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  • 1. Alexeyenko, Andrey
    et al.
    Nystedt, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Vezzi, Francesco
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sherwood, Ellen
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ye, Rosa
    Knudsen, Bjarne
    Simonsen, Martin
    Turner, Benjamin
    de Jong, Pieter
    Wu, Cheng-Cang
    Lundeberg, Joakim
    Efficient de novo assembly of large and complex genomes by massively parallel sequencing of Fosmid pools2014In: BMC Genomics, E-ISSN 1471-2164, Vol. 15, p. 439-Article in journal (Refereed)
    Abstract [en]

    Background: Sampling genomes with Fosmid vectors and sequencing of pooled Fosmid libraries on the Illumina platform for massive parallel sequencing is a novel and promising approach to optimizing the trade-off between sequencing costs and assembly quality. Results: In order to sequence the genome of Norway spruce, which is of great size and complexity, we developed and applied a new technology based on the massive production, sequencing, and assembly of Fosmid pools (FP). The spruce chromosomes were sampled with similar to 40,000 bp Fosmid inserts to obtain around two-fold genome coverage, in parallel with traditional whole genome shotgun sequencing (WGS) of haploid and diploid genomes. Compared to the WGS results, the contiguity and quality of the FP assemblies were high, and they allowed us to fill WGS gaps resulting from repeats, low coverage, and allelic differences. The FP contig sets were further merged with WGS data using a novel software package GAM-NGS. Conclusions: By exploiting FP technology, the first published assembly of a conifer genome was sequenced entirely with massively parallel sequencing. Here we provide a comprehensive report on the different features of the approach and the optimization of the process. We have made public the input data (FASTQ format) for the set of pools used in this study: ftp://congenie.org/congenie/Nystedt_2013/Assembly/ProcessedData/FosmidPools/.(alternatively accessible via http://congenie.org/downloads).The software used for running the assembly process is available at http://research.scilifelab.se/andrej_alexeyenko/downloads/fpools/.

  • 2.
    Anderson, Benjamin M.
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Krause, Kirsten
    Petersen, Gitte
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Mitochondrial genomes of two parasitic Cuscuta species lack clear evidence of horizontal gene transfer and retain unusually fragmented ccmF(C) genes2021In: BMC Genomics, E-ISSN 1471-2164, Vol. 22, no 1, article id 816Article in journal (Refereed)
    Abstract [en]

    Background: The intimate association between parasitic plants and their hosts favours the exchange of genetic material, potentially leading to horizontal gene transfer (HGT) between plants. With the recent publication of several parasitic plant nuclear genomes, there has been considerable focus on such non-sexual exchange of genes. To enhance the picture on HGT events in a widely distributed parasitic genus, Cuscuta (dodders), we assembled and analyzed the organellar genomes of two recently sequenced species, C. australis and C. campestris, making this the first account of complete mitochondrial genomes (mitogenomes) for this genus.

    Results: The mitogenomes are 265,696 and 275,898 bp in length and contain a typical set of mitochondrial genes, with 10 missing or pseudogenized genes often lost from angiosperm mitogenomes. Each mitogenome also possesses a structurally unusual ccmF(C) gene, which exhibits splitting of one exon and a shift to trans-splicing of its intron. Based on phylogenetic analysis of mitochondrial genes from across angiosperms and similarity-based searches, there is little to no indication of HGT into the Cuscuta mitogenomes. A few candidate regions for plastome-to-mitogenome transfer were identified, with one suggestive of possible HGT.

    Conclusions: The lack of HGT is surprising given examples from the nuclear genomes, and may be due in part to the relatively small size of the Cuscuta mitogenomes, limiting the capacity to integrate foreign sequences.

  • 3.
    Berckx, Fede
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Bandong, Cyndi Mae
    Lin, Hsiao-Han
    Yamanaka, Takashi
    Katayama, Sae
    Wibberg, Daniel
    Blom, Jochen
    Kalinowski, Jörn
    Tateno, Masaki
    Simbahan, Jessica
    Liu, Chi-Te
    Brachmann, Andreas
    Pawlowski, Katharina
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Van Nguyen, Thanh
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    A tale of two lineages: how the strains of the earliest divergent symbiotic Frankia clade spread over the world2022In: BMC Genomics, E-ISSN 1471-2164, Vol. 23, no 1, article id 602Article in journal (Refereed)
    Abstract [en]

    It is currently assumed that around 100 million years ago, the common ancestor to the Fabales, Fagales, Rosales and Cucurbitales in Gondwana, developed a root nodule symbiosis with a nitrogen-fixing bacterium. The symbiotic trait evolved first in Frankia cluster-2; thus, strains belonging to this cluster are the best extant representatives of this original symbiont. Most cluster-2 strains could not be cultured to date, except for Frankia coriariae, and therefore many aspects of the symbiosis are still elusive. Based on phylogenetics of cluster-2 metagenome-assembled genomes (MAGs), it has been shown that the genomes of strains originating in Eurasia are highly conserved. These MAGs are more closely related to Frankia cluster-2 in North America than to the single genome available thus far from the southern hemisphere, i.e., from Papua New Guinea.

    To unravel more biodiversity within Frankia cluster-2 and predict routes of dispersal from Gondwana, we sequenced and analysed the MAGs of Frankia cluster-2 from Coriaria japonica and Coriaria intermedia growing in Japan, Taiwan and the Philippines. Phylogenetic analyses indicate there is a clear split within Frankia cluster-2, separating a continental from an island lineage. Presumably, these lineages already diverged in Gondwana.

    Based on fossil data on the host plants, we propose that these two lineages dispersed via at least two routes. While the continental lineage reached Eurasia together with their host plants via the Indian subcontinent, the island lineage spread towards Japan with an unknown host plant.

