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

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

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  • 2.
    Abalde, Samuel
    et al.
    Swedish Museum of Natural History, Department of Zoology.
    Crocetta, Fabio
    Department of Integrative Marine Ecology (EMI), Stazione Zoologica Anton Dohrn, Villa Comunale, I-80121 Napoli, Italy.
    Tenorio, Manuel J.
    Departamento CMIM y Q. Inorgánica-INBIO, Facultad de Ciencias, Universidad de Cádiz, 11510 Puerto Real, Cádiz, Spain.
    D'Aniello, Salvatore
    Department of Biology and Evolution of Marine Organisms (BEOM), Stazione Zoologica Anton Dohrn, Villa Comunale, I-80121 Napoli, Italy.
    Fassio, Giulia
    Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, Zoology–Viale dell’Università 32, 00185 Rome, Italy.
    Rodríguez-Flores, Paula C.
    Museum of Comparative Zoology, Department of Organismic and Evolutionary Biology, Harvard University, 26 Oxford Street, Cambridge, MA 02138, USA.
    Uribe, Juan E.
    Departamento de Biodiversidad y Biología Evolutiva, Museo Nacional de Ciencias Naturales (MNCN-CSIC), José Gutiérrez Abascal 2, 28006 Madrid, Spain.
    Afonso, Carlos M.L.
    Centre of Marine Sciences (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005 - 139 Faro, Portugal.
    Oliverio, Marco
    Department of Biology and Biotechnologies “Charles Darwin”, Sapienza University of Rome, Zoology–Viale dell’Università 32, 00185 Rome, Italy.
    Zardoya, Rafael
    Departamento de Biodiversidad y Biología Evolutiva, Museo Nacional de Ciencias Naturales (MNCN-CSIC), José Gutiérrez Abascal 2, 28006 Madrid, Spain.
    Hidden species diversity and mito-nuclear discordance within the Mediterranean cone snail, Lautoconus ventricosus2023In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, E-ISSN 1095-9513, Vol. 186, p. 107838-107838, article id 107838Article in journal (Refereed)
    Abstract [en]

    The Mediterranean cone snail, Lautoconus ventricosus, is currently considered a single species inhabiting the whole Mediterranean basin and the adjacent Atlantic coasts. Yet, no population genetic study has assessed its taxonomic status. Here, we collected 245 individuals from 75 localities throughout the Mediterranean Sea and used cox1 barcodes, complete mitochondrial genomes, and genome skims to test whether L. ventricosus represents a complex of cryptic species. The maximum likelihood phylogeny based on complete mitochondrial genomes recovered six main clades (hereby named blue, brown, green, orange, red, and violet) with sufficient sequence divergence to be considered putative species. On the other hand, phylogenomic analyses based on 437 nuclear genes only recovered four out of the six clades: blue and orange clades were thoroughly mixed and the brown one was not recovered. This mito-nuclear discordance revealed instances of incomplete lineage sorting and introgression, and may have caused important differences in the dating of main cladogenetic events. Species delimitation tests proposed the existence of at least three species: green, violet, and red + blue + orange (i.e., cyan). Green plus cyan (with sympatric distributions) and violet, had West and East Mediterranean distributions, respectively, mostly separated by the Siculo-Tunisian biogeographical barrier. Morphometric analyses of the shell using species hypotheses as factor and shell length as covariate showed that the discrimination power of the studied parameters was only 70.2%, reinforcing the cryptic nature of the uncovered species, and the importance of integrative taxonomic approaches considering morphology, ecology, biogeography, and mitochondrial and nuclear population genetic variation.

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  • 3.
    Abalde, Samuel
    et al.
    Swedish Museum Nat Hist, Dept Zool, Stockholm, Sweden..
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Heintz, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vinnere Pettersson, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jondelius, Ulf
    Swedish Museum Nat Hist, Dept Zool, Stockholm, Sweden.;Stockholm Univ, Dept Zool, Stockholm, Sweden..
    The draft genome of the microscopic Nemertoderma westbladi sheds light on the evolution of Acoelomorpha genomes2023In: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 14, article id 1244493Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

  • 5.
    Abrahamsson, S.
    et al.
    SLU, Umeå, Sweden .
    Ahlinder, J.
    FOI, Umeå, Sweden .
    Waldmann, Patrik
    Linköping University, Department of Computer and Information Science, Statistics. Linköping University, The Institute of Technology.
    García-Gil, M. R.
    SLU, Umeå, Sweden .
    Maternal heterozygosity and progeny fitness association in an inbred Scots pine population2013In: Genetica, ISSN 0016-6707, E-ISSN 1573-6857, Vol. 141, no 1-3, p. 41-50Article in journal (Refereed)
    Abstract [en]

    Associations between heterozygosity and fitness traits have typically been investigated in populations characterized by low levels of inbreeding. We investigated the associations between standardized multilocus heterozygosity (stMLH) in mother trees (obtained from12 nuclear microsatellite markers) and five fitness traits measured in progenies from an inbred Scots pine population. The traits studied were proportion of sound seed, mean seed weight, germination rate, mean family height of one-year old seedlings under greenhouse conditions (GH) and mean family height of three-year old seedlings under field conditions (FH). The relatively high average inbreeding coefficient (F) in the population under study corresponds to a mixture of trees with different levels of co-ancestry, potentially resulting from a recent bottleneck. We used both frequentist and Bayesian methods of polynomial regression to investigate the presence of linear and non-linear relations between stMLH and each of the fitness traits. No significant associations were found for any of the traits except for GH, which displayed negative linear effect with stMLH. Negative HFC for GH could potentially be explained by the effect of heterosis caused by mating of two inbred mother trees (Lippman and Zamir 2006), or outbreeding depression at the most heterozygote trees and its negative impact on the fitness of the progeny, while their simultaneous action is also possible (Lynch. 1991). However,since this effect wasn’t detected for FH, we cannot either rule out that the greenhouse conditions introduce artificial effects that disappear under more realistic field conditions.

  • 6. 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.

