregulation in piglets.

    List of papers
    1. High-resolution comparative mapping of pig Chromosome 4, emphasizing the FAT1 region
    Open this publication in new window or tab >>High-resolution comparative mapping of pig Chromosome 4, emphasizing the FAT1 region
    Show others...
    2004 In: Mamm Genome, Vol. 15, p. 717-31Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94717 (URN)
    Available from: 2006-09-06 Created: 2006-09-06Bibliographically approved
    2. Refined localization of the FAT1 quantitative trait locus on pig chromosome 4 by marker-assisted backcrossing
    Open this publication in new window or tab >>Refined localization of the FAT1 quantitative trait locus on pig chromosome 4 by marker-assisted backcrossing
    Show others...
    2006 (English)In: BMC Genet, Vol. 7, p. 17-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94718 (URN)
    Available from: 2006-09-06 Created: 2006-09-06 Last updated: 2011-06-30Bibliographically approved
    3. Further characterization of the FAT1 locus on pig chromosome 4 – evidence for two quantitative trait loci in the FAT1 region
    Open this publication in new window or tab >>Further characterization of the FAT1 locus on pig chromosome 4 – evidence for two quantitative trait loci in the FAT1 region
    (English)Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94719 (URN)
    Available from: 2006-09-06 Created: 2006-09-06 Last updated: 2011-06-30Bibliographically approved
    4. The uncoupling protein 1 gene (UCP1) is disrupted in the pig lineage: A genetic explanation for poor thermoregulation in piglets
    Open this publication in new window or tab >>The uncoupling protein 1 gene (UCP1) is disrupted in the pig lineage: A genetic explanation for poor thermoregulation in piglets
    2006 (English)In: PLoS Genetics, ISSN 1553-7390, Vol. 2, no 8, p. 1178-1181Article in journal (Refereed) Published
    Abstract [en]

    Piglets appear to lack brown adipose tissue, a specific type of fat that is essential for nonshivering thermogenesis in mammals, and they rely on shivering as the main mechanism for thermoregulation. Here we provide a genetic explanation for the poor thermoregulation in pigs as we demonstrate that the gene for uncoupling protein 1 (UCP1) was disrupted in the pig lineage. UCP1 is exclusively expressed in brown adipose tissue and plays a crucial role for thermogenesis by uncoupling oxidative phosphorylation. We used long-range PCR and genome walking to determine the complete genome sequence of pig UCP1. An alignment with human UCP1 revealed that exons 3 to 5 were eliminated by a deletion in the pig sequence. The presence of this deletion was confirmed in all tested domestic pigs, as well as in European wild boars, Bornean bearded pigs, wart hogs, and red river hogs. Three additional disrupting mutations were detected in the remaining exons. Furthermore, the rate of nonsynonymous substitutions was clearly elevated in the pig sequence compared with the corresponding sequences in humans, cattle, and mice, and we used this increased rate to estimate that UCP1 was disrupted about 20 million years ago.

    National Category
    Veterinary Science
    Identifiers
    urn:nbn:se:uu:diva-94720 (URN)10.1371/journal.pgen.0020129 (DOI)000240006900007 ()
    Available from: 2006-09-06 Created: 2006-09-06 Last updated: 2011-06-21Bibliographically approved
  • 254.
    Berg, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bourneuf, Emmanuelle
    Marklund, Stefan
    Andersson, Leif
    Further characterization of the FAT1 locus on pig chromosome 4 – evidence for two quantitative trait loci in the FAT1 regionManuscript (Other academic)
  • 255.
    Berg, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafson, Ulla
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The uncoupling protein 1 gene (UCP1) is disrupted in the pig lineage: A genetic explanation for poor thermoregulation in piglets2006In: PLoS Genetics, ISSN 1553-7390, Vol. 2, no 8, p. 1178-1181Article in journal (Refereed)
    Abstract [en]

    Piglets appear to lack brown adipose tissue, a specific type of fat that is essential for nonshivering thermogenesis in mammals, and they rely on shivering as the main mechanism for thermoregulation. Here we provide a genetic explanation for the poor thermoregulation in pigs as we demonstrate that the gene for uncoupling protein 1 (UCP1) was disrupted in the pig lineage. UCP1 is exclusively expressed in brown adipose tissue and plays a crucial role for thermogenesis by uncoupling oxidative phosphorylation. We used long-range PCR and genome walking to determine the complete genome sequence of pig UCP1. An alignment with human UCP1 revealed that exons 3 to 5 were eliminated by a deletion in the pig sequence. The presence of this deletion was confirmed in all tested domestic pigs, as well as in European wild boars, Bornean bearded pigs, wart hogs, and red river hogs. Three additional disrupting mutations were detected in the remaining exons. Furthermore, the rate of nonsynonymous substitutions was clearly elevated in the pig sequence compared with the corresponding sequences in humans, cattle, and mice, and we used this increased rate to estimate that UCP1 was disrupted about 20 million years ago.

