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  • 1. Acevedo, Nathalie
    et al.
    Bornacelly, Adriana
    Mercado, Dilia
    Unneberg, Per
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mittermann, Irene
    Valenta, Rudolf
    Kennedy, Malcolm
    Scheynius, Annika
    Caraballo, Luis
    Genetic Variants in CHIA and CHI3L1 Are Associated with the IgE Response to the Ascaris Resistance Marker ABA-1 and the Birch Pollen Allergen Bet v 12016In: plos one, ISSN 1932-6203, Vol. 11, no 12, article id e0167453Article in journal (Refereed)
    Abstract [en]

    Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases- related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response.

  • 2.
    Ahlgren Berg, Alexandra
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Developmental switches in a family of temperate phages2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    P2 is the prototype phage of the non-lambdoid P2 family of temperate phages. A developmental switch determines whether a temperate phage will grow lytically or form lysogeny after infection. P2 related phages have two face-to-face located promoters controlling the lysogenic and the lytic operon respectively, and two repressors. The immunity C repressor of P2 is the first gene of the lysogenic operon and it represses the lytic promoter. The Cox protein, the first gene of the lytic operon, is multifunctional. It represses the lysogenic promoter, acts as a directionality factor in site-specific recombination and activates the PLL promoter of satellite phage P4.

    This thesis focuses on comparisons between the developmental switches of P2 and the two heteroimmune family members, P2 Hy dis and WΦ. A characterization of the developmental switch region of P2 Hy dis identifies a directly repeated sequence which is important for C repression. P2 Hy dis Cox can substitute for P2 Cox in repression of the P2 lysogenic promoter, excision of a P2 prophage and activation of P4 PLL. The P4 ε protein can derepress the developmental switch of P2 Hy dis.

    Functional characterizations of the C repressors and Cox proteins of P2 and WΦ show that both C repressors induce bending of their respective DNA targets. WΦ C, like P2 C, has a strong dimerization activity in vivo, but there are no indications of higher oligomeric forms. Despite the high degree of identity in the C-terminus, required for dimerization in P2 C, they seem to be unable to form heterodimers. The two Cox proteins are predicted to have identical secondary structures containing a helix-turn-helix motif believed to be involved in DNA binding. It is, however, not possible to change the DNA specificity of P2 Cox to that of WΦ Cox by swapping the presumed recognition helix. P2 Cox recognizes a sequence repeated at least six times in the different targets, while WΦ Cox seems to recognize a single direct repeat. In contrast to P2 Cox, WΦ Cox binds with a stronger affinity to the switch region than to the attachment site (attP). The Cox proteins induce a strong bend in their DNA targets, strengthening the hypothesis that they have a structural role at site-specific recombination. Both proteins show a capacity to oligomerize, but P2 Cox has a higher tendency to form oligomers than WΦ Cox.

    The P2 integrase mediates site-specific recombination leading to integration or excision of the P2 genome in or out of the host chromosome. P2 Cox controls the direction by inhibiting integration and promoting excision. In this work it is shown that Cox and Int bind cooperatively to attP.

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  • 3.
    Ahlgren, Hans
    et al.
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies, Archaeological Research Laboratory.
    Bro-Jørgensen, Maiken Hemme
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies, Archaeological Research Laboratory. University of Copenhagen, Denmark.
    Glykou, Aikaterini
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies, Archaeological Research Laboratory.
    Schmölcke, Ulrich
    Angerbjorn, Anders
    Stockholm University, Faculty of Science, Department of Zoology.
    Olsen, Morten Tange
    Lidén, Kerstin
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies, Archaeological Research Laboratory.
    The Baltic grey seal: A 9000-year history of presence and absence2022In: The Holocene, ISSN 0959-6836, E-ISSN 1477-0911, Vol. 32, no 6, p. 569-577Article in journal (Refereed)
    Abstract [en]

    The grey seal (Halichoerus grypus) has been part of the Baltic Sea fauna for more than 9000 years and has ever since been subjected to extensive human hunting, particularly during the early phases of its presence in the Baltic Sea, but also in the early 20th century. In order to study their temporal genetic structure and to investigate whether there has been a genetically continuous grey seal population in the Baltic, we generated mitochondrial control region data from skeletal remains from ancient grey seals from the archaeological sites Stora Förvar (Sweden) and Neustadt (Germany) and compared these with modern grey seal data. We found that the majority of the Mesolithic grey seals represent haplotypes that is not found in contemporary grey seals, indicating that the Baltic Sea population went extinct, likely due to human overexploitation and environmental change. We hypothesize that grey seals recolonised the Baltic Sea from the North Sea. during the Bronze Age or Iron Age, and that the contemporary Baltic grey seal population is direct descendants of this recolonisation. Our study highlights the power of biomolecular archaeology to understand the factors that shape contemporary marine diversity. 

  • 4.
    Andersson, Anastasia
    Stockholm University, Faculty of Science, Department of Zoology.
    Hidden biodiversity in an alpine freshwater top predator: Existence, characteristics, and temporal dynamics of cryptic, sympatric brown trout populations2021Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Intraspecific genetic diversity is imperative to the survival of species in a changing environment, and it plays a vital role in ecosystem function. Since this type of diversity can be difficult to detect it is sometimes referred to as “hidden biodiversity”. When separate and genetically distinct populations of the same species coexist within the same habitat, without apparent barriers to migration and obvious phenotypic divergence, this form of hidden biodiversity is called cryptic sympatry. Knowledge of cryptic sympatry is limited, however, and the aim of this thesis is to increase our understanding of this phenomenon by focusing on a species group where several cases of sympatry have been documented – the salmonids.

    Using the brown trout (Salmo trutta) as a model, I characterized two previously reported cases of cryptic sympatry occurring in small Swedish alpine lakes with respect to both phenotypic and genetic characteristics. I explored the hypothesis that cryptic sympatry is more common than currently recognized by reviewing literature documenting sympatry, as well as by assessing the statistical power to detect sympatric populations with varying degrees of divergence using commonly applied sample sizes for loci and individuals. Further, I performed a large-scale search for sympatric populations in alpine lakes in central Sweden.

    I found that cryptic, sympatric populations can coexist while apparently utilizing the same food resources and exhibiting the same adaptive plasticity to their shared environment (Paper I). In one of the empirical cases there were indications that the populations used different creeks for spawning, suggesting that segregation in spawning location contributes to the maintenance of sympatry (Paper II). Further, I found that differences between cryptic, sympatric populations of the same lake may be large with respect to levels of genetic diversity, inbreeding, and connectivity with populations in nearby lakes (Papers II and III). 

    I found support for the hypothesis that cryptic sympatry is more common than generally acknowledged (Papers IV and V). In the literature, cryptic sympatry is rarely reported and typically associated with higher divergence levels than between sympatric populations that differ phenotypically. My results suggest that this to a large extent may be due to limited statistical power when commonly used sample sizes in terms of individuals and loci are applied and the amount of divergence between populations is small (Paper IV). Cryptic sympatry was observed in over 40% of the screened localities (27 lakes), and was shown to be temporally stable over at least 40 years (Paper V).

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    Hidden biodiversity in an alpine freshwater top predator: Existence, characteristics, and temporal dynamics of cryptic, sympatric brown trout populations
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  • 5.
    Andersson, Anastasia
    et al.
    Stockholm University, Faculty of Science, Department of Zoology, Population Genetics.
    Karlsson, Sten
    Ryman, Nils
    Stockholm University, Faculty of Science, Department of Zoology, Population Genetics.
    Laikre, Linda
    Stockholm University, Faculty of Science, Department of Zoology, Population Genetics.
    Mapping and monitoring genetic diversity in brown trout population systems in alpine lakes by applying newly proposed indicatorsManuscript (preprint) (Other academic)
  • 6. André, Carl
    et al.
    Larsson, Lena C
    Stockholm University, Faculty of Science, Department of Zoology.
    Laikre, Linda
    Stockholm University, Faculty of Science, Department of Zoology.
    Bekkevold, D
    Brigham, J
    Carvalho, GR
    Dahlgren, TG
    Hutchinson, WF
    Mariani, S
    Mudde, K
    Ruzzante, DE
    Ryman, Nils
    Stockholm University, Faculty of Science, Department of Zoology.
    Detecting population structure in a high gene-flow species, Atlantic herring (Clupea harengus): direct, simultaneous evaluation of neutral vs putatively selected loci2011In: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 106, no 2, p. 270-280Article in journal (Refereed)
    Abstract [en]

    In many marine fish species, genetic population structure is typically weak because populations are large, evolutionarily young and have a high potential for gene flow. We tested whether genetic markers influenced by natural selection are more efficient than the presumed neutral genetic markers to detect population structure in Atlantic herring (Clupea harengus), a migratory pelagic species with large effective population sizes. We compared the spatial and temporal patterns of divergence and statistical power of three traditional genetic marker types, microsatellites, allozymes and mitochondrial DNA, with one microsatellite locus, Cpa112, previously shown to be influenced by divergent selection associated with salinity, and one locus located in the major histocompatibility complex class IIA (MHC-IIA) gene, using the same individuals across analyses. Samples were collected in 2002 and 2003 at two locations in the North Sea, one location in the Skagerrak and one location in the low-saline Baltic Sea. Levels of divergence for putatively neutral markers were generally low, with the exception of single outlier locus/sample combinations; microsatellites were the most statistically powerful markers under neutral expectations. We found no evidence of selection acting on the MHC locus. Cpa112, however, was highly divergent in the Baltic samples. Simulations addressing the statistical power for detecting population divergence showed that when using Cpa112 alone, compared with using eight presumed neutral microsatellite loci, sample sizes could be reduced by up to a tenth while still retaining high statistical power. Our results show that the loci influenced by selection can serve as powerful markers for detecting population structure in high gene-flow marine fish species.