  • 7.
    Adler, Marlen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mechanisms and Dynamics of Carbapenem Resistance in Escherichia coli2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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  • 8.
    Adler, Marlen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Anjum, Mehreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Otto, G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    High Fitness Costs and Instability of Gene Duplications Reduce Rates of Evolution of New Genes by Duplication-Divergence Mechanisms2014In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 31, no 6, p. 1526-1535Article in journal (Refereed)
    Abstract [sv]

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

  • 9. Adrian-Kalchhauser, I
    et al.
    Svensson, Ola
    University of Borås, Faculty of Librarianship, Information, Education and IT.
    Kutschera, VE
    Alm Rosenblad, M
    Pippel, M
    Winkler, S
    Schloissnig, S
    Blomberg, A
    Burkhardt-Holm, P
    Pomatoschistus minutus voucher NRM:NRM69326 mitochondrion, complete genome: GenBank: MW0928272020Other (Refereed)
    Abstract [en]

    The complete Pomatoschistus minutus mitochondrion genome. The voucher NRM:NRM69326 is stored at The Swedish Museum of Natural History, Stockholm, Sweden. The Genbank Accession number of the annotated sequence MW092827.

  • 10.
    af Klercker, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    The impact of the ribosomal 16S rRNA modifications on the antibiotic susceptibility and fitness in Escherichia coli  2024Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The rRNA molecules which make up the two subunits of the Escherichia coli ribosome are extensively post-transcriptionally modified. The specific purpose of each modification is still unknown. It is proposed that they provide a structure for the ribosomal assembly, which would indicate that they are essential. However, previous literature in this area using E. coli shows that when the modification enzymes are removed individually the effects on growth fitness and antibiotic sensitivity are limited. This makes their role in ribosomal assembly unclear. The effect of removing multiple ribosomal modification enzymes is largely unexplored. The position of many of the modifications are found in clusters, usually in the catalytic domains of the ribosome, which are often targeted by antibiotics, indicating that removing the modification enzymes could affect antibiotic sensitivity. Most of the previous studies on strains with these modification enzymes removed were performed with traditional lambda-red that leaves behind FRT scars, which can cause unwanted spontaneous excisions via recombination between the FRT scars. Here, DIRex lambda-red was used to create clean deletions, which does not produce FRT scars and therefore, allows for more reliable analysis of the ribosomal modification enzymes’ role. The results show that there is a fitness cost and change in antibiotic sensitivity due to multiple of the deletions of the ribosomal modification enzymes. For some of the modifications, this is true when that particular site alone is left unmodified, while for other positions, these effects are only observed when multiple sites are modified simultaneously. For example, the methyltransferase RsmG knockout has a big effect on streptomycin resistance but no fitness cost, while the methyltransferase RsmA and RsmF knockouts causes a fitness cost in combination and causes tetracycline and gentamycin resistance respectively. This indicates that the ribosomal modifications significantly affect the interaction with antibiotics and fitness, and therefore, have a significant part in ribosomal function. 

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  • 11.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts: Integrative Bioinformatic and Experimental Approaches2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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  • 12. Agler, Caryline
    et al.
    Nielsen, Dahlia M.
    Urkasemsin, Ganokon
    Singleton, Andrew
    Tonomura, Noriko
    Sigurdsson, Snaevar
    Tang, Ruqi
    Linder, Keith
    Arepalli, Sampath
    Hernandez, Dena
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    van de Leemput, Joyce
    Motsinger-Reif, Alison
    O'Brien, Dennis P.
    Bell, Jerold
    Harris, Tonya
    Steinberg, Steven
    Olby, Natasha J.
    Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB242014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 2, p. e1003991-Article in journal (Refereed)
    Abstract [en]

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

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  • 13.
    Agnvall, Beatrix
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Jensen, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering.
    Effects of Divergent Selection for Fear of Humans on Behaviour in Red Junglefowl2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 11, p. 1-12Article in journal (Refereed)
    Abstract [en]

    Domestication has caused a range of similar phenotypic changes across taxa, relating to physiology, morphology and behaviour. It has been suggested that this recurring domesticated phenotype may be a result of correlated responses to a central trait, namely increased tameness. We selected Red Junglefowl, the ancestors of domesticated chickens, during five generations for reduced fear of humans. This caused a marked and significant response in tameness, and previous studies have found correlated effects on growth, metabolism, reproduction, and some behaviour not directly selected for. Here, we report the results from a series of behavioural tests carried out on the initial parental generation (P0) and the fifth selected generation (S5), focusing on behaviour not functionally related to tameness, in order to study any correlated effects. Birds were tested for fear of humans, social reinstatement tendency, open field behaviour at two different ages, foraging/exploration, response to a simulated aerial predator attack and tonic immobility. In S5, there were no effects of selection on foraging/exploration or tonic immobility, while in the social reinstatement and open field tests there were significant interactions between selection and sex. In the aerial predator test, there were significant main effects of selection, indicating that fear of humans may represent a general wariness towards predators. In conclusion, we found only small correlated effects on behaviours not related to the tameness trait selected for, in spite of them showing high genetic correlations to fear of humans in a previous study on the same population. This suggests that species-specific behaviour is generally resilient to changes during domestication.

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  • 14.
    Agrillo, Caroline
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    DNA methylation modifications in human mesenchymal stem cells  induced by exposure to endocrine disrupting plasticiser metabolites MBP, MEP, MBzP, MEHP and MINCH2022Independent thesis Advanced level (degree of Master (Two Years)), 80 credits / 120 HE creditsStudent thesis
    Abstract [en]

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

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  • 15.
    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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  • 16.
    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. 

