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  • 1.
    Aase-Remedios, Madeleine E.
    et al.
    Univ Durham, Dept Biosci, Durham DH1 3LE, England..
    Janssen, Ralf
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Leite, Daniel J.
    Univ Durham, Dept Biosci, Durham DH1 3LE, England..
    Sumner-Rooney, Lauren
    Leibniz Inst Evolut & Biodiversitatsforsch, Museum Nat Kunde, D-10115 Berlin, Germany..
    McGregor, Alistair P.
    Univ Durham, Dept Biosci, Durham DH1 3LE, England..
    Wittkopp, Patricia
    Evolution of the Spider Homeobox Gene Repertoire by Tandem and Whole Genome Duplication2023In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 40, no 12, article id msad239Article in journal (Refereed)
    Abstract [en]

    Gene duplication generates new genetic material that can contribute to the evolution of gene regulatory networks and phenotypes. Duplicated genes can undergo subfunctionalization to partition ancestral functions and/or neofunctionalization to assume a new function. We previously found there had been a whole genome duplication (WGD) in an ancestor of arachnopulmonates, the lineage including spiders and scorpions but excluding other arachnids like mites, ticks, and harvestmen. This WGD was evidenced by many duplicated homeobox genes, including two Hox clusters, in spiders. However, it was unclear which homeobox paralogues originated by WGD versus smaller-scale events such as tandem duplications. Understanding this is a key to determining the contribution of the WGD to arachnopulmonate genome evolution. Here we characterized the distribution of duplicated homeobox genes across eight chromosome-level spider genomes. We found that most duplicated homeobox genes in spiders are consistent with an origin by WGD. We also found two copies of conserved homeobox gene clusters, including the Hox, NK, HRO, Irx, and SINE clusters, in all eight species. Consistently, we observed one copy of each cluster was degenerated in terms of gene content and organization while the other remained more intact. Focussing on the NK cluster, we found evidence for regulatory subfunctionalization between the duplicated NK genes in the spider Parasteatoda tepidariorum compared to their single-copy orthologues in the harvestman Phalangium opilio. Our study provides new insights into the relative contributions of multiple modes of duplication to the homeobox gene repertoire during the evolution of spiders and the function of NK genes.

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  • 2.
    Abalde, Samuel
    et al.
    Swedish Museum Nat Hist, Dept Zool, Stockholm, Sweden..
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heintz, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vinnere Pettersson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jondelius, Ulf
    Swedish Museum Nat Hist, Dept Zool, Stockholm, Sweden.;Stockholm Univ, Dept Zool, Stockholm, Sweden..
    The draft genome of the microscopic Nemertoderma westbladi sheds light on the evolution of Acoelomorpha genomes2023In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 14, article id 1244493Article in journal (Refereed)
    Abstract [en]

    Background: Xenacoelomorpha is a marine clade of microscopic worms that is an important model system for understanding the evolution of key bilaterian novelties, such as the excretory system. Nevertheless, Xenacoelomorpha genomics has been restricted to a few species that either can be cultured in the lab or are centimetres long. Thus far, no genomes are available for Nemertodermatida, one of the group’s main clades and whose origin has been dated more than 400 million years ago.

    Methods: DNA was extracted from a single specimen and sequenced with HiFi following the PacBio Ultra-Low DNA Input protocol. After genome assembly, decontamination, and annotation, the genome quality was benchmarked using two acoel genomes and one Illumina genome as reference. The gene content of three cnidarians, three acoelomorphs, four deuterostomes, and eight protostomes was clustered in orthogroups to make inferences of gene content evolution. Finally, we focused on the genes related to the ultrafiltration excretory system to compare patterns of presence/absence and gene architecture among these clades.

    Results: We present the first nemertodermatid genome sequenced from a single specimen of Nemertoderma westbladi. Although genome contiguity remains challenging (N50: 60 kb), it is very complete (BUSCO: 80.2%, Metazoa; 88.6%, Eukaryota) and the quality of the annotation allows fine-detail analyses of genome evolution. Acoelomorph genomes seem to be relatively conserved in terms of the percentage of repeats, number of genes, number of exons per gene and intron size. In addition, a high fraction of genes present in both protostomes and deuterostomes are absent in Acoelomorpha. Interestingly, we show that all genes related to the excretory system are present in Xenacoelomorpha except Osr, a key element in the development of these organs and whose acquisition seems to be interconnected with the origin of the specialised excretory system.

    Conclusion: Overall, these analyses highlight the potential of the Ultra-Low Input DNA protocol and HiFi to generate high-quality genomes from single animals, even for relatively large genomes, making it a feasible option for sequencing challenging taxa, which will be an exciting resource for comparative genomics analyses.

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  • 3.
    Abbey-Lee, Robin N.
    et al.
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Uhrig, Emily J.
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Zidar, Josefina
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Favati, Anna
    Stockholm Univ, Dept Zool, Stockholm, Sweden.
    Almberg, Johan
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    Dahlbom, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Winberg, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lövlie, Hanne
    Linkoping Univ, IFM Biol, Dept Phys Chem & Biol, SE-58183 Linkoping, Sweden.
    The Influence of Rearing on Behavior, Brain Monoamines, and Gene Expression in Three-Spined Sticklebacks2018In: Brain, behavior, and evolution, ISSN 0006-8977, E-ISSN 1421-9743, Vol. 91, no 4, p. 201-213Article in journal (Refereed)
    Abstract [en]

    The causes of individual variation in behavior are often not well understood, and potential underlying mechanisms include both intrinsic and extrinsic factors, such as early environmental, physiological, and genetic differences. In an exploratory laboratory study, we raised three-spined sticklebacks (Gasterosteus aculeatus) under 4 different environmental conditions (simulated predator environment, complex environment, variable social environment, and control). We investigated how these manipulations related to behavior, brain physiology, and gene expression later in life, with focus on brain dopamine and serotonin levels, turnover rates, and gene expression. The different rearing environments influenced behavior and gene expression, but did not alter monoamine levels or metabolites. Specifically, compared to control fish, fish exposed to a simulated predator environment tended to be less aggressive, more exploratory, and more neophobic; and fish raised in both complex and variable social environments tended to be less neophobic. Exposure to a simulated predator environment tended to lower expression of dopamine receptor DRD4A, a complex environment increased expression of dopamine receptor DRD1B, while a variable social environment tended to increase serotonin receptor 5-HTR2B and serotonin transporter SLC6A4A expression. Despite both behavior and gene expression varying with early environment, there was no evidence that gene expression mediated the relationship between early environment and behavior. Our results confirm that environmental conditions early in life can affect phenotypic variation. However, the mechanistic pathway of the monoaminergic systems translating early environmental variation into observed behavioral responses was not detected.

  • 4.
    Adler, Marlen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mechanisms and Dynamics of Carbapenem Resistance in Escherichia coli2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The emergence of extended spectrum β-lactamase (ESBL) producing Enterobacteriaceae worldwide has led to an increased use of carbapenems and may drive the development of carbapenem resistance. Existing mechanisms are mainly due to acquired carbapenemases or the combination of ESBL-production and reduced outer membrane permeability. The focus of this thesis was to study the development of carbapenem resistance in Escherichia coli in the presence and absence of acquired β-lactamases. To this end we used the resistance plasmid pUUH239.2 that caused the first major outbreak of ESBL-producing Enterobacteriaceae in Scandinavia.

    Spontaneous carbapenem resistance was strongly favoured by the presence of the ESBL-encoding plasmid and different mutational spectra and resistance levels arose for different carbapenems. Mainly, loss of function mutations in the regulators of porin expression caused reduced influx of antibiotic into the cell and in combination with amplification of β-lactamase genes on the plasmid this led to high resistance levels. We further used a pharmacokinetic model, mimicking antibiotic concentrations found in patients during treatment, to test whether ertapenem resistant populations could be selected even at these concentrations. We found that resistant mutants only arose for the ESBL-producing strain and that an increased dosage of ertapenem could not prevent selection of these resistant subpopulations. In another study we saw that carbapenem resistance can even develop in the absence of ESBL-production. We found mutants in export pumps and the antibiotic targets to give high level resistance albeit with high fitness costs in the absence of antibiotics. In the last study, we used selective amplification of β-lactamases on the pUUH239.2 plasmid by carbapenems to determine the cost and stability of gene amplifications. Using mathematical modelling we determined the likelihood of evolution of new gene functions in this region. The high cost and instability of the amplified state makes de novo evolution very improbable, but constant selection of the amplified state may balance these factors until rare mutations can establish a new function.

    In my studies I observed the influence of β-lactamases on carbapenem resistance and saw that amplification of these genes would further contribute to resistance. The rapid disappearance of amplified arrays of resistance genes in the absence of antibiotic selection may lead to the underestimation of gene amplification as clinical resistance mechanism. Amplification of β-lactamase genes is an important stepping-stone and might lead to the evolution of new resistance genes.

    List of papers
    1. Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli
    Open this publication in new window or tab >>Influence of acquired β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli
    2013 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 1, p. 51-59Article in journal (Refereed) Published
    Abstract [en]

    Objectives: To investigate the influence of plasmid-borne β-lactamases on the evolution of spontaneous carbapenem resistance in Escherichia coli and the fitness costs associated with resistance. Methods: Stepwise selection of carbapenem-resistant mutants with or without the extended-spectrum β-lactamase (ESBL)-encoding plasmid pUUH239.2 was performed. Mutation rates and mutational pathways to resistance were determined. In vitro-selected and constructed mutants were characterized regarding the MICs of the carbapenems, porin expression profiles, growth rates and the presence of mutations in the porins ompC/ompF and their regulatory genes. The influence of the plasmid-encoded β-lactamases TEM-1, OXA-1 and CTX-M-15 on resistance development was determined. Results: Results show that E. coli readily developed reduced carbapenem susceptibility and clinical resistance levels by a combination of porin loss and increased β-lactamase expression, especially towards ertapenem. All tested β-lactamases (CTX-M-15, TEM-1 and OXA-1) contributed to reduced carbapenem susceptibility in the absence of porin expression. However, complete loss of porin expression conferred a 20% fitness cost on the bacterial growth rate. Increased β-lactamase expression through spontaneous gene amplification on the plasmid was a major resistance factor. Conclusions: Plasmid-encoded β-lactamases, including non-ESBL enzymes, have a strong influence on the frequency and resistance level of spontaneous carbapenem-resistant mutants. The fitness cost associated with the loss of OmpC/OmpF in E. coli most likely reduces the survivability of porin mutants and could explain why they have not emerged as a clinical problem in this species.

    Keywords
    Fitness cost, Gene amplification, Mutations, Plasmids
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-192026 (URN)10.1093/jac/dks368 (DOI)000312646300010 ()
    Available from: 2013-01-24 Created: 2013-01-15 Last updated: 2017-12-06Bibliographically approved
    2. Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model
    Open this publication in new window or tab >>Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model
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    2013 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 6, p. 1319-1326Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES:

    Ertapenem resistance is increasing in Enterobacteriaceae. The production of extended-spectrum β-lactamases (ESBLs) and reduced expression of outer membrane porins are major mechanisms of resistance in ertapenem-resistant Klebsiella pneumoniae. Less is known of ertapenem resistance in Escherichia coli. The aim of this study was to explore the impact of ESBL production in E. coli on the antibacterial activity of ertapenem.

    METHODS:

    Two E. coli strains, with and without ESBL production, were exposed to ertapenem in vitro for 48 h at concentrations simulating human pharmacokinetics with conventional and higher dosages.

    RESULTS:

    Isolates with non-susceptibility to ertapenem (MICs 0.75-1.5 mg/L) were detected after five of nine time-kill experiments with the ESBL-producing strain. All of these isolates had ompR mutations, which reduce the expression of outer membrane porins OmpF and OmpC. Higher dosage did not prevent selection of porin-deficient subpopulations. No mutants were detected after experiments with the non-ESBL-producing strain. Compared with other experiments, experiments with ompR mutants detected in endpoint samples showed significantly less bacterial killing after the second dose of ertapenem. Impaired antibacterial activity against E. coli with ESBL production and ompR mutation was also demonstrated in time-kill experiments with static antibiotic concentrations.

    CONCLUSIONS:

    The combination of ESBL production and porin loss in E. coli can result in reduced susceptibility to ertapenem. Porin-deficient subpopulations frequently emerged in ESBL-producing E. coli during exposure to ertapenem at concentrations simulating human pharmacokinetics. Inappropriate use of ertapenem should be avoided to minimize the risk of selection of ESBL-producing bacteria with reduced susceptibility to carbapenems.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-197878 (URN)10.1093/jac/dkt044 (DOI)000319468900016 ()23478794 (PubMedID)
    Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06Bibliographically approved
    3. Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli
    Open this publication in new window or tab >>Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli
    2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1188-1198Article in journal (Refereed) Published
    Abstract [en]

    The worldwide spread of ESBL-producing Enterobacteriaceae has led to an increased use of carbapenems, the group of beta-lactams with the broadest spectrum of activity. Bacterial resistance to carbapenems is mainly due to acquired carbapenemases or a combination of ESBL production and reduced drug influx via loss of outer-membrane porins. Here, we have studied the development of carbapenem resistance in Escherichia coli in the absence of beta-lactamases. We selected mutants with high-level carbapenem resistance through repeated serial passage in the presence of increasing concentrations of meropenem or ertapenem for similar to 60 generations. Isolated clones were whole-genome sequenced, and the order in which the identified mutations arose was determined in the passaged populations. Key mutations were reconstructed, and bacterial growth rates of populations and isolated clones and resistance levels to 23 antibiotics were measured. High-level resistance to carbapenems resulted from a combination of downstream effects of envZ mutation and target mutations in AcrAB-TolC-mediated drug export, together with PBP genes [mrdA (PBP2) after meropenem exposure or ftsI (PBP3) after ertapenem exposure]. Our results show that antibiotic resistance evolution can occur via several parallel pathways and that new mechanisms may appear after the most common pathways (i.e. beta-lactamases and loss of porins) have been eliminated. These findings suggest that strategies to target the most commonly observed resistance mechanisms might be hampered by the appearance of previously unknown parallel pathways to resistance.