  • 4.
    Celorio-Mancera, Maria de la Paz
    et al.
    Stockholm University, Faculty of Science, Department of Zoology.
    Ahn, Seung-Joon
    Vogel, Heiko
    Heckel, David G.
    Transcriptional responses underlying the hormetic and detrimental effects of the plant secondary metabolite gossypol on the generalist herbivore Helicoverpa armigera2011In: BMC Genomics, E-ISSN 1471-2164, Vol. 12, p. 575-Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    Dussex, Nicolas
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    Alberti, Federica
    Heino, Matti T.
    Olsen, Remi-André
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    van der Valk, Tom
    Ryman, Nils
    Stockholm University, Faculty of Science, Department of Zoology.
    Laikre, Linda
    Stockholm University, Faculty of Science, Department of Zoology.
    Ahlgren, Hans
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Askeyev, Igor
    Askeyev, Oleg
    Shaymuratova, Dilyara N.
    Askeyev, Arthur O.
    Döppes, Doris
    Friedrich, Ronny
    Lindauer, Susanne
    Rosendahl, Wilfried
    Aspi, Jouni
    Hofreiter, Michael
    Lidén, Kerstin
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies.
    Dalén, Love
    Díez-del-Molino, David
    Stockholm University, Faculty of Science, Department of Zoology. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    Moose genomes reveal past glacial demography and the origin of modern lineages2020In: BMC Genomics, E-ISSN 1471-2164, Vol. 21, no 1, article id 854Article in journal (Refereed)
    Abstract [en]

    Background: Numerous megafauna species from northern latitudes went extinct during the Pleistocene/Holocene transition as a result of climate-induced habitat changes. However, several ungulate species managed to successfully track their habitats during this period to eventually flourish and recolonise the holarctic regions. So far, the genomic impacts of these climate fluctuations on ungulates from high latitudes have been little explored. Here, we assemble a de-novo genome for the European moose (Alces alces) and analyse it together with re-sequenced nuclear genomes and ancient and modern mitogenomes from across the moose range in Eurasia and North America.

    Results: We found that moose demographic history was greatly influenced by glacial cycles, with demographic responses to the Pleistocene/Holocene transition similar to other temperate ungulates. Our results further support that modern moose lineages trace their origin back to populations that inhabited distinct glacial refugia during the Last Glacial Maximum (LGM). Finally, we found that present day moose in Europe and North America show low to moderate inbreeding levels resulting from post-glacial bottlenecks and founder effects, but no evidence for recent inbreeding resulting from human-induced population declines.

    Conclusions: Taken together, our results highlight the dynamic recent evolutionary history of the moose and provide an important resource for further genomic studies.

  • 6.
    Feuerborn, Tatiana R.
    et al.
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. University of Copenhagen, Denmark; Swedish Museum of Natural History, Sweden; Centre for Palaeogenetics, Sweden.
    Palkopoulou, Eleftheria
    van der Valk, Tom
    von Seth, Johanna
    Stockholm University, Faculty of Science, Department of Zoology. Swedish Museum of Natural History, Sweden; Centre for Palaeogenetics, Sweden.
    Munters, Arielle R.
    Pečnerová, Patrícia
    Dehasque, Marianne
    Stockholm University, Faculty of Science, Department of Zoology. Swedish Museum of Natural History, Sweden; Centre for Palaeogenetics, Sweden.
    Ureña, Irene
    Ersmark, Erik
    Kempe Lagerholm, Vendela
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Centre for Palaeogenetics, Sweden.
    Krzewińska, Maja
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Centre for Palaeogenetics, Sweden.
    Rodríguez-Varela, Ricardo
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Centre for Palaeogenetics, Sweden.
    Götherström, Anders
    Stockholm University, Faculty of Humanities, Department of Archaeology and Classical Studies. Centre for Palaeogenetics, Sweden.
    Dalén, Love
    Stockholm University, Faculty of Science, Department of Zoology. Swedish Museum of Natural History, Sweden; Centre for Palaeogenetics, Sweden.
    Díez-del-Molino, David
    Stockholm University, Faculty of Science, Department of Zoology. Swedish Museum of Natural History, Sweden; Centre for Palaeogenetics, Sweden.
    Competitive mapping allows for the identification and exclusion of human DNA contamination in ancient faunal genomic datasets2020In: BMC Genomics, E-ISSN 1471-2164, Vol. 21, no 1, article id 844Article in journal (Refereed)
    Abstract [en]

    Background: After over a decade of developments in field collection, laboratory methods and advances in high-throughput sequencing, contamination remains a key issue in ancient DNA research. Currently, human and microbial contaminant DNA still impose challenges on cost-effective sequencing and accurate interpretation of ancient DNA data.

    Results: Here we investigate whether human contaminating DNA can be found in ancient faunal sequencing datasets. We identify variable levels of human contamination, which persists even after the sequence reads have been mapped to the faunal reference genomes. This contamination has the potential to affect a range of downstream analyses.

    Conclusions: We propose a fast and simple method, based on competitive mapping, which allows identifying and removing human contamination from ancient faunal DNA datasets with limited losses of true ancient data. This method could represent an important tool for the ancient DNA field.

  • 7. Gómez-Navarro, Natalia
    et al.
    Jordán-Pla, Antonio
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Universitat de València, Spain.
    Estruch, Francisco
    Pérez-Ortín, José E.
    Defects in the NC2 repressor affect both canonical and non-coding RNA polymerase II transcription initiation in yeast2016In: BMC Genomics, E-ISSN 1471-2164, Vol. 17Article in journal (Refereed)
    Abstract [en]

    Background: The formation of the pre-initiation complex in eukaryotic genes is a key step in transcription initiation. The TATA-binding protein (TBP) is a universal component of all pre-initiation complexes for all kinds of RNA polymerase II (RNA pol II) genes, including those with a TATA or a TATA-like element, both those that encode proteins and those that transcribe non-coding RNAs. Mot1 and the negative cofactor 2 (NC2) complex are regulators of TBP, and it has been shown that depletion of these factors in yeast leads to defects in the control of transcription initiation that alter cryptic transcription levels in selected yeast loci. Results: In order to cast light on the molecular functions of NC2, we performed genome-wide studies in conditional mutants in yeast NC2 essential subunits Ydr1 and Bur6. Our analyses show a generally increased level of cryptic transcription in all kinds of genes upon depletion of NC2 subunits, and that each kind of gene (canonical or ncRNAs, TATA or TATA-like) shows some differences in the cryptic transcription pattern for each NC2 mutant. Conclusions: We conclude that NC2 plays a general role in transcription initiation in RNA polymerase II genes that is related with its known TBP interchange function from free to promoter bound states. Therefore, loss of the NC2 function provokes increases in cryptic transcription throughout the yeast genome. Our results also suggest functional differences between NC2 subunits Ydr1 and Bur6.