  • 7.
    Appelgren, Henrik
    Stockholm University.
    Spontaneous and induced mutations at the human minisatellite MS32 in yeast1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tandem repetitive DNA including minisatellites make up a large part of eukaryotic genomes, and some tandem repetitive loci are associated with human disease. Little is known about the functions and dynamics of these sequences. Hypervariable minisatellites are used as naturally occurring genetic markers and form the basis of DNA fingerprinting. Studies in human have shown that minisatellite alleles frequently mutate to new lengths by recombination-based mechanisms that operate in the germline, possibly in meiosis. In addition to the variability in length, all hypervariable minisatellites characterised to date also show variation in the DNA sequence of repeat units. The order of variant repeat units can be revealed by MVR-PCR (Minisatellite Variant Repeat mapping by PCR), and this has greatly contributed to mutation analysis by comparing structures of alleles before and after mutation. Certain aspects of minisatellite mutation and general eukaryotic meiotic recombination, cannot be studies in human or any other mammalian system. It was therefore necessary to develop a manipulable eukaryotic model system in the yeast Saccharomyces cerevisiae. The best characterised human minisatellite MS32 was integrated in the vicinity of a hotspot for meiotic recombination in chromosome III. This thesis presents the construction of the model system and analyses of MS32 mutation in yeast.

    The results proved that MS32 mutation is induced in meiosis. Mutant structures were strikingly similar to mutant structures seen in man. Tetrad analysis demonstrated that gene conversion is the major pathway leading to interallelic exchanges. The data also suggested that a hyper-recombinogenic state is formed, and it was shown that entire alleles can be transferred from a chromatid to another. An allele that displays reduced mutation rate in man showed a reduced mutation rate also in yeast. The results have implications for general eukaryotic meiotic recombination. Mutations at MS32 were induced in meiosis by PCB, suggesting that the model system can be used as an in vitro bioassay for the screening of environmental contaminants capable of inducing genomic damage in meiosis. It is concluded that the yeast model constitute a suitable system for the molecular dissection of pathways in spontaneous and induced minisatellite mutations and for elucidating general eukaryotic meiotic recombination mechanisms.

  • 8.
    Arefin, Md. Badrul
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University.
    Molecular characterization of the Drosophila responses towards nematodes2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A sophisticated evolutionary conserved innate immune system has evolved in insects to fight pathogens and to restrict damage in harmful (danger) situations including cancer. A significant amount of knowledge about different infection models in Drosophila has been generated in past decades, which revealed functional resemblances and implications for vertebrate systems. However, how Drosophila responds towards multicellular parasitic nematodes and in danger situations is still little understood. Therefore, the aim of the thesis was to characterize multiple aspects of the host defense in the two important contexts mentioned above.

    We analyzed the transcriptome profiles of nematode-infected Drosophila larvae with uninfected samples. For this we employed the entomopathogenic nematode Heterorhabditis bacteriophora with its symbiont Photorhabdus luminescence to infect Drosophila larvae. We found 642 genes were differentially regulated upon infection. Among them a significant portion belonged to immune categories. Further functional analysis identified a thioester containing protein TEP3, a recognition protein GNBP-like 3, the basement membrane component protein Glutactin and several other small peptides. Upon loss or reduced expression of these genes hosts showed mortality during nematode infections. This study uncovers a novel function for several of the genes in immunity.

    Furthermore, we investigated the cellular response towards nematodes. When we eliminated hemocytes genetically (referred to as hml-apo) in Drosophila, we found hml-apo larvae are resistant to nematodes. Subsequent characterization of hml-apo larvae showed massive lamellocyte differentiation (another blood cell type which is rare in naïve larvae), emergence of melanotic masses, up- and down-regulation of Toll and Imd signaling respectively suggesting a pro-inflammatory response. Moreover, a striking defective leg phenotype in adult escapers from pupal lethality was observed. We identified nitric oxide (NO) as a key regulator of these processes. We also showed that imaginal disc growth factors 3 (IDGF3): (a) protects hosts against nematodes, (b) is a clotting component and (c) negatively regulates Wnt and JAK/STAT signaling. To follow larval behavior in the presence or absence of nematodes we monitored Drosophila larval locomotion behaviors using FIMtrack (a recently devised automated method) to elucidate evasive strategies of hosts. Finally, we characterized host defenses in three Drosophila leukemia models with and without nematode infection. Taken together, these studies shed light on host responses in two crucial circumstances, nematode infections and danger situations.

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  • 9.
    Arnaudeau, Catherine
    Stockholm University.
    Mitotic recombination in mammalian cells2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Recombination is usually defined as the exchange of genetic material between two strands or regions of nucleic acids. This process occurs in all known organisms and is highly conserved, especially among higher eukaryotes. Various types of recombination, involving homologous or non-homologous nucleic acid sequences, are known to exist. Recombination is a double-edged sword that may be beneficial or harmful for the cell. On one hand, it fulfills essential functions in connection with, e.g., repair of DNA double- strand breaks and maintenance of genomic stability; but, at the same time, this process is also partly responsible for, among other things, error prone repair and genomic instability, which can lead to cancer.

    The aim of the present study has been to investigate molecular mechanisms underlying spontaneous and induced mitotic recombination in mammalian cells and, in particular, to characterize the role of the RAD51 protein in these processes. For this purpose, V79 Chinese hamster cell lines containing spontaneous partial duplications of the hprt gene were employed. A new approach to investigate homologous recombination, which offers the unique possibility of determining the type of homologous recombination involved, was developed. This assay procedure was compared to other systems used previously for detection of induced recombination. Use of this newly developed method to characterize mechanisms underlying induction of homologous recombination revealed that inhibition of DNA synthesis is a potent pathway for such induction.

    Subsequently, the effect of overexpressing RAD51 on two different assays for recombination was determined. Our findings suggest that the RAD51 protein supports spontaneous homologous recombination via an exchange mechanism, as well as being involved in spontaneous non-homologous recombination, possibly with respect to class switch recombination. However, RAD51 was found not to affect induced non-homologous recombination, suggesting that this protein might not be involved in repairing DNA damage via non-homologous end-joining.

    Finally, the repair of DNA double-strand breaks induced in the S phase of the cell cycle was examined. Our observations in this case suggest that homologous recombination by strand invasion, employing an exchange mechanism, is a major feature of such repair and, furthermore, that a functional pathway for recombination is essential for the survival of cells in which DNA double-strand breaks have occurred.

    In summary, the work described here improves our understanding of the molecular mechanisms underlying spontaneous and induced recombination, as well as the repair of DNA double-strand breaks in mammalian cells.

  • 10. Arnqvist, Göran
    et al.
    Westerberg, Ivar
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Uppsala University, Sweden.
    Galbraith, James
    Sayadi, Ahmed
    Scofield, Douglas G.
    Olsen, Remi-André
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Immonen, Elina
    Bonath, Franziska
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ewels, Philip
    Suh, Alexander
    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. 

  • 11.
    Asgard, Rikard
    et al.
    Uppsala Univ, Dept Pharmaceut Biosci., Uppsala, Sweden.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Golkar, Siv Osterman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hellman, Bjorn
    Uppsala Univ, Dept Pharmaceut Biosci., Uppsala, Sweden.
    Czene, Stefan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Evidence for different mechanisms of action behind the mutagenic effects of 4-NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool2013In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 28, no 6, p. 637-644Article in journal (Refereed)
    Abstract [en]

    The mutagenicity of 4-nitro-o-phenylenediamine (4-NOPD) and o-phenylenediamine (OPD) was compared using the Mouse Lymphoma Assay (MLA) with or without metabolic activation (S9). As expected, OPD was found to be a more potent mutagen than 4-NOPD. To evaluate possible mechanisms behind their mutagenic effects, the following end points were also monitored in cells that had been exposed to similar concentrations of the compounds as in the MLA: general DNA damage (using a standard protocol for the Comet assay); oxidative DNA damage (using a modified procedure for the Comet assay in combination with the enzyme hOGG1); reactive oxygen species (ROS; using the CM-H(2)DCFDA assay); and the balance of the nucleotide pool (measured after conversion to the corresponding nucleosides dC, dT, dG and dA using high-performance liquid chromatography). Both compounds increased the level of general DNA damage. Again, OPD was found to be more potent than 4-NOPD (which only increased the level of general DNA damage in the presence of S9). Although less obvious for OPD, both compounds increased the level of oxidative DNA damage. However, an increase in intracellular ROS was only observed in cells exposed to 4-NOPD, both with and without S9 (which in itself induced oxidative stress). Both compounds decreased the concentrations of dA, dT and dC. A striking effect of OPD was the sharp reduction of dA observed already at very low concentration, both with and without S9 (which in itself affected the precursor pool). Taken together, our results indicate that indirect effects on DNA, possibly related to an unbalanced nucleotide pool, mediate the mutagenicity and DNA-damaging effects of 4-NOPD and OPD to a large extent. Although induction of intracellular oxidative stress seems to be a possible mechanism behind the genotoxicity of 4-NOPD, this pathway seems to be of less importance for the more potent mutagen OPD.

  • 12.
    Assefaw-Redda, Yohannes
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hemolin expression during Cecropia development and its effect on malaria parasites2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hemolin is a lepidopteran member of the immunoglobulin superfamily, initially isolated from the giant silkmoth Hyalophora cecropia. Hemolin is also induced by stimulation with microbial cell wall components and was recently shown to be strongly upregulated by baculovirus and double stranded RNA. An interesting characteristic of the protein is that it is not only highly expressed during infection but also during development.