  • 17. Ahmad, S.
    et al.
    Zhao, W.
    Renström, F.
    Rasheed, A.
    Zaidi, M.
    Samuel, M.
    Shah, N.
    Mallick, N. H.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Odontology.
    Zaman, K. S.
    Ishaq, M.
    Rasheed, S. Z.
    Memon, F-ur-R
    Hanif, B.
    Lakhani, M. S.
    Ahmed, F.
    Kazmi, S. U.
    Deloukas, P.
    Frossard, P.
    Franks, P. W.
    Saleheen, D.
    A novel interaction between theFLJ33534locus and smokingin obesity: a genome-wide study of 14 131 Pakistani adults2016In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 1, p. 186-190Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Obesity is a complex disease caused by the interplay of genetic and lifestyle factors, but identification of gene-lifestyle interactions in obesity has remained challenging. Few large-scale studies have reported use of genome-wide approaches to investigate gene-lifestyle interactions in obesity. METHODS: In the Pakistan Risk of Myocardial Infraction Study, a cross-sectional study based in Pakistan, we calculated body mass index (BMI) variance estimates (square of the residual of inverse-normal transformed BMI z-score) in 14 131 participants and conducted genome-wide heterogeneity of variance analyses (GWHVA) for this outcome. All analyses were adjusted for age, age(2), sex and genetic ancestry. RESULTS: The GWHVA analyses identified an intronic variant, rs140133294, in the FLJ33544 gene in association with BMI variance (P-value = 3.1 x 10(-8)). In explicit tests of gene x lifestyle interaction, smoking was found to significantly modify the effect of rs140133294 on BMI (Pinteraction = 0.0005), whereby the minor allele (T) was associated with lower BMI in current smokers, while positively associated with BMI in never smokers. Analyses of ENCODE data at the FLJ33534 locus revealed features indicative of open chromatin and high confidence DNA-binding motifs for several transcription factors, providing suggestive biological support for a mechanism of interaction. CONCLUSIONS: In summary, we have identified a novel interaction between smoking and variation at the FLJ33534 locus in relation to BMI in people from Pakistan.

  • 18.
    Ain, Noor Ul
    et al.
    School of Biological Sciences, University of the Punjab, Lahore, Pakistan; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Baroncelli, Marta
    Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Costantini, Alice
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Ishaq, Tayyaba
    School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
    Taylan, Fulya
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden.
    Mäkitie, Outi
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Children's Hospital, University of Helsinki, Helsinki, Finland; Folkhälsan Institute of Genetics, Helsinki, Finland.
    Naz, Sadaf
    School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
    Novel form of rhizomelic skeletal dysplasia associated with a homozygous variant in GNPNAT12021In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 58, no 5, p. 351-356Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Studies exploring molecular mechanisms underlying congenital skeletal disorders have revealed novel regulators of skeletal homeostasis and shown protein glycosylation to play an important role.

    OBJECTIVE: To identify the genetic cause of rhizomelic skeletal dysplasia in a consanguineous Pakistani family.

    METHODS: Clinical investigations were carried out for four affected individuals in the recruited family. Whole genome sequencing (WGS) was completed using DNA from two affected and two unaffected individuals from the family. Sequencing data were processed, filtered and analysed. In silico analyses were performed to predict the effects of the candidate variant on the protein structure and function. Small interfering RNAs (siRNAs) were used to study the effect of Gnpnat1 gene knockdown in primary rat chondrocytes.

    RESULTS: The patients presented with short stature due to extreme shortening of the proximal segments of the limbs. Radiographs of one individual showed hip dysplasia and severe platyspondyly. WGS data analyses identified a homozygous missense variant c.226G>A; p.(Glu76Lys) in GNPNAT1, segregating with the disease. Glucosamine 6-phosphate N-acetyltransferase, encoded by the highly conserved gene GNPNAT1, is one of the enzymes required for synthesis of uridine diphosphate N-acetylglucosamine, which participates in protein glycosylation. Knockdown of Gnpnat1 by siRNAs decreased cellular proliferation and expression of chondrocyte differentiation markers collagen type 2 and alkaline phosphatase, indicating that Gnpnat1 is important for growth plate chondrocyte proliferation and differentiation.

    CONCLUSIONS: This study describes a novel severe skeletal dysplasia associated with a biallelic, variant in GNPNAT1. Our data suggest that GNPNAT1 is important for growth plate chondrogenesis.

  • 19.
    Akhter, Shirin
    et al.
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala Bioctr, Dept Plant Biol, Uppsala, Sweden..
    Kretzschmar, Warren W.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nordal, Veronika
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala Bioctr, Dept Plant Biol, Uppsala, Sweden..
    Delhomme, Nicolas
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, Umea Plant Sci Ctr, Umea, Sweden..
    Street, Nathaniel R.
    Umea Sweden, Dept Plant Physiol, Umea Plant Sci Ctr, Umea, Sweden..
    Nilsson, Ove
    Swedish Univ Agr Sci, Dept Forest Genet & Plant Physiol, Umea Plant Sci Ctr, Umea, Sweden..
    Emanuelsson, Olof
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sundström, Jens F.
    Swedish Univ Agr Sci, Linnean Ctr Plant Biol, Uppsala Bioctr, Dept Plant Biol, Uppsala, Sweden..
    Integrative Analysis of Three RNA Sequencing Methods Identifies Mutually Exclusive Exons of MADS-Box Isoforms During Early Bud Development in Picea abies2018In: Frontiers in Plant Science, E-ISSN 1664-462X, Vol. 9, article id 1625Article in journal (Refereed)
    Abstract [en]