  • 256.
    Berg, Frida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stern, Susanne
    Andersson, Kjell
    Andersson, Leif
    Moller, Maria
    Refined localization of the FAT1 quantitative trait locus on pig chromosome 4 by marker-assisted backcrossing2006In: BMC Genet, Vol. 7, p. 17-Article in journal (Refereed)
  • 257.
    Berg, Frida
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stern, Susanne
    Andersson, Kjell
    Andersson, Leif
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Moller, Maria
    Refined localization of the FAT1 quantitative trait locus on pig chromosome 4 by marker-assisted backcrossing.2006In: BMC Genet, ISSN 1471-2156, Vol. 7, p. 17-Article in journal (Other scientific)
  • 258. Berg, S
    et al.
    Engman, A
    Holmgren, S
    Lundahl, T
    Laurent, TC
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Increased plasma hyaluronan in severe pre-eclampsia and eclampsia.2001In: Scand J Clin Lab Invest, Vol. 61, p. 131-Article in journal (Refereed)
  • 259. Berg, S
    et al.
    Engman, A
    Laurent, T.C.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Increased plasma hyaluronan in pre-eclampsia1998In: Critical Care Medicine, Vol. 26, p. 78-Article, book review (Other scientific)
  • 260. Berg, S
    et al.
    Hesselvik, J.F.
    Jorfeldt, L
    Lindqvist, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Laurent, T.C.
    Department of Medical Biochemistry and Microbiology.
    Hepatic uptake of interstitial matrix molecules in human septic shock1998In: Critical Care of MedicineArticle in journal (Refereed)
  • 261.
    Bergfors, Monica
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Improved diagnosis of Carpal tunnel syndrome using amplitude difference between m. Abductor pollicis brevis and m. Pronator quadratus?2008Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The purpose of this study was to investigate the difference in amplitude between M-response from m. Abductor pollicis brevis/m. Pronator quadratus and m. Abductor pollicis brevis/m. Abductor digiti minimi on patients with carpal tunnel syndrome, compared with control subjects. We wanted to see if m. Pronator quadratus is a better alternative than m. Abductor digiti minimi as comparison with m. Abductor pollicis brevis on patients with carpal tunnel syndrome.

    Nerve conduction studies were performed on 20 patients with carpal tunnel syndrome and on 31 healthy subjects.

    The test-retest result shows that this method was reproducible. The amplitude difference of m. Abductor pollicis brevis-m. Abductor digiti minimi, for the patients, was 1,5mV lower and the amplitude for m. Abductor pollicis brevis-m. Pronator quadratus was 2mV lower than for healthy subjects. Two of the patients were outside the 2SD for the m. Abductor pollicis brevis-m. Pronator quadratus difference but not on the m. Abductor pollicis brevis-m. Abductor digiti minimi. This may indicate that m. Pronator quadratus was better than m. Abductor digiti minimi in the comparison with the m. Abductor pollicis brevis amplitude.

  • 262.
    Berghoff, Bork A.
    et al.
    Justus Liebig Univ, Inst Mikrobiol & Mol Biol, Giessen, Germany..
    Karlsson, Torgny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Kallman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wagner, Gerhart E. H.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Grabherr, Manfred G.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    RNA-sequence data normalization through in silico prediction of reference genes: the bacterial response to DNA damage as case study2017In: BioData Mining, ISSN 1756-0381, E-ISSN 1756-0381, Vol. 10, article id 30Article in journal (Refereed)
    Abstract [en]

    Background: Measuring how gene expression changes in the course of an experiment assesses how an organism responds on a molecular level. Sequencing of RNA molecules, and their subsequent quantification, aims to assess global gene expression changes on the RNA level (transcriptome). While advances in high-throughput RNA-sequencing (RNA-seq) technologies allow for inexpensive data generation, accurate post-processing and normalization across samples is required to eliminate any systematic noise introduced by the biochemical and/or technical processes. Existing methods thus either normalize on selected known reference genes that are invariant in expression across the experiment, assume that the majority of genes are invariant, or that the effects of up-and down-regulated genes cancel each other out during the normalization.

    Results: Here, we present a novel method, moose(2), which predicts invariant genes in silico through a dynamic programming (DP) scheme and applies a quadratic normalization based on this subset. The method allows for specifying a set of known or experimentally validated invariant genes, which guides the DP. We experimentally verified the predictions of this method in the bacterium Escherichia coli, and show how moose(2) is able to (i) estimate the expression value distances between RNA-seq samples, (ii) reduce the variation of expression values across all samples, and (iii) to subsequently reveal new functional groups of genes during the late stages of DNA damage. We further applied the method to three eukaryotic data sets, on which its performance compares favourably to other methods. The software is implemented in C++ and is publicly available from http://grabherr.github.io/moose2/.

    Conclusions: The proposed RNA-seq normalization method, moose(2), is a valuable alternative to existing methods, with two major advantages: (i) in silico prediction of invariant genes provides a list of potential reference genes for downstream analyses, and (ii) non-linear artefacts in RNA-seq data are handled adequately to minimize variations between replicates.

  • 263.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Meiotic Recombination in Human and Dog: Targets, Consequences and Implications for Genome Evolution2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Understanding the mechanism of recombination has important implications for genome evolution and genomic variability. The work presented in this thesis studies the properties of recombination by investigating the effects it has on genome evolution in humans and dogs.