    National Category
    Biochemistry and Molecular Biology Microbiology
    Identifiers
    urn:nbn:se:uu:diva-221428 (URN)10.1093/jac/dkv475 (DOI)000376291300008 ()26869688 (PubMedID)
    Funder
    Swedish Research Council Formas, 2013-5476-25194-9EU, European Research Council, 282004
    Available from: 2014-03-31 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved
    4. High Fitness Costs and Instability of Gene Duplications Reduce Rates of Evolution of New Genes by Duplication-Divergence Mechanisms
    Open this publication in new window or tab >>High Fitness Costs and Instability of Gene Duplications Reduce Rates of Evolution of New Genes by Duplication-Divergence Mechanisms
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    2014 (English)In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 31, no 6, p. 1526-1535Article in journal (Refereed) Published
    Abstract [sv]

    An important mechanism for generation of new genes is by duplication-divergence of existing genes. Duplication-divergence includes several different sub-models, such as subfunctionalization where after accumulation of neutral mutations the original function is distributed between two partially functional and complementary genes, and neofunctionalization where a new function evolves in one of the duplicated copies while the old function is maintained in another copy. The likelihood of these mechanisms depends on the longevity of the duplicated state, which in turn depends on the fitness cost and genetic stability of the duplications. Here, we determined the fitness cost and stability of defined gene duplications/amplifications on a low copy number plasmid. Our experimental results show that the costs of carrying extra gene copies are substantial and that each additional kbp of DNA reduces fitness by approximately 0.15%. Furthermore, gene amplifications are highly unstable and rapidly segregate to lower copy numbers in absence of selection. Mathematical modelling shows that the fitness costs and instability strongly reduces the likelihood of both sub- and neofunctionalization, but that these effects can be off-set by positive selection for novel beneficial functions.

    National Category
    Microbiology Biochemistry and Molecular Biology Genetics
    Identifiers
    urn:nbn:se:uu:diva-221431 (URN)10.1093/molbev/msu111 (DOI)000337067400019 ()
    Available from: 2014-03-31 Created: 2014-03-31 Last updated: 2017-12-05Bibliographically approved
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  • 5.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Otto, G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    High Fitness Costs and Instability of Gene Duplications Reduce Rates of Evolution of New Genes by Duplication-Divergence Mechanisms2014In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 31, no 6, p. 1526-1535Article in journal (Refereed)
    Abstract [sv]

    An important mechanism for generation of new genes is by duplication-divergence of existing genes. Duplication-divergence includes several different sub-models, such as subfunctionalization where after accumulation of neutral mutations the original function is distributed between two partially functional and complementary genes, and neofunctionalization where a new function evolves in one of the duplicated copies while the old function is maintained in another copy. The likelihood of these mechanisms depends on the longevity of the duplicated state, which in turn depends on the fitness cost and genetic stability of the duplications. Here, we determined the fitness cost and stability of defined gene duplications/amplifications on a low copy number plasmid. Our experimental results show that the costs of carrying extra gene copies are substantial and that each additional kbp of DNA reduces fitness by approximately 0.15%. Furthermore, gene amplifications are highly unstable and rapidly segregate to lower copy numbers in absence of selection. Mathematical modelling shows that the fitness costs and instability strongly reduces the likelihood of both sub- and neofunctionalization, but that these effects can be off-set by positive selection for novel beneficial functions.

  • 6.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts: Integrative Bioinformatic and Experimental Approaches2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology.

    In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM.

    In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted.

    In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.

    List of papers
    1. Polycomb target genes are silenced in multiple myeloma
    Open this publication in new window or tab >>Polycomb target genes are silenced in multiple myeloma
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    2010 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 5, no 7, p. e11483-Article in journal (Refereed) Published
    Abstract [en]

    Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-133207 (URN)10.1371/journal.pone.0011483 (DOI)000279715300003 ()20634887 (PubMedID)
    Available from: 2010-11-03 Created: 2010-11-03 Last updated: 2021-06-14Bibliographically approved
    2. The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy
    Open this publication in new window or tab >>The epigenomic map of multiple myeloma reveals the importance of Polycomb gene silencing for the malignancy
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Multiple myeloma (MM) is characterized by accumulation of post-germinal center, isotype switched, long-living plasma cells with retained proliferation capacity within the bone marrow. MM is highly heterogeneous and remains fatal. This heterogeneity has hampered identification of a common underlying mechanism for disease establishment and the development of targeted therapy. We recently provided proof-of-principle that gene silencing associated with H3K27me3 contributes to the malignancy of MM. Here we present the first epigenomic map of MM for H3K27me3 and H3K4me3 derived by ChIP- and RNA sequencing from freshly-isolated bone marrow plasma cells from four patients. We compile lists of targets common among the patients as well as unique to MM when compared with PBMCs. Indicating the clinical relevance of our findings, we find increased silencing of H3K27me3 targets with disease progression and in patients presenting with a poor prognosis. Bivalent genes further significantly correlated to under-expressed genes in MM and were unique to MM when compared to PBMCs. Furthermore, bivalent genes, unlike H3K27me3 targets, significantly associated with transcriptional activation upon Polycomb inhibition indicating a potential for drug targeting. Thus, we suggest that gene silencing by Polycomb plays an important role in the development of the malignant phenotype of the MM cell during tumor progression.

    National Category
    Cell and Molecular Biology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-199492 (URN)
    Available from: 2013-05-06 Created: 2013-05-06 Last updated: 2018-01-11Bibliographically approved
    3. Tumor-initiating capacity of CD138- and CD138+ tumor cells in the 5T33 multiple myeloma model
    Open this publication in new window or tab >>Tumor-initiating capacity of CD138- and CD138+ tumor cells in the 5T33 multiple myeloma model
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    2012 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, no 6, p. 1436-1439Article in journal, Letter (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-177948 (URN)10.1038/leu.2011.373 (DOI)000305081000040 ()22289925 (PubMedID)
    Available from: 2012-07-25 Created: 2012-07-20 Last updated: 2017-12-07Bibliographically approved
    4. Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
    Open this publication in new window or tab >>Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs
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    2016 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 15, no 12, p. 1558-1571Article in journal (Refereed) Published
    Abstract [en]

    CGGBP1 (CGG triplet repeat-binding protein 1) regulates cell proliferation, stress response,cytokinesis, telomeric integrity and transcription. It could affect these processes by modulatingtarget gene expression under different conditions. Identification of CGGBP1-target genes andtheir regulation could reveal how a transcription regulator affects such diverse cellular processes.Here we describe the mechanisms of differential gene expression regulation by CGGBP1 inquiescent or growing cells. By studying global gene expression patterns and genome-wide DNAbindingpatterns of CGGBP1, we show that a possible mechanism through which it affects theexpression of RNA Pol II-transcribed genes in trans depends on Alu RNA. We also show that itregulates Alu transcription in cis by binding to Alu promoter. Our results also indicate thatpotential phosphorylation of CGGBP1 upon growth stimulation facilitates its nuclear retention,Alu-binding and dislodging of RNA Pol III therefrom. These findings provide insights into howAlu transcription is regulated in response to growth signals.

    Keywords
    Alu-SINEs; CGGBP1; ChIP-seq; growth signals; RNA Pol III; transcription; tyrosine phosphorylation
    National Category
    Cell Biology
    Research subject
    Bioinformatics; Biology
    Identifiers
    urn:nbn:se:uu:diva-230959 (URN)10.4161/15384101.2014.967094 (DOI)000379743800011 ()25483050 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
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  • 7. Agler, Caryline
    et al.
    Nielsen, Dahlia M.
    Urkasemsin, Ganokon
    Singleton, Andrew
    Tonomura, Noriko
    Sigurdsson, Snaevar
    Tang, Ruqi
    Linder, Keith
    Arepalli, Sampath
    Hernandez, Dena
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van de Leemput, Joyce
    Motsinger-Reif, Alison
    O'Brien, Dennis P.
    Bell, Jerold
    Harris, Tonya
    Steinberg, Steven
    Olby, Natasha J.
    Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB242014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 2, p. e1003991-Article in journal (Refereed)
    Abstract [en]

    Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia. Author Summary Neurodegenerative diseases are one of the most important causes of decline in an aging population. An important subset of these diseases are known as the hereditary ataxias, familial neurodegenerative diseases that affect the cerebellum causing progressive gait disturbance in both humans and dogs. We identified a mutation in RAB24, a gene associated with autophagy, in Old English Sheepdogs and Gordon Setters with hereditary ataxia. Autophagy is a process by which cell proteins and organelles are removed and recycled and its critical role in maintenance of the continued health of cells is becoming clear. We evaluated the brains of affected dogs and identified accumulations of autophagosomes within the cerebellum, suggesting a defect in the autophagy pathway. Our results suggest that a defect in the autophagy pathway results in neuronal death in a naturally occurring disease in dogs. The autophagy pathway should be investigated in human hereditary ataxia and may represent a therapeutic target in neurodegenerative diseases.

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  • 8.
    Agrillo, Caroline
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    DNA methylation modifications in human mesenchymal stem cells  induced by exposure to endocrine disrupting plasticiser metabolites MBP, MEP, MBzP, MEHP and MINCH2022Independent thesis Advanced level (degree of Master (Two Years)), 80 credits / 120 HE creditsStudent thesis
    Abstract [en]

    Endocrine disrupting chemicals (EDCs) are exogenous substances which can modify the function of the endocrine system and lead to adverse health effects. Humans experience daily uncontrolled exposure to EDC mixtures. Predicting mixture effects is complicated since the chemicals may produce different effects when combined together. EDCs may produce epigenetic effects such as alterations of the DNA methylation, which could modify the expression of the gene. Previously, 14 chemicals linked to metabolism (mixture G1) were reported to induce DNA methylation changes in an in vitro model. Mixture G1 were based on a Swedish longitudinal study which had identified the chemical burden of >2300 pregnant women. This project aimed to study single chemical driver effects of five individual chemicals from mixture G1, namely the four phthalate metabolites monobutyl phthalate (MBP), monoethyl phthalate (MEP), monobenzyl pthtalate (MBzP), mono-(2-ethylhexyl) phthalate (MEHP) and the non-phthalate plasticiser Bis(7-methyloctyl) Cyclohexane-1,2-dicarboxylate (DINCH) metabolite 2-4-methyl-7-oxyoctyl-oxycarbonyl-cyclohexane carboxylic acid (MINCH). Human mesenchymal stem cells (hMSCs) were exposed to the five compounds individually at the same concentrations as in mixture G1. After exposure, DNA methylation changes in four CpG sites within PGM1, MYOF and HCFC1 genes were analysed. While som chemicals did not show statistically significant effects, one chemical showed significant effects and thus could be a potential driver. The discrepancy between the observed DNA methylation alterations in the analysed genes and the alterations in mixture G1 highlights the need for comparing mixture to single chemical effects to identify drivers within mixes and for increased understanding of mixture effects.

    The full text will be freely available from 2026-01-01 15:14
  • 9.
    Al-Ani, Abdullah
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre. University of Northampton.
    Investigating the subcellular localisation and function(s) of dystrophin protein Dp71 isoforms in glioma2022Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

    The Dp71 protein is the most expressed product of the DMD gene in the nervous system. Mutation in the region codes dystrophin protein (Dp71) linked to cognitive disturbances in Duchenne muscular dystrophy (DMD) patients. There is growing evidence that the gene is contributing to the development of Central Nervous System related cancers. The aim of this study is to characterise the role of the main 4 Dp71 isoforms by investigating its subcellular localisation and putative cellular functions in glioblastoma cells, the most aggressive and common type of glioma. By transfecting the four GFP-Dp71 constructs into a well characterised human glioblastoma cell line – U251-MG. Immunoblotting was used to assess Dp71 expression in human glioblastoma cell line. Moreover, we examined the subcellular localisation and the effect of Dp71 over expression on the nuclear Lamin B1, cell migration immunofluorescence, and scratch assay. A 71 kDa endogenous Dp71 was expressed in all glioblastoma cells and only GFP-Dp71a (99 kDa) isoform was overexpressed in the transfected cells. Lower Lamin B1 fluorescence intensity and abnormal nuclear shape was observed in cells overexpressing GFP-Dp71a. Furthermore, cytoplasmic and nuclear localisation of Dp71 isoform was found in both cytoplasm and nucleus, but higher in the nucleus. Overexpression of Dp71a transfected cells reduced the cell migration and covering the scratched tissue gaps with 5% and 6%, whilst that of the control cells were 29% and 50% at time 24 and 48 hours, respectively compared to the that at time 0. Dp71ab transfected cells showed similar cell migration to the control. We concluded that Dp71 overexpression had a clear effect on the expression of Lamin B1 and cell migration. Additionally, localisation of Dp71a was higher in the nucleus than in the cytoplasm.

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  • 10. Ala-Poikela, M.
    et al.
    Svensson, 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.
    Rojas, A.
    Horko, T.
    Paulin, L.
    Valkonen, J.
    Kvarnheden, A.
    Genetic diversity and mixed infections of begomoviruses in tomato, pepper and cucurbit crops in Nicaragua2005In: Plant Pathology, no 54, p. 448-459Article in journal (Refereed)
  • 11.
    Alatalo, Juha M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Little, Chelsea J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Jagerbrand, Annika K.
    Molau, Ulf
    Vascular plant abundance and diversity in an alpine heath under observed and simulated global change2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 10197Article in journal (Refereed)
    Abstract [en]

    Global change is predicted to cause shifts in species distributions and biodiversity in arctic tundra. We applied factorial warming and nutrient manipulation to a nutrient and species poor alpine/arctic heath community for seven years. Vascular plant abundance in control plots increased by 31%. There were also notable changes in cover in the nutrient and combined nutrient and warming treatments, with deciduous and evergreen shrubs declining, grasses overgrowing these plots. Sedge abundance initially increased significantly with nutrient amendment and then declined, going below initial values in the combined nutrient and warming treatment. Nutrient addition resulted in a change in dominance hierarchy from deciduous shrubs to grasses. We found significant declines in vascular plant diversity and evenness in the warming treatment and a decline in diversity in the combined warming and nutrient addition treatment, while nutrient addition caused a decline in species richness. The results give some experimental support that species poor plant communities with low diversity may be more vulnerable to loss of species diversity than communities with higher initial diversity. The projected increase in nutrient deposition and warming may therefore have negative impacts on ecosystem processes, functioning and services due to loss of species diversity in an already impoverished environment.