    Recent efforts to sequence the genomes and transcriptomes of several gymnosperm species have revealed an increased complexity in certain gene families in gymnosperms as compared to angiosperms. One example of this is the gymnosperm sister Glade to angiosperm TM3-like MADS-box genes, which at least in the conifer lineage has expanded in number of genes. We have previously identified a member of this subclade, the conifer gene DEFICIENS AGAMOUS LIKE 19 (DAL19), as being specifically upregulated in cone-setting shoots. Here, we show through Sanger sequencing of mRNA-derived cDNA and mapping to assembled conifer genomic sequences that DAL19 produces six mature mRNA splice variants in Picea abies. These splice variants use alternate first and last exons, while their four central exons constitute a core region present in all six transcripts. Thus, they are likely to be transcript isoforms. Quantitative Real-Time PCR revealed that two mutually exclusive first DAL19 exons are differentially expressed across meristems that will form either male or female cones, or vegetative shoots. Furthermore, mRNA in situ hybridization revealed that two mutually exclusive last DAL19 exons were expressed in a cell-specific pattern within bud meristems. Based on these findings in DAL19, we developed a sensitive approach to transcript isoform assembly from short-read sequencing of mRNA. We applied this method to 42 putative MADS-box core regions in P abies, from which we assembled 1084 putative transcripts. We manually curated these transcripts to arrive at 933 assembled transcript isoforms of 38 putative MADS-box genes. 152 of these isoforms, which we assign to 28 putative MADS-box genes, were differentially expressed across eight female, male, and vegetative buds. We further provide evidence of the expression of 16 out of the 38 putative MADS-box genes by mapping PacBio Iso-Seq circular consensus reads derived from pooled sample sequencing to assembled transcripts. In summary, our analyses reveal the use of mutually exclusive exons of MADS-box gene isoforms during early bud development in P. abies, and we find that the large number of identified MADS-box transcripts in P. abies results not only from expansion of the gene family through gene duplication events but also from the generation of numerous splice variants.

  • 20. Aktürk, Şevva
    et al.
    Mapelli, Igor
    Güler, Merve N.
    Gürün, Kanat
    Katırcıoğlu, Büşra
    Vural, Kıvılcım Başak
    Sağlıcan, Ekin
    Çetin, Mehmet
    Yaka, Reyhan
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Middle East Technical University, Turkey; Centre for Palaeogenetics, Sweden.
    Sürer, Elif
    Atağ, Gözde
    Çokoğlu, Sevim Seda
    Sevkar, Arda
    Altınışık, N. Ezgi
    Koptekin, Dilek
    Somel, Mehmet
    Benchmarking kinship estimation tools for ancient genomes using pedigree simulations2024In: Molecular Ecology Resources, ISSN 1755-098X, E-ISSN 1755-0998Article in journal (Refereed)
    Abstract [en]

    There is growing interest in uncovering genetic kinship patterns in past societies using low-coverage palaeogenomes. Here, we benchmark four tools for kinship estimation with such data: lcMLkin, NgsRelate, KIN, and READ, which differ in their input, IBD estimation methods, and statistical approaches. We used pedigree and ancient genome sequence simulations to evaluate these tools when only a limited number (1 to 50 K, with minor allele frequency ≥0.01) of shared SNPs are available. The performance of all four tools was comparable using ≥20 K SNPs. We found that first-degree related pairs can be accurately classified even with 1 K SNPs, with 85% F1 scores using READ and 96% using NgsRelate or lcMLkin. Distinguishing third-degree relatives from unrelated pairs or second-degree relatives was also possible with high accuracy (F1 > 90%) with 5 K SNPs using NgsRelate and lcMLkin, while READ and KIN showed lower success (69 and 79% respectively). Meanwhile, noise in population allele frequencies and inbreeding (first-cousin mating) led to deviations in kinship coefficients, with different sensitivities across tools. We conclude that using multiple tools in parallel might be an effective approach to achieve robust estimates on ultra-low-coverage genomes. 

  • 21.
    Al-Ani, Abdullah
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre. University of Northampton.
    Investigating the subcellular localisation and function(s) of dystrophin protein Dp71 isoforms in glioma2022Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
    Abstract [en]

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

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  • 22. Ala-Poikela, M.
    et al.
    Svensson, E.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Department of Evolution, Genomics and Systematics, Evolutionary Biology. Evolutionsbiologi.
    Rojas, A.
    Horko, T.
    Paulin, L.
    Valkonen, J.
    Kvarnheden, A.
    Genetic diversity and mixed infections of begomoviruses in tomato, pepper and cucurbit crops in Nicaragua2005In: Plant Pathology, no 54, p. 448-459Article in journal (Refereed)
  • 23.
    Alatalo, Juha M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Little, Chelsea J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Jagerbrand, Annika K.
    Molau, Ulf
    Vascular plant abundance and diversity in an alpine heath under observed and simulated global change2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 10197Article in journal (Refereed)
    Abstract [en]

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

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  • 24.
    Alatalo, Juha M.
    et al.
    Uppsala universitet, Växtekologi och evolution.
    Little, Chelsea J.
    Uppsala universitet, Växtekologi och evolution.
    Jägerbrand, Annika K.
    Statens väg- och transportforskningsinstitut, Samhälle, miljö och transporter, SAMT, Miljö, MILJÖ.
    Molau, Ulf
    Vascular plant abundance and diversity in an alpine heath under observed and simulated global change2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 10197Article in journal (Refereed)
    Abstract [en]

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

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  • 25.
    Alatalo, Juha M.
    et al.
    Uppsala universitet, Växtekologi och evolution.
    Little, Chelsea J.
    Uppsala universitet, Växtekologi och evolution.
    Jägerbrand, Annika
    Statens väg- och transportforskningsinstitut, Samhälle, miljö och transporter, SAMT, Miljö, MILJÖ.
    Molau, Ulf
    Vascular plant abundance and diversity in an alpine heath under observed and simulated global change2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 10197Article in journal (Refereed)
    Abstract [en]