    Using alignments of human genes with chimpanzee and macaque orthologues we studied substitution patterns along the human lineage and scanned for evidence of positive selection. The properties mirror the situation in human non-coding sequences with the fixation bias ‘GC-biased gene conversion’ (gBGC) as a driving force in the most rapidly evolving regions. By assigning candidate genes to distinct classes of evolutionary forces we quantified the extent of those genes affected by gBGC to 20%. This suggests that human-specific characters can be prompted by the fixation bias of gBGC, which can be mistaken for selection.

    The gene PRDM9 controls recombination in most mammals, but is lacking in dogs. Using whole-genome alignments of dog with related species we examined the effects of PRDM9 inactivation. Additionally, we analyzed genomic variation in the genomes of several dog breeds. We identified that non-allelic homologous recombination (NAHR) via sequence identity, often GC-rich, creates structural variants of genomic regions. We show that these regions, which are also found in dog recombination hotspots, are a subset of unmethylated CpG-islands (CGIs). We inferred that CGIs have experienced a drastic increase in biased substitution rates, concurrent with a shift of recombination to target these regions. This enables recurrent episodes of gBGC to shape their distribution.

    The work presented in this thesis demonstrates the importance of meiotic recombination on patterns of molecular evolution and genomic variability in humans and dogs. Bioinformatic analyses identified mechanisms that regulate genome composition. gBGC is presented as an alternative to positive selection and is revealed as a major factor affecting allele configuration and the emergence of accelerated evolution on the human lineage. Characterization of recombination-induced sequence patterns highlights the potential of non-methylation and establishes unmethylated CGIs as targets of meiotic recombination in dogs. These observations describe recombination as an interesting process in genome evolution and provide further insights into the mechanisms of genomic variability.

    List of papers
    1. Hotspots of biased nucleotide substitutions in human genes
    Open this publication in new window or tab >>Hotspots of biased nucleotide substitutions in human genes
    2009 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 7, no 1, p. e26-Article in journal (Refereed) Published
    Abstract [en]

    Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome. This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.

    National Category
    Medical and Health Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-119520 (URN)10.1371/journal.pbio.1000026 (DOI)000262811000008 ()19175294 (PubMedID)
    Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12Bibliographically approved
    2. Detecting positive selection within genomes: the problem of biased gene conversion
    Open this publication in new window or tab >>Detecting positive selection within genomes: the problem of biased gene conversion
    Show others...
    2010 (English)In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 365, no 1552, p. 2571-2580Article in journal (Refereed) Published
    Abstract [en]

    The identification of loci influenced by positive selection is a major goal of evolutionary genetics. A popular approach is to perform scans of alignments on a genome-wide scale in order to find regions evolving at accelerated rates on a particular branch of a phylogenetic tree. However, positive selection is not the only process that can lead to accelerated evolution. Notably, GC-biased gene conversion (gBGC) is a recombination-associated process that results in the biased fixation of G and C nucleotides. This process can potentially generate bursts of nucleotide substitutions within hotspots of meiotic recombination. Here, we analyse the results of a scan for positive selection on genes on branches across the primate phylogeny. We show that genes identified as targets of positive selection have a significant tendency to exhibit the genomic signature of gBGC. Using a maximum-likelihood framework, we estimate that more than 20 per cent of cases of significantly elevated non-synonymous to synonymous substitution rates ratio (d(N)/d(S)), particularly in shorter branches, could be due to gBGC. We demonstrate that in some cases, gBGC can lead to very high d(N)/d(S) (more than 2). Our results indicate that gBGC significantly affects the evolution of coding sequences in primates, often leading to patterns of evolution that can be mistaken for positive selection.

    Keywords
    biased gene conversion, selection, recombination
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-135631 (URN)10.1098/rstb.2010.0007 (DOI)000280097000017 ()20643747 (PubMedID)
    Available from: 2010-12-07 Created: 2010-12-07 Last updated: 2017-12-11Bibliographically approved
    3. Novel origins of copy number variation in the dog genome
    Open this publication in new window or tab >>Novel origins of copy number variation in the dog genome
    Show others...
    2012 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, no 8, p. R73-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-194244 (URN)10.1186/gb-2012-13-8-r73 (DOI)000315867500007 ()22916802 (PubMedID)
    Note

    Additional author: The LUPA Consortium (www.eurolupa.org)

    Available from: 2013-02-11 Created: 2013-02-11 Last updated: 2017-12-06Bibliographically approved
    4. Germline Metyhlation Patterns Determine The Distribution Of Recombination Events In The Dog Genome
    Open this publication in new window or tab >>Germline Metyhlation Patterns Determine The Distribution Of Recombination Events In The Dog Genome
    (English)In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653Article in journal (Refereed) Submitted
    National Category
    Genetics
    Identifiers
    urn:nbn:se:uu:diva-233190 (URN)
    Available from: 2014-09-30 Created: 2014-09-30 Last updated: 2017-12-05Bibliographically approved
  • 264.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nevalainen, Elisa M
    Molin, Anna-Maja
    Perloski, Michele
    André, Catherine
    Zody, Michael C
    Sharpe, Ted
    Hitte, Christophe
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lohi, Hannes
    Webster, Matthew T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Novel origins of copy number variation in the dog genome2012In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, no 8, p. R73-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution.

  • 265.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pollard, Katherine S.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hotspots of biased nucleotide substitutions in human genes2009In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 7, no 1, p. e26-Article in journal (Refereed)
    Abstract [en]

    Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome. This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.

