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  • 1.
    Adrian-Kalchhauser, Irene
    et al.
    Univ Basel, Program Man Soc Environm, Dept Environm Sci, Vesalgasse 1, CH-4051 Basel, Switzerland..
    Svensson, Ola
    Univ Gothenburg, Dept Biol & Environm Sci, Medicinaregatan 18A, S-41390 Gothenburg, Sweden.;Univ Gothenburg, Linnaeus Ctr Marine Evolutionary Biol, POB 46040530, Gothenburg, Sweden..
    Kutschera, Verena E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Rosenblad, Magnus Alm
    Univ Gothenburg, Linnaeus Ctr Marine Evolutionary Biol, POB 46040530, Gothenburg, Sweden.;Univ Gothenburg, Dept Marine Sci, NBIS Bioinformat Infrastruct Life Sci, Medicinaregatan 9C, S-41390 Gothenburg, Sweden..
    Pippel, Martin
    Heidelberg Inst Theoret Studies, Schloss Wolfsbrunnenweg 35, D-69118 Heidelberg, Germany..
    Winkler, Sylke
    Max Planck Inst Mol Cell Biol & Genet, Pfotenhauerstr 108, D-01307 Dresden, Germany..
    Schloissnig, Siegfried
    Heidelberg Inst Theoret Studies, Schloss Wolfsbrunnenweg 35, D-69118 Heidelberg, Germany..
    Blomberg, Anders
    Univ Gothenburg, Linnaeus Ctr Marine Evolutionary Biol, POB 46040530, Gothenburg, Sweden.;Univ Gothenburg, Dept Marine Sci, Medicinaregatan 9C, S-41390 Gothenburg, Sweden..
    Burkhardt-Holm, Patricia
    Univ Basel, Program Man Soc Environm, Dept Environm Sci, Vesalgasse 1, CH-4051 Basel, Switzerland.;Univ Alberta, Dept Biol Sci, 11455 Saskatchewan Dr, Edmonton, AB, Canada..
    The mitochondrial genome sequences of the round goby and the sand goby reveal patterns of recent evolution in gobiid fish2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 177Article in journal (Refereed)
    Abstract [en]

    Background: Vertebrate mitochondrial genomes are optimized for fast replication and low cost of RNA expression. Accordingly, they are devoid of introns, are transcribed as polycistrons and contain very little intergenic sequences. Usually, vertebrate mitochondrial genomes measure between 16.5 and 17 kilobases ( kb). Results: During genome sequencing projects for two novel vertebrate models, the invasive round goby and the sand goby, we found that the sand goby genome is exceptionally small (16.4 kb), while the mitochondrial genome of the round goby is much larger than expected for a vertebrate. It is 19 kb in size and is thus one of the largest fish and even vertebrate mitochondrial genomes known to date. The expansion is attributable to a sequence insertion downstream of the putative transcriptional start site. This insertion carries traces of repeats from the control region, but is mostly novel. To get more information about this phenomenon, we gathered all available mitochondrial genomes of Gobiidae and of nine gobioid species, performed phylogenetic analyses, analysed gene arrangements, and compared gobiid mitochondrial genome sizes, ecological information and other species characteristics with respect to the mitochondrial phylogeny. This allowed us amongst others to identify a unique arrangement of tRNAs among Ponto-Caspian gobies. Conclusions: Our results indicate that the round goby mitochondrial genome may contain novel features. Since mitochondrial genome organisation is tightly linked to energy metabolism, these features may be linked to its invasion success. Also, the unique tRNA arrangement among Ponto- Caspian gobies may be helpful in studying the evolution of this highly adaptive and invasive species group. Finally, we find that the phylogeny of gobiids can be further refined by the use of longer stretches of linked DNA sequence.

  • 2.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Collier, Paul
    Fritz, Markus Hsi-Yang
    Benes, Vladimir
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Singh, Umashankar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    CGGBP1 mitigates cytosine methylation at repetitive DNA sequences2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 390Article in journal (Refereed)
    Abstract [en]

    Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.

  • 3.
    Andersson, Anders F.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Evolution. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Pelve, Erik A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Lindeberg, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Lundgren, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Nilsson, Peter
    Bernander, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Replication-biased genome organisation in the crenarchaeon Sulfolobus2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, p. 454-Article in journal (Refereed)
    Abstract [en]

    Background: Species of the crenarchaeon Sulfolobus harbour three replication origins in their single circular chromosome that are synchronously initiated during replication. Results: We demonstrate that global gene expression in two Sulfolobus species is highly biased, such that early replicating genome regions are more highly expressed at all three origins. The bias by far exceeds what would be anticipated by gene dosage effects alone. In addition, early replicating regions are denser in archaeal core genes (enriched in essential functions), display lower intergenic distances, and are devoid of mobile genetic elements. Conclusion: The strong replication-biased structuring of the Sulfolobus chromosome implies that the multiple replication origins serve purposes other than simply shortening the time required for replication. The higher-level chromosomal organisation could be of importance for minimizing the impact of DNA damage, and may also be linked to transcriptional regulation.

  • 4.
    Andersson, Jan O.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Sjögren, Åsa M.
    Horner, David S.
    Murphy, Colleen A.
    Dyal, Patricia L.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Logsdon, Jr., John M.
    Ragan, Mark A.
    Hirt, Robert P.
    Roger, Andrew J.
    A genomic survey of the fish parasite Spironucleus salmonicida indicates genomic plasticity among diplomonads and significant lateral gene transfer in eukaryote genome evolution2007In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, p. 51-Article, review/survey (Refereed)
    Abstract [en]

    Background: Comparative genomic studies of the mitochondrion-lacking protist group Diplomonadida (diplomonads) has been lacking, although Giardia lamblia has been intensively studied. We have performed a sequence survey project resulting in 2341 expressed sequence tags (EST) corresponding to 853 unique clones, 5275 genome survey sequences (GSS), and eleven finished contigs from the diplomonad fish parasite Spironucleus salmonicida (previously described as S. barkhanus). Results: The analyses revealed a compact genome with few, if any, introns and very short 3′ untranslated regions. Strikingly different patterns of codon usage were observed in genes corresponding to frequently sampled ESTs versus genes poorly sampled, indicating that translational selection is influencing the codon usage of highly expressed genes. Rigorous phylogenomic analyses identified 84 genes - mostly encoding metabolic proteins - that have been acquired by diplomonads or their relatively close ancestors via lateral gene transfer (LGT). Although most acquisitions were from prokaryotes, more than a dozen represent likely transfers of genes between eukaryotic lineages. Many genes that provide novel insights into the genetic basis of the biology and pathogenicity of this parasitic protist were identified including 149 that putatively encode variant-surface cysteine-rich proteins which are candidate virulence factors. A number of genomic properties that distinguish S. salmonicida from its human parasitic relative G. lamblia were identified such as nineteen putative lineage-specific gene acquisitions, distinct mutational biases and codon usage and distinct polyadenylation signals. Conclusion: Our results highlight the power of comparative genomic studies to yield insights into the biology of parasitic protists and the evolution of their genomes, and suggest that genetic exchange between distantly-related protist lineages may be occurring at an appreciable rate in eukaryote genome evolution.

  • 5.
    Ankarklev, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Franzen, Oscar
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden. KISP, Sci Life Lab, S-17165 Solna, Sweden..
    Peirasmaki, Dimitra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jerlstrom-Hultqvist, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lebbad, Marianne
    Publ Hlth Agcy Sweden, Dept Microbiol, SE-17182 Solna, Sweden..
    Andersson, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Bjorn
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden.;KISP, Sci Life Lab, S-17165 Solna, Sweden..
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comparative genomic analyses of freshly isolated Giardia intestinalis assemblage A isolates2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 697Article in journal (Refereed)
    Abstract [en]

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

  • 6.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Krishnan, Arunkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pivotti, Valentina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Yazdi, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Almén, Markus Sällman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome2016In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, article id 268Article in journal (Refereed)
    Abstract [en]

    Background: Membrane proteins are key components in a large spectrum of diverse functions and thus account for the major proportion of the drug-targeted portion of the genome. From a structural perspective, the a-helical transmembrane proteins can be categorized into major groups based on the number of transmembrane helices and these groups are often associated with specific functions. When compared to the well-characterized seven-transmembrane containing proteins (7TM), other TM groups are less explored and in particular the 4TM group. In this study, we identify the complete 4TM complement from the latest release of the human genome and assess the 4TM structure group as a whole. We functionally characterize this dataset and evaluate the resulting groups and ubiquitous functions, and furthermore describe disease and drug target involvement.