    The work presented in this thesis investigated the expression of hemolin during oogenesis and embryogenesis in H. cecropia. Vitellogenic follicles from ovaries were analysed for the presence of the protein by immunohistochemistry in whole-mount preparations and in cryosections. PCR was used to show the presence of Hemolin transcripts throughout vitellogenesis and choriogenesis and in fertilized and unfertilized mature eggs and Western blots showed the protein in unfertilized eggs, yolk cells and embryo.

    Injection of the moulting hormone 20-hydroxyecdysone (20E) into hibernating diapausing pupae (low metabolic state), upregulates Hemolin. When diapausing pupae were treated with 20E and the protein synthesis inhibitor cycloheximide, its expression stayed low. This shows that the hormone indirectly regulates Hemolin by some factor(s) induced by 20E. When both bacteria and 20E were injected into diapausing pupae, an enhanced induction of hemolin gene expression occurred. Despite the seemingly indirect 20E regulation, several putative hormone responsive elements were found in the upstream region of the Hemolin (HRE-IR, HRE-M and MRE). When these elements were analysed by gel electrophoresis mobility shift assays (EMSA) to investigate their binding to nuclear factors, all the sites resulted in specific retarded bands. The HRE-IR binding factor was clearly increased by ecdysone. Last but not least we have investigated the effect of Hemolin on development of the malaria parasite Plasmodium falciparum in the midgut of the Anopheles mosquitoes. Hemolin completely inhibits the development of the parasite into its final transmission stage, the sporozoite. A future goal is to generate para-transgenic mosquitoes, enforced by hemolin, to stop malaria transmission. Importantly, hemolin did not affect the mosquito fecundity when fed to the mosquito. We are currently constructing truncated forms of hemolin to gain insight into which parts are important for its effect on the parasite.

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  • 13.
    Bachmann, Jörg A.
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Tedder, Andrew
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Genete, Mathieu
    Ferreira de Carvalho, Julie
    Castric, Vincent
    Slotte, Tanja
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Evolutionary stability of genetic dominance in the Brassicaceae self-incompatibility systemManuscript (preprint) (Other academic)
    Abstract [en]

    The question of whether dominance-recessivity relationships between associated alleles in a diploid genotype can evolve independently from the activity of the gene products encoded has been a hot topic in evolutionary genetics throughout the 20th century. In hermaphroditic plants of the Brassicaceae family, the self-incompatibility locus (S-locus) confers the ability to recognize and reject self-pollen. Dominance relationships between self-incompatibility alleles (S-alleles) in pollen are governed by small RNA (sRNA) transcriptional regulators produced by dominant S-alleles and their target sites on recessive S-alleles. These regulators and their target sites segregate together with but are distinct from the genes encoding self-recognition specificities themselves, providing the opportunity for dominance to evolve independently from the recognition specificities. Dominance interactions between the many segregating S-alleles have been described in the distantly related Arabidopsis and Brassica, but little is known about the evolutionary stability of the dominance networks given that divergent sets of S-alleles are segregating in these two genera. In this study, we take advantage of the extensive trans-specific sharing of S-haplotypes between the self-incompatible species Capsella grandiflora and Arabidopsis halleri to investigate the conservation of S-locus dominance relationships across their approximately 8 million years of divergence. For this purpose, we use a combination of controlled crosses and full-length long-read sequencing of S-haplotypes. We find that the dominance network among six C. grandiflora S-alleles has a largely parallel structure to that among their orthologous S-alleles in A. halleri. We test the theoretical prediction that dominant S-alleles should be found at lower population frequencies using a large sample of a natural C. grandiflora population. Finally, we test whether dominant C. grandiflora S-alleles show increased accumulation of repeats (TEs) than recessive S-alleles, as expected due to their lower chance of recombination and lower effective population sizes. Our results contribute to an improved understanding of the maintenance of dominance relationships at loci under balancing selection.

  • 14.
    Bachmann, Jörg Alexander
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Evolutionary consequences of dominance at the Brassicaceae self-incompatibility locus2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Self-incompatibility (SI) is a genetic mechanism that allows plants to enforce outcrossing by rejecting self-pollen and pollen from close relatives. In the Brassicaceae, SI is sporophytic and controlled by the self-incompatibility locus (S-locus). The S-locus harbors two tightly linked genes SRK and SCR, which encode the female and male SI specificity determinants, respectively. S-locus heterozygotes often only express the S-specificity of the more dominant allele, and at the pollen level such dominance relationships are mediated by small RNAs (sRNAs). The S-locus is thus an example of a locus under strong balancing selection, where dominance modifiers have evolved.

    In this thesis, I investigate the consequences of S-locus dominance for plant mating system evolution and allopolyploid speciation. I further investigate evolutionary conservation and sequence-level effects of dominance relationships among S-alleles. For this purpose, I used the crucifer genus Capsella as a model system.

    First, I demonstrated that targeted long-read sequencing results in structurally accurate assemblies of full-length S-haplotype sequences, and that indel errors in such assemblies can be corrected using short reads. Second, I investigated the genetic basis of loss of SI, the first step in the evolution of self-fertilisation, in the self-compatible (SC) Capsella orientalis. I found that loss of SI was dominant and mapped to the S-locus, where C. orientalis harbored a fixed coding frameshift deletion in SCR that is likely to lead to loss of male specificity. I further identified a sRNA-based dominance modifier that is associated with dominant suppression of recessive SCR alleles. Taken together, these results suggest that loss of SI in C. orientalis involved a dominant S-haplotype, suggesting that dominant haplotypes may be favored under conditions that select for loss of SI. Third, I show that a dominant S-haplotype may also have contributed to the shift to SC in the widespread allotetraploid Capsella bursa-pastoris. Fourth, I showed that dominance relationships at the S-locus are largely conserved between the SI outcrossing species C. grandiflora and Arabidopsis halleri which diverged ~8 Mya. I also found that dominant S-haplotypes accumulate more transposable elements than recessive S-haplotypes, in line with expected sequence-level consequences of S-locus dominance. In sum, this thesis provides new insights into the broad conservation of dominance hierarchies at the Brassicaceae S-locus, and the role of dominant S-alleles in allopolyploid speciation and plant mating system shifts.

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  • 15.
    Bajinskis, Ainars
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Natarajan, Adayapalam T.
    Erixon, Klaus
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Harms-Ringdahl, Mats
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    DNA double strand breaks induced by the indirect effect of radiation are more efficiently repaired by non-homologous end joining compared to homologous recombination repair2013In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 756, no 1-2, p. 21-29Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the relative involvement of three major DNA repair pathways, i.e., non-homologous end joining (NHEJ), homologous recombination (HRR) and base excision (BER) in repair of DNA lesions of different complexity induced by low- or high-LET radiation with emphasis on the contribution of the indirect effect of radiation for these radiation qualities. A panel of DNA repair-deficient CHO cell lines was irradiated by Cs-137 gamma-rays or radon progeny alpha-particles. Irradiation was also performed in the presence of 2 M DMSO to reduce the indirect effect of radiation and the complexity of the DNA damage formed. Clonogenic survival and micronucleus assays were used to estimate efficiencies of the different repair pathways for DNA damages produced by direct and indirect effects. Removal of the indirect effect of low-LET radiation by DMSO increased clonogenic survival and decreased MN formation for all cell lines investigated. A direct contribution of the indirect effect of radiation to DNA base damage was suggested by the significant protection by DMSO seen for the BER deficient cell line. Lesions formed by the indirect effect are more readily repaired by the NHEJ pathway than by HRR after irradiation with gamma-rays or alpha-particles as evaluated by cell survival and the yields of MN. The results obtained with BER- and NHEJ-deficient cells suggest that the indirect effect of radiation contributes significantly to the formation of repair substrates for these pathways.

  • 16. Barcala, Maximiliano Estravis
    et al.
    van der Valk, Tom
    Chen, Zhiqiang
    Funda, Tomas
    Chaudhary, Rajiv
    Klingberg, Adam
    Fundova, Irena
    Suontama, Mari
    Hallingbäck, Henrik
    Bernhardsson, Carolina
    Nystedt, Björn
    Ingvarsson, Pär K.
    Sherwood, Ellen
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Street, Nathaniel
    Gyllensten, Ulf
    Nilsson, Ove
    Wu, Harry X.
    Whole-genome resequencing facilitates the development of a 50K single nucleotide polymorphism genotyping array for Scots pine (Pinus sylvestris L.) and its transferability to other pine species2023In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313XArticle in journal (Refereed)
    Abstract [en]

    Scots pine (Pinus sylvestris L.) is one of the most widespread and economically important conifer species in the world. Applications like genomic selection and association studies, which could help accelerate breeding cycles, are challenging in Scots pine because of its large and repetitive genome. For this reason, genotyping tools for conifer species, and in particular for Scots pine, are commonly based on transcribed regions of the genome. In this article, we present the Axiom Psyl50K array, the first single nucleotide polymorphism (SNP) genotyping array for Scots pine based on whole-genome resequencing, that represents both genic and intergenic regions. This array was designed following a two-step procedure: first, 192 trees were sequenced, and a 430K SNP screening array was constructed. Then, 480 samples, including haploid megagametophytes, full-sib family trios, breeding population, and range-wide individuals from across Eurasia were genotyped with the screening array. The best 50K SNPs were selected based on quality, replicability, distribution across the draft genome assembly, balance between genic and intergenic regions, and genotype–environment and genotype–phenotype associations. Of the final 49 877 probes tiled in the array, 20 372 (40.84%) occur inside gene models, while the rest lie in intergenic regions. We also show that the Psyl50K array can yield enough high-confidence SNPs for genetic studies in pine species from North America and Eurasia. This new genotyping tool will be a valuable resource for high-throughput fundamental and applied research of Scots pine and other pine species.