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  • 12.
    Albrecht, Lisa M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antibiotic Resistance: Selection in the Presence of Metals and Antimicrobials2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The external environment is complex: Antibiotics, metals and antimicrobials do not exist in isolation but in mixtures. Human activities such as animal husbandry, fertilization of agricultural fields and human medicine release high amounts these compounds into the environment. The work in this thesis contributes to our understanding of how the selection of bacterial antibiotic resistance can be facilitated by the pollution by metals and antimicrobials. We show that low levels of antibiotics, metals and combinations thereof can lead to the selection of chromosomally encoded antibiotic resistance genes as well as a multidrug resistance plasmid. The underlying genetic and cellular mechanisms of selection identified relate to mutational changes in a plasmid-encoded metal resistance operon, and metal-associated increases in cellular membrane permeability. We further show that exposure to quaternary ammonium compounds can result in cross-resistance to antibiotics following genetic changes in genes related to efflux, membrane synthesis and transcription/translation. Taken together, the work in this thesis suggests that the stewardship of antibiotics should include prudent use of metals and antimicrobials. 

    List of papers
    1. Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals
    Open this publication in new window or tab >>Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals
    Show others...
    2014 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 5, no 5, p. e01918-14-Article in journal (Refereed) Published
    Abstract [en]

    How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid-carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum β-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments.

    IMPORTANCE: Antibiotic resistance is in many pathogenic bacteria caused by genes that are carried on large conjugative plasmids. These plasmids typically contain multiple antibiotic resistance genes as well as genes that confer resistance to biocides and heavy metals. In this report, we show that very low concentrations of single antibiotics and heavy metals or combinations of compounds can select for a large plasmid that carries resistance to aminoglycosides, β-lactams, tetracycline, macrolides, trimethoprim, sulfonamide, silver, copper, and arsenic. Our findings suggest that the low levels of antibiotics and heavy metals present in polluted external environments and in treated animals and humans could allow for selection and enrichment of bacteria with multiresistance plasmids and thereby contribute to the emergence, maintenance, and transmission of antibiotic-resistant disease-causing bacteria.

    National Category
    Microbiology in the medical area
    Research subject
    Microbiology; Molecular Genetics
    Identifiers
    urn:nbn:se:uu:diva-235222 (URN)10.1128/mBio.01918-14 (DOI)000345459000067 ()25293762 (PubMedID)
    Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2018-08-10Bibliographically approved
    2. Mutation in the Copper-Induced sil Operon Enables High-Level Silver Resistance and Silver Facilitated Co-Selection of Multidrug Resistance Plasmid
    Open this publication in new window or tab >>Mutation in the Copper-Induced sil Operon Enables High-Level Silver Resistance and Silver Facilitated Co-Selection of Multidrug Resistance Plasmid
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Human activities are responsible for an accumulation of metals in health care and agricultural environments, and plasmid-encoded metal tolerance operons enable bacteria to rapidly adapt to metal exposure under such conditions. While the mechanisms of action of many metal resistance systems have been described, there is still limited understanding of their role in co-selection of antibiotic resistance in metal-containing environments. Whether plasmid-encoded metal resistance genes confer significant selective advantages is of interest as it has implications for plasmid enrichment and the spread of plasmid-borne antibiotic resistance genes. To increase our understanding of plasmid-mediated metal resistance, we studied the sil operon and its phenotypes in E. coli during growth in the absence and presence of silver and copper. We found that the sil operon provides resistance to both silver and copper. However, it is induced by copper only, and constitutive expression due to point mutations in the two-component silS gene provides high-level silver resistance. Furthermore, we showed that a high-level silver resistant mutant could be enriched in the presence of silver. This enrichment entailed co-selection of the multidrug resistance plasmid pUUH239.2. Our results show that a copper resistance operon can provide high-level silver resistance following a single point mutation, and that the silver resistance phenotype subsequently can co-select for antibiotic resistance in the presence of silver. 

    National Category
    Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:uu:diva-356961 (URN)
    Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-10
    3. Potentiation of the Selective Effect of Antibiotics by Metal Ions
    Open this publication in new window or tab >>Potentiation of the Selective Effect of Antibiotics by Metal Ions
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Complex mixtures of antibiotics and metals are present in many environments ranging from municipal sewage to irrigation water and manure used as agricultural fertilizer. Such mixtures of drugs and metals exert unique selection pressures on local bacterial communities and could function as hotspots for enrichment of antibiotic resistance genes. The presence of metals in the environment has previously been linked to increases in tolerance to antibiotics. In this study, we investigated metal-potentiated selection of antibiotic resistant Salmonella enterica strains. Six environmentally relevant metals were examined in combinations with three different antibiotics. By performing competitions between an antibiotic resistant mutant and the isogenic wild type in each metal-antibiotic combination, we assessed the minimal selective concentration (MSC) of the antibiotic for the resistant strain. The metals silver, cadmium and mercury all exhibited potentiating effects, reducing the MSC of the antibiotic up to 5-fold as compared to in the absence of the metal. We further show that the potentiating metals increased permeability of the cellular outer membrane. These results demonstrate that the presence of a metal can decrease the concentration of an antibiotic required to select for an antibiotic resistant strain, and they indicate that this process involves metal-facilitated uptake of the antibiotic following damage to the outer membrane.

    Keywords
    Antibiotic resistance, Selection
    National Category
    Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:uu:diva-356966 (URN)
    Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-10
    4. Cross-Resistance to Antibiotics After Exposure to Qaternary Ammonium Compounds
    Open this publication in new window or tab >>Cross-Resistance to Antibiotics After Exposure to Qaternary Ammonium Compounds
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Quaternary ammonium compounds (QACs) are common antimicrobials that are used in a variety of consumer products, such as lotions, sunscreen, hair conditioners and hand sanitizers, to inhibit bacterial growth. However, it has been noted that bacteria exposed to QACs can develop resistance, and additionally, resistance to QACs has been observed to provide cross-resistance to antibiotics. In order to identify genetic adaptations for this resistance pattern, we exposed E. coli to three different QACs at sub-MIC and above-MIC concentrations, and identified genetic changes by whole genome sequencing. We found that initial adaptation, at sub-MIC levels, happened through efflux mechanisms, and that subsequent genetic changes, during above-MIC exposure, involved genes associated with the cell membranes and with transcription/translation. We also found that these genetic changes provided cross-resistance to other QACs as well as to several antibiotics.

    Keywords
    Antibiotic resistance, Antimicrobials, Cross-resistance
    National Category
    Other Medical Sciences not elsewhere specified
    Identifiers
    urn:nbn:se:uu:diva-356967 (URN)
    Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-10
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  • 13.
    Aleix-Mata, Gael
    et al.
    Jaen Univ, Dept Expt Biol, E-23071 Jaen, Spain.;Jaen Univ, Dept Anim & Plant Biol & Ecol, E-23071 Jaen, Spain..
    Exposito, Miriam
    Jaen Univ, Dept Expt Biol, E-23071 Jaen, Spain..
    Ruiz-Ruano, Francisco J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Granada Univ, Fac Sci, Dept Genet, E-18071 Granada, Spain..
    Maria Lopez-Beceiro, Ana
    Univ Santiago de Compostela, Dept Anat Anim Prod & Vet Clin Sci, E-27002 Lugo, Spain..
    Fidalgo, Luis E.
    Univ Santiago de Compostela, Dept Anat Anim Prod & Vet Clin Sci, E-27002 Lugo, Spain..
    Martinez-Carrasco, Carlos
    Murcia Univ, Dept Anim Hlth, E-30100 Murcia, Spain..
    Ruiz de Ybanez, Maria Rocio
    Murcia Univ, Dept Anim Hlth, E-30100 Murcia, Spain..
    Boos, Mathieu
    Naturaconst, Res Agcy Appl Ecol, F-67270 Wilshausen, France.;Federat Natl Chasseurs, Pole Sci, 13 Rue Gen Leclerc, F-92136 Issy Les Moulineaux, France..
    Perez, Jesus M.
    Jaen Univ, Dept Anim & Plant Biol & Ecol, E-23071 Jaen, Spain.;Wildlife Ecol & Hlth Grp WE&H, Barcelona, Spain..
    Sanchez, Antonio
    Jaen Univ, Dept Expt Biol, E-23071 Jaen, Spain..
    Development and characterization of 15 novel polymorphic microsatellite loci for two important bot flies (Diptera, Oestridae) by next-generation sequencing2020In: Parasitology Research, ISSN 0932-0113, E-ISSN 1432-1955, Vol. 119, no 9, p. 2829-2835Article in journal (Refereed)
    Abstract [en]

    Cephenemyia stimulatorandOestrus ovisare two important parasitic bot flies (Oestridae) species causing myiasis, with a potential negative impact on the welfare of the host. Using next-generation sequencing approach and bioinformatics tools, a large panel of possible microsatellites loci was obtained in both species. Primer pairs were designed for 15 selected microsatellite loci inC. stimulatorand other 15 loci inO. ovisfor PCR amplification. Loci amplification and analysis were performed in four populations of each species. The results demonstrated that all selected loci were polymorphic, with the number of alleles ranging from 2 to 6 per locus inC. stimulatorand 3 to 13 per locus inO. ovis. This is the first time to describe these microsatellite loci forC. stimulatorandO. ovis. These two sets of microsatellite markers could be further used for biogeographic and population genetics studies.

  • 14.
    Aleix-Mata, Gael
    et al.
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain.;Univ Jaen, Dept Biol Anim Biol Vegetal & Ecol, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    Gutierrez, Juana
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    Ruiz-Ruano, Francisco J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Lorite, Pedro
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    Marchal, Juan A.
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    Sanchez, Antonio
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    The complete mitochondrial genome of Talpa aquitania (Talpidae; Insectivora), a mole species endemic to northern Spain and southern France2020In: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 47, no 3, p. 2397-2403Article in journal (Refereed)
    Abstract [en]

    The complete mitogenome sequence of Talpa aquitania, a recently described Talpa species, was assembled using whole-genome sequencing data. It varies in length from 16,776 to 16,846 bp, contains 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, one origin of L-strand replication, and a control region. In the control region, which varied from 1320 to 1390 bp, we identified the extended termination-associated sequence (ETAS-1 and ETAS-2) and the conserved sequence blocks (CSB-1, 2, 3, B, C, D, E, F). In addition, this region includes a 10 bp tandem repeat DNA sequence, with a variable number of repeats that suggest the existence of heteroplasmy. Phylogeny reconstructions based on Maximum Likelihood, Neighbor-joining and Bayesian inference analyses yielded phylogenies with similar topologies demonstrating that T. aquitania and T. occidentalis are sister species.

  • 15. Alfonso, Julieta
    et al.
    Pollevick, Guido
    Castensson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Frasch, Alberto
    Analysis of gene expression in the rat hippocampus using Real Time PCR reveals high inter-individual variation in mRNA expression levels2002In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 67, no 2, p. 225-34Article in journal (Refereed)
    Abstract [en]

    In mammals, gene transcription is a step subjected to tight regulation mechanisms. In fact, changes in mRNA levels in the central nervous system (CNS) can account for numerous phenotypic differences in brain function. We performed a high-resolution analysis of mRNA expression levels for 37 genes selected from a normal rat hippocampus cDNA library. mRNA amounts were quantified using a Real Time PCR SYBR Green assay. We found that, in general, individuals from an inbred rat population (n = 20) have shown 2-3 times differences in the basal level of expression of the genes analyzed. Up to several fold differences among individuals were observed for certain genes. These inter-individual differences were obtained after correction for the different amounts of mRNA in each sample. Power calculations were performed to determine the number of individuals required to detect reliable differences in expression levels between a control and an experimental group. These data indicated that, depending on the variability of the candidate gene selected, it was necessary to analyze from five to 135 individuals in each group to detect differences of 50% in the levels of mRNA expression between two groups investigated. The comparison of mRNA abundance from different genes revealed a wide range of expression levels for the 37 genes, showing a 26,000-fold difference between the highest and lowest expressed gene.

  • 16.
    Alfredsson Timmins, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Functional organisation of the cell nucleus in the fission yeast, Schizosaccharomyces pombe2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In eukaryotes the genome adopts a non-random spatial organisation, which is important for gene regulation. However, very little is known about the driving forces behind nuclear organisation. In the simple model eukaryote fission yeast, Schizosaccharomyces pombe, it has been known for a long time that transcriptionally repressed heterochromatin localise to the nuclear membrane (NM); the centromeres attaches to spindle pole body (SPB), while the telomeres are positioned at the NM on the opposite side of the nucleus compared to the SPB. Studies presented in this thesis aimed at advancing our knowledge of nuclear organisation in Schizosaccharomyces pombe.

    We show that the heterochromatic mating-type region localises to the NM in the vicinity of the SPB. This positioning was completely dependent on Clr4, a histone methyl transferase crucial for the formation of heterochromatin. Additional factors important for localisation were also identified: the chromo domain protein Swi6, and the two boundary elements IR-L and IR-R surrounding this locus. We further identify two other chromo domain proteins; Chp1 and Chp2, as crucial factors for correct subnuclear localisation of this region. From these results we suggest that the boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Gene regulation can affect the subnuclear localisation of genes. Using nitrogen starvation in S. pombe as a model for gene induction we determined the subnuclear localisation of two gene clusters repressed by nitrogen: Chr1 and Tel1. When repressed these loci localise to the NM, and this positioning is dependent on the histone deacetylase Clr3. During induction the gene clusters moved towards the nuclear interior in a transcription dependent manner.