  • 8.
    Heidel-Fischer, Hanna
    et al.
    Department of Entomology, Max Planck Institute for Chemical Ecology.
    Freitak, Dalial
    Department of Entomology, Max Planck Institute for Chemical Ecology.
    Janz, Niklas
    Stockholm University, Faculty of Science, Department of Zoology, Animal Ecology.
    Soderlind, Lina
    Stockholm University, Faculty of Science, Department of Zoology, Animal Ecology.
    Vogel, Heiko
    Department of Entomology, Max Planck Institute for Chemical Ecology.
    Nylin, Soren
    Stockholm University, Faculty of Science, Department of Zoology, Animal Ecology.
    Phylogenetic relatedness and host plant growth form influence gene expression of the polyphagous comma butterfly (Polygonia c-album).2009In: BMC Genomics, E-ISSN 1471-2164, Vol. 10, no 1, p. 506-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: The mechanisms that shape the host plant range of herbivorous insect are to date not well understood but knowledge of these mechanisms and the selective forces that influence them can expand our understanding of the larger ecological interaction. Nevertheless, it is well established that chemical defenses of plants influence the host range of herbivorous insects. While host plant chemistry is influenced by phylogeny, also the growth forms of plants appear to influence the plant defense strategies as first postulated by Feeny (the "plant apparency" hypothesis). In the present study we aim to investigate the molecular basis of the diverse host plant range of the comma butterfly (Polygonia c-album) by testing differential gene expression in the caterpillars on three host plants that are either closely related or share the same growth form. RESULTS: In total 120 differentially expressed genes were identified in P. c-album after feeding on different host plants, 55 of them in the midgut and 65 in the restbody of the caterpillars. Expression patterns could be confirmed with an independent method for 14 of 27 tested genes. Pairwise similarities in upregulation in the midgut of the caterpillars were higher between plants that shared either growth form or were phylogenetically related. No known detoxifying enzymes were found to be differently regulated in the midgut after feeding on different host plants. CONCLUSIONS: Our data suggest a complex picture of gene expression in response to host plant feeding. While each plant requires a unique gene regulation in the caterpillar, both phylogenetic relatedness and host plant growth form appear to influence the expression profile of the polyphagous comma butterfly, in agreement with phylogenetic studies of host plant utilization in butterflies.

  • 9.
    Henricson, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Forslund, Kristoffer
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Sonnhammer, Erik L. L.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Orthology confers intron position conservation2010In: BMC Genomics, E-ISSN 1471-2164, Vol. 11:412Article in journal (Refereed)
    Abstract [en]

    Background: With the wealth of genomic data available it has become increasingly important to assign putative protein function through functional transfer between orthologs. Therefore, correct elucidation of the evolutionary relationships among genes is a critical task, and attempts should be made to further improve the phylogenetic inference by adding relevant discriminating features. It has been shown that introns can maintain their position over long evolutionary timescales. For this reason, it could be possible to use conservation of intron positions as a discriminating factor when assigning orthology. Therefore, we wanted to investigate whether orthologs have a higher degree of intron position conservation (IPC) compared to non-orthologous sequences that are equally similar in sequence.

    Results: To this end, we developed a new score for IPC and applied it to ortholog groups between human and six other species. For comparison, we also gathered the closest non-orthologs, meaning sequences close in sequence space, yet falling just outside the ortholog cluster. We found that ortholog-ortholog gene pairs on average have a significantly higher degree of IPC compared to ortholog-closest non-ortholog pairs. Also pairs of inparalogs were found to have a higher IPC score than inparalog-closest non-inparalog pairs. We verified that these differences can not simply be attributed to the generally higher sequence identity of the ortholog-ortholog and the inparalog-inparalog pairs. Furthermore, we analyzed the agreement between IPC score and the ortholog score assigned by the InParanoid algorithm, and found that it was consistently high for all species comparisons. In a minority of cases, the IPC and InParanoid score ranked inparalogs differently. These represent cases where sequence and intron position divergence are discordant. We further analyzed the discordant clusters to identify any possible preference for protein functions by looking for enriched GO terms and Pfam protein domains. They were enriched for functions important for multicellularity, which implies a connection between shifts in intronic structure and the origin of multicellularity.

    Conclusions: We conclude that orthologous genes tend to have more conserved intron positions compared to non-orthologous genes. As a consequence, our IPC score is useful as an additional discriminating factor when assigning orthology.

  • 10. Jakhetia, Richa
    et al.
    Marri, Aruna
    Ståhle, Jonas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Verma, Naresh K.
    Serotype-conversion in Shigella flexneri: identification of a novel bacteriophage, Sf101, from a serotype 7a strain2014In: BMC Genomics, E-ISSN 1471-2164, Vol. 15, p. 742-Article in journal (Refereed)
    Abstract [en]

    Background: Shigella flexneri is the major cause of bacillary dysentery in the developing countries. The lipopolysaccharide (LPS) O-antigen of S. flexneri plays an important role in its pathogenesis and also divides S. flexneri into 19 serotypes. All the serotypes with an exception for serotype 6 share a common O-antigen backbone comprising of N-acetylglucosamine and three rhamnose residues. Different serotypes result from modification of the basic backbone conferred by phage-encoded glucosyltransferase and/or acetyltransferase genes, or plasmid-encoded phosphoethanolamine transferase. Recently, a new site for O-acetylation at positions 3 and 4 of Rha(III), in serotypes 1a, 1b, 2a, 5a and Y was shown to be mediated by the oacB gene. Additionally, this gene was shown to be carried by a transposon-like structure inserted upstream of the adrA region on the chromosome. Results: In this study, a novel bacteriophage Sf101, encoding the oacB gene was isolated and characterised from a serotype 7a strain. The complete sequence of its 38,742 bp genome encoding 66 open reading frames (orfs) was determined. Comparative analysis revealed that phage Sf101 has a mosaic genome, and most of its proteins were >90% identical to the proteins from 12 previously characterised lambdoid phages. In addition, the organisation of Sf101 genes was found to be highly similar to bacteriophage Sf6. Analysis of the Sf101 OacB identified two amino acid substitutions in the protein; however, results obtained by NMR spectroscopy confirmed that Sf101-OacB was functional. Inspection of the chromosomal integration site of Sf101 phage revealed that this phage integrates in the sbcB locus, thus unveiling a new site for integration of serotype-converting phages of S. flexneri, and determining an alternative location of oacB gene in the chromosome. Furthermore, this study identified oacB gene in several serotype 7a isolates from various regions providing evidence of O-acetyl modification in serotype 7a. Conclusions: This is the first report on the isolation of bacteriophage Sf101 which contains the S. flexneri O-antigen modification gene oacB. Sf101 has a highly mosaic genome and was found to integrate in the sbcB locus. These findings contribute an advance in our current knowledge of serotype converting phages of S. flexneri.