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

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  • 26.
    Albrecht, Lisa M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Antibiotic Resistance: Selection in the Presence of Metals and Antimicrobials2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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  • 27.
    Al-Douri, Yamur
    et al.
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Hamodi, Hussan
    Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Operation, Maintenance and Acoustics.
    Data imputing using genetic algorithms (GA): A case study of cost data for tunnel fans2017Conference paper (Refereed)
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  • 28.
    Aleix-Mata, Gael
    et al.
    Jaen Univ, Dept Expt Biol, E-23071 Jaen, Spain.;Jaen Univ, Dept Anim & Plant Biol & Ecol, E-23071 Jaen, Spain..
    Exposito, Miriam
    Jaen Univ, Dept Expt Biol, E-23071 Jaen, Spain..
    Ruiz-Ruano, Francisco J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Granada Univ, Fac Sci, Dept Genet, E-18071 Granada, Spain..
    Maria Lopez-Beceiro, Ana
    Univ Santiago de Compostela, Dept Anat Anim Prod & Vet Clin Sci, E-27002 Lugo, Spain..
    Fidalgo, Luis E.
    Univ Santiago de Compostela, Dept Anat Anim Prod & Vet Clin Sci, E-27002 Lugo, Spain..
    Martinez-Carrasco, Carlos
    Murcia Univ, Dept Anim Hlth, E-30100 Murcia, Spain..
    Ruiz de Ybanez, Maria Rocio
    Murcia Univ, Dept Anim Hlth, E-30100 Murcia, Spain..
    Boos, Mathieu
    Naturaconst, Res Agcy Appl Ecol, F-67270 Wilshausen, France.;Federat Natl Chasseurs, Pole Sci, 13 Rue Gen Leclerc, F-92136 Issy Les Moulineaux, France..
    Perez, Jesus M.
    Jaen Univ, Dept Anim & Plant Biol & Ecol, E-23071 Jaen, Spain.;Wildlife Ecol & Hlth Grp WE&H, Barcelona, Spain..
    Sanchez, Antonio
    Jaen Univ, Dept Expt Biol, E-23071 Jaen, Spain..
    Development and characterization of 15 novel polymorphic microsatellite loci for two important bot flies (Diptera, Oestridae) by next-generation sequencing2020In: Parasitology Research, ISSN 0932-0113, E-ISSN 1432-1955, Vol. 119, no 9, p. 2829-2835Article in journal (Refereed)
    Abstract [en]

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

  • 29.
    Aleix-Mata, Gael
    et al.
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain.;Univ Jaen, Dept Biol Anim Biol Vegetal & Ecol, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    Gutierrez, Juana
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    Ruiz-Ruano, Francisco J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Lorite, Pedro
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    Marchal, Juan A.
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    Sanchez, Antonio
    Univ Jaen, Dept Biol Expt, Area Genet, Campus Las Lagunillas S-N, Jaen 23071, Spain..
    The complete mitochondrial genome of Talpa aquitania (Talpidae; Insectivora), a mole species endemic to northern Spain and southern France2020In: Molecular Biology Reports, ISSN 0301-4851, E-ISSN 1573-4978, Vol. 47, no 3, p. 2397-2403Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 31.
    Alfredsson Timmins, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Functional organisation of the cell nucleus in the fission yeast, Schizosaccharomyces pombe2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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  • 32.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjoblöm, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, p. 7743-7748Article in journal (Refereed)
    Abstract [en]

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

  • 33.
    Ali, Raja Hashim
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Khan, Ammad Aslam
    Tracing the evolution of FERM domain of Kindlins2014In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, E-ISSN 1095-9513, Vol. 80, p. 193-204Article in journal (Refereed)
    Abstract [en]

    Kindlin proteins represent a novel family of evolutionarily conserved FERM domain containing proteins (FDCPs) and are members of B4.1 superfamily. Kindlins consist of three conserved protein homologs in vertebrates: Kindlin-1, Kindlin-2 and Kindlin-3. All three homologs are associated with focal adhesions and are involved in Integrin activation. FERM domain of each Kindlin is bipartite and plays a key role in Integrin activation. A single ancestral Kindlin protein can be traced back to earliest metazoans, e.g., to Parazoa. This protein underwent multiple rounds of duplication in vertebrates, leading to the present Kindlin family. In this study, we trace phylogenetic and evolutionary history of Kindlin FERM domain with respect to FERM domain of other FDCPs. We show that FERM domain in Kindlin homologs is conserved among Kindlins but amount of conservation is less in comparison with FERM domain of other members in B4.1 superfamily. Furthermore, insertion of Pleckstrin Homology like domain in Kindlin FERM domain has important evolutionary and functional consequences. Important residues in Kindlins are traced and ranked according to their evolutionary significance. The structural and functional significance of high ranked residues is highlighted and validated by their known involvement in Kindlin associated diseases. In light of these findings, we hypothesize that FERM domain originated from a proto-Talin protein in unicellular or proto-multicellular organism and advent of multi-cellularity was accompanied by burst of FDCPs, which supported multi-cellularity functions required for complex organisms. This study helps in developing a better understanding of evolutionary history of FERM domain of FDCPs and the role of FERM domain in metazoan evolution.

  • 34.
    Aliakbari, Massume
    et al.
    Department of Crop Production and Plant Breeding, Shiraz University, Shiraz, Iran.
    Cohen, Stephen P.
    Department of Plant Pathology, The Ohio State University, USA.
    Lindlöf, Angelica
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Shamloo-Dashtpagerdi, Roohollah
    Department of Agriculture and Natural Resources, Higher Education Center of Eghlid, Iran.
    Rubisco activase A (RcaA) is a central node in overlapping gene network of drought and salinity in Barley (Hordeum vulgare L.) and may contribute to combined stress tolerance2021In: Plant physiology and biochemistry (Paris), ISSN 0981-9428, E-ISSN 1873-2690, Vol. 161, p. 248-258Article in journal (Refereed)
    Abstract [en]

    Co-occurrence of abiotic stresses, especially drought and salinity, is a natural phenomenon in field conditions and is worse for crop production than any single stress. Nowadays, rigorous methods of meta-analysis and systems biology have made it possible to perform cross-study comparisons of single stress experiments, which can uncover main overlapping mechanisms underlying tolerance to combined stress. In this study, a meta-analysis of RNA-Seq data was conducted to obtain the overlapping gene network of drought and salinity stresses in barley (Hordeum vulgare L.), which identified Rubisco activase A (RcaA) as a hub gene in the dual-stress response. Thereafter, a greenhouse experiment was carried out using two barley genotypes with different abiotic stress tolerance and evaluated several physiochemical properties as well as the expression profile and protein activity of RcaA. Finally, machine learning analysis was applied to uncover relationships among combined stress tolerance and evaluated properties. We identified 441 genes which were differentially expressed under both drought and salinity stress. Results revealed that the photosynthesis pathway and, in particular, the RcaA gene are major components of the dual-stress responsive transcriptome. Comparative physiochemical and molecular evaluations further confirmed that enhanced photosynthesis capability, mainly through regulation of RcaA expression and activity as well as accumulation of proline content, have a significant association with combined drought and salinity stress tolerance in barley. Overall, our results clarify the importance of RcaA in combined stress tolerance and may provide new insights for future investigations. 