  • 17. Bascon-Cardozo, Karen
    et al.
    Bours, Andrea
    Manthey, Georg
    Durieux, Gillian
    Dutheil, Julien Y.
    Pruisscher, Peter
    Stockholm University, Faculty of Science, Department of Zoology. Max Planck Institute for Evolutionary Biology, Germany.
    Odenthal-Hesse, Linda
    Liedvogel, Miriam
    Fine-Scale Map Reveals Highly Variable Recombination Rates Associated with Genomic Features in the Eurasian Blackcap2024In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 16, no 1, article id evad233Article in journal (Refereed)
    Abstract [en]

    Recombination is responsible for breaking up haplotypes, influencing genetic variability, and the efficacy of selection. Bird genomes lack the protein PR domain-containing protein 9, a key determinant of recombination dynamics in most metazoans. Historical recombination maps in birds show an apparent stasis in positioning recombination events. This highly conserved recombination pattern over long timescales may constrain the evolution of recombination in birds. At the same time, extensive variation in recombination rate is observed across the genome and between different species of birds. Here, we characterize the fine-scale historical recombination map of an iconic migratory songbird, the Eurasian blackcap (Sylvia atricapilla), using a linkage disequilibrium–based approach that accounts for population demography. Our results reveal variable recombination rates among and within chromosomes, which associate positively with nucleotide diversity and GC content and negatively with chromosome size. Recombination rates increased significantly at regulatory regions but not necessarily at gene bodies. CpG islands are associated strongly with recombination rates, though their specific position and local DNA methylation patterns likely influence this relationship. The association with retrotransposons varied according to specific family and location. Our results also provide evidence of heterogeneous intrachromosomal conservation of recombination maps between the blackcap and its closest sister taxon, the garden warbler. These findings highlight the considerable variability of recombination rates at different scales and the role of specific genomic features in shaping this variation. This study opens the possibility of further investigating the impact of recombination on specific population-genomic features.

  • 18.
    Bauer, Stefanie L.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Thaisen Grochalski, Thomas Nagel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Smialowska, Agata
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Åström, Stefan U.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sir2 and Reb1 antagonistically regulate nucleosome occupancy in subtelomeric X-elements and repress TERRAs by distinct mechanisms2022In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 18, no 9, article id e1010419Article in journal (Refereed)
    Abstract [en]

    Telomere chromatin structure is pivotal for maintaining genome stability by regulating the binding of telomere-associated proteins and inhibiting the DNA damage response. In Saccharomyces cerevisiae, silent information regulator (Sir) proteins bind to terminal repeats and to subtelomeric X-elements, resulting in transcriptional silencing. Herein, we show that sir2 mutant strains display a specific loss of a nucleosome residing in the X-elements and that this deficiency is remarkably consistent between different telomeres. The X-elements contain several binding sites for the transcription factor Reb1 and we found that Sir2 and Reb1 compete for stabilizing/destabilizing this nucleosome, i.e. inactivation of Reb1 in a sir2 background reinstated the lost nucleosome. The telomeric-repeat-containing RNAs (TERRAs) originate from subtelomeric regions and extend into the terminal repeats. Both Sir2 and Reb1 repress TERRAs and in a sir2 reb1 double mutant, TERRA levels increased synergistically, showing that Sir2 and Reb1 act in different pathways for repressing TERRAs. We present evidence that Reb1 restricts TERRAs by terminating transcription. Mapping the 5′-ends of TERRAs from several telomeres revealed that the Sir2-stabilized nucleosome is the first nucleosome downstream from the transcriptional start site for TERRAs. Finally, moving an X-element to a euchromatic locus changed nucleosome occupancy and positioning, demonstrating that X-element nucleosome structure is dependent on the local telomere environment.

  • 19.
    Belotserkovsky, Jaroslav
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Studies on the functional interaction of translation initiation factor IF1 with ribosomal RNA2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Translation initiation factor IF1 is a small, essential and ubiquitous protein factor encoded by a single infA gene in bacteria. Although several important functions have been attributed to IF1, the precise reason for its indispensability is yet to be defined. It is known that IF1 binds to the ribosomal A-site during initiation, where it primarily contacts ribosomal RNA (rRNA) and induces large scale conformational changes in the small ribosomal subunit. To shed more light on the function of IF1 and its interaction with the ribosome, we have employed a genetic approach to elucidate structure-function interactions between IF1 and rRNA. A selection has been used to isolate second site suppressor mutations in rRNA that restore the growth of a cold sensitive mutant IF1 with an arginine to leucine substitution in position 69 (R69L).  This yielded two classes of suppressors – one class that mapped to the processing stem of 23S rRNA – a transient structure important for proper maturation of 23S rRNA; and the other class to the functional sequence of 16S rRNA. Suppressor mutations in the processing stem of 23S rRNA were shown to disrupt efficient processing of 23S rRNA. In addition, we report that at least one of the manifestations of cold sensitivity associated with the mutant IF1 is at the level of ribosomal subunit association. These results led to a model whereby the cold sensitive R69L mutant IF1 results in aberrant ribosomal subunit association properties, while the 23S processing stem mutations indirectly suppress this effect by decreasing the pool of mature 50S subunits available for association.  Spontaneous suppressor mutations in 16S rRNA were diverse in position and phenotypic properties, but all mutations affected ribosomal subunit association, in most cases by directly decreasing the affinity of the 30S for 50S subunits. Site directed mutagenesis of select positions in 16S rRNA yielded additional suppressor mutations that were localized to the mRNA and streptomycin binding sites on the small ribosomal subunit. We suggest that the 16S rRNA suppressors occur in positions that affect the conformational dynamics brought about by IF1. Taken together, this work indicates that the major function of IF1 is the modulation of ribosomal subunit association brought about through conformational changes of the 30S subunit.

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  • 20.
    Belotserkovsky, Jaroslav
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Isaksson, Leif
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mutations in the streptomycin and mRNA binding sites on 16S rRNA suppress a cold sensitive initiation factor IF1Manuscript (preprint) (Other academic)
  • 21.
    Belotserkovsky, Jaroslav M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Dabbs, Eric R.
    Isaksson, Leif A.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mutations in 16S rRNA that suppress cold-sensitive initiation factor 1 affect ribosomal subunit association2011In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 278, no 18, p. 3508-3517Article in journal (Refereed)
    Abstract [en]

    A mutation in the infA gene encoding initiation factor 1 (IF1) gives rise to a cold-sensitive phenotype. An Escherichia coli strain with this mutation was used as a tool to select for second-site suppressors that compensate for the cold sensitivity and map specifically to rRNA. Several suppressor mutants with altered 16S rRNA that partially restore growth of an IF1 mutant strain in the cold were isolated and characterized. Suppressor mutations were found in helix (h) 18, h32, h34 and h41 in 16S rRNA. These mutations are not clustered to any particular region in 16S rRNA and none overlap previously reported sites of interaction with IF1. While the isolated suppressors are structurally diverse, they are functionally related because all affect ribosomal subunit association in vivo. Furthermore, in vitro subunit-association experiments indicate that most of the suppressor mutations directly influence ribosomal subunit association even though none of these are confined to any of the known intersubunit bridges. These results are consistent with the model that IF1 is an rRNA chaperone that induces large-scale conformational changes in the small ribosomal subunit, and as a consequence modulates initiation of translation by affecting subunit association.

  • 22.
    Belotserkovsky, Jaroslav M.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Isak, Georgina I.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Isaksson, Leif A.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Suppression of a cold-sensitive mutant initiation factor 1 by alterations in the 23S rRNA maturation region2011In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 278, no 10, p. 1745-1756Article in journal (Refereed)
    Abstract [en]

    Genetic selection has been used to isolate second-site suppressors of a defective cold-sensitive initiation factor I (IF1) R69L mutant of Escherichia coli. The suppressor mutants specifically map to a single rRNA operon on a plasmid in a strain with all chromosomal rRNA operons deleted. Here, we describe a set of suppressor mutations that are located in the processing stem of precursor 23S rRNA. These mutations interfere with processing of the 23S rRNA termini. A lesion of RNase III also suppresses the cold sensitivity. Our results suggest that the mutant IF1 strain is perturbed at the level of ribosomal subunit association, and the suppressor mutations partially compensate for this defect by disrupting rRNA maturation. These results support the notion that IF1 is an RNA chaperone and that translation initiation is coupled to ribosomal maturation.

  • 23.
    Berg, Ingrid
    Stockholm University.
    Instability of the human minisatellite MS1 in yeast and man2003Doctoral thesis, comprehensive summary (Other academic)
  • 24. Bergman, Ingvar
    et al.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    The effect of age on fluid intelligence is fully mediated by physical health2013In: Archives of gerontology and geriatrics (Print), ISSN 0167-4943, E-ISSN 1872-6976, Vol. 57, no 1, p. 100-109Article in journal (Refereed)
    Abstract [en]

    The present study investigated the extent to which the effect of age on cognitive ability is predicted by individual differences in physical health. The sample consisted of 118 volunteer subjects who were healthy and ranging in age from 26 to 91. The examinations included a clinical investigation, magnetic resonance imaging (MRI) brain neuroimaging, and a comprehensive neuropsychological assessment. The effect of age on fluid IQ with and without visual spatial praxis and on crystallized IQ was tested whether being fully-, partially-or non-mediated by physical health. Structural equation analyses showed that the best and most parsimonious fit to the data was provided by models that were fully mediated for fluid IQ without praxis, non-mediated for crystallized IQ and partially mediated for fluid IQ with praxis. The diseases of the circulatory and nervous systems were the major mediators. It was concluded from the pattern of findings that the effect of age on fluid intelligence is fully mediated by physical health, while crystallized intelligence is non-mediated and visual spatial praxis is partially mediated, influenced mainly by direct effects of age. Our findings imply that improving health by acting against the common age-related circulatory-and nervous system diseases and risk factors will oppose the decline in fluid intelligence with age.