  • 266.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Quilez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arndt, Peter F.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Germ line Methylation Patterns Determine the Distribution of Recombination Events in the Dog Genome2015In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 7, no 2, p. 522-530Article in journal (Refereed)
    Abstract [en]

    The positive-regulatory domain containing nine gene, PROMO, which strongly associates with the location of recombination events in several vertebrates, is inferred to be inactive in the dog genome. Here, we address several questions regarding the control of recombination and its influence on genome evolution in dogs. First, we address whether the association between CpG islands (CGIs) and recombination hotspots is generated by lack of methylation, GC-biased gene conversion (gBGC), or both. Using a genome-wide dog single nucleotide polymorphism data set and comparisons of the dog genome with related species, we show that recombination-associated CGIs have low CpG mutation rates, and that CpG mutation rate is negatively correlated with recombination rate genome wide, indicating that nonmethylation attracts the recombination machinery. We next use a neighbor-dependent model of nucleotide substitution to disentangle the effects of CpG mutability and gBGC and analyze the effects that loss of PROMO has on these rates. We infer that methylation patterns have been stable during canid genome evolution, but that dog CGIs have experienced a drastic increase in substitution rate due to gBGC, consistent with increased levels of recombination in these regions. We also show that gBGC is likely to have generated many new CGIs in the dog genome, but these mostly occur away from genes, whereas the number of C GIs in gene promoter regions has not increased greatly in recent evolutionary history. Recombination has a major impact on the distribution of CGIs that are detected in the dog genome due to the interaction between methylation and gBGC. The results indicate that germline methylation patterns are the main determinant of recombination rates in the absence of PRDM9.

  • 267.
    Berglund, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Quilez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Webster, Matthew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Germline Metyhlation Patterns Determine The Distribution Of Recombination Events In The Dog GenomeIn: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653Article in journal (Refereed)
  • 268.
    Bergman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ding, Zhoujie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antigen-Specific IgM Causes Deposition of C3 on Sheep Red Blood Cells Within Seconds After Immunization2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 442-442Article in journal (Other academic)
  • 269.
    Bergman, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hammarlöf, Disa L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Reducing ppGpp Level Rescues an Extreme Growth Defect Caused by Mutant EF-Tu2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e90486-Article in journal (Other academic)
    Abstract [en]

    Salmonella enterica grows extremely slowly when it depends on tufA499 (encoding the Gln125Arg mutant form of EF-Tu) to drive protein synthesis. We screened a plasmid library for multi-copy suppressors of the slow growth phenotype and identified spoT as a candidate. The spoT gene encodes a dual function enzyme with both ppGpp synthetase and hydrolase activities. When spoT was cloned behind an arabinose-inducible promoter the growth rate of the mutant strain increased in response to arabinose addition. We found that the slow-growing mutant strain had a relatively high basal level of ppGpp during exponential growth in rich medium. Overexpression of spoT significantly reduced this level of ppGpp suggesting that inappropriately high ppGpp levels might cause the slow growth rate associated with tufA499. We tested this hypothesis by inactivating relA (codes for RelA, a ribosome-associated ppGpp synthetase) in the mutant strain. This inactivation decreased the level of ppGpp in the mutant strain and increased its growth rate. Based on these data we propose that ribosomes depending on tufA499 for their supply of ternary complex (EF-Tu•GTP•aa-tRNA) experience amino acid starvation and that RelA on these starving ribosomes produces an excess of the alarmone ppGpp. This results in a suboptimal partitioning of transcription activity between genes important for fast growth in rich medium and genes important for growth in a poor medium. Accordingly, mutant bacteria growing in a rich medium act physiologically as though they were growing in a nutrient-poor environment. We propose that this generates a vicious circle and contributes to the extreme slow-growth phenotype associated with mutant EF-Tu. Reducing the level of ppGpp increases the growth rate of the mutant because it breaks this circle and reduces the wasteful misdirection of resources in the cell.

  • 270.
    Bergman, Jessica M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Genetics and Growth Regulation in Salmonella enterica2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Most free-living bacteria will encounter different environments and it is therefore critical to be able to rapidly adjust to new growth conditions in order to be competitively successful. Responding to changes requires efficient gene regulation in terms of transcription, RNA stability, translation and post-translational modifications.

    Studies of an extremely slow-growing mutant of Salmonella enterica, with a Glu125Arg mutant version of EF-Tu, revealed it to be trapped in a stringent response. The perceived starvation was demonstrated to be the result of increased mRNA cleavage of aminoacyl-tRNA synthetase genes leading to lower prolyl-tRNA levels. The mutant EF-Tu caused an uncoupling of transcription and translation, leading to increased turnover of mRNA, which trapped the mutant in a futile stringent response.

    To examine the essentiality of RNase E, we selected and mapped three classes of extragenic suppressors of a ts RNase E phenotype. The ts RNase E mutants were defective in the degradation of mRNA and in the processing of tRNA and rRNA. Only the degradation of mRNA was suppressed by the compensatory mutations. We therefore suggest that degradation of at least a subset of cellular mRNAs is an essential function of RNase E.