    The knowledge gained from work presented in this thesis, regarding nuclear organisation in the S. pombe model system, can hopefully aid to a better understanding of human nuclear organisation.

    List of papers
    1. The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
    Open this publication in new window or tab >>The Clr4 methyltransferase determines the subnuclear localization of the mating-type region in fission yeast
    2007 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 120, no 11, p. 1935-1943Article in journal (Refereed) Published
    Abstract [en]

    The genome has a non-random spatial distribution in the cell nucleus. In Schizosaccharomyces pombe, it has been shown that the centromeres, telomeres and the mating-type region localize to the nuclear membrane (NM), the former by attaching to the spindle pole body (SPB). In addition, reporter genes inserted into these areas are transcriptionally repressed due to the formation of specialized chromatin structures. Performing live cell analysis we found that in a wild-type strain the mating-type region was positioned in the proximity of the SPB, the location where the pericentromeric heterochromatin is also found. In a strain lacking the histone methyltransferase, Clr4, crucial for the formation of heterochromatin, the mating-type region had a random localization in the nucleus. Moreover, in a strain where the two boundary elements IR-L and IR-R had been deleted the mating-type region was displaced from its position at the proximity of the SPB, but remained in the vicinity of the NM. Moreover, in all investigated strains with silencing deficiencies the distance between the mating-type region and the SPB increased. This result indicates a correlation between transcriptional derepression and displacement of the region. Two different models of how the mating-type chromatin is organized in the nucleus are discussed.

    Keywords
    fission yeast, heterochromatin, silencing, subnuclear localization
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-13023 (URN)10.1242/jcs.03457 (DOI)000246665300013 ()17504808 (PubMedID)
    Available from: 2009-08-05 Created: 2009-08-05 Last updated: 2022-01-28Bibliographically approved
    2. Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeast
    Open this publication in new window or tab >>Chromo domain proteins in balanced dosage together with boundary elements cooperate in organising the mating-type chromatin in fission yeast
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    The chromatin in the cell nucleus has a spatial organisation. For example, in the fission yeast, Schizosaccharomyces pombe, transcriptionally repressed heterochromatin is found at the nuclear membrane (NM). The centromeres and the mating-type region localise in the proximity of the spindle pole body (SPB), while the telomeres are found on the opposite side of the nucleus in the proximity of the nucleolus. In a previous study we used the mating-type region as a model to study the driving force behind nuclear organisation. We proposed two mutually exclusive models to explain what determines the localisation of the mating-type region. The first model suggests that solely the amount of heterochromatin in the region affects the localisation, while the other model stipulates that the boundary elements together with heterochromatin formation anchor the mating-type region in the NM in the vicinity of the SPB. Here, we present data that disproves the first model. We found that in a strain expressing tripled amounts of the chromodomain protein Swi6, a structural component of heterochromatin, the mating-type region was delocalised from the proximity of the SPB. A strain deleted of the histone deacetylase clr3+ also had a delocalised mating-type locus. Interestingly, a strain with a point-mutation in clr3-735 producing an enzymatically inactive protein in normal amounts showed an intermediate phenotype. Most importantly, we identify the chromodomain proteins, Chp1 and Chp2, as crucial factors for correct subnuclear localisation of the mating-type region. We suggest that boundary elements together with chromodomain proteins in balanced dosage and composition cooperate in organising the mating-type chromatin.

    Identifiers
    urn:nbn:se:uu:diva-107280 (URN)
    Available from: 2009-08-04 Created: 2009-08-04 Last updated: 2010-01-14Bibliographically approved
    3. Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe
    Open this publication in new window or tab >>Reorganization of chromatin is an early response to nitrogen starvation in Schizosaccharomyces pombe
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    2009 (English)In: Chromosoma, ISSN 0009-5915, E-ISSN 1432-0886, Vol. 118, no 1, p. 99-112Article in journal (Refereed) Published
    Abstract [en]

    There are several documented events of changes in subnuclear localization during gene activation. However, there are conflicting data on whether the nuclear periphery is a compartment for gene repression or activation, and whether genes are moved to the pores at the nuclear membrane (NM) or not during gene activation. Nitrogen starvation of fission yeast serves as a good model system for studying gene induction since it causes fast regulation of hundreds of genes. In this study the subnuclear localization of two gene clusters repressed by nitrogen was investigated. During normal growth conditions the gene clusters localized to the nuclear periphery at the opposite side of the nucleus as compared to the spindle pole body (SPB). This constrained localization was dependent on the histone deacetylase Clr3, known to transcriptionally repress genes in these clusters. Already 20 minutes after nitrogen depletion drastic changes in subnuclear localization of the two loci were observed, away from the NM towards the nuclear interior. At least for one of the clusters the movement was clearly transcription dependent. Data presented here illustrates how interconnected events of gene activation and nuclear reorganization are, as well as provides a suggestion of how nuclear organization might be maintained.

    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-107289 (URN)10.1007/s00412-008-0180-6 (DOI)000262504300009 ()
    Available from: 2009-08-05 Created: 2009-08-05 Last updated: 2022-01-28Bibliographically approved
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  • 17.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjoblöm, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, p. 7743-7748Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 18.
    Almeida, Pedro
    et al.
    UCL, Dept Genet Evolut & Environm, London, England.
    Proux-Wera, Estelle
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Stockholm, Sweden.
    Churcher, Allison
    Umeå Univ, Dept Mol Biol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Umeå, Sweden.
    Soler, Lucile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dainat, Jacques
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pucholt, Pascal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Swedish Univ Agr Sci, Uppsala BioCtr, Linnean Ctr Plant Biol, Dept Plant Biol, Uppsala, Sweden.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, Tom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnberg-Wästljung, Ann-Christin
    Swedish Univ Agr Sci, Uppsala BioCtr, Linnean Ctr Plant Biol, Dept Plant Biol, Uppsala, Sweden.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berlin, Sofia
    Swedish Univ Agr Sci, Uppsala BioCtr, Linnean Ctr Plant Biol, Dept Plant Biol, Uppsala, Sweden.
    Mank, Judith E.
    UCL, Dept Genet Evolut & Environm, London, England; Univ British Columbia, Dept Zool, Vancouver, BC, Canada; Univ British Columbia, Biodivers Res Ctr, Vancouver, BC, Canada.
    Genome assembly of the basket willow, Salix viminalis, reveals earliest stages of sex chromosome expansion2020In: BMC Biology, E-ISSN 1741-7007, Vol. 18, no 1, article id 78Article in journal (Refereed)
    Abstract [en]

    Background

    Sex chromosomes have evolved independently multiple times in eukaryotes and are therefore considered a prime example of convergent genome evolution. Sex chromosomes are known to emerge after recombination is halted between a homologous pair of chromosomes, and this leads to a range of non-adaptive modifications causing gradual degeneration and gene loss on the sex-limited chromosome. However, the proximal causes of recombination suppression and the pace at which degeneration subsequently occurs remain unclear.

    Results

    Here, we use long- and short-read single-molecule sequencing approaches to assemble and annotate a draft genome of the basket willow, Salix viminalis, a species with a female heterogametic system at the earliest stages of sex chromosome emergence. Our single-molecule approach allowed us to phase the emerging Z and W haplotypes in a female, and we detected very low levels of Z/W single-nucleotide divergence in the non-recombining region. Linked-read sequencing of the same female and an additional male (ZZ) revealed the presence of two evolutionary strata supported by both divergence between the Z and W haplotypes and by haplotype phylogenetic trees. Gene order is still largely conserved between the Z and W homologs, although the W-linked region contains genes involved in cytokinin signaling regulation that are not syntenic with the Z homolog. Furthermore, we find no support across multiple lines of evidence for inversions, which have long been assumed to halt recombination between the sex chromosomes.

    Conclusions

    Our data suggest that selection against recombination is a more gradual process at the earliest stages of sex chromosome formation than would be expected from an inversion and may result instead from the accumulation of transposable elements. Our results present a cohesive understanding of the earliest genomic consequences of recombination suppression as well as valuable insights into the initial stages of sex chromosome formation and regulation of sex differentiation.

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  • 19.
    Almlöf, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ge, Bing
    Pastinen, Tomi
    Goodall, Alison H
    Cambien, François
    Deloukas, Panos
    Ouwehand, Willem H
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 7, p. e102612-Article in journal (Refereed)
    Abstract [en]

    We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10-7 to 9.5×10-89. The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.

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  • 20.
    Alva, Omar
    et al.
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Leroy, Anais
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Heiske, Margit
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Pereda-Loth, Veronica
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Tisseyre, Lenka
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Boland, Anne
    Ctr Natl Genotypage, Inst Genom, Commissariat Energie Atom, F-91000 Evry, France..
    Deleuze, Jean-Francois
    Ctr Natl Genotypage, Inst Genom, Commissariat Energie Atom, F-91000 Evry, France..
    Rocha, Jorge
    Univ Porto, InBIO Lab Associado, Ctr Invest Biodiversidade & Recursos, CIBIO, Campus Vairao, P-4485661 Vairao, Portugal.;Univ Porto, Fac Ciencias, Dept Biol, P-4099002 Porto, Portugal.;CIBIO, BIOPOLIS Program Genom Biodivers & Land Planning, Campus Vairao, P-4485661 Vairao, Portugal..
    Schlebusch, Carina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Fortes-Lima, Cesar A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Stoneking, Mark
    Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany.;Univ Lyon 1, Lab Biometrie & Biol Evolut, CNRS, UMR 5558, Villeurbanne, France..
    Radimilahy, Chantal
    Univ Antananarivo, Musee Art & Archeol, Antananarivo, Madagascar..
    Rakotoarisoa, Jean-Aime
    Univ Antananarivo, Musee Art & Archeol, Antananarivo, Madagascar..
    Letellier, Thierry
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Pierron, Denis
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    The loss of biodiversity in Madagascar is contemporaneous with major demographic events2022In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 32, no 23, p. 4997-+Article in journal (Refereed)
    Abstract [en]

    Only 400 km off the coast of East Africa, the island of Madagascar is one of the last large land masses to have been colonized by humans. While many questions surround the human occupation of Madagascar, recent studies raise the question of human impact on endemic biodiversity and landscape transformation. Previous genetic and linguistic analyses have shown that the Malagasy population has emerged from an admixture that happened during the last millennium, between Bantu-speaking African populations and Austronesian-speaking Asian populations. By studying the sharing of chromosome segments between individuals (IBD determination), local ancestry information, and simulated genetic data, we inferred that the Malagasy ancestral Asian population was isolated for more than 1,000 years with an effective size of just a few hundred individuals. This isolation ended around 1,000 years before present (BP) by admixture with a small African population. Around the admixture time, there was a rapid demographic expansion due to intrinsic population growth of the newly admixed population, which coincides with extensive changes in Madagascar's landscape and the extinction of all endemic large- bodied vertebrates. Therefore, our approach can provide new insights into past human demography and associated impacts on ecosystems.

  • 21.
    Ament-Velasquez, Sandra Lorena
    et al.
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Gilchrist, Ciaran
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Rego, Alexandre
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Bendixsen, Devin P.
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Brice, Claire
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Grosse-Sommer, Julie Michelle
    Maastricht Univ, Fac Sci & Engn, Paul Henri Spaaklaan 1, NL-6229 EN Maastricht, Netherlands..
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stelkens, Rike
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    The Dynamics of Adaptation to Stress from Standing Genetic Variation and de novo Mutations2022In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 39, no 11, article id msac242Article in journal (Refereed)
    Abstract [en]

    Adaptation from standing genetic variation is an important process underlying evolution in natural populations, but we rarely get the opportunity to observe the dynamics of fitness and genomic changes in real time. Here, we used experimental evolution and Pool-Seq to track the phenotypic and genomic changes of genetically diverse asexual populations of the yeast Saccharomyces cerevisiae in four environments with different fitness costs. We found that populations rapidly and in parallel increased in fitness in stressful environments. In contrast, allele frequencies showed a range of trajectories, with some populations fixing all their ancestral variation in <30 generations and others maintaining diversity across hundreds of generations. We detected parallelism at the genomic level (involving genes, pathways, and aneuploidies) within and between environments, with idiosyncratic changes recurring in the environments with higher stress. In particular, we observed a tendency of becoming haploid-like in one environment, whereas the populations of another environment showed low overall parallelism driven by standing genetic variation despite high selective pressure. This work highlights the interplay between standing genetic variation and the influx of de novo mutations in populations adapting to a range of selective pressures with different underlying trait architectures, advancing our understanding of the constraints and drivers of adaptation.