  • 25. Bertrand, Yann
    et al.
    Topel, Mats
    Elvang, Annelie
    Melik, Wessam
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Johansson, Magnus
    First Dating of a Recombination Event in Mammalian Tick-Borne Flaviviruses2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 2, p. e31981-Article in journal (Refereed)
    Abstract [en]

    The mammalian tick-borne flavivirus group (MTBFG) contains viruses associated with important human and animal diseases such as encephalitis and hemorrhagic fever. In contrast to mosquito-borne flaviviruses where recombination events are frequent, the evolutionary dynamic within the MTBFG was believed to be essentially clonal. This assumption was challenged with the recent report of several homologous recombinations within the Tick-borne encephalitis virus (TBEV). We performed a thorough analysis of publicly available genomes in this group and found no compelling evidence for the previously identified recombinations. However, our results show for the first time that demonstrable recombination (i.e., with large statistical support and strong phylogenetic evidences) has occurred in the MTBFG, more specifically within the Louping ill virus lineage. Putative parents, recombinant strains and breakpoints were further tested for statistical significance using phylogenetic methods. We investigated the time of divergence between the recombinant and parental strains in a Bayesian framework. The recombination was estimated to have occurred during a window of 282 to 76 years before the present. By unravelling the temporal setting of the event, we adduce hypotheses about the ecological conditions that could account for the observed recombination.

  • 26.
    Bettencourt, Raul
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hemolin, a versatile immune protein from the Cecropia moth1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Insects have become useful models for the study of innate immune mechanisms, due to their lack of antibodies and receptors involved in adaptive immune response. However, the molecules and mechanisms involved in primordial immune recognition are still poorly understood. Hemolin, originally cloned from Hyalophora cecropia, is a soluble and membrane associated Ig-related molecule which meets the criteria for a pattern recognition molecule. It is constitutively expressed in the hemolymph and up-regulated after bacterial injection. It was shown to bind specifically to the Lipid A moiety of LPS from bacteria and to associate with aggregates formed by hemocytes and bacteria. The aim of the present studies was to characterize the binding of hemolin to insect cells and further investigate the mechanisms behind. Earlier results shown in Manduca sexta were confirmed and it was shown that soluble hemolin has a deaggregating effect on naive hemocytes of H. cecropia. Moreover, hemolin increases phagocytic activity of hemocytes, especially when combined with LPS. This enhanced phagocytosis was correlated to the activity of protein kinase C and tyrosine phosphorylation. We revealed a number of cell adhesion characteristics of hemolin 1) a membrane associated form, (2) Ca2+-dependent homophilic binding, (3) glycosylation (4) importance of Ca2+ and carbohydrates on the binding to hemocytes. Based on our present results and the hemolin crystal structure, we have proposed a model for the interactions between soluble hemolin and its membrane form. The close relatedness to NCAMs prompted us to investigate its expression in other tissues than those originally described. It was found that hemolin is present in the retinal eye discs of pupae, in developing follicles during oogenesis and in embryos of H. cecropia. It was inferred that hemolin has a role in developmental processes in addition to its putative immune functions in insects. From a phylogenetic point of view, hemolin function is consistent with the assumption that non-self recognition molecules of the IgSF arose from cell-adhesion molecules with multiple functions.

  • 27.
    Brehwens, Karl
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bajinskis, Ainars
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Staaf, Elina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cederwall, Bo
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    A NEW DEVICE TO EXPOSE CELLS TO CHANGING DOSE RATES OF IONISING RADIATION2012In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 148, no 3, p. 366-371Article in journal (Refereed)
    Abstract [en]

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

  • 28. Burnett, Hamish A.
    et al.
    Bieker, Vanessa C.
    Le Moullec, Mathilde
    Peeters, Bart
    Rosvold, Jørgen
    Ønvik Pedersen, Åshild
    Dalén, Love
    Stockholm University, Faculty of Science, Department of Zoology. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    Loe, Leif Egil
    Jensen, Henrik
    Hansen, Brage B.
    Martin, Michael D.
    Contrasting genomic consequences of anthropogenic reintroduction and natural recolonization in high-arctic wild reindeer2023In: Evolutionary Applications, E-ISSN 1752-4571, Vol. 16, no 9, p. 1531-1548Article in journal (Refereed)
    Abstract [en]

    Anthropogenic reintroduction can supplement natural recolonization in reestablishing a species' distribution and abundance. However, both reintroductions and recolonizations can give rise to founder effects that reduce genetic diversity and increase inbreeding, potentially causing the accumulation of genetic load and reduced fitness. Most current populations of the endemic high-arctic Svalbard reindeer (Rangifer tarandus platyrhynchus) originate from recent reintroductions or recolonizations following regional extirpations due to past overharvesting. We investigated and compared the genomic consequences of these two paths to reestablishment using whole-genome shotgun sequencing of 100 Svalbard reindeer across their range. We found little admixture between reintroduced and natural populations. Two reintroduced populations, each founded by 12 individuals around four decades (i.e. 8 reindeer generations) ago, formed two distinct genetic clusters. Compared to the source population, these populations showed only small decreases in genome-wide heterozygosity and increases in inbreeding and lengths of runs of homozygosity. In contrast, the two naturally recolonized populations without admixture possessed much lower heterozygosity, higher inbreeding and longer runs of homozygosity, possibly caused by serial population founder effects and/or fewer or more genetically related founders than in the reintroduction events. Naturally recolonized populations can thus be more vulnerable to the accumulation of genetic load than reintroduced populations. This suggests that in some organisms even small-scale reintroduction programs based on genetically diverse source populations can be more effective than natural recolonization in establishing genetically diverse populations. These findings warrant particular attention in the conservation and management of populations and species threatened by habitat fragmentation and loss. 

  • 29.
    Caputo, Andrea
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Genomic and morphological diversity of marine planktonic diatom-diazotroph associations: a continuum of integration and diversification through geological time2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Symbioses between eukaryotes and nitrogen (N2)-fixing cyanobacteria (or diazotrophs) are quite common in the plankton community. A few genera of diatoms (Bacillariophyceae) such as Rhizosolenia, Hemiaulus and Chaetoceros are well known to form symbioses with the heterocystous diazotrophic cyanobacteria Richelia intracellularis and Calothrix rhizosoleniae. The latter are also called diatom-diazotroph associations, or DDAs. Up to now, the prokaryotic partners have been morphologically and genetically characterized, and the phylogenetic reconstruction of the well conserved nifH gene (encodes for the nitrogenase enzyme) placed the symbionts in 3 clusters based on their host-specificity, i.e. het-1 (Rhizosolenia-R. intracellularis), het-2 (Hemiaulus-R. intracellularis), and het-3 (Chaetoceros-C- rhizosoleniae). Conversely, the diatom-hosts, major representative of the phytoplankton community and crucial contributors to the carbon (C) biogeochemical cycle, have been understudied.

    The first aim of this thesis was to genetically and morphologically characterize the diatom-hosts, and to reconstruct the evolutionary background of the partnerships and the symbiont integration in the host. The molecular-clock analysis reconstruction showed the ancient appearance of the DDAs, and the traits characterizing the ancestors. In addition, diatom-hosts bearing internal symbionts (with more eroded draft genomes) appeared earlier than diatom-hosts with external symbionts. Finally a blast survey highlighted a broader distribution of the DDAs than expected.

    The second aim of this thesis was to compare genetic and physiological characteristics of the DDAs symbionts with the other eukaryote-diazotroph symbiosis, i.e. prymnesiophyte-UCYN-A (or Candidatus Atelocyanobacterium thalassa). The genome comparison highlighted more genes for transporters in het-3 (external symbiont) and in the UCYN-A based symbiosis, suggesting that symbiont location might be relevant also for metabolic exchanges and interactions with the host and/or environment. Moreover, a summary of methodological biases that brought to an underestimation of the DDAs is reported.

    The third aim of this thesis was to determine the distribution of the DDAs in the South Pacific Ocean using a quantitative polymerase chain reaction (qPCR) approach and to outline the environmental drivers of such distribution. Among the het-groups, het-1 was the most abundant/detected and co-occurred with the other 2 symbiotic strains, all responding similarly to the influence of abiotic factors, such as temperature and salinity (positive and negative correlation, respectively). Globally, Trichodesmium dominated the qPCR detections, followed by UCYN-B. UCYN-A phylotypes (A-1, A-2) were detected without their proposed hosts, for which new oligonucleotides were designed. The latter suggested a facultative symbiosis. Finally, microscopy observations of the het-groups highlighted a discrepancy with the qPCR counts (i.e. the former were several order of magnitudes lower), leading to the idea of developing a new approach to quantify the DDAs.  