    Results: We classified 373 proteins, which represents similar to 7 % of the human membrane proteome, and includes 69 more proteins than our previous estimate. We have characterized the 4TM dataset based on functional, structural, and/or evolutionary similarities. Proteins that are involved in transport activity constitute 37 % of the dataset, 23 % are receptor-related, and 13 % have enzymatic functions. Intriguingly, proteins involved in transport are more than double the 15 % of transporters in the entire human membrane proteome, which might suggest that the 4TM topological architecture is more favored for transporting molecules over other functions. Moreover, we found an interesting exception to the ubiquitous intracellular N- and C-termini localization that is found throughout the entire membrane proteome and 4TM dataset in the neurotransmitter gated ion channel families. Overall, we estimate that 58 % of the dataset has a known association to disease conditions with 19 % of the genes possibly involved in different types of cancer.

    Conclusions: We provide here the most robust and updated classification of the 4TM complement of the human genome as a platform to further understand the characteristics of 4TM functions and to explore pharmacological opportunities.

  • 7. Baker, Michelle L
    et al.
    Indiviglio, Sandra
    Nyberg, April M
    Rosenberg, George H
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Miller, Robert D
    Papenfuss, Anthony T
    Analysis of a set of Australian northern brown bandicoot expressed sequence tags with comparison to the genome sequence of the South American grey short tailed opossum2007In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, p. 50-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Expressed sequence tags (ESTs) have been used for rapid gene discovery in a variety of organisms and provide a valuable resource for whole genome annotation. Although the genome of one marsupial, the opossum Monodelphis domestica, has now been sequenced, no EST datasets have been reported from any marsupial species. In this study we describe an EST dataset from the bandicoot, Isoodon macrourus, providing information on the transcriptional profile of the bandicoot thymus and the opportunity for a genome wide comparison between the bandicoot and opossum, two distantly related marsupial species. RESULTS: A set of 1319 ESTs was generated from sequencing randomly chosen clones from a bandicoot thymus cDNA library. The nucleic acid and deduced amino acid sequences were compared with sequences both in GenBank and the recently completed whole genome sequence of M. domestica. This study provides information on the transcriptional profile of the bandicoot thymus with the identification of genes involved in a broad range of activities including protein metabolism (24%), transcription and/or nucleic acid metabolism (10%), metabolism/energy pathways (9%), immunity (5%), signal transduction (5%), cell growth and maintenance (3%), transport (3%), cell cycle (0.7%) and apoptosis (0.5%) and a proportion of genes whose function is unknown (5.8%). Thirty four percent of the bandicoot ESTs found no match with annotated sequences in any of the public databases. Clustering and assembly of the 1319 bandicoot ESTs resulted in a set of 949 unique sequences of which 375 were unannotated ESTs. Of these, seventy one unannotated ESTs aligned to non-coding regions in the opossum, human, or both genomes, and were identified as strong non-coding RNA candidates. Eighty-four percent of the 949 assembled ESTs aligned with the M. domestica genome sequence indicating a high level of conservation between these two distantly related marsupials. CONCLUSION: This study is among the first reported marsupial EST datasets with a significant inter-species genome comparison between marsupials, providing a valuable resource for transcriptional analyses in marsupials and for future annotation of marsupial whole genome sequences.

  • 8.
    Berglund, Eva C.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Ehrenborg, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Vinnere Pettersson, Olga
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Granberg, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Näslund, Kristina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Holmberg, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Genome dynamics of Bartonella grahamii in micro-populations of woodland rodents2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, p. 152-Article in journal (Refereed)
    Abstract [en]

    Background: Rodents represent a high-risk reservoir for the emergence of new human pathogens. The recent completion of the 2.3 Mb genome of Bartonella grahamii, one of the most prevalent blood-borne bacteria in wild rodents, revealed a higher abundance of genes for host-cell interaction systems than in the genomes of closely related human pathogens. The sequence variability within the global B. grahamii population was recently investigated by multi locus sequence typing, but no study on the variability of putative host-cell interaction systems has been performed.

    Results: To study the population dynamics of B. grahamii, we analyzed the genomic diversity on a whole-genome scale of 27 B. grahamii strains isolated from four different species of wild rodents in three geographic locations separated by less than 30 km. Even using highly variable spacer regions, only 3 sequence types were identified. This low sequence diversity contrasted with a high variability in genome content. Microarray comparative genome hybridizations identified genes for outer surface proteins, including a repeated region containing the fha gene for filamentous hemaggluttinin and a plasmid that encodes a type IV secretion system, as the most variable. The estimated generation times in liquid culture medium for a subset of strains ranged from 5 to 22 hours, but did not correlate with sequence type or presence/absence patterns of the fha gene or the plasmid.

    Conclusion: Our study has revealed a geographic microstructure of B. grahamii in wild rodents. Despite near-identity in nucleotide sequence, major differences were observed in gene presence/absence patterns that did not segregate with host species. This suggests that genetically similar strains can infect a range of different hosts.

  • 9.
    Berglund, Eva C
    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.
    Lindqvist, Carl Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hayat, Shahina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Overnäs, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Henriksson, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Wahlberg, 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.
    Forestier, Erik
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    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.
    Accurate detection of subclonal single nucleotide variants in whole genome amplified and pooled cancer samples using HaloPlex target enrichment2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, no 1, p. 856-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Target enrichment and resequencing is a widely used approach for identification of cancer genes and genetic variants associated with diseases. Although cost effective compared to whole genome sequencing, analysis of many samples constitutes a significant cost, which could be reduced by pooling samples before capture. Another limitation to the number of cancer samples that can be analyzed is often the amount of available tumor DNA. We evaluated the performance of whole genome amplified DNA and the power to detect subclonal somatic single nucleotide variants in non-indexed pools of cancer samples using the HaloPlex technology for target enrichment and next generation sequencing.

    RESULTS:

    We captured a set of 1528 putative somatic single nucleotide variants and germline SNPs, which were identified by whole genome sequencing, with the HaloPlex technology and sequenced to a depth of 792--1752. We found that the allele fractions of the analyzed variants are well preserved during whole genome amplification and that capture specificity or variant calling is not affected. We detected a large majority of the known single nucleotide variants present uniquely in one sample with allele fractions as low as 0.1 in non-indexed pools of up to ten samples. We also identified and experimentally validated six novel variants in the samples included in the pools.

    CONCLUSION:

    Our work demonstrates that whole genome amplified DNA can be used for target enrichment equally well as genomic DNA and that accurate variant detection is possible in non-indexed pools of cancer samples. These findings show that analysis of a large number of samples is feasible at low cost, even when only small amounts of DNA is available, and thereby significantly increases the chances of indentifying recurrent mutations in cancer samples.

  • 10. Berlin, Sofia
    et al.
    Lagercrantz, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Functional Genomics.
    von Arnold, Sara
    Öst, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnberg-Wästljung, Ann Christin
    High-density linkage mapping and evolution of paralogs and orthologs in Salix and Populus2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, no 1, p. 129-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Salix (willow) and Populus (poplar) are members of the Salicaceae family and they share many ecological as well as genetic and genomic characteristics. The interest of using willow for biomass production is growing, which has resulted in increased pressure on breeding of high yielding and resistant clones adapted to different environments. The main purpose of this work was to develop dense genetic linkage maps for mapping of traits related to yield and resistance in willow. We used the Populus trichocarpa genome to extract evenly spaced markers and mapped the orthologous loci in the willow genome. The marker positions in the two genomes were used to study genome evolution since the divergence of the two lineages some 45 mya. RESULTS: We constructed two linkage maps covering the 19 linkage groups in willow. The most detailed consensus map, S1, contains 495 markers with a total genetic distance of 2477 cM and an average distance of 5.0 cM between the markers. The S3 consensus map contains 221 markers and has a total genetic distance of 1793 cM and an average distance of 8.1 cM between the markers. We found high degree of synteny and gene order conservation between willow and poplar. There is however evidence for two major interchromosomal rearrangements involving poplar LG I and XVI and willow LG Ib, suggesting a fission or a fusion in one of the lineages, as well as five intrachromosomal inversions. The number of silent substitutions were three times lower (median: 0.12) between orthologs than between paralogs (median: 0.37 - 0.41). CONCLUSIONS: The relatively slow rates of genomic change between willow and poplar mean that the genomic resources in poplar will be most useful in genomic research in willow, such as identifying genes underlying QTLs of important traits. Our data suggest that the whole-genome duplication occurred long before the divergence of the two genera, events which have until now been regarded as contemporary. Estimated silent substitution rates were 1.28 x 10-9 and 1.68 x 10-9 per site and year, which are close to rates found in other perennials but much lower than rates in annuals.