    Bioinformatically, we discovered that the mRNA of tufB, one of the two genes encoding EF-Tu, could form a stable structure masking the ribosomal binding site. This, together with previous studies that suggested that the level of EF-Tu protein could affect the expression of tufB, led us to propose three models for how this could occur. The stability of the tufB RNA structure could be affected by the elongation rate of tufB-translating ribosomes, possibly influenced by the presence of rare codons early in the in tufB mRNA.

    Using proteomic and genetic assays we concluded that two previously isolated RNAP mutants, each with a growth advantage when present as subpopulations on aging wild-type colonies, were dependent on the utilization of acetate for this phenotype. Increased growth of a subpopulation of wild-type cells on a colony unable to re-assimilate acetate demonstrated that in aging colonies, acetate is available in levels sufficient to sustain the growth of at least a small subpopulation of bacteria. 

    List of papers
    1. Reducing ppGpp Level Rescues an Extreme Growth Defect Caused by Mutant EF-Tu
    Open this publication in new window or tab >>Reducing ppGpp Level Rescues an Extreme Growth Defect Caused by Mutant EF-Tu
    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e90486-Article in journal (Other academic) Published
    Abstract [en]

    Salmonella enterica grows extremely slowly when it depends on tufA499 (encoding the Gln125Arg mutant form of EF-Tu) to drive protein synthesis. We screened a plasmid library for multi-copy suppressors of the slow growth phenotype and identified spoT as a candidate. The spoT gene encodes a dual function enzyme with both ppGpp synthetase and hydrolase activities. When spoT was cloned behind an arabinose-inducible promoter the growth rate of the mutant strain increased in response to arabinose addition. We found that the slow-growing mutant strain had a relatively high basal level of ppGpp during exponential growth in rich medium. Overexpression of spoT significantly reduced this level of ppGpp suggesting that inappropriately high ppGpp levels might cause the slow growth rate associated with tufA499. We tested this hypothesis by inactivating relA (codes for RelA, a ribosome-associated ppGpp synthetase) in the mutant strain. This inactivation decreased the level of ppGpp in the mutant strain and increased its growth rate. Based on these data we propose that ribosomes depending on tufA499 for their supply of ternary complex (EF-Tu•GTP•aa-tRNA) experience amino acid starvation and that RelA on these starving ribosomes produces an excess of the alarmone ppGpp. This results in a suboptimal partitioning of transcription activity between genes important for fast growth in rich medium and genes important for growth in a poor medium. Accordingly, mutant bacteria growing in a rich medium act physiologically as though they were growing in a nutrient-poor environment. We propose that this generates a vicious circle and contributes to the extreme slow-growth phenotype associated with mutant EF-Tu. Reducing the level of ppGpp increases the growth rate of the mutant because it breaks this circle and reduces the wasteful misdirection of resources in the cell.

    Keywords
    tufA; ppGpp; RelA; Salmonella enterica; growth regulation
    National Category
    Microbiology
    Research subject
    Microbiology; Molecular Cellbiology
    Identifiers
    urn:nbn:se:uu:diva-159663 (URN)10.1371/journal.pone.0090486 (DOI)000332396200210 ()
    Note

    Jessica M. Bergman and Disa L. Hammarlöf contributed equally to this work.

    Available from: 2011-10-06 Created: 2011-10-05 Last updated: 2017-12-08Bibliographically approved
    2. Turnover of mRNAs is an essential function of RNase E
    Open this publication in new window or tab >>Turnover of mRNAs is an essential function of RNase E
    (English)Manuscript (preprint) (Other academic)
    Keywords
    rpsA, vacB, RNaseR, RelBE, RNA turnover
    National Category
    Microbiology in the medical area
    Research subject
    Biology with specialization in Microbiology; Microbiology; Molecular Genetics
    Identifiers
    urn:nbn:se:uu:diva-235199 (URN)
    Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2018-01-11
    3. Autoregulation of the tufB operon in Salmonella
    Open this publication in new window or tab >>Autoregulation of the tufB operon in Salmonella
    2016 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 100, no 6, p. 1004-1016Article in journal (Refereed) Published
    Abstract [en]

    In Salmonella enterica and related species, translation elongation factor EF-Tu is encoded by two widely separated but near-identical genes, tufA and tufB. Two thirds of EF-Tu is expressed from tufA with the remaining one third coming from tufB. Inactivation of tufA is partly compensated by a doubling in the amount of EF-TuB but the mechanism of this up-regulation is unknown. By experimental evolution selecting for improved growth rate in a strain with an inactive tufA we selected six different noncoding or synonymous point mutations close to the tufB start codon. Based on these results we constructed a total of 161 different point mutations around the tufB start codon, as well as tufB 3'-truncations, and measured tufB expression using tufB-yfp transcriptional and translational fusions. The expression data support the presence of two competing stem-loop structures that can form in the 5'-end of the tufB mRNA. Formation of the 'closed' structure leads to Rho-dependent transcriptional termination of the tufB mRNA. We propose a model in which translational speed is used as a sensor for EF-Tu concentration and where the expression of tufB is post-transcriptionally regulated. This model describes for the first time how expression of the most abundant Salmonella protein is autoregulated.