  • 35.
    Alkaissi, Hammoudi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Nielsen, Jesper Bo
    Univ Southern Denmark, Denmark.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 7, article id e0199979Article in journal (Refereed)
    Abstract [en]

    Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkbl (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9,II6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, II6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkbl (produced in most immune cells) as key regulators of ANoA development in HgIA.

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  • 36.
    Almeida, Pedro
    et al.
    UCL, Dept Genet Evolut & Environm, London, England.
    Proux-Wera, Estelle
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Stockholm, Sweden.
    Churcher, Allison
    Umeå Univ, Dept Mol Biol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Umeå, Sweden.
    Soler, Lucile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dainat, Jacques
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pucholt, Pascal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Swedish Univ Agr Sci, Uppsala BioCtr, Linnean Ctr Plant Biol, Dept Plant Biol, Uppsala, Sweden.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, Tom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnberg-Wästljung, Ann-Christin
    Swedish Univ Agr Sci, Uppsala BioCtr, Linnean Ctr Plant Biol, Dept Plant Biol, Uppsala, Sweden.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berlin, Sofia
    Swedish Univ Agr Sci, Uppsala BioCtr, Linnean Ctr Plant Biol, Dept Plant Biol, Uppsala, Sweden.
    Mank, Judith E.
    UCL, Dept Genet Evolut & Environm, London, England; Univ British Columbia, Dept Zool, Vancouver, BC, Canada; Univ British Columbia, Biodivers Res Ctr, Vancouver, BC, Canada.
    Genome assembly of the basket willow, Salix viminalis, reveals earliest stages of sex chromosome expansion2020In: BMC Biology, E-ISSN 1741-7007, Vol. 18, no 1, article id 78Article in journal (Refereed)
    Abstract [en]

    Background

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

    Results

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

    Conclusions

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

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  • 37.
    Almlöf, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ge, Bing
    Pastinen, Tomi
    Goodall, Alison H
    Cambien, François
    Deloukas, Panos
    Ouwehand, Willem H
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 7, p. e102612-Article in journal (Refereed)
    Abstract [en]

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

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  • 38.
    Alneberg, Johannes
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Garcia, M. U.
    Karolinska Inst, Dept Oncol, Solna, Sweden..
    Peltzer, A.
    Univ Tubingen, Quantitat Biol Ctr QBiC, Tubingen, Germany..
    Koch, T.
    Univ Tubingen, Quantitat Biol Ctr QBiC, Tubingen, Germany..
    Proks, M.
    Univ Southern Denmark, Odense, Denmark..
    Wilm, A.
    ASTAR, Genome Inst Singapore, Bioinformat Core Unit, Singapore, Singapore..
    Ewels, P. A.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Natl Genom Infrastruct Stockholm, Stockholm, Sweden..
    Analysis of genome sequencing data with a minimal investment IT-infrastructure2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 1706-1706Article in journal (Other academic)
  • 39.
    Alva, Omar
    et al.
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Leroy, Anais
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Heiske, Margit
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Pereda-Loth, Veronica
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Tisseyre, Lenka
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Boland, Anne
    Ctr Natl Genotypage, Inst Genom, Commissariat Energie Atom, F-91000 Evry, France..
    Deleuze, Jean-Francois
    Ctr Natl Genotypage, Inst Genom, Commissariat Energie Atom, F-91000 Evry, France..
    Rocha, Jorge
    Univ Porto, InBIO Lab Associado, Ctr Invest Biodiversidade & Recursos, CIBIO, Campus Vairao, P-4485661 Vairao, Portugal.;Univ Porto, Fac Ciencias, Dept Biol, P-4099002 Porto, Portugal.;CIBIO, BIOPOLIS Program Genom Biodivers & Land Planning, Campus Vairao, P-4485661 Vairao, Portugal..
    Schlebusch, Carina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Fortes-Lima, Cesar A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Stoneking, Mark
    Max Planck Inst Evolutionary Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany.;Univ Lyon 1, Lab Biometrie & Biol Evolut, CNRS, UMR 5558, Villeurbanne, France..
    Radimilahy, Chantal
    Univ Antananarivo, Musee Art & Archeol, Antananarivo, Madagascar..
    Rakotoarisoa, Jean-Aime
    Univ Antananarivo, Musee Art & Archeol, Antananarivo, Madagascar..
    Letellier, Thierry
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    Pierron, Denis
    Univ Toulouse III, EVOLSAN Fac Chirurg Dent, Equipe Med Evolut, Toulouse, France..
    The loss of biodiversity in Madagascar is contemporaneous with major demographic events2022In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 32, no 23, p. 4997-+Article in journal (Refereed)
    Abstract [en]

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

  • 40. Alvarez-Castro, J.M.
    et al.
    Carlborg, Ö.
    Rönnegård, Lars
    Dalarna University, School of Technology and Business Studies, Statistics.
    Estimation and interpretation of genetic effects with epistasis using the NOIA model2012In: Quantitative trait loci (QTL): Methods and Protocols / [ed] Scott A. Rifkin, Humana Press, 2012, p. 191-204Chapter in book (Other academic)
    Abstract [en]

    We introduce this communication with a brief outline of the historical landmarks in genetic modeling, especially concerning epistasis. Then, we present methods for the use of genetic modeling in QTL analyses. In particular, we summarize the essential expressions of the natural and orthogonal interactions (NOIA) model of genetic effects. Our motivation for reviewing that theory here is twofold. First, this review presents a digest of the expressions for the application of the NOIA model, which are often mixed with intermediate and additional formulae in the original articles. Second, we make the required theory handy for the reader to relate the genetic concepts to the particular mathematical expressions underlying them. We illustrate those relations by providing graphical interpretations and a diagram summarizing the key features for applying genetic modeling with epistasis in comprehensive QTL analyses. Finally, we briefly review some examples of the application of NOIA to real data and the way it improves the interpretability of the results.