  • 11. Boekel, Jorrit
    et al.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Rydén-Aulin, Monica
    Rhen, Mikael
    Richter-Dahlfors, Agneta
    Comparative tissue transcriptomics reveal prompt inter-organ communication in response to local bacterial kidney infection2011In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 12, p. 123-Article in journal (Refereed)
    Abstract [en]

    Background: Mucosal infections elicit inflammatory responses via regulated signaling pathways. Infection outcome depends strongly on early events occurring immediately when bacteria start interacting with cells in the mucosal membrane. Hitherto reported transcription profiles on host-pathogen interactions are strongly biased towards in vitro studies. To detail the local in vivo genetic response to infection, we here profiled host gene expression in a recent experimental model that assures high spatial and temporal control of uropathogenic Escherichia coli (UPEC) infection within the kidney of a live rat. Results: Transcriptional profiling of tissue biopsies from UPEC-infected kidney tissue revealed 59 differentially expressed genes 8 h post-infection. Their relevance for the infection process was supported by a Gene Ontology (GO) analysis. Early differential expression at 3 h and 5 h post-infection was of low statistical significance, which correlated to the low degree of infection. Comparative transcriptomics analysis of the 8 h data set and online available studies of early local infection and inflammation defined a core of 80 genes constituting a "General tissue response to early local bacterial infections". Among these, 25% were annotated as interferon-gamma (IFN-gamma) regulated. Subsequent experimental analyses confirmed a systemic increase of IFN-gamma in rats with an ongoing local kidney infection, correlating to splenic, rather than renal Ifng induction and suggested this inter-organ communication to be mediated by interleukin (IL)-23. The use of comparative transcriptomics allowed expansion of the statistical data handling, whereby relevant data could also be extracted from the 5 h data set. Out of the 31 differentially expressed core genes, some represented specific 5 h responses, illustrating the value of comparative transcriptomics when studying the dynamic nature of gene regulation in response to infections. Conclusion: Our hypothesis-free approach identified components of infection-associated multi-cellular tissue responses and demonstrated how a comparative analysis allows retrieval of relevant information from lower-quality data sets. The data further define marked representation of IFN-gamma responsive genes and a prompt inter-organ communication as a hallmark of an early local tissue response to infection.

  • 12.
    Bornelöv, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Different distribution of histone modifications in genes with unidirectional and bidirectional transcription and a role of CTCF and cohesin in directing transcription2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 300Article in journal (Refereed)
    Abstract [en]

    Background: Several post-translational histone modifications are mainly found in gene promoters and are associated with the promoter activity. It has been hypothesized that histone modifications regulate the transcription, as opposed to the traditional view with transcription factors as the key regulators. Promoters of most active genes do not only initiate transcription of the coding sequence, but also a substantial amount of transcription of the antisense strand upstream of the transcription start site (TSS). This promoter feature has generally not been considered in previous studies of histone modifications and transcription factor binding.

    Results: We annotated protein-coding genes as bi- or unidirectional depending on their mode of transcription and compared histone modifications and transcription factor occurrences between them. We found that H3K4me3, H3K9ac, and H3K27ac were significantly more enriched upstream of the TSS in bidirectional genes compared with the unidirectional ones. In contrast, the downstream histone modification signals were similar, suggesting that the upstream histone modifications might be a consequence of transcription rather than a cause. Notably, we found well-positioned CTCF and RAD21 peaks approximately 60-80 bp upstream of the TSS in the unidirectional genes. The peak heights were related to the amount of antisense transcription and we hypothesized that CTCF and cohesin act as a barrier against antisense transcription.

    Conclusions: Our results provide insights into the distribution of histone modifications at promoters and suggest a novel role of CTCF and cohesin as regulators of transcriptional direction.

  • 13.
    Bornelöv, Susanne
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Cambridge, Wellcome Trust Med Res Council Cambridge Stem Cel, Cambridge, England.
    Seroussi, Eyal
    Volcani Ctr, Agr Res Org, Rishon Leziyyon, Israel.
    Yosefi, Sara
    Volcani Ctr, Agr Res Org, Rishon Leziyyon, Israel.
    Benjamini, Sharon
    Volcani Ctr, Agr Res Org, Rishon Leziyyon, Israel; Hebrew Univ Jerusalem, Robert H Smith Fac Agr Food & Environm, Rehovot, Israel.
    Miyara, Shoval
    Volcani Ctr, Agr Res Org, Rishon Leziyyon, Israel.
    Ruzal, Mark
    Volcani Ctr, Agr Res Org, Rishon Leziyyon, Israel.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Med Biochem & Microbiol, Sci Life Lab, SE-75123 Uppsala, Sweden;Uppsala Univ, Bioinformat Infrastruct Life Sci, Uppsala, Sweden.
    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.
    Molin, Anna-Maja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pendavis, Ken
    Univ Arizona, Coll Agr & Life Sci, Tucson, AZ USA.
    Burgess, Shane C.
    Univ Arizona, Coll Agr & Life Sci, Tucson, AZ USA.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden; Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, USA.
    Friedman-Einat, Miriam
    Volcani Ctr, Agr Res Org, Rishon Leziyyon, Israel.
    Comparative omics and feeding manipulations in chicken indicate a shift of the endocrine role of visceral fat towards reproduction2018In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 19, article id 295Article in journal (Refereed)
    Abstract [en]

    Background: The mammalian adipose tissue plays a central role in energy-balance control, whereas the avian visceral fat hardly expresses leptin, the key adipokine in mammals. Therefore, to assess the endocrine role of adipose tissue in birds, we compared the transcriptome and proteome between two metabolically different types of chickens, broilers and layers, bred towards efficient meat and egg production, respectively.

    Results: Broilers and layer hens, grown up to sexual maturation under free-feeding conditions, differed 4.0-fold in weight and 1.6-fold in ovarian-follicle counts, yet the relative accumulation of visceral fat was comparable. RNA-seq and mass-spectrometry (MS) analyses of visceral fat revealed differentially expressed genes between broilers and layers, 1106 at the mRNA level (FDR ≤ 0.05), and 203 at the protein level (P ≤ 0.05). In broilers, Ingenuity Pathway Analysis revealed activation of the PTEN-pathway, and in layers increased response to external signals. The expression pattern of genes encoding fat-secreted proteins in broilers and layers was characterized in the RNA-seq and MS data, as well as by qPCR on visceral fat under free feeding and 24 h-feed deprivation. This characterization was expanded using available RNA-seq data of tissues from red junglefowl, and of visceral fat from broilers of different types. These comparisons revealed expression of new adipokines and secreted proteins (LCAT, LECT2, SERPINE2, SFTP1, ZP1, ZP3, APOV1, VTG1 and VTG2) at the mRNA and/or protein levels, with dynamic gene expression patterns in the selected chicken lines (except for ZP1; FDR/P ≤ 0.05) and feed deprivation (NAMPT, SFTPA1 and ZP3) (P ≤ 0.05). In contrast, some of the most prominent adipokines in mammals, leptin, TNF, IFNG, and IL6 were expressed at a low level (FPKM/RPKM< 1) and did not show differential mRNA expression neither between broiler and layer lines nor between fed vs. feed-deprived chickens.

    Conclusions: Our study revealed that RNA and protein expression in visceral fat changes with selective breeding, suggesting endocrine roles of visceral fat in the selected phenotypes. In comparison to gene expression in visceral fat of mammals, our findings points to a more direct cross talk of the chicken visceral fat with the reproductive system and lower involvement in the regulation of appetite, inflammation and insulin resistance.