    The fourth aim of this thesis was to develop highly specific in situ hybridization assays (CARD-FISH) to determine the presence of alternative life-stages and/or free-living partners. The new assays were applied to samples collected in the South China Sea and compared with abundance estimates from qPCR assays for the 3 symbiotic strains. Free-living cells were indeed detected along the transect, mainly at deeper depths. Free-living symbionts had two morphotypes: trichomes and single-cells. The latter were interpreted as temporary life-stages. Consistent co-occurrence of the 3 het-groups was also found in the SCS and application of a SEM model predicted positive interactions between the het groups. We interpreted the positive interaction as absence of intra-specific competition, and consistent with the previous study, temperature and salinity were predicted as major drivers of the DDAs distribution.

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  • 30.
    Cardoso Palacios, Carlos
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Site-specific recombination in P2-like coliphages2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

  • 31.
    Cardoso-Palacios, Carlos
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Sylwan, Lina
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Mandali, Sridhar
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Frumerie, Clara
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    Haggård-Ljungquist, Elisabeth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    A structure-function analysis of P2 integraseManuscript (preprint) (Other academic)
    Abstract [en]

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

  • 32.
    Celorio-Mancera, Maria de la Paz
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Ahn, Seung-Joon
    Vogel, Heiko
    Heckel, David G.
    Transcriptional responses underlying the hormetic and detrimental effects of the plant secondary metabolite gossypol on the generalist herbivore Helicoverpa armigera2011In: BMC Genomics, E-ISSN 1471-2164, Vol. 12, p. 575-Article in journal (Refereed)
    Abstract [en]

    Background: Hormesis is a biphasic biological response characterized by the stimulatory effect at relatively low amounts of chemical compounds which are otherwise detrimental at higher concentrations. A hormetic response in larval growth rates has been observed in cotton-feeding insects in response to increasing concentrations of gossypol, a toxic metabolite found in the pigment glands of some plants in the family Malvaceae. We investigated the developmental effect of gossypol in the cotton bollworm, Helicoverpa armigera, an important heliothine pest species, by exposing larvae to different doses of this metabolite in their diet. In addition, we sought to determine the underlying transcriptional responses to different gossypol doses. Results: Larval weight gain, pupal weight and larval development time were measured in feeding experiments and a hormetic response was seen for the first two characters. On the basis of net larval weight gain responses to gossypol, three concentrations (0%, 0.016% and 0.16%) were selected for transcript profiling in the gut and the rest of the body in a two-color double reference design microarray experiment. Hormesis could be observed at the transcript level, since at the low gossypol dose, genes involved in energy acquisition such as beta-fructofuranosidases were up-regulated in the gut, and genes involved in cell adhesion were down-regulated in the body. Genes with products predicted to be integral to the membrane or associated with the proteasome core complex were significantly affected by the detrimental dose treatment in the body. Oxidoreductase activity-related genes were observed to be significantly altered in both tissues at the highest gossypol dose. Conclusions: This study represents the first transcriptional profiling approach investigating the effects of different concentrations of gossypol in a lepidopteran species. H. armigera's transcriptional response to gossypol feeding is tissue-and dose-dependent and involves diverse detoxifying mechanisms not only to alleviate direct effects of gossypol but also indirect damage such as pH disturbance and oxygen radical formation. Genes discovered through this transcriptional approach may be additional candidates for understanding gossypol detoxification and coping with gossypol-induced stress. In a generalist herbivore that has evolved transcriptionally-regulated responses to a variety of different plant compounds, hormesis may be due to a lower induction threshold of growth-promoting, stress-coping responses and a higher induction threshold of detoxification pathways that are costly and cause collateral damage to the cell.

  • 33.
    Daniel, Chammiran
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Silberberg, Gilad
    Behm, Mikaela
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Alu elements shape the primate transcriptome by cis-regulation of RNA editing2014In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, no 2, article id R28Article in journal (Refereed)
    Abstract [en]

    Background: RNA editing by adenosine to inosine deamination is a widespread phenomenon, particularly frequent in the human transcriptome, largely due to the presence of inverted Alu repeats and their ability to form double-stranded structures - a requisite for ADAR editing. While several hundred thousand editing sites have been identified within these primate-specific repeats, the function of Alu-editing has yet to be elucidated. Results: We show that inverted Alu repeats, expressed in the primate brain, can induce site-selective editing in cis on sites located several hundred nucleotides from the Alu elements. Furthermore, a computational analysis, based on available RNA-seq data, finds that site-selective editing occurs significantly closer to edited Alu elements than expected. These targets are poorly edited upon deletion of the editing inducers, as well as in homologous transcripts from organisms lacking Alus. Sequences surrounding sites near edited Alus in UTRs, have been subjected to a lesser extent of evolutionary selection than those far from edited Alus, indicating that their editing generally depends on cis-acting Alus. Interestingly, we find an enrichment of primate-specific editing within encoded sequence or the UTRs of zinc finger-containing transcription factors. Conclusions: We propose a model whereby primate-specific editing is induced by adjacent Alu elements that function as recruitment elements for the ADAR editing enzymes. The enrichment of site-selective editing with potentially functional consequences on the expression of transcription factors indicates that editing contributes more profoundly to the transcriptomic regulation and repertoire in primates than previously thought.

  • 34. de Oliveira Galvão, Marcos Felipe
    et al.
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Batistuzzo de Medeiros, Silvia R.
    Dreij, Kristian
    DNA damage signaling and genotoxic effects induced by complex mixtures of PAHs generated by biomass burning air particulate matter in human lung cells2019In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 314, no SI, p. S132-S133Article in journal (Refereed)
    Abstract [en]

    Most research concerning the effects of air pollutants on human health focuses on urban centers and on the role of vehicular and industrial emissions as major sources of pollution. However, approximately 3 billion people world-wide are exposed to air pollution from biomass burning [1]. Herein, particulate matter (PM) emitted from artisanal cashew nut roasting, an important economic and social activity worldwide [2,3], was investigated. This study focused on: i) chemical characterization of polycyclic aromatic hydrocarbons (PAHs) and their oxy-PAH derivatives; ii) time-dependent activation of DNA damage signaling and genotoxic effects, and iii) differential expression of genes involved in xenobiotic metabolism, inflammation, cell cycle arrest and DNA repair using A549 lung cells. Among the PAHs, chrysene, benzo[a]pyrene (B[a]P), benzo[b]fluoranthene, and benz[a]anthracene showed the highest concentrations (7.8-10 ng/m3), while among oxy-PAHs, benzanthrone and 9,10-anthraquinone were the most abundant. Testing of PM extracts was based on B[a]P equivalent doses (B[a]Peq). IC50 values for viability was 5.7 and 3.0 nM B[a]Peq at 24 h and 48 h, respectively. Based on this, all other experiments were conducted at doses up to 2 nM B[a]Peq. At these low doses, we observed a dose-dependent activation of DNA damage signaling (phosphorylation of Chk1) and genotoxicity (double strand breaks). In comparison, effects of B[a]P alone was observed at micromolar range. To our knowledge, no other study has demonstrated an activation of pChk1, a biomarker used to estimate the carcinogenic potency of PAHs in vitro [4], in lung cells exposed to biomass burning extracts. Persistent increased gene expression of several important stress response mediators of xenobiotic metabolism (CYP1A1, CYP1B1), inflammation (IL-8, TNF-α), cell cycle arrest (CDKN1A), and DNA repair (DDB2) was also identified. In conclusion, our data show high potency of biomass burning PM to induce cellular stress including genotoxicity, and more potently so when compared to B[a]P alone. Our study provides new data that will help elucidate the mechanism of lung cancer development associated with biomass burning. In addition, the results of this study support the establishment of new guidelines for human health protection in regions strongly impacted by biomass burning.

  • 35. de Oliveira Galvão, Marcos Felipe
    et al.
    Sadiktsis, Ioannis
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Batistuzzo de Medeiros, Silvia Regina
    Dreij, Kristian
    Genotoxicity and DNA damage signaling in response to complex mixtures of PAHs in biomass burning particulate matter from cashew nut roasting2020In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 256, article id 113381Article in journal (Refereed)
    Abstract [en]

    Approximately 3 billion people world-wide are exposed to air pollution from biomass burning. Herein, particulate matter(PM) emitted from artisanal cashew nut roasting, an important economic activity worldwide, was investigated. This study focused on: i) chemical characterization of polycyclic aromatic hydrocarbons (PAHs) and oxygenated (oxy-) PAHs; ii) intracellular levels of reactive oxygen species (ROS); iii) genotoxic effects and time- and dose-dependent activation of DNA damage signaling, and iv) differential expression of genes involved in xenobiotic metabolism, inflammation, cell cycle arrest and DNA repair, using A549 lung cells. Among the PAHs, chrysene, benzo[a]pyrene (B[a]P), benzo[b]fluoranthene, and benz[a]anthracene showed the highest concentrations (7.8–10 ng/m3), while benzanthrone and 9,10-anthraquinone were the most abundant oxy-PAHs. Testing of PM extracts was based on B[a]P equivalent doses (B[a]Peq). IC50 values for viability were 5.7 and 3.0 nM B[a]Peq at 24 h and 48 h, respectively. At these low doses, we observed a time- and dose-dependent increase in intracellular levels of ROS, genotoxicity (DNA strand breaks) and DNA damage signaling (phosphorylation of the protein checkpoint kinase 1 – Chk1). In comparison, effects of B[a]P alone was observed at micromolar range. To our knowledge, no previous study has demonstrated an activation of pChk1, a biomarker used to estimate the carcinogenic potency of PAHs in vitro, in lung cells exposed to cashew nut roasting extracts. Sustained induction of expression of several important stress response mediators of xenobiotic metabolism (CYP1A1, CYP1B1), ROS and pro-inflammatory response (IL-8, TNF-α, IL-2,COX2), and DNA damage response (CDKN1A and DDB2) was also identified. In conclusion, our data show high potency of cashew nut roasting PM to induce cellular stress including genotoxicity, and more potently when compared to B[a]P alone. Our study provides new data that will help elucidate the toxic effects of low-levels of PAH mixtures from air PM generated by cashew nut roasting.