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  • 22.
    Ament-Velásquez, Sandra Lorena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Drivers of evolutionary change in Podospora anserina2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genomic diversity is shaped by a myriad of forces acting in different directions. Some genes work in concert with the interests of the organism, often shaped by natural selection, while others follow their own interests. The latter genes are considered “selfish”, behaving either neutrally to the host, or causing it harm. In this thesis, I focused on genes that have substantial fitness effects on the fungus Podospora anserina and relatives, but whose effects are very contrasting. In Papers I and II, I explored the evolution of a particular type of selfish genetic elements that cause meiotic drive. Meiotic drivers manipulate the outcome of meiosis to achieve overrepresentation in the progeny, thus increasing their likelihood of invading and propagating in a population. In P. anserina there are multiple meiotic drivers but their genetic basis was previously unknown. In Paper I, we demonstrated that drive is caused by members of the Spok gene family. We discovered two new Spok genes, Spok3 and Spok4, which locate in different chromosomes in different strains. In Paper II, we showed that Spok3 and Spok4 are found on a gigantic (up to 247 Kb long) variant of Enterprise, a Crypton-like transposable element. Enterprise likely mobilize through the action of a putative tyrosine-recombinase that we call Kirc. When carrying the Spoks, this element has double selfish properties: transposition and meiotic drive. In addition, we found that homologs of the Spoks (Paper I) and of Kirc (Paper II) are widespread in fungi but their phylogenies are discordant with that of the species, suggesting that they have undergone horizontal gene transfer. In Papers III and IV, I turned the focus into genes that have an adaptive function. In fungi, the het genes control conspecific self/non-self recognition. Such genes are expected to evolve under frequency-dependent balancing selection. In Paper III, we found evidence of balancing selection acting on some het genes across the P. anserina species complex. Unexpectedly, we also discovered that het genes of the HNWD gene family are duplicated in a transposon-like manner, broadening our understanding of their potential fitness effects. Finally, in Paper IV we show how het genes with pleiotropic effects on sexual recognition lead to the evolution of strong reproductive isolation, and hence speciation. Overall, the results of my thesis highlight the functional intersection between mobile selfish genetic elements and other genes, either selfish or adaptive, and their effects on genome architecture and population structure.

    List of papers
    1. Combinations of Spok genes create multiple meiotic drivers in Podospora
    Open this publication in new window or tab >>Combinations of Spok genes create multiple meiotic drivers in Podospora
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    2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e46454Article in journal (Refereed) Published
    Abstract [en]

    Meiotic drive is the preferential transmission of a particular allele during sexual reproduction. The phenomenon is observed as spore killing in multiple fungi. In natural populations of Podospora anserina, seven spore killer types (Psks) have been identified through classical genetic analyses. Here we show that the Spok gene family underlies the Psks. The combination of Spok genes at different chromosomal locations defines the spore killer types and creates a killing hierarchy within a population. We identify two novel Spok homologs located within a large (74-167 kbp) region (the Spok block) that resides in different chromosomal locations in different strains. We confirm that the SPOK protein performs both killing and resistance functions and show that these activities are dependent on distinct domains, a predicted nuclease and kinase domain. Genomic and phylogenetic analyses across ascomycetes suggest that the Spok genes disperse through cross-species transfer, and evolve by duplication and diversification within lineages.

    Place, publisher, year, edition, pages
    ELIFE SCIENCES PUBLICATIONS LTD, 2019
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-391362 (URN)10.7554/eLife.46454 (DOI)000477678700001 ()31347500 (PubMedID)
    Funder
    EU, Horizon 2020, ERC-2014-CoGSwedish Research Council
    Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2020-03-28Bibliographically approved
    2. The Enterprise, a massive transposon carrying Spok meiotic drive genes
    Open this publication in new window or tab >>The Enterprise, a massive transposon carrying Spok meiotic drive genes
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    2021 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 31, no 5, p. 789-798Article in journal (Refereed) Published
    Abstract [en]

    The genomes of eukaryotes are full of parasitic sequences known as transposable elements (TEs). Most TEs studied to date are relatively small (50 — 12000 bp), but can contribute to very large proportions of genomes. Here we report the discovery of a giant tyrosine-recombinase-mobilized DNA transposon, Enterprise, from the model fungus Podospora anserina. Previously, we described a large genomic feature called the Spok block which is notable due to the presence of meiotic drive genes of the Spok gene family. The Spok block ranges from 110 kb to 247 kb and can be present in at least four different genomic locations within P. anserina, despite what is an otherwise highly conserved genome structure. We have determined that the reason for its varying positions is that the Spok block is not only capable of meiotic drive, but is also capable of transposition. More precisely, the Spok block represents a unique case where the Enterprise has captured the Spoks, thereby parasitizing a resident genomic parasite to become a genomic hyperparasite. Furthermore, we demonstrate that Enterprise (without the Spoks) is found in other fungal lineages, where it can be as large as 70 kb. Lastly, we provide experimental evidence that the Spok block is deleterious, with detrimental effects on spore production in strains which carry it. In contrast to the selfish role of the Enterprise in P. anserina, we speculate that the mobility of the Enterprise may also play an adaptive role in many other fungi, through the horizontal transfer of metabolic genes. This union of meiotic drivers and a transposon has created a selfish element of impressive size in Podospora, challenging our perception of how TEs influence genome evolution and broadening the horizons in terms of what the upper limit of transposition may be.

    Place, publisher, year, edition, pages
    Cold Spring Harbor Laboratory Press (CSHL), 2021
    Keywords
    Spok, Podospora, Transposable elements, Enterprise, meiotic drive, Fungi, spore killing
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-406885 (URN)10.1101/gr.267609.120 (DOI)000646754400004 ()33875482 (PubMedID)
    Funder
    EU, European Research Council, 648143Swedish Research Council, 2015-04649Lars Hierta Memorial FoundationSwedish National Infrastructure for Computing (SNIC), SNIC 2017/1-567Swedish National Infrastructure for Computing (SNIC), SNIC 2019/8-371
    Note

    De två första författarna delar förstaförfattarskapet

    Title in thesis list of papers: The Enterprise: A massive transposon carrying Spok meiotic drive genes

    Available from: 2020-03-27 Created: 2020-03-27 Last updated: 2024-01-15Bibliographically approved
    3. The evolution of the allorecognition gene repertoire in the Podospora anserina species complex
    Open this publication in new window or tab >>The evolution of the allorecognition gene repertoire in the Podospora anserina species complex
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Across the Tree of Life, self/non-self recognition is typically achieved through highly polymorphic loci under balancing selection. In fungi, vegetative conspecific recognition, or allorecognition, is defined by the compatibility interactions between loci known as het genes. In this study we explore the evolution of the het genes in the model fungus Podospora anserina and its closest relatives (the Podospora anserina species complex). First, we used chromosome-level genome assemblies to resolve their phylogenetic relationships. We found that the species in the complex are well defined but diversified recently and rapidly, leading to high degrees of conflict at deep branches of the phylogeny. Unlike typical orthologous genes from the complex, some allorecognition genes (het-z and het-s) show trans-species polymorphism, a hallmark of long-term balancing selection. By contrast, the het genes belonging to the HNWD family exhibit a high turn-over, with losses and duplications happening often. In particular, the species P. pseudocomata has a considerable increase of HNWD genes. Unexpectedly, we show that the HNWD paralogs have clean defined boundaries flanked by a target site duplication (TSD), implicating a DNA transposon-like mechanism in the genesis of new duplicates. Overall, our data highlights the diversity of evolutionary histories behind individual self/non-self recognition genes at short evolutionary timescales.

    Keywords
    Podospora, Allorecognition, heterokaryon incompatibility, vegetative incompatibility, balancing selection, Transposable elements, NLRs
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-406881 (URN)
    Available from: 2020-03-27 Created: 2020-03-27 Last updated: 2020-03-28
    4. Allorecognition genes drive reproductive isolation in Podospora anserina
    Open this publication in new window or tab >>Allorecognition genes drive reproductive isolation in Podospora anserina
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    2022 (English)In: Nature Ecology & Evolution, E-ISSN 2397-334X, Vol. 6, no 7, p. 910-923Article in journal (Refereed) Published
    Abstract [en]

    Allorecognition, the capacity to discriminate self from conspecific non-self, is a ubiquitous organismal feature typically governed by genes evolving under balancing selection. Here, we show that in the fungus Podospora anserina, allorecognition loci controlling vegetative incompatibility (het genes), define two reproductively isolated groups through pleiotropic effects on sexual compatibility. These two groups emerge from the antagonistic interactions of the unlinked loci het-r (encoding a NOD-like receptor) and het-v (encoding a methyltransferase and an MLKL/HeLo domain protein). Using a combination of genetic and ecological data, supported by simulations, we provide a concrete and molecularly defined example whereby the origin and coexistence of reproductively isolated groups in sympatry is driven by pleiotropic genes under balancing selection.

    Place, publisher, year, edition, pages
    Springer Nature, 2022
    Keywords
    Podospora, Genetics, Speciation, Reproductive isolation, allorecognition, heterokaryon incompatibility genes, vegetative incompatibility, balancing selection, selfing
    National Category
    Evolutionary Biology
    Research subject
    Biology with specialization in Systematics; Biology with specialization in Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-406878 (URN)10.1038/s41559-022-01734-x (DOI)000794102000002 ()35551248 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC), 2017/1-567Swedish National Infrastructure for Computing (SNIC), 2019/8-371EU, European Research Council, ERC-2014-CoGEU, European Research Council, 648143Swedish Research Council, 2015-04649Stiftelsen Anna Maria Lundins stipendiefond
    Available from: 2020-03-27 Created: 2020-03-27 Last updated: 2022-09-22Bibliographically approved
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  • 23.
    Ament-Velásquez, Sandra Lorena
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Tuovinen, Veera
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Bergström, Linnea
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Spribille, Toby
    Biological Sciences CW 405, University of Alberta, Edmonton, AB, Canada.
    Vanderpool, Dan
    Department of Biology, Indiana University, Bloomington, IN, United States.
    Nascimbene, Juri
    Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.
    Yamamoto, Yoshikazu
    Department of Bioproduction Science, Faculty of Bioresource Sciences, Akita Prefectural University, Akita, Japan.
    Thor, Göran
    Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Johannesson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    The plot thickens: haploid and triploid-like thalli, hybridization, and biased mating type ratios in Letharia2021In: Frontiers in Fungal Biology, E-ISSN 2673-6128, Vol. 2, article id 656386Article in journal (Refereed)
    Abstract [en]

    The study of the reproductive biology of lichen fungal symbionts has been traditionally challenging due to their complex lifestyles. Against the common belief of haploidy, a recent genomic study found a triploid-like signal in Letharia. Here, we infer the genome organization and reproduction in Letharia by analyzing genomic data from a pure culture and from thalli, and performing a PCR survey of the MAT locus in natural populations. We found that the read count variation in the four Letharia specimens, including the pure culture derived from a single sexual spore of L. lupina, is consistent with haploidy. By contrast, the L. lupina read counts from a thallus’ metagenome are triploid-like. Characterization of the mating-type locus revealed a conserved heterothallic configuration across the genus, along with auxiliary genes that we identified. We found that the mating-type distributions are balanced in North America for L. vulpina and L. lupina, suggesting widespread sexual reproduction, but highly skewed in Europe for L. vulpina, consistent with predominant asexuality. Taken together, we propose that Letharia fungi are heterothallic and typically haploid, and provide evidence that triploid-like individuals are hybrids between L. lupina and an unknown Letharia lineage, reconciling classic systematic and genetic studies with recent genomic observations.

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  • 24.
    Ameur, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Che, Huiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, Marcel
    Stockholm Univ, DBB, Sci Life Lab, S-11419 Stockholm, Sweden.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75236 Uppsala, Sweden.
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Höijer, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Häggqvist, Susana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vezzi, Francesco
    Stockholm Univ, DBB, Sci Life Lab, S-11419 Stockholm, Sweden.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Med Sci, Sci Life Lab, Mol Med, S-75236 Uppsala, Sweden.
    Olason, Pall
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data2018In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 9, no 10, article id 486Article in journal (Refereed)
    Abstract [en]

    The current human reference sequence (GRCh38) is a foundation for large-scale sequencing projects. However, recent studies have suggested that GRCh38 may be incomplete and give a suboptimal representation of specific population groups. Here, we performed a de novo assembly of two Swedish genomes that revealed over 10 Mb of sequences absent from the human GRCh38 reference in each individual. Around 6 Mb of these novel sequences (NS) are shared with a Chinese personal genome. The NS are highly repetitive, have an elevated GC-content, and are primarily located in centromeric or telomeric regions. Up to 1 Mb of NS can be assigned to chromosome Y, and large segments are also missing from GRCh38 at chromosomes 14, 17, and 21. Inclusion of NS into the GRCh38 reference radically improves the alignment and variant calling from short-read whole-genome sequencing data at several genomic loci. A re-analysis of a Swedish population-scale sequencing project yields > 75,000 putative novel single nucleotide variants (SNVs) and removes > 10,000 false positive SNV calls per individual, some of which are located in protein coding regions. Our results highlight that the GRCh38 reference is not yet complete and demonstrate that personal genome assemblies from local populations can improve the analysis of short-read whole-genome sequencing data.

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  • 25.
    Anava, Sarit
    et al.
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Neuhof, Moran
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Gingold, Hila
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Sagy, Or
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Munters, Arielle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Emma M.
    Uppsala Univ, Dept Organismal Biol, Human Evolut, S-75105 Uppsala, Sweden.;Uppsala Univ, SciLife Lab, S-75105 Uppsala, Sweden..
    Afshinnekoo, Ebrahim
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.;WorldQuant Initiat Quantitate Predict, New York, NY 10065 USA..
    Danko, David
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.;WorldQuant Initiat Quantitate Predict, New York, NY 10065 USA..
    Foox, Jonathan
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.;WorldQuant Initiat Quantitate Predict, New York, NY 10065 USA..
    Shor, Pnina
    Israel Antiqu Author, Dead Sea Scroll Projects, IL-91710 Jerusalem, Israel..
    Riestra, Beatriz
    Israel Antiqu Author, Dead Sea Scroll Projects, IL-91710 Jerusalem, Israel..
    Huchon, Dorothee
    Tel Aviv Univ, Steinhardt Museum Nat Hist, IL-6997801 Tel Aviv, Israel.;Tel Aviv Univ, Israel Natl Ctr Biodivers Studies, IL-6997801 Tel Aviv, Israel.;Tel Aviv Univ, Dept Zool, George S Wise Fac Life Sci, IL-6997801 Tel Aviv, Israel..
    Mason, Christopher E.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.;WorldQuant Initiat Quantitate Predict, New York, NY 10065 USA..
    Mizrahi, Noam
    Tel Aviv Univ, Lester & Sally Entin Fac Humanities, Dept Bibl Studies, IL-6997801 Tel Aviv, Israel..
    Jakobsson, Mattias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Rechavi, Oded
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Illuminating Genetic Mysteries of the Dead Sea Scrolls2020In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 181, no 6, p. 1218-+Article in journal (Refereed)
    Abstract [en]

    The discovery of the 2,000-year-old Dead Sea Scrolls had an incomparable impact on the historical understanding of Judaism and Christianity. "Piecing together'' scroll fragments is like solving jigsaw puzzles with an unknown number of missing parts. We used the fact that most scrolls are made from animal skins to "fingerprint'' pieces based on DNA sequences. Genetic sorting of the scrolls illuminates their textual relationship and historical significance. Disambiguating the contested relationship between Jeremiah fragments supplies evidence that some scrolls were brought to the Qumran caves from elsewhere; significantly, they demonstrate that divergent versions of Jeremiah circulated in parallel throughout Israel (ancient Judea). Similarly, patterns discovered in non-biblical scrolls, particularly the Songs of the Sabbath Sacrifice, suggest that the Qumran scrolls represent the broader cultural milieu of the period. Finally, genetic analysis divorces debated fragments from the Qumran scrolls. Our study demonstrates that interdisciplinary approaches enrich the scholar's toolkit.