    Keywords
    Salmonella enterica, tufA, tufB, EF-Tu, Rho, post-transcriptional regulation
    National Category
    Microbiology in the medical area
    Research subject
    Biology with specialization in Microbiology; Microbiology; Molecular Genetics
    Identifiers
    urn:nbn:se:uu:diva-235218 (URN)10.1111/mmi.13364 (DOI)000379687100008 ()26934594 (PubMedID)
    Funder
    Knut and Alice Wallenberg Foundation, KAW 2009.0251Swedish Research Council, 621-2012-2188; 521-2013-2904
    Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2018-01-11Bibliographically approved
    4. Acetate availability and utilization supports the growth of mutant sub-populations on aging bacterial colonies
    Open this publication in new window or tab >>Acetate availability and utilization supports the growth of mutant sub-populations on aging bacterial colonies
    2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e109255-Article in journal (Refereed) Published
    Abstract [en]

    When bacterial colonies age most cells enter a stationary phase, but sub-populations of mutant bacteria can continue to grow and accumulate. These sub-populations include bacteria with mutations in rpoB (RNA polymerase β-subunit) or rpoS (RNA polymerase stress-response sigma factor). Here we have identified acetate as a nutrient present in the aging colonies that is utilized by these mutant subpopulations to support their continued growth. Proteome analysis of aging colonies showed that several proteins involved in acetate conversion and utilization were upregulated during aging. Acetate is known to be excreted during the exponential growth phase but can be imported later during the transition to stationary phase and converted to acetyl-CoA. Acetyl-CoA is used in multiple processes, including feeding into the TCA cycle, generating ATP via the glyoxylate shunt, as a source of acetyl groups for protein modification, and to support fatty acid biosynthesis. We showed that deletion of acs (encodes acetyl-CoA synthetase; converts acetate into acetyl-CoA) significantly reduced the accumulation of rpoB and rpoS mutant subpopulations on aging colonies. Measurement of radioactive acetate uptake showed that the rate of conversion decreased in aging wild-type colonies, was maintained at a constant level in the rpoB mutant, and significantly increased in the aging rpoS mutant. Finally, we showed that the growth of subpopulations on aging colonies was greatly enhanced if the aging colony itself was unable to utilize acetate, leaving more acetate available for mutant subpopulations to use. Accordingly, the data show that the accumulation of subpopulations of rpoB and rpoS mutants on aging colonies is supported by the availability in the aging colony of acetate, and by the ability of the subpopulation cells to convert the acetate to acetyl-CoA.

    Keywords
    aceBAK, ackA-pta, acs, pka, growth in stationary phase, Salmonella Typhimurium
    National Category
    Microbiology in the medical area
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:uu:diva-234281 (URN)10.1371/journal.pone.0109255 (DOI)000342591500086 ()25275605 (PubMedID)
    Available from: 2014-10-15 Created: 2014-10-15 Last updated: 2018-01-11Bibliographically approved
  • 271.
    Bergman, Jessica M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wrande, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Paul G. Allen School for Global Animal Health, Washington State University, Pullman, Washington, United States of America.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Acetate availability and utilization supports the growth of mutant sub-populations on aging bacterial colonies2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e109255-Article in journal (Refereed)
    Abstract [en]

    When bacterial colonies age most cells enter a stationary phase, but sub-populations of mutant bacteria can continue to grow and accumulate. These sub-populations include bacteria with mutations in rpoB (RNA polymerase β-subunit) or rpoS (RNA polymerase stress-response sigma factor). Here we have identified acetate as a nutrient present in the aging colonies that is utilized by these mutant subpopulations to support their continued growth. Proteome analysis of aging colonies showed that several proteins involved in acetate conversion and utilization were upregulated during aging. Acetate is known to be excreted during the exponential growth phase but can be imported later during the transition to stationary phase and converted to acetyl-CoA. Acetyl-CoA is used in multiple processes, including feeding into the TCA cycle, generating ATP via the glyoxylate shunt, as a source of acetyl groups for protein modification, and to support fatty acid biosynthesis. We showed that deletion of acs (encodes acetyl-CoA synthetase; converts acetate into acetyl-CoA) significantly reduced the accumulation of rpoB and rpoS mutant subpopulations on aging colonies. Measurement of radioactive acetate uptake showed that the rate of conversion decreased in aging wild-type colonies, was maintained at a constant level in the rpoB mutant, and significantly increased in the aging rpoS mutant. Finally, we showed that the growth of subpopulations on aging colonies was greatly enhanced if the aging colony itself was unable to utilize acetate, leaving more acetate available for mutant subpopulations to use. Accordingly, the data show that the accumulation of subpopulations of rpoB and rpoS mutants on aging colonies is supported by the availability in the aging colony of acetate, and by the ability of the subpopulation cells to convert the acetate to acetyl-CoA.