  • 36. Dessimoz, Christophe
    et al.
    Gabaldón, Toni
    Roos, David S.
    Sonnhammer, Erik L. L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Herrero, Javier
    Toward community standards in the quest for orthologs2012In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 28, no 6, p. 900-904Article in journal (Other academic)
    Abstract [en]

    The identification of orthologs-genes pairs descended from a common ancestor through speciation, rather than duplication-has emerged as an essential component of many bioinformatics applications, ranging from the annotation of new genomes to experimental target prioritization. Yet, the development and application of orthology inference methods is hampered by the lack of consensus on source proteomes, file formats and benchmarks. The second 'Quest for Orthologs' meeting brought together stakeholders from various communities to address these challenges. We report on achievements and outcomes of this meeting, focusing on topics of particular relevance to the research community at large. The Quest for Orthologs consortium is an open community that welcomes contributions from all researchers interested in orthology research and applications.

  • 37.
    Dinca, Vlad
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Wiklund, Christer
    Stockholm University, Faculty of Science, Department of Zoology.
    Lukhtanov, V. A.
    Kodandaramaiah, U.
    Norén, Karin
    Stockholm University, Faculty of Science, Department of Zoology.
    Dapporto, L.
    Wahlberg, N.
    Vila, R.
    Friberg, Mange
    Stockholm University, Faculty of Science, Department of Zoology.
    Reproductive isolation and patterns of genetic differentiation in a cryptic butterfly species complex2013In: Journal of Evolutionary Biology, ISSN 1010-061X, E-ISSN 1420-9101, Vol. 26, no 10, p. 2095-2106Article in journal (Refereed)
    Abstract [en]

    Molecular studies of natural populations are often designed to detect and categorize hidden layers of cryptic diversity, and an emerging pattern suggests that cryptic species are more common and more widely distributed than previously thought. However, these studies are often decoupled from ecological and behavioural studies of species divergence. Thus, the mechanisms by which the cryptic diversity is distributed and maintained across large spatial scales are often unknown. In 1988, it was discovered that the common Eurasian Wood White butterfly consisted of two species (Leptidea sinapis and Leptidea reali), and the pair became an emerging model for the study of speciation and chromosomal evolution. In 2011, the existence of a third cryptic species (Leptidea juvernica) was proposed. This unexpected discovery raises questions about the mechanisms preventing gene flow and about the potential existence of additional species hidden in the complex. Here, we compare patterns of genetic divergence across western Eurasia in an extensive data set of mitochondrial and nuclear DNA sequences with behavioural data on inter- and intraspecific reproductive isolation in courtship experiments. We show that three species exist in accordance with both the phylogenetic and biological species concepts and that additional hidden diversity is unlikely to occur in Europe. The Leptidea species are now the best studied cryptic complex of butterflies in Europe and a promising model system for understanding the formation of cryptic species and the roles of local processes, colonization patterns and heterospecific interactions for ecological and evolutionary divergence.

  • 38.
    Domingo Prim, Judit
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The exosome and the maintenance of genome integrity2016Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The RNA exosome acts on different RNA substrates and plays important roles in RNA metabolism. The fact that short non-coding RNAs are involved in the DNA damage response led us to investigate whether the exosome plays a role in DNA repair. We have shown that the exosome catalytic subunit RRP6/EXOSC10 is recruited to DNA double-strand breaks (DSBs) in Drosophila S2 cells and human HeLa cells exposed to either ionizing radiation or I-PpoI endonuclease cleavage. DIS3, the other catalytic subunit of the nuclear exosome, is also recruited to DSBs, whereas the exosome core subunit EXOSC7 is not. Depletion of different exosome subunits does not interfere with the phosphorylation of the histone variants H2Av (Drosophila) or H2AX (humans), but depletion of RRP6/EXOSC10 impairs the recruitment of the homologous recombination factor RAD51 to the damaged sites, without affecting RAD51 levels. The recruitment of RAD51 to DSBs in S2 cells is also inhibited by overexpression of RRP6-Y361A–V5, a catalytically inactive RRP6 mutant. Furthermore, cells depleted of RRP6 or EXOSC10 are more sensitive to radiation, which is consistent with RRP6/EXOSC10 playing a role in DNA repair. RRP6/EXOSC10 can be co-immunoprecipitated with RAD51, which links RRP6/EXOSC10 to the homologous recombination pathway in animal cells. Taken together, our results suggest that a 3’-5’ ribonucleolytic activity is required for efficient DNA repair. 

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  • 39.
    Dussex, Nicolas
    et al.
    Stockholm University, Faculty of Science, Department of Zoology, Population Genetics. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden; Norwegian University of Science and Technology, Sweden.
    Kurland, Sara
    Stockholm University, Faculty of Science, Department of Zoology, Population Genetics. Stockholm Univ, Dept Zool, Div Populat Genet, SE-10691 Stockholm, Sweden.
    Olsen, Remi-André
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Spong, Göran
    Ericsson, Göran
    Ekblom, Robert
    Ryman, Nils
    Stockholm University, Faculty of Science, Department of Zoology, Population Genetics.
    Dalén, Love
    Stockholm University, Faculty of Science, Department of Zoology, Population Genetics. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    Laikre, Linda
    Stockholm University, Faculty of Science, Department of Zoology, Population Genetics.
    Range-wide and temporal genomic analyses reveal the consequences of near-extinction in Swedish moose2023In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 1035Article in journal (Refereed)
    Abstract [en]

    Ungulate species have experienced severe declines over the past centuries through overharvesting and habitat loss. Even if many game species have recovered thanks to strict hunting regulation, the genome-wide impacts of overharvesting are still unclear. Here, we examine the temporal and geographical differences in genome-wide diversity in moose (Alces alces) over its whole range in Sweden by sequencing 87 modern and historical genomes. We found limited impact of the 1900s near-extinction event but local variation in inbreeding and load in modern populations, as well as suggestion of a risk of future reduction in genetic diversity and gene flow. Furthermore, we found candidate genes for local adaptation, and rapid temporal allele frequency shifts involving coding genes since the 1980s, possibly due to selective harvesting. Our results highlight that genomic changes potentially impacting fitness can occur over short time scales and underline the need to track both deleterious and selectively advantageous genomic variation.

  • 40.
    Däcker, Bjarne
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Deducing Cultural Context from Genetic Information2022Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Genetic analysis is traditionally carried out on individuals from known excavations. Thus the age of the individual is known and also the cultural context. This essay describes an experiment where this process was reversed. The genetic analysis was instead performed on samples from three anonymous individuals in order to see whether the cultural context could be derived from the genetics alone. Two samples from femurs were of inferior quality but the third sample from a premolar could be shown to come from an individual from the Corded Ware Culture. Thus it could not be older than ~2.800 B.C. At the end of the project the true facts were revealed and the individual was, in fact, dated to ~1.600 B.C. and came from a Late Neolithic cist. The result from the experiment is that it is possible to draw some conclusions about date and context provided a sample can be associated with a known population group. However, the results may not be very detailed since people move and genetic traits remain for a long time.

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  • 41.
    Eiche, Andrievs
    Stockholm University.
    Response to X-rays in Drosophila melanogaster populations with different irradiation backgrounds1973Doctoral thesis, comprehensive summary (Other academic)
  • 42.
    Ellencrona, Karin
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Functional characterization of interactions between the flavivirus NS5 protein and PDZ proteins of the mammalian host2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Flaviviruses are found all over the world and affect and infect millions of people every year. Flavivirus infection can lead to severe clinical outcomes resulting in neuronal damages e.g. Tick-borne encephalitis virus (TBEV), or severe hemorrhagic fevers e.g. Dengue virus (DENV). In order to effectively treat infected patients and to prevent these diseases we must understand how these viruses work and how they interfere with the mammalian host. This thesis is focusing on interactions between the virus protein NS5 and human host cell proteins. The interactions presented here might be key factors for out-come of viral disease. NS5 is the largest of the non-structural proteins and is essential for the replication and the capping as it contains both RNA dependent RNA polymerase and Methyltransferase domains. We found that TBEV NS5 interacts with human PDZ domain protein Scribble, a polarization protein important e.g. in regulating membrane trafficking. We determined that the interaction depend on a novel internal motif in TBEVNS5. This interaction could be correlated to NS5s ability to interfere with the immune system as absence of Scribble prevented NS5 from blocking phosphorylation of STAT upon Interferon induction. The role of NS5 in human PDZ domain targeting was addressed further by using a PDZ array system. Both TBEVNS5 and DENVNS5 bind additional PDZ domains using the internal motif. The tight junction protein ZO-1 binds both DENVNS5 and TBEVNS5. DENVNS5 is mainly present in the nucleus and co-localize with ZO-1 in un-polarized cells. In polarized cells TBEVNS5 and ZO-1 co-localize at the plasmamembrane. Putative C-terminal PDZ binding motifs of TBEVNS5 and WNVNS5 were characterized using the PDZ array system. This detected four novel binding partners of TBEVNS5 but numerous of potential WNVNS5 binding partners. We found that TBEVNS5 co-localizes with ZO-2 in the cellular membrane. Further, we found that TBEVNS5 induce the AP-1 by a 2 fold over the control.