  • 26.
    Andersson, Anna-Carin
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Ecology and Evolution, Conservation Biology and Genetics.
    Postglacial Population History of the Common Shrew (Sorex araneus) in Fennoscandia: Molekylära studier av återkolonisation, könsbundet genflöde och kromosomrasbildning.2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The common shrew, Sorex araneus, has one of the most variable karyotypes among mammals, displaying numerous chromosomes races throughout its distribution, which can be categorized into different karyotypic groups. The objective of this thesis was to examine the postglacial population history of Fennoscandian common shrews using autosomal microsatellites, mitochondrial DNA (mtDNA) and a Y chromosome specific microsatellite (L8Y).

    Autosomal microsatellites and mtDNA revealed weak genetic structure over a hybrid zone between the karyotypically divergent Northern and Western karyotypic groups. However, the genetic structure displayed by the Y chromosome microsatellite was orders of magnitude higher. Hence, considerable chromosomal differences between the groups do not prevent female gene flow, while male gene flow is reduced (cf. Haldane's rule). Further, the results suggest that the Haldane effect may be caused by the chromosomal differences between the karyotypic groups.

    No mtDNA differentiation was observed either between chromosome races or between the Northern and Western karyotypic groups in Fennoscandia. The combined pattern of karyotypic and mtDNA variation of Fennoscandian common shrews, suggest bi-directional postglacial recolonisation from a single refugium in Europe. The variation of the Y-linked microsatellite supported this conclusion. In contrast, significant mtDNA structure, discordant with the karyotypic variation, revealed that common shrews in southern Finland belong to a different lineage than remaining Fennoscandian regions, implying postglacial recolonisation from a different source.

    MtDNA variation of the chromosome races in Sweden supports the hypothesis that three races of the Western karyotypic group have been formed through whole arm reciprocal translocations (WARTs), as suggested by their mutual karyotypic variation. The variation of the molecular markers supports the theory of rapid karyotypic evolution in the common shrew.

    List of papers
    1. No apparent reduction of gene flow in a hybrid zone between the West and North European karyotypic groups of the common shrew, Sorex araneus.
    Open this publication in new window or tab >>No apparent reduction of gene flow in a hybrid zone between the West and North European karyotypic groups of the common shrew, Sorex araneus.
    2004 In: Molecular Ecology, ISSN 1365-294X, Vol. 13, no 5, p. 1205-1215.Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91849 (URN)
    Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
    2. Lack of mitochondrial DNA structure between chromosome races of the common shrew, Sorex araneus, in Sweden. Implications for chromosomal evolution.
    Open this publication in new window or tab >>Lack of mitochondrial DNA structure between chromosome races of the common shrew, Sorex araneus, in Sweden. Implications for chromosomal evolution.
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91850 (URN)
    Available from: 2004-05-13 Created: 2004-05-13 Last updated: 2010-01-13Bibliographically approved
    3. Fennoscandian phylogeography of the common shrew Sorex araneus. Postglacial recolonisation-combining information from chromosomal variation with mitochondrial DNA data
    Open this publication in new window or tab >>Fennoscandian phylogeography of the common shrew Sorex araneus. Postglacial recolonisation-combining information from chromosomal variation with mitochondrial DNA data
    2011 (English)In: Acta Theriologica, ISSN 0001-7051, E-ISSN 2190-3743, Vol. 56, no 2, p. 103-116Article in journal (Refereed) Published
    Abstract [en]

    We examine mtDNA variation of the common shrew in Fennoscandia to explore the incongruence found in previous studies using chromosomal and mitochondrial markers, aiming to reveal post-glacial recolonisation patterns. A total of 241 common shrews from 51 localities in Fennoscandia were analysed. This area includes a secondary contact zone between two groups (the Northern group and the Western group) showing distinct karyotypes. All individuals were sequenced for 447 bp of the mitochondrial control region. No significant differentiation in the mtDNA variation was observed between the two major chromosomal groups in Fennoscandia. The star-like shape of the sequence network for the entire study area shows the most common haplotype A as ancestral in all regions but one, in situ formation of most haplotypes and population expansion. The only significant mtDNA structure observed occurs between south Finland and the rest of Fennoscandia. We propose that the Northern and Western group shared a common refugium during the Last Glacial Maximum but recolonised Fennoscandia via two routes. Karyotypic differences between south and north Finland has led researchers to suggest that both regions originate from the same ancestral population east of Finland. The observed divergence of mtDNA variation between these two regions supports this hypothesis.

    Keywords
    Control region, Common shrew, Glacial refugia, Colonization history, Chromosome race
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-91851 (URN)10.1007/s13364-010-0022-9 (DOI)000290689600001 ()
    Available from: 2004-05-13 Created: 2004-05-13 Last updated: 2017-12-14Bibliographically approved
    4. Reduced levels of male gene flow in a hybrid zone between the North and West European karyotypic groups of the common shrew, Sorex araneus. Chromosomally based explanation for Haldane's rule?
    Open this publication in new window or tab >>Reduced levels of male gene flow in a hybrid zone between the North and West European karyotypic groups of the common shrew, Sorex araneus. Chromosomally based explanation for Haldane's rule?
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91852 (URN)
    Available from: 2004-05-13 Created: 2004-05-13 Last updated: 2010-01-13Bibliographically approved
    5. Y-chromosome microsatellite variation among common shrews (Sorex araneus) in northern Europe.
    Open this publication in new window or tab >>Y-chromosome microsatellite variation among common shrews (Sorex araneus) in northern Europe.
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91853 (URN)
    Available from: 2004-05-13 Created: 2004-05-13 Last updated: 2010-01-13Bibliographically approved
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  • 27.
    Andersson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Developing a protocol for RT-qPCR of wing-tissue gene expression and investigating the dynamics of photoperiodically induced polyphenism in the water strider Gerris buenoi2023Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Wing polyphenism in insects is a type of phenotypic plasticity where environmental factors trigger the development of a set of discrete wing morphologies. In the water strider Gerris buenoi, photoperiods are the main environmental cue that trigger wing morph determination. The genetic mechanisms connecting environmental cues and the determination of wing morph in G. buenoi are not clear. However, recent experimental work suggests that engagement of the Hippo pathway via ecdysone signalling is a promising model for further investigation. In this study, a reverse-transcription quantitative PCR (RT-qPCR) protocol was developed, aimed at elucidating this potential transduction pathway by quantifying gene expression of Fat, Dachsous, Yorkie, EcR, E75 and E74. This was done using melt curve analysis, gel electrophoresis, sequencing of RT-qPCR products and qPCR standard curves. Additionally, wing morph distribution in extreme and intermediate photoperiods were examined. Wing morph proportions were significantly different between adults emerging in the intermediate photoperiods 15.30:8.30 and 15:9 (hours light : hours dark). An effect of sex was observed, with a higher probability of males becoming long-winged compared to females. This has likely evolved as a result of a dispersal-reproduction trade-off. Taken together, this study provided insight for future investigations of periodically induced wing morph determination and its genetic mechanisms in G. buenoi that will contribute to the understanding of phenotypic plasticity.

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  • 28.
    Andersson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA.
    Bekkevold, Dorte
    Tech Univ Denmark, Natl Inst Aquat Resources, Silkeborg, Denmark..
    Berg, Florian
    Inst Marine Res, Bergen, Norway..
    Farrell, Edward D.
    Killybegs Fishermens Org, Killybegs, County Donegal, Ireland..
    Felkel, Sabine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ferreira, Mafalda S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fuentes-Pardo, Angela P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Goodall, Jake
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    How Fish Population Genomics Can Promote Sustainable Fisheries: A Road Map2024In: Annual Review of Animal Biosciences, ISSN 2165-8102, E-ISSN 2165-8110, Vol. 12, p. 1-20Article, review/survey (Refereed)
    Abstract [en]

    Maintenance of genetic diversity in marine fishes targeted by commercial fishing is a grand challenge for the future. Most of these species are abundant and therefore important for marine ecosystems and food security. Here, we present a road map of how population genomics can promote sustainable fisheries. In these species, the development of reference genomes and whole genome sequencing is key, because genetic differentiation at neutral loci is usually low due to large population sizes and gene flow. First, baseline allele frequencies representing genetically differentiated populations within species must be established. These can then be used to accurately determine the composition of mixed samples, forming the basis for population demographic analysis to inform sustainably set fish quotas. SNP-chip analysis is a cost-effective method for determining baseline allele frequencies and for population identification in mixed samples. Finally, we describe how genetic marker analysis can transform stock identification and management.

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  • 29. Andersson, Martin N
    et al.
    Videvall, Elin
    Walden, Kimberly KO
    Harris, Marion O
    Robertson, Hugh M
    Löfstedt, Christer
    Sex- and tissue-specific profiles of chemosensory gene expression in a herbivorous gall-inducing fly (Diptera: Cecidomyiidae)2014In: BMC Genomics, ISSN 1471-2164, Vol. 15, no 1, p. 501-501Article in journal (Refereed)
  • 30.
    Anderung, Cecilia
    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.
    Persson, P
    Carretero, J. M.
    Ortega, A. I.
    Arasuaga, J. L.
    Elburg, R.
    Smith, C.
    Ellegren, Hans
    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.
    Götherström, Anders
    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.
    Genetics of Iberian Bronze Age cattle remains indicate prehistoric contacts over the Strait of Gibraltar.2005In: Proceedings of the National Academy of Sciences USA, no 102, p. 8431-8435Article in journal (Refereed)
  • 31.
    Andreaggi, Kimberly
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology. Armed Forces Medical Examiner System’s Armed Forces DNA Identification Laboratory (AFMES-AFDIL), Dover Air Force Base, DE 19902, USA;SNA International, LLC, Alexandria, VI 22314, USA.
    Bodner, Martin
    Institute of Legal Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria.
    Ring, Joseph D.
    Armed Forces Medical Examiner System’s Armed Forces DNA Identification Laboratory (AFMES-AFDIL), Dover Air Force Base, DE 19902, USA;SNA International, LLC, Alexandria, VI 22314, USA.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gyllensten, Ulf B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Parson, Walther
    Institute of Legal Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria;Forensic Science Program, The Pennsylvania State University, University Park, State College, PA 16801, USA.
    Marshall, Charla
    Armed Forces Medical Examiner System’s Armed Forces DNA Identification Laboratory (AFMES-AFDIL), Dover Air Force Base, DE 19902, USA;Forensic Science Program, The Pennsylvania State University, University Park, State College, PA 16801, USA.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics and Neurobiology.
    Complete Mitochondrial DNA Genome Variation in the Swedish Population2023In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 14, no 11, p. 1989-1989Article in journal (Refereed)
    Abstract [en]

    The development of complete mitochondrial genome (mitogenome) reference data for inclusion in publicly available population databases is currently underway, and the generation of more high-quality mitogenomes will only enhance the statistical power of this forensically useful locus. To characterize mitogenome variation in Sweden, the mitochondrial DNA (mtDNA) reads from the SweGen whole genome sequencing (WGS) dataset were analyzed. To overcome the interference from low-frequency nuclear mtDNA segments (NUMTs), a 10% variant frequency threshold was applied for the analysis. In total, 934 forensic-quality mitogenome haplotypes were characterized. Almost 45% of the SweGen haplotypes belonged to haplogroup H. Nearly all mitogenome haplotypes (99.1%) were assigned to European haplogroups, which was expected based on previous mtDNA studies of the Swedish population. There were signature northern Swedish and Finnish haplogroups observed in the dataset (e.g., U5b1, W1a), consistent with the nuclear DNA analyses of the SweGen data. The complete mitogenome analysis resulted in high haplotype diversity (0.9996) with a random match probability of 0.15%. Overall, the SweGen mitogenomes provide a large mtDNA reference dataset for the Swedish population and also contribute to the effort to estimate global mitogenome haplotype frequencies.

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    fulltext
  • 32.
    Andrews, Gregory
    et al.
    Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA..
    Fan, Kaili
    Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA..
    Pratt, Henry E.
    Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA..
    Phalke, Nishigandha
    Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA..
    Karlsson, Elinor K.
    Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.;Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.;Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA..
    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. Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA..
    Gazal, Steven
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.;Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA..
    Moore, Jill E.
    Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA..
    Weng, Zhiping
    Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA..
    Mammalian evolution of human cis-regulatory elements and transcription factor binding sites2023In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 380, no 6643, article id eabn7930Article in journal (Refereed)
    Abstract [en]

    Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element-derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.