  • 11. Joannin, Nicolas
    et al.
    Abhiman, Saraswathi
    Sonnhammer, Erik L
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholms Bioinformatikcentrum.
    Wahlgren, Mats
    Sub-grouping and sub-functionalization of the RIFIN multi-copy protein family.2008In: BMC Genomics, E-ISSN 1471-2164, Vol. 9, p. 19-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Parasitic protozoans possess many multicopy gene families which have central roles in parasite survival and virulence. The number and variability of members of these gene families often make it difficult to predict possible functions of the encoded proteins. The families of extra-cellular proteins that are exposed to a host immune response have been driven via immune selection to become antigenically variant, and thereby avoid immune recognition while maintaining protein function to establish a chronic infection. RESULTS: We have combined phylogenetic and function shift analyses to study the evolution of the RIFIN proteins, which are antigenically variant and are encoded by the largest multicopy gene family in Plasmodium falciparum. We show that this family can be subdivided into two major groups that we named A- and B-RIFIN proteins. This suggested sub-grouping is supported by a recently published study that showed that, despite the presence of the Plasmodium export (PEXEL) motif in all RIFIN variants, proteins from each group have different cellular localizations during the intraerythrocytic life cycle of the parasite. In the present study we show that function shift analysis, a novel technique to predict functional divergence between sub-groups of a protein family, indicates that RIFINs have undergone neo- or sub-functionalization. CONCLUSION: These results question the general trend of clustering large antigenically variant protein groups into homogenous families. Assigning functions to protein families requires their subdivision into meaningful groups such as we have shown for the RIFIN protein family. Using phylogenetic and function shift analysis methods, we identify new directions for the investigation of this broad and complex group of proteins.

  • 12.
    Jordán-Pla, Antonio
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Yu, Simei
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Waldholm, Johan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Källman, Thomas
    Östlund Farrants, Ann-Kristin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    SWI/SNF regulates half of its targets without the need of ATP-driven nucleosome remodeling by Brahma2018In: BMC Genomics, E-ISSN 1471-2164, Vol. 19, article id 367Article in journal (Refereed)
    Abstract [en]

    Background: Brahma (BRM) is the only catalytic subunit of the SVVI/SNF chromatin-remodeling complex of Drosophila melanogaster. The function of SWI/SNF in transcription has long been attributed to its ability to remodel nucleosomes, which requires the ATPase activity of BRM. However, recent studies have provided evidence for a non-catalytic function of BRM in the transcriptional regulation of a few specific genes.

    Results: Here we have used RNA-seq and ChIP-seq to identify the BRM target genes in 52 cells, and we have used a catalytically inactive BRM mutant (K804R) that is unable to hydrolyze ATP to investigate the magnitude of the non-catalytic function of BRM in transcription regulation. We show that 49% of the BRM target genes in 52 cells are regulated through mechanisms that do not require BRM to have an ATPase activity. We also show that the catalytic and non-catalytic mechanisms of SVVI/SNF regulation operate on two subsets of genes that differ in promoter architecture and are linked to different biological processes.

    Conclusions: This study shows that the non-catalytic role of SWI/SNF in transcription regulation is far more prevalent than previously anticipated and that the genes that are regulated by SVVI/SNF through ATPase-dependent and ATPase-independent mechanisms have specialized roles in different cellular and developmental processes.

  • 13. Kemmer, Danielle
    et al.
    Podowski, Raf M
    Arenillas, David
    Lim, Jonathan
    Hodges, Emily
    Roth, Peggy
    Sonnhammer, Erik L L
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Höög, Christer
    Wasserman, Wyeth W
    NovelFam3000--uncharacterized human protein domains conserved across model organisms.2006In: BMC Genomics, E-ISSN 1471-2164, Vol. 7, p. 48-Article in journal (Refereed)
  • 14. Kjellin, Jonas
    et al.
    Pränting, Maria
    Bach, Frauke
    Vaid, Roshan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Uppsala University, Sweden.
    Edelbroek, Bart
    Li, Zhiru
    Hoeppner, Marc P.
    Grabherr, Manfred
    Isberg, Ralph R.
    Hagedorn, Monica
    Söderbom, Fredrik
    Investigation of the host transcriptional response to intracellular bacterial infection using Dictyostelium discoideum as a host model2019In: BMC Genomics, E-ISSN 1471-2164, Vol. 20, no 1, article id 961Article in journal (Refereed)
    Abstract [en]

    Background: During infection by intracellular pathogens, a highly complex interplay occurs between the infected cell trying to degrade the invader and the pathogen which actively manipulates the host cell to enable survival and proliferation. Many intracellular pathogens pose important threats to human health and major efforts have been undertaken to better understand the host-pathogen interactions that eventually determine the outcome of the infection. Over the last decades, the unicellular eukaryote Dictyostelium discoideum has become an established infection model, serving as a surrogate macrophage that can be infected with a wide range of intracellular pathogens. In this study, we use high-throughput RNA-sequencing to analyze the transcriptional response of D. discoideum when infected with Mycobacterium marinum and Legionella pneumophila. The results were compared to available data from human macrophages.

    Results: The majority of the transcriptional regulation triggered by the two pathogens was found to be unique for each bacterial challenge. Hallmark transcriptional signatures were identified for each infection, e.g. induction of endosomal sorting complexes required for transport (ESCRT) and autophagy genes in response to M. marinum and inhibition of genes associated with the translation machinery and energy metabolism in response to L. pneumophila. However, a common response to the pathogenic bacteria was also identified, which was not induced by non-pathogenic food bacteria. Finally, comparison with available data sets of regulation in human monocyte derived macrophages shows that the elicited response in D. discoideum is in many aspects similar to what has been observed in human immune cells in response to Mycobacterium tuberculosis and L. pneumophila.

    Conclusions: Our study presents high-throughput characterization of D. discoideum transcriptional response to intracellular pathogens using RNA-seq. We demonstrate that the transcriptional response is in essence distinct to each pathogen and that in many cases, the corresponding regulation is recapitulated in human macrophages after infection by mycobacteria and L. pneumophila. This indicates that host-pathogen interactions are evolutionary conserved, derived from the early interactions between free-living phagocytic cells and bacteria. Taken together, our results strengthen the use of D. discoideum as a general infection model.

  • 15.
    Kucerova, Lucie
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kubrak, Olga I.
    Stockholm University, Faculty of Science, Department of Zoology.
    Bengtsson, Jonas M.
    Stockholm University, Faculty of Science, Department of Zoology.
    Strnad, Hynek
    Nylin, Sören
    Stockholm University, Faculty of Science, Department of Zoology.
    Theopold, Ulrich
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nässel, Dick R.
    Stockholm University, Faculty of Science, Department of Zoology.
    Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster2016In: BMC Genomics, E-ISSN 1471-2164, Vol. 17, article id 50Article in journal (Refereed)
    Abstract [en]

    Background: In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. Results: A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin-IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll-dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. Conclusions: We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan.