  • 14. Broadbent, Kate M.
    et al.
    Broadbent, Jill C.
    Ribacke, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Wirth, Dyann
    Rinn, John L.
    Sabeti, Pardis C.
    Strand-specific RNA sequencing in Plasmodium falciparum malaria identifies developmentally regulated long non-coding RNA and circular RNA2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 454Article in journal (Refereed)
    Abstract [en]

    Background: The human malaria parasite Plasmodium falciparum has a complex and multi-stage life cycle that requires extensive and precise gene regulation to allow invasion and hijacking of host cells, transmission, and immune escape. To date, the regulatory elements orchestrating these critical parasite processes remain largely unknown. Yet it is becoming increasingly clear that long non-coding RNAs (lncRNAs) could represent a missing regulatory layer across a broad range of organisms. Results: To investigate the regulatory capacity of lncRNA in P. falciparum, we harvested fifteen samples from two time-courses. Our sample set profiled 56 h of P. falciparum blood stage development. We then developed and validated strand-specific, non-polyA-selected RNA sequencing methods, and pursued the first assembly of P. falciparum strand-specific transcript structures from RNA sequencing data. This approach enabled the annotation of over one thousand lncRNA transcript models and their comprehensive global analysis: coding prediction, periodicity, stage-specificity, correlation, GC content, length, location relative to annotated transcripts, and splicing. We validated the complete splicing structure of three lncRNAs with compelling properties. Non-polyA-selected deep sequencing also enabled the prediction of hundreds of intriguing P. falciparum circular RNAs, six of which we validated experimentally. Conclusions: We found that a subset of lncRNAs, including all subtelomeric lncRNAs, strongly peaked in expression during invasion. By contrast, antisense transcript levels significantly dropped during invasion. As compared to neighboring mRNAs, the expression of antisense-sense pairs was significantly anti-correlated during blood stage development, indicating transcriptional interference. We also validated that P. falciparum produces circRNAs, which is notable given the lack of RNA interference in the organism, and discovered that a highly expressed, five-exon antisense RNA is poised to regulate P. falciparum gametocyte development 1 (PfGDV1), a gene required for early sexual commitment events.

  • 15.
    Chen, Jun
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Uebbing, Severin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Gyllenstrand, Niclas
    Department of Plant Biology and Forest Genetics, Swedish University of Agriculture Science.
    Lagercrantz, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Källman, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution.
    Sequencing of the needle transcriptome from Norway spruce (Picea abies Karst L.) reveals lower substitution rates, but similar selective constraints in gymnosperms compared to angiosperms2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 589-Article in journal (Other academic)
    Abstract [en]

    Background: A detailed knowledge about which genes are expressed in which tissues and at which developmental stage is important for understanding both the function of genes and their evolution. For the vast majority of species, transcriptomes are still largely uncharacterized and even in those where substantial information is available it is often in the form of partially sequenced transcriptomes. With the development of next generation sequencing, a single experiment can now give both a snap-shot of the transcribed part of a species genome and simultaneously estimate levels of gene expression.

    Results: mRNA from actively growing needles of Norway spruce (Picea abies) was sequenced using next generation sequencing technology. In total, close to 70 million fragments with a length of 76 bp were sequenced resulting in 5 Gbp of raw data. A de novo assembly of these reads were, together with publicly available expressed sequence tag (EST) data from Norway spruce, used to create a reference transcriptome. Of the 38,419 PUTs (putative unique transcripts) longer than 150 bp in this reference assembly, 59% show similarity to ESTs from other spruce species and of the remaining PUTs, 3,704 show similarity to protein sequences from other plant species, leaving 4,167 PUTs with limited similarity to currently available plant proteins. By predicting coding frames and comparing not only the Norway spruce PUTs, but also PUTs from the close relatives Picea glauca and Picea sitchensis to both Pinus taeda and Taxus mairei, we obtained estimates of synonymous and non-synonymous divergence among conifer species. In addition, we detected close to 15,000 SNPs of high quality and estimated gene expression difference between samples collected during dark and light conditions.

    Conclusions: Our study yielded a large number of single nucleotide polymorphisms as well as estimates of gene expression on transcriptome scale. In agreement with a recent study we find that the synonymous substitution rate per year (0.6 × 10-09 and 1.1 × 10-09) is an order of magnitude smaller than values reported for angiosperm herbs, but if one takes generation time in to account, most of this difference disappear. The estimates of the non-synonymous over the synonymous divergence (dN/dS ratio) reported here is in general much lower than 1 and only a few genes showed a ratio larger than 1.

  • 16. Darai-Ramqvist, Eva
    et al.
    Díaz de Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sandlund, Agneta
    Mantripragada, Kiran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Klein, George
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Imreh, Stefan
    Kost-Alimova, Maria
    Array-CGH and multipoint FISH to decode complex chromosomal rearrangements2006In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 7, p. 330-Article in journal (Refereed)
    Abstract [en]

    Background: Recently, several high-resolution methods of chromosome analysis have been developed. It is important to compare these methods and to select reliable combinations of techniques to analyze complex chromosomal rearrangements in tumours. In this study we have compared array-CGH (comparative genomic hybridization) and multipoint FISH (mpFISH) for their ability to characterize complex rearrangements on human chromosome 3 (chr3) in tumour cell lines. We have used 179 BAC/PAC clones covering chr3 with an approximately 1 Mb resolution to analyze nine carcinoma lines. Chr3 was chosen for analysis, because of its frequent rearrangements in human solid tumours. Results: The ploidy of the tumour cell lines ranged from near-diploid to near-pentaploid. Chr3 locus copy number was assessed by interphase and metaphase mpFISH. Totally 53 chr3 fragments were identified having copy numbers from 0 to 14. MpFISH results from the BAC/PAC clones and array-CGH gave mainly corresponding results. Each copy number change on the array profile could be related to a specific chromosome aberration detected by metaphase mpFISH. The analysis of the correlation between real copy number from mpFISH and the average normalized inter-locus fluorescence ratio (ANILFR) value detected by array-CGH demonstrated that copy number is a linear function of parameters that include the variable, ANILFR, and two constants, ploidy and background normalized fluorescence ratio. Conclusion: In most cases, the changes in copy number seen on array-CGH profiles reflected cumulative chromosome rearrangements. Most of them stemmed from unbalanced translocations. Although our chr3 BAC/PAC array could identify single copy number changes even in pentaploid cells, mpFISH provided a more accurate analysis in the dissection of complex karyotypes at high ploidy levels.

  • 17. Das, Radhika
    et al.
    Anderson, Nathan
    Koran, MaryEllen I.
    Weidman, Jennifer R.
    Mikkelsen, Tarjei S.
    Kamal, Michael
    Murphy, Susan K.
    Linblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Greally, John M.
    Jirtle, Randy L.
    Convergent and divergent evolution of genomic imprinting in the marsupial Monodelphis domestica2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 394-Article in journal (Refereed)
    Abstract [en]

    Background: Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin specific monoallelic gene expression. It is postulated to have evolved in placental mammals to modulate intrauterine resource allocation to the offspring. In this study, we determined the imprint status of metatherian orthologues of eutherian imprinted genes. Results: L3MBTL and HTR2A were shown to be imprinted in Monodelphis domestica (the gray short-tailed opossum). MEST expressed a monoallelic and a biallelic transcript, as in eutherians. In contrast, IMPACT, COPG2, and PLAGL1 were not imprinted in the opossum. Differentially methylated regions (DMRs) involved in regulating imprinting in eutherians were not found at any of the new imprinted loci in the opossum. Interestingly, a novel DMR was identified in intron 11 of the imprinted IGF2R gene, but this was not conserved in eutherians. The promoter regions of the imprinted genes in the opossum were enriched for the activating histone modification H3 Lysine 4 dimethylation. Conclusions: The phenomenon of genomic imprinting is conserved in Therians, but the marked difference in the number and location of imprinted genes and DMRs between metatherians and eutherians indicates that imprinting is not fully conserved between the two Therian infra-classes. The identification of a novel DMR at a non-conserved location as well as the first demonstration of histone modifications at imprinted loci in the opossum suggest that genomic imprinting may have evolved in a common ancestor of these two Therian infra-classes with subsequent divergence of regulatory mechanisms in the two lineages.