  • 272. Bergman, Peter
    et al.
    Johansson, Linda
    Asp, Vendela
    Plant, Laura
    Gudmundsson, Gudmundur H
    Jonsson, Ann-Beth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Agerberth, Birgitta
    Neisseria gonorrhoeae downregulates expression of the human antimicrobial peptide LL-37.2005In: Cell Microbiol, ISSN 1462-5814, Vol. 7, no 7, p. 1009-17Article in journal (Refereed)
  • 273. Bergman, Peter
    et al.
    Johansson, Linda
    Wan, Hong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jones, Allison
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gallo, Richard L.
    Gudmundsson, Gudmundur H.
    Hökfelt, Tomas
    Jonsson, Ann-Beth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Agerberth, Birgitta
    Induction of the antimicrobial peptide CRAMP in the blood-brain barrier and meninges after meningococcal infection2006In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 74, no 12, p. 6982-6991Article in journal (Refereed)
    Abstract [en]

    Antimicrobial peptides are present in most living species and constitute important effector molecules of innate immunity. Recently, we and others have detected antimicrobial peptides in the brain. This is an organ that is rarely infected, which has mainly been ascribed to the protective functions of the blood-brain barrier (BBB) and meninges. Since the bactericidal properties of the BBB and meninges are not known, we hypothesized that antimicrobial peptides could play a role in these barriers. We addressed this hypothesis by infecting mice with the neuropathogenic bacterium Neisseria meningitidis. Brains were analyzed for expression of the antimicrobial peptide CRAMP by immunohistochemistry in combination with confocal microscopy. After infection, we observed induction of CRAMP in endothelial cells of the BBB and in cells of the meninges. To explore the functional role of CRAMP in meningococcal disease, we infected mice deficient of the CRAMP gene. Even though CRAMP did not appear to protect the brain from invasion of meningococci, CRAMP knockout mice were more susceptible to meningococcal infection than wild-type mice and exhibited increased meningococcal growth in blood, liver, and spleen. Moreover, we could demonstrate that carbonate, a compound that accumulates in the circulation during metabolic acidosis, makes meningococci more susceptible to CRAMP.

  • 274. Bergman, Peter
    et al.
    Termén, Stefan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Johansson, Linda
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nyström, Lisbeth
    Arenas, Ernest
    Jonsson, Ann-Beth
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hökfelt, Tomas
    Gudmundsson, Gudmundur H
    Agerberth, Birgitta
    The antimicrobial peptide rCRAMP is present in the central nervous system of the rat.2005In: J Neurochem, ISSN 0022-3042, Vol. 93, no 5, p. 1132-40Article in journal (Refereed)
  • 275.
    Bergquist, Helen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Inturi, Raviteja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zain, Rula
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    RNA triplex formation in human adenovirus type 4 VA RNAI and its implication on virus growthArticle in journal (Refereed)
  • 276.
    Bergquist, Helen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Dept Lab Med, Clin Res Ctr, SE-14186 Huddinge, Sweden..
    Rocha, Cristina S. J.
    Karolinska Inst, Dept Lab Med, Clin Res Ctr, SE-14186 Huddinge, Sweden..
    Alvarez-Asencio, Ruben
    KTH Royal Inst Technol, Sch Chem Sci & Engn, Dept Chem, Stockholm, Sweden.;Fdn IMDEA Nanociencia, 9 Campus Univ Cantoblanco, Madrid, Spain..
    Nguyen, Chi-Hung
    Rutland, Mark. W.
    KTH Royal Inst Technol, Sch Chem Sci & Engn, Dept Chem, Stockholm, Sweden..
    Smith, C. I. Edvard
    Karolinska Inst, Dept Lab Med, Clin Res Ctr, SE-14186 Huddinge, Sweden..
    Good, Liam
    Univ London, Dept Pathol & Infect Dis, Royal Vet Coll, London WC1E 7HU, England..
    Nielsen, Peter E.
    Univ Copenhagen, Panum Inst, Fac Hlth & Med Sci, Dept Cellular & Mol Med, Copenhagen, Denmark..
    Zain, Rula
    Karolinska Inst, Dept Lab Med, Clin Res Ctr, SE-14186 Huddinge, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Ctr Rare Dis, SE-17176 Stockholm, Sweden..
    Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)(n) Repeats by PNA or LNA Targeting2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0165788Article in journal (Refereed)
    Abstract [en]

    Expansion of (GAA)(n) repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich's ataxia. (GAA)(n) expansions form non-canonical structures, including intramolecular triplex (H-DNA), and Rloops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)(n) expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)(n) repeats of different lengths (short: n= 9, medium: n= 75 or long: n= 115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA) 4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT) 5-PNA did not. We present evidence that (GAA) 4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT) 5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression.

  • 277. Bergqvist, A
    et al.
    Nilsson, M
    Bondeson, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Magnusson, G
    Loss of DNA-binding and new transcriptional trans-activation function in polyomavirus large T-antigen with mutation of zinc finger motif.1990In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 18, no 9, p. 2715-20Article in journal (Refereed)
    Abstract [en]

    A putative zinc finger in polyomavirus large T-antigen was investigated. We were unable to demonstrate unequivocally a requirement for zinc in specific DNA-binding using the chelating agent 1, 10-phenanthroline. An involvement of the putative zinc finger in specific DNA-binding was nevertheless suggested by the properties of a mutant protein with a cys----ser replacement in the finger motif. Probably as a result of the defective DNA-binding, the mutant protein had lost its activity in initiation of viral DNA-replication and in negative regulation of viral early transcription. However, the trans-activation of the viral late promoter was normal. The analysis also revealed a previously unrecognized activity of large T-antigen. The mutant protein trans-activated the viral early promoter. In the wild-type protein this activity is probably concealed by the separate, negative regulatory function.