  • 16.
    Kutsenko, Alexey
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Svensson, Thomas
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Nystedt, Björn
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Lundeberg, Joakim
    Björk, Petra
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sonnhammer, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Giacomello, Stefania
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Visa, Neus
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wieslander, Lars
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The Chironomus tentans genome sequence and the organization of the Balbiani ring genes2014In: BMC Genomics, E-ISSN 1471-2164, Vol. 15, p. 819-Article in journal (Refereed)
    Abstract [en]

    Background: The polytene nuclei of the dipteran Chironomus tentans (Ch. tentans) with their Balbiani ring (BR) genes constitute an exceptional model system for studies of the expression of endogenous eukaryotic genes. Here, we report the first draft genome of Ch. tentans and characterize its gene expression machineries and genomic architecture of the BR genes. Results: The genome of Ch. tentans is approximately 200 Mb in size, and has a low GC content (31%) and a low repeat fraction (15%) compared to other Dipteran species. Phylogenetic inference revealed that Ch. tentans is a sister clade to mosquitoes, with a split 150-250 million years ago. To characterize the Ch. tentans gene expression machineries, we identified potential orthologus sequences to more than 600 Drosophila melanogaster (D. melanogaster) proteins involved in the expression of protein-coding genes. We report novel data on the organization of the BR gene loci, including a novel putative BR gene, and we present a model for the organization of chromatin bundles in the BR2 puff based on genic and intergenic in situ hybridizations. Conclusions: We show that the molecular machineries operating in gene expression are largely conserved between Ch. tentans and D. melanogaster, and we provide enhanced insight into the organization and expression of the BR genes. Our data strengthen the generality of the BR genes as a unique model system and provide essential background for in-depth studies of the biogenesis of messenger ribonucleoprotein complexes.

  • 17. Liang Qi Wee, Jocelyn
    et al.
    Murugesan, Suriya Narayanan
    Wheat, Christopher W.
    Stockholm University, Faculty of Science, Department of Zoology.
    Monteiro, Antonia
    The genetic basis of wing spots in Pieris canidia butterflies2023In: BMC Genomics, E-ISSN 1471-2164, Vol. 24, no 1, article id 169Article in journal (Refereed)
    Abstract [en]

    Spots in pierid butterflies and eyespots in nymphalid butterflies are likely non-homologous wing colour pattern elements, yet they share a few features in common. Both develop black scales that depend on the function of the gene spalt, and both might have central signalling cells. This suggests that both pattern elements may be sharing common genetic circuitry. Hundreds of genes have already been associated with the development of nymphalid butterfly eyespot patterns, but the genetic basis of the simpler spot patterns on the wings of pierid butterflies has not been investigated. To facilitate studies of pierid wing patterns, we report a high-quality draft genome assembly for Pieris canidia, the Indian cabbage white. We then conducted transcriptomic analyses of pupal wing tissues sampled from the spot and non-spot regions of P. canidia at 3-6 h post-pupation. A total of 1352 genes were differentially regulated between wing tissues with and without the black spot, including spaltKrüppel-like factor 10, genes from the Toll, Notch, TGF-β, and FGFR signalling pathways, and several genes involved in the melanin biosynthetic pathway. We identified 14 genes that are up-regulated in both pierid spots and nymphalid eyespots and propose that spots and eyespots share regulatory modules despite their likely independent origins.

  • 18. Lindskog, Cecilia
    et al.
    Linne, Jerker
    Fagerberg, Linn
    Hallström, Björn M.
    Sundberg, Carl Johan
    Lindholm, Malene
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kampf, Caroline
    Choi, Howard
    Liem, David A.
    Ping, Peipei
    Varemo, Leif
    Mardinoglu, Adil
    Nielsen, Jens
    Larsson, Erik
    Ponten, Fredrik
    Uhlen, Mathias
    The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling2015In: BMC Genomics, E-ISSN 1471-2164, Vol. 16, article id 475Article in journal (Refereed)
    Abstract [en]

    Background: To understand cardiac and skeletal muscle function, it is important to define and explore their molecular constituents and also to identify similarities and differences in the gene expression in these two different striated muscle tissues. Here, we have investigated the genes and proteins with elevated expression in cardiac and skeletal muscle in relation to all other major human tissues and organs using a global transcriptomics analysis complemented with antibody-based profiling to localize the corresponding proteins on a single cell level. Results: Our study identified a comprehensive list of genes expressed in cardiac and skeletal muscle. The genes with elevated expression were further stratified according to their global expression pattern across the human body as well as their precise localization in the muscle tissues. The functions of the proteins encoded by the elevated genes are well in line with the physiological functions of cardiac and skeletal muscle, such as contraction, ion transport, regulation of membrane potential and actomyosin structure organization. A large fraction of the transcripts in both cardiac and skeletal muscle correspond to mitochondrial proteins involved in energy metabolism, which demonstrates the extreme specialization of these muscle tissues to provide energy for contraction. Conclusions: Our results provide a comprehensive list of genes and proteins elevated in striated muscles. A number of proteins not previously characterized in cardiac and skeletal muscle were identified and localized to specific cellular subcompartments. These proteins represent an interesting starting point for further functional analysis of their role in muscle biology and disease.

  • 19. Liu, Han
    et al.
    Wang, Kun
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindås, Ann-Christin
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Peeters, Eveline
    The genome-scale DNA-binding profile of BarR, a beta-alanine responsive transcription factor in the archaeon Sulfolobus acidocaldarius2016In: BMC Genomics, E-ISSN 1471-2164, Vol. 17, article id 569Article in journal (Refereed)
    Abstract [en]