  • 33.
    Ankarklev, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Franzen, Oscar
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden. KISP, Sci Life Lab, S-17165 Solna, Sweden..
    Peirasmaki, Dimitra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jerlstrom-Hultqvist, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lebbad, Marianne
    Publ Hlth Agcy Sweden, Dept Microbiol, SE-17182 Solna, Sweden..
    Andersson, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Bjorn
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden.;KISP, Sci Life Lab, S-17165 Solna, Sweden..
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comparative genomic analyses of freshly isolated Giardia intestinalis assemblage A isolates2015In: BMC Genomics, E-ISSN 1471-2164, Vol. 16, article id 697Article in journal (Refereed)
    Abstract [en]

    Background: The diarrhea-causing protozoan Giardia intestinalis makes up a species complex of eight different assemblages (A-H), where assemblage A and B infect humans. Comparative whole-genome analyses of three of these assemblages have shown that there is significant divergence at the inter-assemblage level, however little is currently known regarding variation at the intra-assemblage level. We have performed whole genome sequencing of two sub-assemblage AII isolates, recently axenized from symptomatic human patients, to study the biological and genetic diversity within assemblage A isolates. Results: Several biological differences between the new and earlier characterized assemblage A isolates were identified, including a difference in growth medium preference. The two AII isolates were of different sub-assemblage types (AII-1 [AS175] and AII-2 [AS98]) and showed size differences in the smallest chromosomes. The amount of genetic diversity was characterized in relation to the genome of the Giardia reference isolate WB, an assemblage AI isolate. Our analyses indicate that the divergence between AI and AII is approximately 1 %, represented by similar to 100,000 single nucleotide polymorphisms (SNP) distributed over the chromosomes with enrichment in variable genomic regions containing surface antigens. The level of allelic sequence heterozygosity (ASH) in the two AII isolates was found to be 0.25-0.35 %, which is 25-30 fold higher than in the WB isolate and 10 fold higher than the assemblage AII isolate DH (0.037 %). 35 protein-encoding genes, not found in the WB genome, were identified in the two AII genomes. The large gene families of variant-specific surface proteins (VSPs) and high cysteine membrane proteins (HCMPs) showed isolate-specific divergences of the gene repertoires. Certain genes, often in small gene families with 2 to 8 members, localize to the variable regions of the genomes and show high sequence diversity between the assemblage A isolates. One of the families, Bactericidal/ Permeability Increasing-like protein (BPIL), with eight members was characterized further and the proteins were shown to localize to the ER in trophozoites. Conclusions: Giardia genomes are modular with highly conserved core regions mixed up by variable regions containing high levels of ASH, SNPs and variable surface antigens. There are significant genomic variations in assemblage A isolates, in terms of chromosome size, gene content, surface protein repertoire and gene polymorphisms and these differences mainly localize to the variable regions of the genomes. The large genetic differences within one assemblage of G. intestinalis strengthen the argument that the assemblages represent different Giardia species.

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  • 34. Antolín, Roberto
    et al.
    Nettelblad, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gorjanc, Gregor
    Money, Daniel
    Hickey, John M.
    A hybrid method for the imputation of genomic data in livestock populations2017In: Genetics Selection Evolution, ISSN 0999-193X, E-ISSN 1297-9686, Vol. 49, article id 30Article in journal (Refereed)
  • 35.
    Apuli, Rami-Petteri
    et al.
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala BioCtr, Dept Plant Biol, Uppsala, Sweden..
    Richards, Thomas J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala BioCtr, Dept Plant Biol, Uppsala, Sweden..
    Rendon-Anaya, Martha
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala BioCtr, Dept Plant Biol, Uppsala, Sweden..
    Karacic, Almir
    Swedish Univ Agr Sci, Inst Crop Prod Ecol, Uppsala, Sweden..
    Rönnberg-Wästljung, Ann-Christin
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala BioCtr, Dept Plant Biol, Uppsala, Sweden..
    Ingvarsson, Pär K.
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala BioCtr, Dept Plant Biol, Uppsala, Sweden..
    The genetic basis of adaptation in phenology in an introduced population of Black Cottonwood (Populus trichocarpa, Torr. & Gray)2021In: BMC Plant Biology, E-ISSN 1471-2229, Vol. 21, article id 317Article in journal (Refereed)
    Abstract [en]

    Background: Entering and exiting winter dormancy present important trade-offs between growth and survival at northern latitudes. Many forest trees display local adaptation across latitude in traits associated with these phenology transitions. Transfers of a species outside its native range introduce the species to novel combinations of environmental conditions potentially requiring different combinations of alleles to optimize growth and survival. In this study, we performed genome wide association analyses and a selection scan in a P. trichocarpa mapping population derived from crossings between clones collected across the native range and introduced into Sweden. GWAS analyses were performed using phenotypic data collected across two field seasons and in a controlled phytotron experiment.

    Results: We uncovered 584 putative candidate genes associated with spring and autumn phenology traits as well as with growth. Many regions harboring variation significantly associated with the initiation of leaf shed and leaf autumn coloring appeared to have been evolving under positive selection in the native environments of P. trichocarpa. A comparison between the candidate genes identified with results from earlier GWAS analyses performed in the native environment found a smaller overlap for spring phenology traits than for autumn phenology traits, aligning well with earlier observations that spring phenology transitions have a more complex genetic basis than autumn phenology transitions.

    Conclusions: In a small and structured introduced population of P. trichocarpa, we find complex genetic architectures underlying all phenology and growth traits, and identify multiple putative candidate genes despite the limitations of the study population.

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  • 36. Arandjelovic, M.
    et al.
    Guschanski, Katerina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
    Schubert, G.
    Harris, T. R.
    Thalmann, O.
    Siedel, H.
    Vigilant, L.
    Two-step multiplex polymerase chain reaction improves the speed and accuracy of genotyping using DNA from noninvasive and museum samples2009In: Molecular Ecology Resources, ISSN 1755-098X, E-ISSN 1755-0998, Vol. 9, no 1, p. 28-36Article in journal (Refereed)
    Abstract [en]

    Many studies in molecular ecology rely upon the genotyping of large numbers of low‐quantity DNA extracts derived from noninvasive or museum specimens. To overcome low amplification success rates and avoid genotyping errors such as allelic dropout and false alleles, multiple polymerase chain reaction (PCR) replicates for each sample are typically used. Recently, two‐step multiplex procedures have been introduced which drastically increase the success rate and efficiency of genotyping. However, controversy still exists concerning the amount of replication needed for suitable control of error. Here we describe the use of a two‐step multiplex PCR procedure that allows rapid genotyping using at least 19 different microsatellite loci. We applied this approach to quantified amounts of noninvasive DNAs from western chimpanzee, western gorilla, mountain gorilla and black and white colobus faecal samples, as well as to DNA from ~100‐year‐old gorilla teeth from museums. Analysis of over 45 000 PCRs revealed average success rates of > 90% using faecal DNAs and 74% using museum specimen DNAs. Average allelic dropout rates were substantially reduced compared to those obtained using conventional singleplex PCR protocols, and reliable genotyping using low (< 25 pg) amounts of template DNA was possible. However, four to five replicates of apparently homozygous results are needed to avoid allelic dropout when using the lowest concentration DNAs (< 50 pg/reaction), suggesting that use of protocols allowing routine acceptance of homozygous genotypes after as few as three replicates may lead to unanticipated errors when applied to low‐concentration DNAs.

  • 37. Araújo, Naiara Pereira
    et al.
    de Lima, Leonardo Gomes
    Dias, Guilherme
    Kuhn, Gustavo Campos Silva
    de Melo, Alan Lane
    Yonenaga-Yassuda, Yatiyo
    Stanyon, Roscoe
    Svartman, Marta
    Identification and characterization of a subtelomeric satellite DNA in Callitrichini monkeys.2017In: DNA research, ISSN 1340-2838, E-ISSN 1756-1663, Vol. 24, no 4, p. 377-385Article in journal (Refereed)
    Abstract [en]

    Repetitive DNAs are abundant fast-evolving components of eukaryotic genomes, which often possess important structural and functional roles. Despite their ubiquity, repetitive DNAs are poorly studied when compared with the genic fraction of genomes. Here, we took advantage of the availability of the sequenced genome of the common marmoset Callithrix jacchus to assess its satellite DNAs (satDNAs) and their distribution in Callitrichini. After clustering analysis of all reads and comparisons by similarity, we identified a satDNA composed by 171 bp motifs, named MarmoSAT, which composes 1.09% of the C. jacchus genome. Fluorescent in situ hybridization on chromosomes of species from the genera Callithrix, Mico and Callimico showed that MarmoSAT had a subtelomeric location. In addition to the common monomeric, we found that MarmoSAT was also organized in higher-order repeats of 338 bp in Callimico goeldii. Our phylogenetic analyses showed that MarmoSAT repeats from C. jacchus lack chromosome-specific features, suggesting exchange events among subterminal regions of non-homologous chromosomes. MarmoSAT is transcribed in several tissues of C. jacchus, with the highest transcription levels in spleen, thymus and heart. The transcription profile and subtelomeric location suggest that MarmoSAT may be involved in the regulation of telomerase and modulation of telomeric chromatin.

  • 38. Araújo, Naiara Pereira
    et al.
    Dias, Guilherme
    Amaro, Beatriz Dias
    Kuhn, Gustavo Campos Silva
    Svartman, Marta
    The complete mitochondrial genomes of two Atlantic spiny rats, genus Trinomys (Rodentia: Echimyidae), from low-pass shotgun sequencing2016In: Gene Reports, ISSN 2452-0144, Vol. 5, p. 18-22Article in journal (Refereed)
  • 39.
    Arct, Aneta
    et al.
    Jagiellonian Univ, Inst Environm Sci, Gronostajowa 7, PL-30387 Krakow, Poland.
    Drobniak, Szymon M.
    Jagiellonian Univ, Inst Environm Sci, Gronostajowa 7, PL-30387 Krakow, Poland.
    Mellinger, Samantha
    Jagiellonian Univ, Inst Environm Sci, Gronostajowa 7, PL-30387 Krakow, Poland.
    Gustafsson, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Cichon, Mariusz
    Jagiellonian Univ, Inst Environm Sci, Gronostajowa 7, PL-30387 Krakow, Poland.
    Parental genetic similarity and offspring performance in blue tits in relation to brood size manipulation2019In: Ecology and Evolution, E-ISSN 2045-7758, Vol. 9, no 18, p. 10085-10091Article in journal (Refereed)
    Abstract [en]

    In birds, as in many other taxa, higher genetic similarity of mates has long been known to reduce offspring fitness. To date, the majority of avian studies have focused on examination whether the genetic similarity of social mates predicts hatching success. Yet, increased genetic similarity of mates may also reduce offspring fitness during later life stages, including the nestling period and beyond. Here, we investigated whether parental genetic similarity influences offspring performance using data from free-living blue tits (Cyanistes caeruleus) collected across three breeding seasons. Additionally, we tested whether brood size manipulation affects the magnitude and direction of the relationship between genetic similarity of mates and offspring performance. Sixteen microsatellite markers were used to measure genetic similarity between biological parents. We found that the genetic similarity of parents negatively affects offspring immune response and this effect was independent of the experimental brood size manipulation.

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  • 40.
    Arendt, Maja
    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.
    Cairns, K. M.
    Univ New South Wales, Sch Biotechnol & Biomol Sci, Fac Sci, Sydney, NSW, Australia..
    Ballard, J. W. O.
    Univ New South Wales, Sch Biotechnol & Biomol Sci, Fac Sci, Sydney, NSW, Australia..
    Savolainen, P.
    Royal Inst Technol KTH, Sch Biotechnol, Sci Life Lab, Solna, Sweden..
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Diet adaptation in dog reflects spread of prehistoric agriculture2016In: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 117, no 5, p. 301-306Article in journal (Refereed)
    Abstract [en]

    Adaptations allowing dogs to thrive on a diet rich in starch, including a significant AMY2B copy number gain, constituted a crucial step in the evolution of the dog from the wolf. It is however not clear whether this change was associated with the initial domestication, or represents a secondary shift related to the subsequent development of agriculture. Previous efforts to study this process were based on geographically limited data sets and low-resolution methods, and it is therefore not known to what extent the diet adaptations are universal among dogs and whether there are regional differences associated with alternative human subsistence strategies. Here we use droplet PCR to investigate worldwide AMY2B copy number diversity among indigenous as well as breed dogs and wolves to elucidate how a change in dog diet was associated with the domestication process and subsequent shifts in human subsistence. We find that AMY2B copy numbers are bimodally distributed with high copy numbers (median 2n(AMY2B)=11) in a majority of dogs but no, or few, duplications (median 2n(AMY2B)=3) in a small group of dogs originating mostly in Australia and the Arctic. We show that this pattern correlates geographically to the spread of prehistoric agriculture and conclude that the diet change may not have been associated with initial domestication but rather the subsequent development and spread of agriculture to most, but not all regions of the globe.

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  • 41.
    Arendt, Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Amylase activity is associated with AMY2B copy numbers in dog: implications for dog domestication, diet and diabetes2014In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 45, no 5, p. 716-722Article in journal (Refereed)
    Abstract [en]

    High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.

  • 42.
    Arendt, Maja Louise
    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. Univ Copenhagen, Fac Hlth & Med Sci, Dept Vet Clin Sci, Copenhagen, Denmark..
    Ambrosen, Aime
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Kierczak, Marcin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Tengvall, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lagerstedt, Anne-Sofie
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Bergström, Tomas
    Andersson, Göran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    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. Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Hagman, Ragnvi
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    The ABCC4 gene is associated with pyometra in golden retriever dogs2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, article id 16647Article in journal (Refereed)
    Abstract [en]

    Pyometra is one of the most common diseases in female dogs, presenting as purulent inflammation and bacterial infection of the uterus. On average 20% of intact female dogs are affected before 10 years of age, a proportion that varies greatly between breeds (3-66%). The clear breed predisposition suggests that genetic risk factors are involved in disease development. To identify genetic risk factors associated with the disease, we performed a genome-wide association study (GWAS) in golden retrievers, a breed with increased risk of developing pyometra (risk ratio: 3.3). We applied a mixed model approach comparing 98 cases, and 96 healthy controls and identified an associated locus on chromosome 22 (p = 1.2 x 10(-6), passing Bonferroni corrected significance). This locus contained five significantly associated SNPs positioned within introns of the ATP-binding cassette transporter 4 (ABCC4) gene. This gene encodes a transmembrane transporter that is important for prostaglandin transport. Next generation sequencing and genotyping of cases and controls subsequently identified four missense SNPs within the ABCC4 gene. One missense SNP at chr22:45,893,198 (p.Met787Val) showed complete linkage disequilibrium with the associated GWAS SNPs suggesting a potential role in disease development. Another locus on chromosome 18 overlapping the TESMIN gene, is also potentially implicated in the development of the disease.