  • 18. Dawson, Deborah
    et al.
    Ball, Alexander
    Spurgin, Lewis
    Martin-Galvez, David
    Stewart, Ian RK
    Horsburgh, Gavin
    Potter, Jonathan
    Molina-Morales, Mercedes
    Bicknell, Anthony W J
    Preston, Stephanie A J
    Ekblom, Robert
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Slate, Jon
    Burke, Terry
    High-utility conserved avian microsatellite markers enable parentage and population studies across a wide range of species2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, no 1, p. 176-Article in journal (Refereed)
    Abstract [en]

    Background: Microsatellites are widely used for many genetic studies. In contrast to single nucleotide polymorphism (SNP) and genotyping-by-sequencing methods, they are readily typed in samples of low DNA quality/concentration (e.g. museum/non-invasive samples), and enable the quick, cheap identification of species, hybrids, clones and ploidy. Microsatellites also have the highest cross-species utility of all types of markers used for genotyping, but, despite this, when isolated from a single species, only a relatively small proportion will be of utility. Marker development of any type requires skill and time. The availability of sufficient "off-the-shelf" markers that are suitable for genotypinga wide range of species would not only save resources but also uniquely enablenew comparisons of diversity among taxa at the same set of loci. No other marker types are capable of enabling this. We therefore developed a set of avianmicrosatellite markers with enhanced cross-species utility. Results: We selected highly-conserved sequences with a high number of repeat units in both of two genetically distant species. Twenty-four primer sets were designed from homologous sequences that possessed at least eight repeat units in both the zebra finch (Taeniopygia guttata) and chicken (Gallus gallus). Each primer sequence was a complete match to zebra finch and, after accounting for degenerate bases, at least 86% similar to chicken. We assessed primer-set utilityby genotyping individuals belonging to eight passerine and four non-passerinespecies. The majority of the new Conserved Avian Microsatellite (CAM) markersamplified in all 12 species tested (on average, 94% in passerines and 95% in non-passerines). This new marker set is of especially high utility in passerines, with amean 68% of loci polymorphic per species, compared with 42% in non-passerinespecies. Conclusions: When combined with previously described conserved loci, this new set of conserved markers will not only reduce the necessity and expense ofmicrosatellite isolation for a wide range of genetic studies, including avianparentage and population analyses, but will also now enable comparisons ofgenetic diversity among different species (and populations) at the same set of loci, with no or reduced bias. Finally, the approach used here can be applied to other taxa in which appropriate genome sequences are available.

  • 19. de Rinaldis, Emanuele
    et al.
    Gazinska, Patrycja
    Mera, Anca
    Modrusan, Zora
    Fedorowicz, Grazyna M
    Burford, Brian
    Gillett, Cheryl
    Marra, Pierfrancesco
    Grigoriadis, Anita
    Dornan, David
    Holmberg, Lars
    Regional Oncologic Centre Uppsala/Örebro, Uppsala, Sweden.
    Pinder, Sarah
    Tutt, Andrew
    Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 643-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: This study focuses on the analysis of miRNAs expression data in a cohort of 181 well characterised breast cancer samples composed primarily of triple-negative (ER/PR/HER2-negative) tumours with associated genome-wide DNA and mRNA data, extensive patient follow-up and pathological information.

    RESULTS: We identified 7 miRNAs associated with prognosis in the triple-negative tumours and an additional 7 when the analysis was extended to the set of all ER-negative cases. miRNAs linked to an unfavourable prognosis were associated with a broad spectrum of motility mechanisms involved in the invasion of stromal tissues, such as cell-adhesion, growth factor-mediated signalling pathways, interaction with the extracellular matrix and cytoskeleton remodelling. When we compared different intrinsic molecular subtypes we found 46 miRNAs that were specifically expressed in one or more intrinsic subtypes. Integrated genomic analyses indicated these miRNAs to be influenced by DNA genomic aberrations and to have an overall influence on the expression levels of their predicted targets. Among others, our analyses highlighted the role of miR-17-92 and miR-106b-25, two polycistronic miRNA clusters with known oncogenic functions. We showed that their basal-like subtype specific up-regulation is influenced by increased DNA copy number and contributes to the transcriptional phenotype as well as the activation of oncogenic pathways in basal-like tumours.

    CONCLUSIONS: This study analyses previously unreported miRNA, mRNA and DNA data and integrates these with pathological and clinical information, from a well-annotated cohort of breast cancers enriched for triple-negative subtypes. It provides a conceptual framework, as well as integrative methods and system-level results and contributes to elucidate the role of miRNAs as biomarkers and modulators of oncogenic processes in these types of tumours.

  • 20. Eckalbar, Walter L.
    et al.
    Hutchins, Elizabeth D.
    Markov, Glenn J.
    Allen, April N.
    Corneveaux, Jason J.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Di Palma, Federica
    Alfoeldi, Jessica
    Huentelman, Matthew J.
    Kusumi, Kenro
    Genome reannotation of the lizard Anolis carolinensis based on 14 adult and embryonic deep transcriptomes2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 49-Article in journal (Refereed)
    Abstract [en]

    Background: The green anole lizard, Anolis carolinensis, is a key species for both laboratory and field-based studies of evolutionary genetics, development, neurobiology, physiology, behavior, and ecology. As the first non-avian reptilian genome sequenced, A. carolinesis is also a prime reptilian model for comparison with other vertebrate genomes. The public databases of Ensembl and NCBI have provided a first generation gene annotation of the anole genome that relies primarily on sequence conservation with related species. A second generation annotation based on tissue-specific transcriptomes would provide a valuable resource for molecular studies. Results: Here we provide an annotation of the A. carolinensis genome based on de novo assembly of deep transcriptomes of 14 adult and embryonic tissues. This revised annotation describes 59,373 transcripts, compared to 16,533 and 18,939 currently for Ensembl and NCBI, and 22,962 predicted protein-coding genes. A key improvement in this revised annotation is coverage of untranslated region (UTR) sequences, with 79% and 59% of transcripts containing 5' and 3' UTRs, respectively. Gaps in genome sequence from the current A. carolinensis build (Anocar2.0) are highlighted by our identification of 16,542 unmapped transcripts, representing 6,695 orthologues, with less than 70% genomic coverage. Conclusions: Incorporation of tissue-specific transcriptome sequence into the A. carolinensis genome annotation has markedly improved its utility for comparative and functional studies. Increased UTR coverage allows for more accurate predicted protein sequence and regulatory analysis. This revised annotation also provides an atlas of gene expression specific to adult and embryonic tissues.

  • 21.
    Ekblom, Robert
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Population and Conservation Biology.
    Balakrishnan, Christopher N.
    Burke, Terry
    Slate, Jon
    Digital gene expression analysis of the zebra finch genome2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, p. 219-Article in journal (Refereed)
    Abstract [en]

    Background: In order to understand patterns of adaptation and molecular evolution it is important to quantify both variation in gene expression and nucleotide sequence divergence. Gene expression profiling in non-model organisms has recently been facilitated by the advent of massively parallel sequencing technology. Here we investigate tissue specific gene expression patterns in the zebra finch (Taeniopygia guttata) with special emphasis on the genes of the major histocompatibility complex (MHC). Results: Almost 2 million 454-sequencing reads from cDNA of six different tissues were assembled and analysed. A total of 11,793 zebra finch transcripts were represented in this EST data, indicating a transcriptome coverage of about 65%. There was a positive correlation between the tissue specificity of gene expression and non-synonymous to synonymous nucleotide substitution ratio of genes, suggesting that genes with a specialised function are evolving at a higher rate (or with less constraint) than genes with a more general function. In line with this, there was also a negative correlation between overall expression levels and expression specificity of contigs. We found evidence for expression of 10 different genes related to the MHC. MHC genes showed relatively tissue specific expression levels and were in general primarily expressed in spleen. Several MHC genes, including MHC class I also showed expression in brain. Furthermore, for all genes with highest levels of expression in spleen there was an overrepresentation of several gene ontology terms related to immune function. Conclusions: Our study highlights the usefulness of next-generation sequence data for quantifying gene expression in the genome as a whole as well as in specific candidate genes. Overall, the data show predicted patterns of gene expression profiles and molecular evolution in the zebra finch genome. Expression of MHC genes in particular, corresponds well with expression patterns in other vertebrates.

  • 22.
    Ekblom, Robert
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Smeds, Linnea
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Patterns of sequencing coverage bias revealed by ultra-deep sequencing of vertebrate mitochondria2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 467-Article in journal (Refereed)
    Abstract [en]

    Background: Genome and transcriptome sequencing applications that rely on variation in sequence depth can be negatively affected if there are systematic biases in coverage. We have investigated patterns of local variation in sequencing coverage by utilising ultra-deep sequencing (>100,000X) of mtDNA obtained during sequencing of two vertebrate genomes, wolverine (Gulo gulo) and collared flycatcher (Ficedula albicollis). With such extreme depth, stochastic variation in coverage should be negligible, which allows us to provide a very detailed, fine-scale picture of sequence dependent coverage variation and sequencing error rates. Results: Sequencing coverage showed up to six-fold variation across the complete mtDNA and this variation was highly repeatable in sequencing of multiple individuals of the same species. Moreover, coverage in orthologous regions was correlated between the two species and was negatively correlated with GC content. We also found a negative correlation between the site-specific sequencing error rate and coverage, with certain sequence motifs "CCNGCC" being particularly prone to high rates of error and low coverage. Conclusions: Our results demonstrate that inherent sequence characteristics govern variation in coverage and suggest that some of this variation, like GC content, should be controlled for in, for example, RNA-Seq and detection of copy number variation.