    Background: The Leucine-responsive Regulatory Protein (Lrp) family is a widespread family of regulatory transcription factors in prokaryotes. BarR is an Lrp-like transcription factor in the model archaeon Sulfolobus acidocaldarius that activates the expression of a beta-alanine aminotransferase gene, which is involved in beta-alanine degradation. In contrast to classical Lrp-like transcription factors, BarR is not responsive to any of the alpha-amino acids but interacts specifically with beta-alanine. Besides the juxtaposed beta-alanine aminotransferase gene, other regulatory targets of BarR have not yet been identified although beta-alanine is the precursor of coenzyme A and thus an important central metabolite. The aim of this study is to extend the knowledge of the DNA-binding characteristics of BarR and of its corresponding regulon from a local to a genome-wide perspective. Results: We characterized the genome-wide binding profile of BarR using chromatin immunoprecipation combined with high-throughput sequencing (ChIP-seq). This revealed 21 genomic binding loci. High-enrichment binding regions were validated to interact with purified BarR protein in vitro using electrophoretic mobility shift assays and almost all targets were also shown to harbour a conserved semi-palindromic binding motif. Only a small subset of enriched genomic sites are located in intergenic regions at a relative short distance to a promoter, and qRT-PCR analysis demonstrated that only one additional operon is under activation of BarR, namely the glutamine synthase operon. The latter is also a target of other Lrp-like transcription factors. Detailed inspection of the BarR ChIP-seq profile at the beta-alanine aminotransferase promoter region in combination with binding motif predictions indicate that the operator structure is more complicated than previously anticipated, consisting of multiple (major and auxiliary) operators. Conclusions: BarR has a limited regulon, and includes also glutamine synthase genes besides the previously characterized beta-alanine aminotransferase. Regulation of glutamine synthase is suggestive of a link between beta-alanine and alpha-amino acid metabolism in S. acidocaldarius. Furthermore, this work reveals that the BarR regulon overlaps with that of other Lrp-like regulators.

  • 20.
    Lundin, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biology and Functional Genomics.
    RNRdb, a curated database of the universal enzyme familyribonucleotide reductase, reveals a high level of misannotation insequences deposited to Genbank2009In: BMC Genomics, E-ISSN 1471-2164, Vol. 10, p. 589-Article in journal (Refereed)
    Abstract [en]

    Background: Ribonucleotide reductases (RNRs) catalyse the only known de novo pathway fordeoxyribonucleotide synthesis, and are therefore essential to DNA-based life. Whileribonucleotide reduction has a single evolutionary origin, significant differences between RNRsnevertheless exist, notably in cofactor requirements, subunit composition and allosteric regulation.These differences result in distinct operational constraints (anaerobicity, iron/oxygen dependenceand cobalamin dependence), and form the basis for the classification of RNRs into three classes.Description: In RNRdb (Ribonucleotide Reductase database), we have collated and curated allknown RNR protein sequences with the aim of providing a resource for exploration of RNRdiversity and distribution. By comparing expert manual annotations with annotations stored inGenbank, we find that significant inaccuracies exist in larger databases. To our surprise, only 23%of protein sequences included in RNRdb are correctly annotated across the key attributes of class,role and function, with 17% being incorrectly annotated across all three categories. This illustratesthe utility of specialist databases for applications where a high degree of annotation accuracy maybe important. The database houses information on annotation, distribution and diversity of RNRs,and links to solved RNR structures, and can be searched through a BLAST interface. RNRdb isaccessible through a public web interface at http://rnrdb.molbio.su.se.Conclusion: RNRdb is a specialist database that provides a reliable annotation and classificationresource for RNR proteins, as well as a tool to explore distribution patterns of RNR classes. Therecent expansion in available genome sequence data have provided us with a picture of RNRdistribution that is more complex than believed only a few years ago; our database indicates thatRNRs of all three classes are found across all three cellular domains. Moreover, we find a numberof organisms that encode all three classes.

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  • 21. Mahmudi, Owais
    et al.
    Sennblad, Bengt
    Arvestad, Lars
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA).
    Nowick, Katja
    Lagergren, Jens
    Gene-pseudogene evolution: a probabilistic approach2015In: BMC Genomics, E-ISSN 1471-2164, Vol. 16, article id S12Article in journal (Refereed)
    Abstract [en]

    Over the last decade, methods have been developed for the reconstruction of gene trees that take into account the species tree. Many of these methods have been based on the probabilistic duplication-loss model, which describes how a gene-tree evolves over a species-tree with respect to duplication and losses, as well as extension of this model, e.g., the DLRS (Duplication, Loss, Rate and Sequence evolution) model that also includes sequence evolution under relaxed molecular clock. A disjoint, almost as recent, and very important line of research has been focused on non protein-coding, but yet, functional DNA. For instance, DNA sequences being pseudogenes in the sense that they are not translated, may still be transcribed and the thereby produced RNA may be functional. We extend the DLRS model by including pseudogenization events and devise an MCMC framework for analyzing extended gene families consisting of genes and pseudogenes with respect to this model, i.e., reconstructing gene-trees and identifying pseudogenization events in the reconstructed gene-trees. By applying the MCMC framework to biologically realistic synthetic data, we show that gene-trees as well as pseudogenization points can be inferred well. We also apply our MCMC framework to extended gene families belonging to the Olfactory Receptor and Zinc Finger superfamilies. The analysis indicate that both these super families contains very old pseudogenes, perhaps so old that it is reasonable to suspect that some are functional. In our analysis, the sub families of the Olfactory Receptors contains only lineage specific pseudogenes, while the sub families of the Zinc Fingers contains pseudogene lineages common to several species.

  • 22. Nachtigall, Pedro G.
    et al.
    Bovolenta, Luiz A.
    Patton, James G.
    Fromm, Bastian
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lemke, Ney
    Pinhal, Danillo
    A comparative analysis of heart microRNAs in vertebrates brings novel insights into the evolution of genetic regulatory networks2021In: BMC Genomics, E-ISSN 1471-2164, Vol. 22, no 1, article id 153Article in journal (Refereed)
    Abstract [en]

    Background: During vertebrate evolution, the heart has undergone remarkable changes that lead to morphophysiological differences in the fully formed heart of these species, such as chamber septation, heart rate frequency, blood pressure, and cardiac output volume. Despite these differences, the heart developmental process is guided by a core gene set conserved across vertebrates. Nonetheless, the regulatory mechanisms controlling the expression of genes involved in heart development and maintenance are largely uncharted. MicroRNAs (miRNAs) have been described as important regulatory elements in several biological processes, including heart biology. These small RNA molecules are broadly conserved in sequence and genomic context in metazoans. Mutations may occur in miRNAs and/or genes that contribute to the establishment of distinct repertoires of miRNA-target interactions, thereby favoring the differential control of gene expression and, consequently, the origin of novel phenotypes. In fact, several studies showed that miRNAs are integrated into genetic regulatory networks (GRNs) governing specific developmental programs and diseases. However, studies integrating miRNAs in vertebrate heart GRNs under an evolutionary perspective are still scarce.