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  • 43.
    Arendt, Maja Louise
    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. Univ Cambridge, Dept Vet Med, Cambridge, England..
    Melin, Malin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Tonomura, Noriko
    Broad Inst MIT & Harvard, Cambridge, MA USA.;Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA..
    Koltookian, Michele
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    Courtay-Cahen, Celine
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Flindall, Netty
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Bass, Joyce
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Boerkamp, Kim
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands..
    Megquir, Katherine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA.;Tufts Univ, Cummings Sch Vet Med, Dept Clin Sci, North Grafton, MA USA..
    Youell, Lisa
    Anim Hlth Trust, Newmarket, Suffolk, England..
    Murphy, Sue
    Anim Hlth Trust, Newmarket, Suffolk, England..
    McCarthy, Colleen
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    London, Cheryl
    Ohio State Univ, Dept Vet Clin Sci, Columbus, OH 43210 USA..
    Rutteman, Gerard R.
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands.;Vet Specialist Ctr De Wagenrenk, Wageningen, Netherlands..
    Starkey, Mike
    Anim Hlth Trust, Newmarket, Suffolk, England..
    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. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 11, article id e1005647Article in journal (Refereed)
    Abstract [en]

    Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10(-16)), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

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  • 44.
    Armstrong, Joel
    et al.
    UC Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA..
    Hickey, Glenn
    UC Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA..
    Diekhans, Mark
    UC Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA..
    Fiddes, Ian T.
    UC Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA..
    Novak, Adam M.
    UC Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA..
    Deran, Alden
    UC Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA..
    Fang, Qi
    BGI Shenzhen, Beishan Ind Zone, Shenzhen, Peoples R China.;Univ Copenhagen, Dept Biol, Sect Ecol & Evolut, Copenhagen, Denmark..
    Xie, Duo
    BGI Shenzhen, Beishan Ind Zone, Shenzhen, Peoples R China.;Univ Chinese Acad Sci, BGI Educ Ctr, Shenzhen, Peoples R China..
    Feng, Shaohong
    BGI Shenzhen, Beishan Ind Zone, Shenzhen, Peoples R China.;Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming, Yunnan, Peoples R China..
    Stiller, Josefin
    Univ Copenhagen, Dept Biol, Sect Ecol & Evolut, Copenhagen, Denmark..
    Genereux, Diane
    Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA..
    Johnson, Jeremy
    Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA..
    Marinescu, Voichita Dana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alföldi, Jessica
    Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA..
    Harris, Robert S.
    Penn State Univ, Dept Biol, University Pk, PA 16802 USA..
    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. Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA..
    Haussler, David
    Howard Hughes Med Inst, Chevy Chase, MD USA..
    Karlsson, Elinor
    Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA.;Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA.;Univ Massachusetts, Sch Med, Bioinformat & Integrat Biol, Worcester, MA USA..
    Jarvis, Erich D.
    Howard Hughes Med Inst, Chevy Chase, MD USA.;Rockefeller Univ, Lab Neurogenet Language, 1230 York Ave, New York, NY 10021 USA..
    Zhang, Guojie
    Univ Copenhagen, Dept Biol, Sect Ecol & Evolut, Copenhagen, Denmark.;Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming, Yunnan, Peoples R China.;Chinese Acad Sci, Ctr Excellence Anim Evolut & Genet, Kunming, Yunnan, Peoples R China.;BGI Shenzhen, China Natl GeneBank, Shenzhen, Peoples R China..
    Paten, Benedict
    UC Santa Cruz, Genom Inst, Santa Cruz, CA 95064 USA..
    Progressive Cactus is a multiple-genome aligner for the thousand-genome era2020In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 587, no 7833, p. 246-251Article in journal (Refereed)
    Abstract [en]

    New genome assemblies have been arriving at a rapidly increasing pace, thanks to decreases in sequencing costs and improvements in third-generation sequencing technologies(1-3). For example, the number of vertebrate genome assemblies currently in the NCBI (National Center for Biotechnology Information) database(4) increased by more than 50% to 1,485 assemblies in the year from July 2018 to July 2019. In addition to this influx of assemblies from different species, new human de novo assemblies(5) are being produced, which enable the analysis of not only small polymorphisms, but also complex, large-scale structural differences between human individuals and haplotypes. This coming era and its unprecedented amount of data offer the opportunity to uncover many insights into genome evolution but also present challenges in how to adapt current analysis methods to meet the increased scale. Cactus(6), a reference-free multiple genome alignment program, has been shown to be highly accurate, but the existing implementation scales poorly with increasing numbers of genomes, and struggles in regions of highly duplicated sequences. Here we describe progressive extensions to Cactus to create Progressive Cactus, which enables the reference-free alignment of tens to thousands of large vertebrate genomes while maintaining high alignment quality. We describe results from an alignment of more than 600 amniote genomes, which is to our knowledge the largest multiple vertebrate genome alignment created so far. The Progressive Cactus program can create reference-free alignments of hundreds of large vertebrate genomes efficiently, and is used for the alignment of more than 600 amniote genomes.

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  • 45.
    Arnqvist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Novicic, Zorana Kurbalija
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Univ Belgrade, Inst Biol Res Sinisa Stankovic, Despot Stefan Blvd 142, Belgrade 11000, Serbia..
    Castro, Jose A.
    Univ Illes Balears, Fac Ciencies, Dept Biol, Lab Genet, Edifici Guillem Colom,Campus UIB, Palma de Mallorca 07122, Balears, Spain..
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Negative frequency dependent selection on sympatric mtDNA haplotypes in Drosophila subobscura2016In: Hereditas, ISSN 0018-0661, E-ISSN 1601-5223, Vol. 153, article id 15Article in journal (Refereed)
    Abstract [en]

    Background: Recent experimental evidence for selection on mitochondrial DNA (mtDNA) has prompted the question as to what processes act to maintain within-population variation in mtDNA. Balancing selection though negative frequency dependent selection (NFDS) among sympatric haplotypes is a possibility, but direct empirical evidence for this is very scarce. Findings: We extend the previous findings of a multi-generation replicated cage experiment in Drosophila subobscura, where mtDNA polymorphism was maintained in a laboratory setting. First, we use a set of Monte Carlo simulations to show that the haplotype frequency dynamics observed are inconsistent with genetic drift alone and most closely match those expected under NFDS. Second, we show that haplotype frequency changes over time were significantly different from those expected under either genetic drift or positive selection but were consistent with those expected under NFSD. Conclusions: Collectively, our analyses provide novel support for NFDS on mtDNA haplotypes, suggesting that mtDNA polymorphism may at least in part be maintained by balancing selection also in natural populations. We very briefly discuss the possible mechanisms that might be involved.

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  • 46.
    Arnqvist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    A possible genomic footprint of polygenic adaptation on population divergence in seed beetles?2022In: Ecology and Evolution, E-ISSN 2045-7758, Vol. 12, no 10, article id e9440Article in journal (Refereed)
    Abstract [en]

    Efforts to unravel the genomic basis of incipient speciation are hampered by a mismatch between our toolkit and our understanding of the ecology and genetics of adaptation. While the former is focused on detecting selective sweeps involving few independently acting or linked speciation genes, the latter states that divergence typically occurs in polygenic traits under stabilizing selection. Here, we ask whether a role of stabilizing selection on polygenic traits in population divergence may be unveiled by using a phenotypically informed integrative approach, based on genome-wide variation segregating in divergent populations. We compare three divergent populations of seed beetles (Callosobruchus maculatus) where previous work has demonstrated a prominent role for stabilizing selection on, and population divergence in, key life history traits that reflect rate-dependent metabolic processes. We derive and assess predictions regarding the expected pattern of covariation between genetic variation segregating within populations and genetic differentiation between populations. Population differentiation was considerable (mean F-ST = 0.23-0.26) and was primarily built by genes showing high selective constraints and an imbalance in inferred selection in different populations (positive Tajima's D-NS in one and negative in one), and this set of genes was enriched with genes with a metabolic function. Repeatability of relative population differentiation was low at the level of individual genes but higher at the level of broad functional classes, again spotlighting metabolic genes. Absolute differentiation (d(XY)) showed a very different general pattern at this scale of divergence, more consistent with an important role for genetic drift. Although our exploration is consistent with stabilizing selection on polygenic metabolic phenotypes as an important engine of genome-wide relative population divergence and incipient speciation in our study system, we note that it is exceedingly difficult to firmly exclude other scenarios.

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  • 47.
    Arnqvist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Immonen, Elina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Hotzy, Cosima
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Rankin, Daniel
    Univ Zurich, Inst Evolutionary Biol & Environm Studies, Zurich, Switzerland..
    Tuda, Midori
    Kyushu Univ, Dept Bioresource Sci, Lab Insect Nat Enemies, Fukuoka 8128581, Japan.;Kyushu Univ, Inst Biol Control, Fac Agr, Fukuoka 8128581, Japan..
    Hjelmen, Carl E.
    Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA..
    Johnston, J. Spencer
    Texas A&M Univ, Dept Entomol, College Stn, TX 77843 USA..
    Genome size correlates with reproductive fitness in seed beetles2015In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 282, no 1815, article id 20151421Article in journal (Refereed)
    Abstract [en]

    The ultimate cause of genome size (GS) evolution in eukaryotes remains a major and unresolved puzzle in evolutionary biology. Large-scale comparative studies have failed to find consistent correlations between GS and organismal properties, resulting in the 'C-value paradox'. Current hypotheses for the evolution of GS are based either on the balance between mutational events and drift or on natural selection acting upon standing genetic variation in GS. It is, however, currently very difficult to evaluate the role of selection because within-species studies that relate variation in life-history traits to variation in GS are very rare. Here, we report phylogenetic comparative analyses of GS evolution in seed beetles at two distinct taxonomic scales, which combines replicated estimation of GS with experimental assays of life-history traits and reproductive fitness. GS showed rapid and bidirectional evolution across species, but did not show correlated evolution with any of several indices of the relative importance of genetic drift. Within a single species, GS varied by 4-5% across populations and showed positive correlated evolution with independent estimates of male and female reproductive fitness. Collectively, the phylogenetic pattern of GS diversification across and within species in conjunction with the pattern of correlated evolution between GS and fitness provide novel support for the tenet that natural selection plays a key role in shaping GS evolution.

  • 48.
    Arnqvist, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Westerberg, Ivar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Stockholm Univ, Dept Ecol Environm & Plant Sci, SE-10691 Stockholm, Sweden.
    Galbraith, James
    Univ Adelaide, Sch Biol Sci, Adelaide 5005, Australia.;Univ Exeter, Fac Environm Sci & Econ, Cornwall TR10 9FE, England..
    Sayadi, Ahmed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Scofield, Douglas G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Olsen, Remi-André
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, SE-10691 Stockholm, Sweden..
    Immonen, Elina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Bonath, Franziska
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Sci Life Lab, SE-10691 Stockholm, Sweden..
    Ewels, Philip
    Seqera Labs, Barcelona 08005, Spain..
    Suh, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    A chromosome-level assembly of the seed beetle Callosobruchus maculatus genome with annotation of its repetitive elements2024In: G3: Genes, Genomes, Genetics, E-ISSN 2160-1836, Vol. 14, no 2, article id jkad266Article in journal (Refereed)
    Abstract [en]

    Callosobruchus maculatus is a major agricultural pest of legume crops worldwide and an established model system in ecology and evolution. Yet, current molecular biological resources for this species are limited. Here, we employ Hi-C sequencing to generate a greatly improved genome assembly and we annotate its repetitive elements in a dedicated in-depth effort where we manually curate and classify the most abundant unclassified repeat subfamilies. We present a scaffolded chromosome-level assembly, which is 1.01 Gb in total length with 86% being contained within the 9 autosomes and the X chromosome. Repetitive sequences accounted for 70% of the total assembly. DNA transposons covered 18% of the genome, with the most abundant superfamily being Tc1-Mariner (9.75% of the genome). This new chromosome-level genome assembly of C. maculatus will enable future genetic and evolutionary studies not only of this important species but of beetles more generally.

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  • 49. Arrendal, J.S.E.
    et al.
    Walker, C.W.
    Sundqvist, A.-K.
    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.
    Hellborg, L.C.
    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.
    Vilà, Carles
    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.
    Genetic assessment of a demographically successful translocation program.2004In: Conservation Genetics, no 5, p. 79-88Article in journal (Other scientific)
  • 50. Aswad, Amr
    et al.
    Aimola, Giulia
    Wight, Darren
    Roychoudhury, Pavitra
    Zimmermann, Cosima
    Hill, Joshua
    Lassner, Dirk
    Xie, Hong
    Huang, Meei-Li
    Parrish, Nicholas F
    Schultheiss, Heinz-Peter
    Venturini, Cristina
    Lager, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Smith, Gordon C S
    Charnock-Jones, D Stephen
    Breuer, Judith
    Greninger, Alexander L
    Kaufer, Benedikt B
    Evolutionary history of endogenous Human Herpesvirus 6 reflects human migration out of Africa2021In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 38, no 1, p. 96-107Article in journal (Refereed)
    Abstract [en]

    Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result about 70 million people harbour the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if i) these integrations are ancient, ii) if they still occur, and iii) whether circulating virus strains differ from integrated ones. Here we used next generation sequencing and mining of public human genome datasets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly-related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or "reactivation" of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa.

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