  • 23.
    Ellegaard, Kirsten M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Tamarit, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Javelind, Emelie
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Olofsson, Tobias C.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Vasquez, Alejandra
    Extensive intra-phylotype diversity in lactobacilli and bifidobacteria from the honeybee gut2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 284Article in journal (Refereed)
    Abstract [en]

    Background: In the honeybee Apis mellifera, the bacterial gut community is consistently colonized by eight distinct phylotypes of bacteria. Managed bee colonies are of considerable economic interest and it is therefore important to elucidate the diversity and role of this microbiota in the honeybee. In this study, we have sequenced the genomes of eleven strains of lactobacilli and bifidobacteria isolated from the honey crop of the honeybee Apis mellifera. Results: Single gene phylogenies confirmed that the isolated strains represent the diversity of lactobacilli and bifidobacteria in the gut, as previously identified by 16S rRNA gene sequencing. Core genome phylogenies of the lactobacilli and bifidobacteria further indicated extensive divergence between strains classified as the same phylotype. Phylotype-specific protein families included unique surface proteins. Within phylotypes, we found a remarkably high level of gene content diversity. Carbohydrate metabolism and transport functions contributed up to 45% of the accessory genes, with some genomes having a higher content of genes encoding phosphotransferase systems for the uptake of carbohydrates than any previously sequenced genome. These genes were often located in highly variable genomic segments that also contained genes for enzymes involved in the degradation and modification of sugar residues. Strain-specific gene clusters for the biosynthesis of exopolysaccharides were identified in two phylotypes. The dynamics of these segments contrasted with low recombination frequencies and conserved gene order structures for the core genes. Hits for CRISPR spacers were almost exclusively found within phylotypes, suggesting that the phylotypes are associated with distinct phage populations. Conclusions: The honeybee gut microbiota has been described as consisting of a modest number of phylotypes; however, the genomes sequenced in the current study demonstrated a very high level of gene content diversity within all three described phylotypes of lactobacilli and bifidobacteria, particularly in terms of metabolic functions and surface structures, where many features were strain-specific. Together, these results indicate niche differentiation within phylotypes, suggesting that the honeybee gut microbiota is more complex than previously thought.

  • 24.
    Gloriam, David E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The G protein-coupled receptor subset of the rat genome2007In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, p. 338-Article in journal (Refereed)
    Abstract [en]

    Background: The superfamily of G protein-coupled receptors (GPCRs) is one of the largest within most mammals. GPCRs are important targets for pharmaceuticals and the rat is one of the most widely used model organisms in biological research. Accurate comparisons of protein families in rat, mice and human are thus important for interpretation of many physiological and pharmacological studies. However, current automated protein predictions and annotations are limited and error prone. Results: We searched the rat genome for GPCRs and obtained 1867 full-length genes and 739 pseudogenes. We identified 1277 new full-length rat GPCRs, whereof 1235 belong to the large group of olfactory receptors. Moreover, we updated the datasets of GPCRs from the human and mouse genomes with 1 and 43 new genes, respectively. The total numbers of full-length genes ( and pseudogenes) identified were 799 ( 583) for human and 1783 ( 702) for mouse. The rat, human and mouse GPCRs were classified into 7 families named the Glutamate, Rhodopsin, Adhesion, Frizzled, Secretin, Taste2 and Vomeronasal1 families. We performed comprehensive phylogenetic analyses of these families and provide detailed information about orthologues and species-specific receptors. We found that 65 human Rhodopsin family GPCRs are orphans and 56 of these have an orthologue in rat. Conclusion: Interestingly, we found that the proportion of one-to-one GPCR orthologues was only 58% between rats and humans and only 70% between the rat and mouse, which is much lower than stated for the entire set of all genes. This is in mainly related to the sensory GPCRs. The average protein sequence identities of the GPCR orthologue pairs is also lower than for the whole genomes. We found these to be 80% for the rat and human pairs and 90% for the rat and mouse pairs. However, the proportions of orthologous and species-specific genes vary significantly between the different GPCR families. The largest diversification is seen for GPCRs that respond to exogenous stimuli indicating that the variation in their repertoires reflects to a large extent the adaptation of the species to their environment. This report provides the first overall roadmap of the GPCR repertoire in rat and detailed comparisons with the mouse and human repertoires.

  • 25. Goldstone, Jared V.
    et al.
    McArthur, Andrew G.
    Kubota, Akira
    Zanette, Juliano
    Parente, Thiago
    Jonsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Nelson, David R.
    Stegeman, John J.
    Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11Article in journal (Refereed)
  • 26. Goldstone, Jared V.
    et al.
    McArthur, Andrew G.
    Kubota, Akira
    Zanette, Juliano
    Parente, Thiago
    Jönsson, Maria E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organism Biology, Environmental Toxicology.
    Nelson, David R.
    Stegeman, John J.
    Identification and developmental expression of the full complement of Cytochrome P450 genes in Zebrafish2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, no 1, p. 643-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Increasing use of zebrafish in drug discovery and mechanistic toxicology demands knowledge of cytochrome P450 (CYP) gene regulation and function. CYP enzymes catalyze oxidative transformation leading to activation or inactivation of many endogenous and exogenous chemicals, with consequences for normal physiology and disease processes. Many CYPs potentially have roles in developmental specification, and many chemicals that cause developmental abnormalities are substrates for CYPs. Here we identify and annotate the full suite of CYP genes in zebrafish, compare these to the human CYP gene complement, and determine the expression of CYP genes during normal development.

    RESULTS: Zebrafish have a total of 94 CYP genes, distributed among 18 gene families found also in mammals. There are 32 genes in CYP families 5 to 51, most of which are direct orthologs of human CYPs that are involved in endogenous functions including synthesis or inactivation of regulatory molecules. The high degree of sequence similarity suggests conservation of enzyme activities for these CYPs, confirmed in reports for some steroidogenic enzymes (e.g. CYP19, aromatase; CYP11A, P450scc; CYP17, steroid 17a-hydroxylase), and the CYP26 retinoic acid hydroxylases. Complexity is much greater in gene families 1, 2, and 3, which include CYPs prominent in metabolism of drugs and pollutants, as well as of endogenous substrates. There are orthologous relationships for some CYP1 s and some CYP3 s between zebrafish and human. In contrast, zebrafish have 47 CYP2 genes, compared to 16 in human, with only two (CYP2R1 and CYP2U1) recognized as orthologous based on sequence. Analysis of shared synteny identified CYP2 gene clusters evolutionarily related to mammalian CYP2 s, as well as unique clusters.

    CONCLUSIONS: Transcript profiling by microarray and quantitative PCR revealed that the majority of zebrafish CYP genes are expressed in embryos, with waves of expression of different sets of genes over the course of development. Transcripts of some CYP occur also in oocytes. The results provide a foundation for the use of zebrafish as a model in toxicological, pharmacological and chemical disease research.

  • 27.
    Haitina, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Foord, Steven M.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gloriam, David E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The G protein-coupled receptor subset of the dog genome is more similar to that in humans than rodents2009In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 10, p. 24-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    The dog is an important model organism and it is considered to be closer to humans than rodents regarding metabolism and responses to drugs. The close relationship between humans and dogs over many centuries has lead to the diversity of the canine species, important genetic discoveries and an appreciation of the effects of old age in another species. The superfamily of G protein-coupled receptors (GPCRs) is one of the largest gene families in most mammals and the most exploited in terms of drug discovery. An accurate comparison of the GPCR repertoires in dog and human is valuable for the prediction of functional similarities and differences between the species.

    RESULTS

    We searched the dog genome for non-olfactory GPCRs and obtained 353 full-length GPCR gene sequences, 18 incomplete sequences and 13 pseudogenes. We established relationships between human, dog, rat and mouse GPCRs resolving orthologous pairs and species-specific duplicates. We found that 12 dog GPCR genes are missing in humans while 24 human GPCR genes are not part of the dog GPCR repertoire. There is a higher number of orthologous pairs between dog and human that are conserved as compared with either mouse or rat. In almost all cases the differences observed between the dog and human genomes coincide with other variations in the rodent species. Several GPCR gene expansions characteristic for rodents are not found in dog.