    Results: We comprehensively examined and compared the heart miRNome of 20 species representatives of the five major vertebrate groups. We found 54 miRNA families with conserved expression and a variable number of miRNA families with group-specific expression in fishes, amphibians, reptiles, birds, and mammals. We also detected that conserved miRNAs present higher expression levels and a higher number of targets, whereas the group-specific miRNAs present lower expression levels and few targets.

    Conclusions: Both the conserved and group-specific miRNAs can be considered modulators orchestrating the core and peripheral genes of heart GRNs of vertebrates, which can be related to the morphophysiological differences and similarities existing in the heart of distinct vertebrate groups. We propose a hypothesis to explain evolutionary differences in the putative functional roles of miRNAs in the heart GRNs analyzed. Furthermore, we present new insights into the molecular mechanisms that could be helping modulate the diversity of morphophysiology in the heart organ of vertebrate species.

  • 23. Nellaker, Christoffer
    et al.
    Li, Fang
    Uhrzander, Fredrik
    Stockholm University.
    Tyrcha, Joanna
    Stockholm University, Faculty of Science, Department of Mathematics.
    Karlsson, Hakan
    Expression profiling of repetitive elements by melting temperature analysis: variation in HERV-W gag expression across human individuals and tissues2009In: BMC Genomics, E-ISSN 1471-2164, Vol. 10, p. 532-Article in journal (Refereed)
    Abstract [en]

    Background: Human endogenous retroviruses (HERV) constitute approximately 8% of the human genome and have long been considered ""junk"". The sheer number and repetitive nature of these elements make studies of their expression methodologically challenging. Hence, little is known of transcription of genomic regions harboring such elements. Results: Applying a recently developed technique for obtaining high resolution melting temperature data, we examined the frequency distributions of HERV-W gag element into 13 Tm categories in human tissues. Transcripts containing HERV-W gag sequences were expressed in non-random patterns with extensive variations in the expression between both tissues, including different brain regions, and individuals. Furthermore, the patterns of such transcripts varied more between individuals in brain regions than other tissues. Conclusion: Thus, regulated expression of non-coding regions of the human genome appears to include the HERV-W family of repetitive elements. Although it remains to be established whether such expression patterns represent leakage from transcription of functional regions or specific transcription, the current approach proves itself useful for studying detailed expression patterns of repetitive regions.

  • 24.
    Nguyen, Thanh Van
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Wibberg, Daniel
    Battenberg, Kai
    Blom, Jochen
    Vanden Heuvel, Brian
    Berry, Alison M.
    Kalinowski, Jörn
    Pawlowski, Katharina
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    An assemblage of Frankia Cluster II strains from California contains the canonical nod genes and also the sulfotransferase gene nodH2016In: BMC Genomics, E-ISSN 1471-2164, Vol. 17, article id 796Article in journal (Refereed)
    Abstract [en]

    Background: The ability to establish root nodule symbioses is restricted to four different plant orders. Soil actinobacteria of the genus Frankia can establish a symbiotic relationship with a diverse group of plants within eight different families from three different orders, the Cucurbitales, Fagales and Rosales. Phylogenetically, Frankia strains can be divided into four clusters, three of which (I, II, III) contain symbiotic strains. Members of Cluster II nodulate the broadest range of host plants with species from four families from two different orders, growing on six continents. Two Cluster II genomes were sequenced thus far, both from Asia.

    Results: In this paper we present the first Frankia cluster II genome from North America (California), Dg2, which represents a metagenome of two major and one minor strains. A phylogenetic analysis of the core genomes of 16 Frankia strains shows that Cluster II the ancestral group in the genus, also ancestral to the non-symbiotic Cluster IV. Dg2 contains the canonical nod genes nodABC for the production of lipochitooligosaccharide Nod factors, but also two copies of the sulfotransferase gene nodH. In rhizobial systems, sulfation of Nod factors affects their host specificity and their stability.

    Conclusions: A comparison with the nod gene region of the previously sequenced Dg1 genome from a Cluster II strain from Pakistan shows that the common ancestor of both strains should have contained nodABC and nodH. Phylogenetically, Dg2 NodH proteins are sister to rhizobial NodH proteins. A glnA-based phylogenetic analysis of all Cluster II strains sampled thus far supports the hypothesis that Cluster II Frankia strains came to North America with Datisca glomerata following the Madrean-Tethyan pattern.

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  • 25. Pazos Obregon, Flavio
    et al.
    Papalardo, Cecilia
    Castro, Sebastian
    Guerberoff, Gustavo
    Cantera, Rafael
    Stockholm University, Faculty of Science, Department of Zoology. Instituto de Investigaciones Biológicas Clemente Estable, Uruguay.
    Putative synaptic genes defined from a Drosophila whole body developmental transcriptome by a machine learning approach2015In: BMC Genomics, E-ISSN 1471-2164, Vol. 16, article id 694Article in journal (Refereed)
    Abstract [en]

    Background: Assembly and function of neuronal synapses require the coordinated expression of a yet undetermined set of genes. Although roughly a thousand genes are expected to be important for this function in Drosophila melanogaster, just a few hundreds of them are known so far. Results: In this work we trained three learning algorithms to predict a synaptic function for genes of Drosophila using data from a whole-body developmental transcriptome published by others. Using statistical and biological criteria to analyze and combine the predictions, we obtained a gene catalogue that is highly enriched in genes of relevance for Drosophila synapse assembly and function but still not recognized as such. Conclusions: The utility of our approach is that it reduces the number of genes to be tested through hypothesis-driven experimentation.

  • 26. Stranneheim, Henrik
    et al.
    Engvall, Martin
    Naess, Karin
    Lesko, Nicole
    Larsson, Pontus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dahlberg, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Andeer, Robin
    Wredenberg, Anna
    Freyer, Chris
    Barbaro, Michela
    Bruhn, Helene
    Emahazion, Tesfail
    Magnusson, Mans
    Wibom, Rolf
    Zetterstrom, Rolf H.
    Wirta, Valtteri
    von Dobeln, Ulrika
    Wedell, Anna
    Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism2014In: BMC Genomics, E-ISSN 1471-2164, Vol. 15, article id 1090Article in journal (Refereed)
    Abstract [en]

    Background: Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine. Results: We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome. Conclusions: We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.