  • 43.
    Emma, Lind
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Södertörns högskola.
    Ohlin, Helena
    Mälardalens högskola.
    Grahn, Mats
    Södertörns högskola.
    Fine scale genetic structure in Thresspine sticklback (Gasterosteus aculeatus) along Sweden's coastManuscript (preprint) (Other academic)
    Abstract [en]

    There are three basic types of population structures in marine environments; populations that are distinct, with a continuous change and without any differentiation. In each type the population units are characterized by groups of individuals with panmixia within groups and site fidelity to a limited geographic area. Earlier studies of the population genetic structure on sticklebacks in the Baltic Sea have shown none or only little structure. We have sampled 8 sites (253 individuals) along Sweden’s coast to estimate the genetic structure, using five microsatellites and 173 Amplified Fragment Length Polymorphism (AFLP) markers and detected a fine scale genetic structure (AFLP FST= 25%, microsatellites FST = 2.7%). With AFLPs the observed variation followed isolation by distance model (but not with microsatellites). Even sites separated by only 2 km of water are significantly separated. Both Bayesian clustering analysis and Capscale separated populations and identified populations from Gulf of Bothnia (4 psu) and from the west coast (20 psu) as genetically distinctly different from Baltic populations (about 7-8 psu).  In conclusion, gene flow is limited between sampled sites, and since no geographic barriers can be distinguished the population structure is likely caused by the sticklebacks’ behavior. Hence, we have probably sampled either stationary populations of marine sticklebacks, or homing sticklebacks. In this study AFLP and microsatellites did not give congruent results; with AFLPs we got high separation, and genetic variation followed isolation by distance model and supported the continuous change type of population structure.

  • 44. Enge, Swantje
    et al.
    Merot, Claire
    Mozuraitis, Raimondas
    Stockholm University, Faculty of Science, Department of Zoology. Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Institute of Ecology, Nature Research Centre, Lithuania.
    Apsegaite, Violeta
    Bernatchez, Louis
    Martens, Gerrit A.
    Radziute, Sandra
    Pavia, Henrik
    Berdan, Emma L.
    A supergene in seaweed flies modulates male traits and female perception2023In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 290, no 2008, article id 20231494Article in journal (Refereed)
    Abstract [en]

    Supergenes, tightly linked sets of alleles, offer some of the most spectacular examples of polymorphism persisting under long-term balancing selection. However, we still do not understand their evolution and persistence, especially in the face of accumulation of deleterious elements. Here, we show that an overdominant supergene in seaweed flies, Coelopa frigida, modulates male traits, potentially facilitating disassortative mating and promoting intraspecific polymorphism. Across two continents, the Cf-Inv(1) supergene strongly affected the composition of male cuticular hydrocarbons (CHCs) but only weakly affected CHC composition in females. Using gas chromatography-electroantennographic detection, we show that females can sense male CHCs and that there may be differential perception between genotypes. Combining our phenotypic results with RNA-seq data, we show that candidate genes for CHC biosynthesis primarily show differential expression for Cf-Inv(1) in males but not females. Conversely, candidate genes for odorant detection were differentially expressed in both sexes but showed high levels of divergence between supergene haplotypes. We suggest that the reduced recombination between supergene haplotypes may have led to rapid divergence in mate preferences as well as increasing linkage between male traits, and overdominant loci. Together this probably helped to maintain the polymorphism despite deleterious effects in homozygotes.

  • 45.
    Eriksson, Harald
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bacterial viruses targeting multi-resistant Klebsiella pneumoniae and Escherichia coli2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The global increase in antibiotic resistance levels in bacteria is a growing concern to our society and highlights the need for alternative strategies to combat bacterial infections. Bacterial viruses (phages) are the natural predators of bacteria and are as diverse as their hosts, but our understanding of them is limited. The current levels of knowledge regarding the role that phage play in the control of bacterial populations are poor, despite the use of phage therapy as a clinical therapy in Eastern Europe.

    The aim of this doctoral thesis is to increase knowledge of the diversity and characteristics of bacterial viruses and to assess their potential as therapeutic agents towards multi-resistant bacteria.

    Paper I is the product of de novo sequencing of newly isolated phages that infect and kill multi-resistant Klebsiella pneumoniae. Based on similarities in gene arrangement, lysis cassette type and conserved RNA polymerase, the creation of a new phage genus within Autographivirinae is proposed.

    Paper II describes the genomic and proteomic analysis of a phage of the rare C3 morphotype, a Podoviridae phage with an elongated head that uses multi-resistant Escherichia coli as its host.

    Paper III describes the study of a pre-made phage cocktail against 125 clinical K. pneumoniae isolates. The phage cocktail inhibited the growth of 99 (79 %) of the bacterial isolates tested. This study also demonstrates the need for common methodologies in the scientific community to determine how to assess phages that infect multiple serotypes to avoid false positive results.

    Paper IV studies the effects of phage predation on bacterial virulence: phages were first allowed to prey on a clinical K. pneumoniae isolate, followed by the isolation of phage-resistant bacteria. The phage resistant bacteria were then assessed for their growth rate, biofilm production in vitro. The virulence of the phage resistant bacteria was then assessed in Galleria mellonella. In the single phage treatments, two out of four phages showed an increased virulence in the in G. mellonella, which was also linked to an increased growth rate of the phage resistant bacteria. In multi-phage treatments however, three out of five phage cocktails decreased the bacterial virulence in G. mellonella compared to an untreated control.

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  • 46.
    Eriksson, Harald
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Maciejewska, Barbara
    Latka, Agnieszka
    Majkowska-Skrobek, Grazyna
    Hellstrand, Marios
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Melefors, Öjar
    Wang, Jin-Town
    Kropinski, Andrew M.
    Drulis-Kawa, Zuzanna
    Nilsson, Anders S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    A suggested new bacteriophage genus, “Kp34likevirus”, within the Autographivirinae subfamily of Podoviridae2015In: Viruses, E-ISSN 1999-4915, Vol. 7, no 4, p. 1804-1822Article in journal (Refereed)
    Abstract [en]

    Klebsiella pneumoniae phages vB_KpnP_SU503 (SU503) and vB_KpnP_SU552A (SU552A) are virulent viruses belonging to theAutographivirinae subfamily of Podoviridae that infect and kill multi-resistant K. pneumoniae isolates. Phages SU503 and SU552A show high pairwise nucleotide identity to Klebsiella phages KP34 (NC_013649), F19 (NC_023567) and NTUH-K2044-K1-1 (NC_025418). Bioinformatic analysis of these phage genomes show high conservation of gene arrangement and gene content, conserved catalytically active residues of their RNA polymerase, a common and specific lysis cassette, and form a joint cluster in phylogenetic analysis of their conserved genes. Also, we have performed biological characterization of the burst size, latent period, host specificity (together with KP34 and NTUH-K2044-K1-1), morphology, and structural genes as well as sensitivity testing to various conditions. Based on the analyses of these phages, the creation of a new phage genus is suggested within the Autographivirinae, called “Kp34likevirus” after their type phage, KP34. This genus should encompass the recently genome sequenced Klebsiella phages KP34, SU503, SU552A, F19 and NTUH-K2044-K1-1.

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  • 47.
    Eriksson, Jesper
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Structure-Function Studies of Bacteriophage P2 Integrase and Cox protein2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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  • 48.
    Fotouhi, Asal
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cornella, Nicola
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ramezani, Mehrafarin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wojcik, Andrzej
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Investigation of micronucleus induction in MTH1 knockdown cells exposed to UVA, UVB or UVC2015In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 793, no SI, p. 161-165Article in journal (Refereed)
    Abstract [en]

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

  • 49. Frantz, Laurent A. F.
    et al.
    Mullin, Victoria E.
    Pionnier-Capitan, Maud
    Lebrasseur, Ophélie
    Ollivier, Morgane
    Perri, Angela
    Linderholm, Anna
    Mattiangeli, Valeria
    Teasdale, Matthew D.
    Dimopoulos, Evangelos A.
    Tresset, Anne
    Duffraisse, Marilyne
    McCormick, Finbar
    Bartosiewicz, László
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Gál, Erika
    Nyerges, Éva A.
    Sablin, Mikhail V.
    Bréhard, Stéphanie
    Mashkour, Marjan
    Balaşescu, Adrian
    Gillet, Benjamin
    Hughes, Sandrine
    Chassaing, Olivier
    Hitte, Christophe
    Vigne, Jean-Denis
    Dobney, Keith
    Hänni, Catherine
    Bradley, Daniel G.
    Larson, Greger
    Genomic and archaeological evidence suggests a dual origin of domestic dogs2016In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 352, no 6290, p. 1228-1231Article in journal (Refereed)
    Abstract [en]

    The geographic and temporal origins of dogs remain controversial. We generated genetic sequences from 59 ancient dogs and a complete (28x) genome of a late Neolithic dog (dated to similar to 4800 calendar years before the present) from Ireland. Our analyses revealed a deep split separating modern East Asian and Western Eurasian dogs. Surprisingly, the date of this divergence (similar to 14,000 to 6400 years ago) occurs commensurate with, or several millennia after, the first appearance of dogs in Europe and East Asia. Additional analyses of ancient and modern mitochondrial DNA revealed a sharp discontinuity in haplotype frequencies in Europe. Combined, these results suggest that dogs may have been domesticated independently in Eastern and Western Eurasia from distinct wolf populations. East Eurasian dogs were then possibly transported to Europe with people, where they partially replaced European Paleolithic dogs.

  • 50.
    Fredriksson, Gunnar
    Stockholm University.
    Thyroid-like systems in endostyles: a study on morphology, function and evolution in "primitive" chordates1988Doctoral thesis, comprehensive summary (Other academic)
1234 1 - 50 of 195
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