    CONCLUSION

    The repertoire of dog non-olfactory GPCRs is more similar to the repertoire in humans as compared with the one in rodents. The comparison of the dog, human and rodent repertoires revealed several examples of species-specific gene duplications and deletions. This information is useful in the selection of model organisms for pharmacological experiments.

  • 28.
    Hansson, Caisa M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Buckley, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grigelioniene, Giedre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Piotrowski, Arkadiusz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hellström, Anders R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mantripragada, Kiran K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jarbo, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mathiesen, Tiit
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus2007In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, p. 16-Article in journal (Refereed)
    Abstract [en]

    Background: Meningiomas are the most common intracranial neoplasias, representing a clinically and histopathologically heterogeneous group of tumors. The neurofibromatosis type 2 (NF2) tumor suppressor is the only gene known to be frequently involved in early development of meningiomas. The objective of this study was to identify genetic and/or epigenetic factors contributing to the development of these tumors. A large set of sporadic meningiomas were analyzed for presence of 22q macro-mutations using array-CGH in order to identify tumors carrying gene dosage aberrations not encompassing NF2. The NF2 locus was also comprehensively studied for point mutations within coding and conserved non-coding sequences. Furthermore, CpG methylation within the NF2 promoter region was thoroughly analyzed. Results: Monosomy 22 was the predominant finding, detected in 47% of meningiomas. Thirteen percent of the tumors contained interstitial/ terminal deletions and gains, present singly or in combinations. We defined at least two minimal overlapping regions outside the NF2 locus that are small enough (∼550 kb and ∼250 kb) to allow analysis of a limited number of candidate genes. Bialleinactivationo the NF2 gne was detected in 36% of meningiomas. Among the monosomy 22 cases, no additional NF2 mutations could be identified in 35% (17 out of 49) of tumors. Furthermore, the majority of tumors (9 out of 12) with interstitial/terminal deletions did not have any detectable NF2 mutations. Methylation within the NF2 promoter region was only identified at a single CpG site in one tumor sample. Conclusion: We confirmed previous findings of pronounced differences in mutation frequency between different histopathological subtypes. There is a higher frequency of biallelic NF2 inactivation in fibroblastic (52%) compared to meningothelial (18%) tumors. The presence of macro-mutations on 22q also shows marked differences between fibroblastic (86%) and meningothelial (39%) subtypes. Thus, inactivation of NF2, often combined with the presence of macro-mutation on 22q, is likely not as important for the development of the meningothelial subtype, as opposed to the fibroblastic form. Analysis of 40 CpG sites distributed within 750 bp of the promoter region suggests that NF2 promoter methylation does not play a major role in meningioma development.

  • 29.
    Harty, Breanne L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Krishnan, Arunkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Sanchez, Nicholas E.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Monk, Kelly R.
    Defining the gene repertoire and spatiotemporal expression profiles of adhesion G protein-coupled receptors in zebrafish2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 62Article in journal (Refereed)
    Abstract [en]

    Background: Adhesion G protein-coupled receptors (aGPCRs) are the second largest of the five GPCR families and are essential for a wide variety of physiological processes. Zebrafish have proven to be a very effective model for studying the biological functions of aGPCRs in both developmental and adult contexts. However, aGPCR repertoires have not been defined in any fish species, nor are aGPCR expression profiles in adult tissues known. Additionally, the expression profiles of the aGPCR family have never been extensively characterized over a developmental time-course in any species. Results: Here, we report that there are at least 59 aGPCRs in zebrafish that represent homologs of 24 of the 33 aGPCRs found in humans; compared to humans, zebrafish lack clear homologs of GPR110, GPR111, GPR114, GPR115, GPR116, EMR1, EMR2, EMR3, and EMR4. We find that several aGPCRs in zebrafish have multiple paralogs, in line with the teleost-specific genome duplication. Phylogenetic analysis suggests that most zebrafish aGPCRs cluster closely with their mammalian homologs, with the exception of three zebrafish-specific expansion events in Groups II, VI, and VIII. Using quantitative real-time PCR, we have defined the expression profiles of 59 zebrafish aGPCRs at 12 developmental time points and 10 adult tissues representing every major organ system. Importantly, expression profiles of zebrafish aGPCRs in adult tissues are similar to those previously reported in mouse, rat, and human, underscoring the evolutionary conservation of this family, and therefore the utility of the zebrafish for studying aGPCR biology. Conclusions: Our results support the notion that zebrafish are a potentially useful model to study the biology of aGPCRs from a functional perspective. The zebrafish aGPCR repertoire, classification, and nomenclature, together with their expression profiles during development and in adult tissues, provides a crucial foundation for elucidating aGPCR functions and pursuing aGPCRs as therapeutic targets.

  • 30. Jensen, Lars Juhl
    et al.
    Skovgaard, Marie
    Sicheritz-Pontén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jørgensen, Merete Kjær
    Lundegaard, Chrstiane
    Pedersen, Corinna Cavan
    Petersen, Nanna
    Ussery, David
    Analysis of two large functionally uncharacterized regions in theMethanopyrus kandleri AV19 genome2003In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 4, p. 12-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: For most sequenced prokaryotic genomes, about a third of the protein coding genes annotated are "orphan proteins", that is, they lack homology to known proteins. These hypothetical genes are typically short and randomly scattered throughout the genome. This trend is seen for most of the bacterial and archaeal genomes published to date. RESULTS: In contrast we have found that a large fraction of the genes coding for such orphan proteins in the Methanopyrus kandleri AV19 genome occur within two large regions. These genes have no known homologs except from other M. kandleri genes. However, analysis of their lengths, codon usage, and Ribosomal Binding Site (RBS) sequences shows that they are most likely true protein coding genes and not random open reading frames.CONCLUSIONS: Although these regions can be considered as candidates for massive lateral gene transfer, our bioinformatics analysis suggests that this is not the case. We predict many of the organism specific proteins to be transmembrane and belong to protein families that are non-randomly distributed between the regions. Consistent with this, we suggest that the two regions are most likely unrelated, and that they may be integrated plasmids.

  • 31.
    Jerlström-Hultqvist, Jon
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Franzen, Oscar
    Ankarklev, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Xu, Feifei
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Nohynkova, Eva
    Andersson, Jan O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Andersson, Björn
    Genome analysis and comparative genomics of a Giardia intestinalis assemblage E isolate.2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, p. 543-Article in journal (Refereed)
    Abstract [en]

    Background

    Giardia intestinalis is a protozoan parasite that causes diarrhea in a wide range of mammalian species. To further understand the genetic diversity between the Giardia intestinalis species, we have performed genome sequencing and analysis of a wild-type Giardia intestinalis sample from the assemblage E group, isolated from a pig.

    Results

    We identified 5012 protein coding genes, the majority of which are conserved compared to the previously sequenced genomes of the WB and GS strains in terms of microsynteny and sequence identity. Despite this, there is an unexpectedly large number of chromosomal rearrangements and several smaller structural changes that are present in all chromosomes. Novel members of the VSP, NEK Kinase and HCMP gene families were identified, which may reveal possible mechanisms for host specificity and new avenues for antigenic variation. We used comparative genomics of the three diverse Giardia intestinalis isolates P15, GS and WB to define a core proteome for this species complex and to identify lineage-specific genes. Extensive analyses of polymorphisms in the core proteome of Giardia revealed differential rates of divergence among cellular processes.

    Conclusions

    Our results indicate that despite a well conserved core of genes there is significant genome variation between Giardia isolates, both in terms of gene content, gene polymorphisms, structural chromosomal variations and surface molecule repertoires. This study improves the annotation of the Giardia genomes and enables the identification of functionally important variation.