  • 41.
    Ament-Velasquez, Sandra Lorena
    et al.
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Gilchrist, Ciaran
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Rego, Alexandre
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Bendixsen, Devin P.
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Brice, Claire
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    Grosse-Sommer, Julie Michelle
    Maastricht Univ, Fac Sci & Engn, Paul Henri Spaaklaan 1, NL-6229 EN Maastricht, Netherlands..
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stelkens, Rike
    Stockholm Univ, Dept Zool, Div Populat Genet, Svante Arrheniusvag 18 B, S-10691 Stockholm, Sweden..
    The Dynamics of Adaptation to Stress from Standing Genetic Variation and de novo Mutations2022In: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 39, no 11, article id msac242Article in journal (Refereed)
    Abstract [en]

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

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  • 42.
    Ament-Velásquez, Sandra Lorena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Drivers of evolutionary change in Podospora anserina2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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  • 43.
    Ament-Velásquez, Sandra Lorena
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Tuovinen, Veera
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Bergström, Linnea
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Spribille, Toby
    Biological Sciences CW 405, University of Alberta, Edmonton, AB, Canada.
    Vanderpool, Dan
    Department of Biology, Indiana University, Bloomington, IN, United States.
    Nascimbene, Juri
    Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy.
    Yamamoto, Yoshikazu
    Department of Bioproduction Science, Faculty of Bioresource Sciences, Akita Prefectural University, Akita, Japan.
    Thor, Göran
    Department of Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Johannesson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    The plot thickens: haploid and triploid-like thalli, hybridization, and biased mating type ratios in Letharia2021In: Frontiers in Fungal Biology, E-ISSN 2673-6128, Vol. 2, article id 656386Article in journal (Refereed)
    Abstract [en]

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

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  • 44.
    Ameur, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Che, Huiwen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, Marcel
    Stockholm Univ, DBB, Sci Life Lab, S-11419 Stockholm, Sweden.
    Bunikis, Ignas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75236 Uppsala, Sweden.
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Höijer, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Häggqvist, Susana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vezzi, Francesco
    Stockholm Univ, DBB, Sci Life Lab, S-11419 Stockholm, Sweden.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Med Sci, Sci Life Lab, Mol Med, S-75236 Uppsala, Sweden.
    Olason, Pall
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data2018In: Genes, E-ISSN 2073-4425, Vol. 9, no 10, article id 486Article in journal (Refereed)
    Abstract [en]

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

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  • 45.
    Anava, Sarit
    et al.
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Neuhof, Moran
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Gingold, Hila
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Sagy, Or
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Munters, Arielle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svensson, Emma M.
    Uppsala Univ, Dept Organismal Biol, Human Evolut, S-75105 Uppsala, Sweden.;Uppsala Univ, SciLife Lab, S-75105 Uppsala, Sweden..
    Afshinnekoo, Ebrahim
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.;WorldQuant Initiat Quantitate Predict, New York, NY 10065 USA..
    Danko, David
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.;WorldQuant Initiat Quantitate Predict, New York, NY 10065 USA..
    Foox, Jonathan
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.;WorldQuant Initiat Quantitate Predict, New York, NY 10065 USA..
    Shor, Pnina
    Israel Antiqu Author, Dead Sea Scroll Projects, IL-91710 Jerusalem, Israel..
    Riestra, Beatriz
    Israel Antiqu Author, Dead Sea Scroll Projects, IL-91710 Jerusalem, Israel..
    Huchon, Dorothee
    Tel Aviv Univ, Steinhardt Museum Nat Hist, IL-6997801 Tel Aviv, Israel.;Tel Aviv Univ, Israel Natl Ctr Biodivers Studies, IL-6997801 Tel Aviv, Israel.;Tel Aviv Univ, Dept Zool, George S Wise Fac Life Sci, IL-6997801 Tel Aviv, Israel..
    Mason, Christopher E.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA.;WorldQuant Initiat Quantitate Predict, New York, NY 10065 USA..
    Mizrahi, Noam
    Tel Aviv Univ, Lester & Sally Entin Fac Humanities, Dept Bibl Studies, IL-6997801 Tel Aviv, Israel..
    Jakobsson, Mattias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Rechavi, Oded
    Tel Aviv Univ, George Wise Fac Life Sci, Dept Neurobiol, IL-6997801 Tel Aviv, Israel..
    Illuminating Genetic Mysteries of the Dead Sea Scrolls2020In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 181, no 6, p. 1218-+Article in journal (Refereed)
    Abstract [en]

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

  • 46.
    Anderson, Judy E.
    et al.
    Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Canada; Manitoba Institute of Child's Health (MICH), University of Manitoba, Winnipeg, Canada.
    Hansen, Lise Lotte
    Institute of Human Genetics, University of Aarhus, Denmark.
    Mooren, Frank C.
    Department of Sports Medicine, Institute of Sport Sciences, University Giessen, Germany.
    Post, Markus
    Department of Sports Medicine, Institute of Sport Sciences, University Giessen, Germany.
    Hug, Hubert
    DSM Nutritional Products Ltd, Research & Development, Kaiseraugst, Switzerland.
    Zuse, Anne
    Manitoba Institute of Cell Biology (MICB), CancerCare Manitoba, 675 McDermot Ave. Rm. ON6010, Winnipeg, Man. R3E 0V9, Canada.
    Los, Marek Jan
    Manitoba Institute of Cell Biology, Cancer Care Manitoba; Manitoba Institute of Child Health; Department of Biochemistry and Medical Genetics; Department of Human Anatomy and Cell Science, University Manitoba, Winnipeg, Canada, .
    Methods and biomarkers for the diagnosis and prognosis of cancer and other diseases: Towards personalized medicine2006In: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 9, no 4-5, p. 198-210Article in journal (Refereed)
    Abstract [en]