  • 278.
    Bergqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Bondeson, Kåre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Loss of DNA-binding and new transcriptional trans-activation function in polyomavirus large T-antigen with mutation of zinc finger motif.1990In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962Article in journal (Refereed)
  • 279.
    Bergqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rice, Charles M.
    Washington University, St Louis.
    Transcriptional activation of the interleukin-2 promoter by hepatitis C virus core protein2001In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 75, no 2, p. 772-781Article in journal (Refereed)
    Abstract [en]

    Most patients infected with hepatitis C virus (HCV) become chronic carriers. Viruses that efficiently establish persistent infections must have effective ways of evading host defenses. In the case of HCV, little is known about how chronic infections are established or maintained. Besides hepatocytes, several reports suggest that HCV can infect T and B lymphocytes. Since T cells are essential for viral clearance, direct or indirect effects of HCV on T-cell function could influence the outcome of infection. Given that T-cell growth and differentiation require the cytokine interleukin 2 (IL-2), we asked whether HCV might modulate synthesis of IL-2. Portions of the HCV polyprotein were expressed in Jurkat cells under a variety of conditions. We found that the highly conserved HCV core protein, in combination with other stimuli, was able to dramatically activate transcription from the IL-2 promoter. The carboxy-terminal hydrophobic portion of the core protein was required for this activity. Activation was dependent on nuclear factor of activated T cells (NFAT), occurred in cells deficient in the tyrosine kinase p56lck, and could be blocked by addition of cyclosporin A and by depletion of calcium. These results suggest that the HCV core protein can activate transcription of the IL-2 promoter through the NFAT pathway. This novel activity may have consequences for T-cell development and establishment of persistent infections.

  • 280.
    Bergqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundström, Sara
    Karolinska Institutet.
    Dimberg, Lina Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gylfe, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Masucci, Maria G.
    Karolinska Institutet.
    The Hepatitis C Virus Core Protein Modulates T Cell Responses by Inducing Spontaneous and Altering T-cell Receptor-triggered Ca2+ Oscillations2003In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, no 21, p. 18877-18883Article in journal (Refereed)
    Abstract [en]

    Alterations of cytokine responses are thought to favor the establishment of persistent hepatitis C virus (HCV) infection, enhancing the risk of liver cirrhosis and hepatocellular carcinoma. Expression of the HCV core (C) protein modulates transcription of the IL-2 promoter in T lymphocytes by activating the nuclear factor of activated T lymphocyte (NFAT) pathway. Here we report on the effect of HCV C on Ca2+ signaling, which is essential for activation of NFAT. Expression of HCV C correlated with increased levels of cytosolic Ca2+ and spontaneous Ca2+ oscillations in transfected Jurkat cells. Triggering of the T-cell receptor induced a prolonged Ca2+ response characterized by vigorous high frequent oscillations in a high proportion of the responding cells. This was associated with decreased sizes and accelerated emptying of the intracellular calcium stores. The effect of HCV C on calcium mobilization was not dependent on phospholipase C-1 (PLC-) activity or increased inositol 1,4,5-trisphosphate (IP3) production and did not require functional IP3 receptors, suggesting that insertion of the viral protein in the endoplasmic reticulum membrane may be sufficient to promote Ca2+ leakage with dramatic downstream consequences on the magnitude and duration of the response. Our data suggest that expression of HCV C in infected T lymphocytes may contribute to the establishment of persistent infections by inducing Ca2+ oscillations that regulate both the efficacy and information content of Ca2+ signals and are ultimately responsible for induction of gene expression and functional differentiation.

  • 281.
    Bergqvist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Söderbärg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Magnusson, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Altered susceptibility to tumor necrosis factor alpha-induced apoptosis of mouse cells expressing polyomavirus middle and small T antigens1997In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 71, no 1, p. 276-283Article in journal (Refereed)
    Abstract [en]

    Infection with some virus types induces susceptibility to the cytotoxic effect of tumor necrosis factor alpha (TNF-alpha). To investigate whether expression of polyomavirus proteins has this effect on cells, the TNF-alpha sensitivity of C127 and L929 mouse cells transfected with viral DNA was analyzed. Expression of all three polyomavirus early proteins, the tumor (T) antigens, had no apparent effect. In contrast, middle T antigen by itself induced hypersensitivity to TNF-alpha. This effect was reversed by retransfection of the cells with DNA encoding small T antigen. Expression of this polypeptide also decreased the sensitivity of bovine papillomavirus type 1-transformed cells to TNF- alpha, showing that the protective function of the polyomavirus small T antigen was not strictly linked to a middle-T-antigen-induced event. Mouse and human TNF-alpha had the same effect on normal and transformed mouse cells, suggesting that this effect was mediated by TNF receptor 1. Consistent with this conclusion, all cell clones used in the experiments expressed TNF receptor 1 at similar levels, while we failed to detect TNF receptor 2. The amount of receptor on the cells was not influenced by binding of the ligand. Addition of TNF-alpha at cytotoxic concentrations to cells expressing middle T antigen by itself resulted in significant fragmentation of chromosomal DNA after only a few hours, indicating induction of apoptosis. Addition of the cytokine to these cells also leads to release of arachidonic acid, showing that phospholipase A2 was activated. However, production of arachidonic acid did not appear to significantly precede loss of cell viability.

  • 282.
    Bergström, Jennie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.