  • 27. Troell, Karin
    et al.
    Hallström, Björn
    Divne, Anna-Maria
    Alsmark, Cecilia
    Arrighi, Romanico
    Huss, Mikael
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Beser, Jessica
    Bertilsson, Stefan
    Cryptosporidium as a testbed for single cell genome characterization of unicellular eukaryotes2016In: BMC Genomics, E-ISSN 1471-2164, Vol. 17, article id 471Article in journal (Refereed)
    Abstract [en]

    Background: Infectious disease involving multiple genetically distinct populations of pathogens is frequently concurrent, but difficult to detect or describe with current routine methodology. Cryptosporidium sp. is a widespread gastrointestinal protozoan of global significance in both animals and humans. It cannot be easily maintained in culture and infections of multiple strains have been reported. To explore the potential use of single cell genomics methodology for revealing genome-level variation in clinical samples from Cryptosporidium-infected hosts, we sorted individual oocysts for subsequent genome amplification and full-genome sequencing. Results: Cells were identified with fluorescent antibodies with an 80 % success rate for the entire single cell genomics workflow, demonstrating that the methodology can be applied directly to purified fecal samples. Ten amplified genomes from sorted single cells were selected for genome sequencing and compared both to the original population and a reference genome in order to evaluate the accuracy and performance of the method. Single cell genome coverage was on average 81 % even with a moderate sequencing effort and by combining the 10 single cell genomes, the full genome was accounted for. By a comparison to the original sample, biological variation could be distinguished and separated from noise introduced in the amplification. Conclusions: As a proof of principle, we have demonstrated the power of applying single cell genomics to dissect infectious disease caused by closely related parasite species or subtypes. The workflow can easily be expanded and adapted to target other protozoans, and potential applications include mapping genome-encoded traits, virulence, pathogenicity, host specificity and resistance at the level of cells as truly meaningful biological units.

  • 28.
    Vigil-Stenman, Theoden
    et al.
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Larsson, John
    Nylander, Johan A. A.
    Bergman, Birgitta
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Local hopping mobile DNA implicated in pseudogene formation and reductive evolution in an obligate cyanobacteria-plant symbiosis2015In: BMC Genomics, E-ISSN 1471-2164, Vol. 16, article id 193Article in journal (Refereed)
    Abstract [en]

    Background: Insertion sequences (ISs) are approximately 1 kbp long jumping genes found in prokaryotes. ISs encode the protein Transposase, which facilitates the excision and reinsertion of ISs in genomes, making these sequences a type of class I (cut-and-paste) Mobile Genetic Elements. ISs are proposed to be involved in the reductive evolution of symbiotic prokaryotes. Our previous sequencing of the genome of the cyanobacterium 'Nostoc azollae' 0708, living in a tight perpetual symbiotic association with a plant (the water fern Azolla), revealed the presence of an eroding genome, with a high number of insertion sequences (ISs) together with an unprecedented large proportion of pseudogenes. To investigate the role of ISs in the reductive evolution of 'Nostoc azollae' 0708, and potentially in the formation of pseudogenes, a bioinformatic investigation of the IS identities and positions in 47 cyanobacterial genomes was conducted. To widen the scope, the IS contents were analysed qualitatively and quantitatively in 20 other genomes representing both free-living and symbiotic bacteria. Results: Insertion Sequences were not randomly distributed in the bacterial genomes and were found to transpose short distances from their original location (local hopping) and pseudogenes were enriched in the vicinity of IS elements. In general, symbiotic organisms showed higher densities of IS elements and pseudogenes than non-symbiotic bacteria. A total of 1108 distinct repeated sequences over 500 bp were identified in the 67 genomes investigated. In the genome of 'Nostoc azollae' 0708, IS elements were apparent at 970 locations (14.3%), with 428 being full-length. Morphologically complex cyanobacteria with large genomes showed higher frequencies of IS elements, irrespective of life style. Conclusions: The apparent co-location of IS elements and pseudogenes found in prokaryotic genomes implies earlier IS transpositions into genes. As transpositions tend to be local rather than genome wide this likely explains the proximity between IS elements and pseudogenes. These findings suggest that ISs facilitate the reductive evolution in for instance in the symbiotic cyanobacterium 'Nostoc azollae' 0708 and in other obligate prokaryotic symbionts.

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  • 29.
    von Seth, Johanna
    et al.
    Stockholm University, Faculty of Science, Department of Zoology. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    van der Valk, Tom
    Lord, Edana
    Stockholm University, Faculty of Science, Department of Zoology. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    Sigeman, Hanna
    Olsen, Remi-André
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Knapp, Michael
    Kardailsky, Olga
    Robertson, Fiona
    Hale, Marie
    Houston, Dave
    Kennedy, Euan
    Dalén, Love
    Stockholm University, Faculty of Science, Department of Zoology. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    Norén, Karin
    Stockholm University, Faculty of Science, Department of Zoology.
    Massaro, Melanie
    Robertson, Bruce C.
    Dussex, Nicolas
    Stockholm University, Faculty of Science, Department of Zoology. Centre for Palaeogenetics, Sweden; Swedish Museum of Natural History, Sweden.
    Genomic trajectories of a near-extinction event in the Chatham Island black robin2022In: BMC Genomics, E-ISSN 1471-2164, Vol. 23, article id 747Article in journal (Refereed)
    Abstract [en]

    Background: Understanding the micro-­evolutionary response of populations to demographic declines is a major goal in evolutionary and conservation biology. In small populations, genetic drift can lead to an accumulation of deleterious mutations, which will increase the risk of extinction. However, demographic recovery can still occur after extreme declines, suggesting that natural selection may purge deleterious mutations, even in extremely small populations. The Chatham Island black robin (Petroica traversi) is arguably the most inbred bird species in the world. It avoided imminent extinction in the early 1980s and after a remarkable recovery from a single pair, a second population was established and the two extant populations have evolved in complete isolation since then. Here, we analysed 52 modern and historical genomes to examine the genomic consequences of this extreme bottleneck and the subsequent translocation.

    Results: We found evidence for two-fold decline in heterozygosity and three- to four-fold increase in inbreeding in modern genomes. Moreover, there was partial support for temporal reduction in total load for detrimental variation. In contrast, compared to historical genomes, modern genomes showed a significantly higher realised load, reflecting the temporal increase in inbreeding. Furthermore, the translocation induced only small changes in the frequency of deleterious alleles, with the majority of detrimental variation being shared between the two populations.

    Conclusion: Our results highlight the dynamics of mutational load in a species that recovered from the brink of extinction, and show rather limited temporal changes in mutational load. We hypothesise that ancestral purging may have been facilitated by population fragmentation and isolation on several islands for thousands of generations and may have already reduced much of the highly deleterious load well before human arrival and introduction of pests to the archipelago. The majority of fixed deleterious variation was shared between the modern populations, but translocation of individuals with low mutational load could possibly mitigate further fixation of high-frequency deleterious variation.

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