    The rapid development of new diagnostic procedures, the mapping of the human genome, progress in mapping genetic polymorphisms, and recent advances in nucleic acid- and protein chip technologies are driving the development of personalized therapies. This breakthrough in medicine is expected to be achieved largely due to the implementation of "lab-on-the-chip" technology capable of performing hundreds, even thousands of biochemical, cellular and genetic tests on a single sample of blood or other body fluid. Focusing on a few disease-specific examples, this review discusses selected technologies and their combinations likely to be incorporated in the "lab-on-the-chip" and to provide rapid and versatile information about specific diseases entities. Focusing on breast cancer and after an overview of single-nucleofide polymorphism (SNP)-screening methodologies, we discuss the diagnostic and prognostic importance of SNPs. Next, using Duchenne muscular dystrophy (DMD) as an example, we provide a brief overview of powerful and innovative integration of traditional immuno-histochemistry techniques with advanced biophysical methods such as NMR-spectroscopy or Fourier-transformed infrared (FT-IR) spectroscopy. A brief overview of the challenges and opportunities provided by protein and aptamer microarrays follows. We conclude by highlighting novel and promising biochemical markers for the development of personalized treatment of cancer and other diseases: serum cytochrome c, cytokeratin-18 and -19 and their proteolytic fragments for the detection and quantitation of malignant tumor mass, tumor cell turn-over, inflammatory processes during hepatitis and Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis and apoptotic/necrotic cancer cell death. (c) 2006 Elsevier Ltd. All rights reserved.

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  • 47.
    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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  • 48.
    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)
  • 49.
    Andersson, Anna-Carin
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Ecology and Evolution, Conservation Biology and Genetics.
    Postglacial Population History of the Common Shrew (Sorex araneus) in Fennoscandia: Molekylära studier av återkolonisation, könsbundet genflöde och kromosomrasbildning.2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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  • 50.
    Andersson, Anneli
    et al.
    Örebro University, School of Medical Sciences.
    Tuvblad, Catherine
    Örebro University, School of Law, Psychology and Social Work. University of Southern California, Department of Psychology, Los Angeles CA, USA.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Chen, Qi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Genetic overlap between ADHD and externalizing, internalizing and neurodevelopmental disorder symptoms: a systematic review and meta-analysis2018In: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 48, no 6, p. 455-456Article in journal (Other academic)
    Abstract [en]

    Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder (Wilens, Biederman & Spencer 2002) and affects approximately 5% of children (Polanczyk, de Lima, Horta, Biederman & Rohde 2007). About half of those diagnosed in childhood continue to have the diagnosis and symptoms in adulthood (Kessler et al. 2006). The co-occurrence of ADHD with other psychiatric disorder symptoms (Burt et al. 2001; Cole et al. 2009; Polderman et al. 2014) has been suggested to be partly explained by a shared genetic vulnerability (Polderman et al. 2014). However, the strength of the genetic overlap is currently unclear. Also, no study has examined whether the genetic correlations differs between age groups (childhood versus adulthood), by rater (self-report, other informant, combined (parent-teacher, parent-twin, teacher-twin)), or by type of psychiatric disorder symptoms (externalizing, internalizing, neu-rodevelopmental). To address this gap, we conducted a systematic literature search to identify relevant twin studies, in PubMed, PsycINFO, and EMBASE. A total of 31 articles were identified and included in the present study. The pooled estimates showed that the comorbidity between ADHD and diverse psychiatric disorder symptoms were explained by shared genetic effectsrg= 0.50 (0.43–0.56). A similar shared genetic overlap between ADHD and psychiatric disorder symptoms was observed in both childhood rg= 0.51(0.42–0.61) and adulthood rg= 0.47 (0.40–0.53). Similar results werealso found for self-reports rg= 0.49 (0.42–0.55), other informants rg= 0.50 (0.40–0.60), and combined raters rg= 0.51 (0.30–0.69). Further, the strength of the genetic correlations of ADHD with the externalizing rg= 0.49 (0.39–0.59), internalizing rg= 0.55 (0.40–0.68) and neurodevelopmental rg= 0.47 (0.40–0.53) spectrums were similar in magnitude. These findings emphasize the presence of a shared genetic liability between ADHD and externalizing, internalizing and neurodevelopmental disorder symptoms, independent of age and rater.

    References

    Burt, S. A., Krueger, R. F., McGue, M., Iacono, W. G. (2001).Sources of covariation among attention-deficit/hyperactivity disorder,oppositional defiant disorder, and conduct disorder: the importance ofshared environment.Journal of Abnormal Psychology, 4, 516–525.

    Cole, J., Ball, H. A., Martin, N. C., Scourfield, J., McGuffin, P.(2009). Genetic overlap between measures of hyperactivity/inatten-tion and mood in children and adolescents.J Am Acad Child AdolescPsychiatry48, 1094–1101.

    Kessler, R. C., Adler, L., Barkley, R., Biederman, J., Conners, C.K., Demler, O., Faraone, S. V., Greenhill, L. L., Howes, M. J., Secnik,K., Spencer, T., Ustun, T. B., Walters, E. E., Zaslavsky, A. M. (2006).The prevalence and correlates of adult ADHD in the United States:results from the National Comorbidity Survey Replication.Am JPsychiatry, 163, 716–723.

    Polanczyk, G., de Lima, M. S., Horta, B. L., Biederman, J., Rohde,L. A. (2007). The worldwide prevalence of ADHD: a systematicreview and metaregression analysis.Am J Psychiatry, 164, 942-8.

    Polderman, T. J., Hoekstra, R. A., Posthuma, D., Larsson, H.(2014). The co-occurrence of autistic and ADHD dimensions inadults: an etiological study in 17,770 twins.Transl Psychiatry2014;4: e435.

    Wilens, T. E., Biederman, J., Spencer, T. J. (2002). Attentiondeficit/hyperactivity disorder across the lifespan.Annual Review Med53:113–131.

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