  • 32.
    Jiao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hooper, Sean D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Djureinovic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Tellgren-Roth, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Gene rearrangements in hormone receptor negative breast cancers revealed by mate pair sequencing2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, article id 165Article in journal (Refereed)
    Abstract [en]

    Background: Chromosomal rearrangements in the form of deletions, insertions, inversions and translocations are frequently observed in breast cancer genomes, and a subset of these rearrangements may play a crucial role in tumorigenesis. To identify novel somatic chromosomal rearrangements, we determined the genome structures of 15 hormone-receptor negative breast tumors by long-insert mate pair massively parallel sequencing. Results: We identified and validated 40 somatic structural alterations, including the recurring fusion between genes DDX10 and SKA3 and translocations involving the EPHA5 gene. Other rearrangements were found to affect genes in pathways involved in epigenetic regulation, mitosis and signal transduction, underscoring their potential role in breast tumorigenesis. RNA interference-mediated suppression of five candidate genes (DDX10, SKA3, EPHA5, CLTC and TNIK) led to inhibition of breast cancer cell growth. Moreover, downregulation of DDX10 in breast cancer cells lead to an increased frequency of apoptotic nuclear morphology. Conclusions: Using whole genome mate pair sequencing and RNA interference assays, we have discovered a number of novel gene rearrangements in breast cancer genomes and identified DDX10, SKA3, EPHA5, CLTC and TNIK as potential cancer genes with impact on the growth and proliferation of breast cancer cells.

  • 33.
    Jordan-Pla, Antonio
    et al.
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
    Yu, Simei
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
    Waldholm, Johan
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
    Källman, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Farrants, Ann-Kristin Ostlund
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
    Visa, Neus
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden.
    SWI/SNF regulates half of its targets without the need of ATP-driven nucleosome remodeling by Brahma2018In: BMC Genomics, ISSN 1471-2164, 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.

  • 34.
    Khaliq, Zeeshan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leijon, Mikael
    Natl Vet Inst SVA, Dept Virol Parasitol & Immunobiol VIP, Uppsala, Sweden.;OIE Collaborating Ctr Biotechnol Based Diag Infec, Ulls Vag 2B & 26, SE-75689 Uppsala, Sweden..
    Belak, Sandor
    OIE Collaborating Ctr Biotechnol Based Diag Infec, Ulls Vag 2B & 26, SE-75689 Uppsala, Sweden.;Swedish Univ Agr Sci SLU, Dept Biomed Sci & Vet Publ Hlth BVF, Uppsala, Sweden..
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab. Polish Acad Sci, Inst Comp Sci, PL-01248 Warsaw, Poland..
    Identification of combinatorial host-specific signatures with a potential to affect host adaptation in influenza A H1N1 and H3N2 subtypes2016In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, article id 529Article in journal (Refereed)
    Abstract [en]

    Background: The underlying strategies used by influenza A viruses (IAVs) to adapt to new hosts while crossing the species barrier are complex and yet to be understood completely. Several studies have been published identifying singular genomic signatures that indicate such a host switch. The complexity of the problem suggested that in addition to the singular signatures, there might be a combinatorial use of such genomic features, in nature, defining adaptation to hosts.

    Results: We used computational rule-based modeling to identify combinatorial sets of interacting amino acid (aa) residues in 12 proteins of IAVs of H1N1 and H3N2 subtypes. We built highly accurate rule-based models for each protein that could differentiate between viral aa sequences coming from avian and human hosts. We found 68 host-specific combinations of aa residues, potentially associated to host adaptation on HA, M1, M2, NP, NS1, NEP, PA, PA-X, PB1 and PB2 proteins of the H1N1 subtype and 24 on M1, M2, NEP, PB1 and PB2 proteins of the H3N2 subtypes. In addition to these combinations, we found 132 novel singular aa signatures distributed among all proteins, including the newly discovered PA-X protein, of both subtypes. We showed that HA, NA, NP, NS1, NEP, PA-X and PA proteins of the H1N1 subtype carry H1N1-specific and HA, NA, PA-X, PA, PB1-F2 and PB1 of the H3N2 subtype carry H3N2-specific signatures. M1, M2, PB1-F2, PB1 and PB2 of H1N1 subtype, in addition to H1N1 signatures, also carry H3N2 signatures. Similarly M1, M2, NP, NS1, NEP and PB2 of H3N2 subtype were shown to carry both H3N2 and H1N1 host-specific signatures (HSSs).

    Conclusions: To sum it up, we computationally constructed simple IF-THEN rule-based models that could distinguish between aa sequences of avian and human IAVs. From the rules we identified HSSs having a potential to affect the adaptation to specific hosts. The identification of combinatorial HSSs suggests that the process of adaptation of IAVs to a new host is more complex than previously suggested. The present study provides a basis for further detailed studies with the aim to elucidate the molecular mechanisms providing the foundation for the adaptation process.

  • 35.
    Kjaerner-Semb, Erik
    et al.
    Inst Marine Res, Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Ayllon, Fernando
    Inst Marine Res, Bergen, Norway..
    Furmanek, Tomasz
    Inst Marine Res, Bergen, Norway..
    Wennevik, Vidar
    Inst Marine Res, Bergen, Norway..
    Dahle, Geir
    Inst Marine Res, Bergen, Norway..
    Niemela, Eero
    Nat Resources Inst Finland, Helsinki, Finland..
    Ozerov, Mikhail
    Univ Turku, Kevo Subarctic Res Inst, Turku, Finland..
    Vaha, Juha-Pekka
    Univ Turku, Kevo Subarctic Res Inst, Turku, Finland.;Assoc Water & Environm Western Uusimaa, Uusimaa, Finland..
    Glover, Kevin A.
    Inst Marine Res, Bergen, Norway.;Univ Bergen, Dept Biol, Bergen, Norway..
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wargelius, Anna
    Inst Marine Res, Bergen, Norway..
    Edvardsen, Rolf B.
    Inst Marine Res, Bergen, Norway..
    Atlantic salmon populations reveal adaptive divergence of immune related genes - a duplicated genome under selection2016In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, article id 610Article in journal (Refereed)
    Abstract [en]

    Background: Populations of Atlantic salmon display highly significant genetic differences with unresolved molecular basis. These differences may result from separate postglacial colonization patterns, diversifying natural selection and adaptation, or a combination. Adaptation could be influenced or even facilitated by the recent whole genome duplication in the salmonid lineage which resulted in a partly tetraploid species with duplicated genes and regions. Results: In order to elucidate the genes and genomic regions underlying the genetic differences, we conducted a genome wide association study using whole genome resequencing data from eight populations from Northern and Southern Norway. From a total of similar to 4.5 million sequencing-derived SNPs, more than 10 % showed significant differentiation between populations from these two regions and ten selective sweeps on chromosomes 5, 10, 11, 13-15, 21, 24 and 25 were identified. These comprised 59 genes, of which 15 had one or more differentiated missense mutation. Our analysis showed that most sweeps have paralogous regions in the partially tetraploid genome, each lacking the high number of significant SNPs found in the sweeps. The most significant sweep was found on Chr 25 and carried several missense mutations in the antiviral mx genes, suggesting that these populations have experienced differing viral pressures. Interestingly the second most significant sweep, found on Chr 5, contains two genes involved in the NF-KB pathway (nkap and nkrf), which is also a known pathogen target that controls a large number of processes in animals. Conclusion: Our results show that natural selection acting on immune related genes has contributed to genetic divergence between salmon populations in Norway. The differences between populations may have been facilitated by the plasticity of the salmon genome. The observed signatures of selection in duplicated genomic regions suggest that the recently duplicated genome has provided raw material for evolutionary adaptation.

  • 36.
    Klasson, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Kumar, Nikhil
    Bromley, Robin
    Sieber, Karsten
    Flowers, Melissa
    Ott, Sandra H.
    Tallon, Luke J.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Hotopp, Julie C. Dunning
    Extensive duplication of the Wolbachia DNA in chromosome four of Drosophila ananassae2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 1097-Article in journal (Refereed)
    Abstract [en]

    Background: Lateral gene transfer (LGT) from bacterial Wolbachia endosymbionts has been detected in similar to 20% of arthropod and nematode genome sequencing projects. Many of these transfers are large and contain a substantial part of the Wolbachia genome. Results: Here, we re-sequenced three D. ananassae genomes from Asia and the Pacific that contain large LGTs from Wolbachia. We find that multiple copies of the Wolbachia genome are transferred to the Drosophila nuclear genome in all three lines. In the D. ananassae line from Indonesia, the copies of Wolbachia DNA in the nuclear genome are nearly identical in size and sequence yielding an even coverage of mapped reads over the Wolbachia genome. In contrast, the D. ananassae lines from Hawaii and India show an uneven coverage of mapped reads over the Wolbachia genome suggesting that different parts of these LGTs are present in different copy numbers. In the Hawaii line, we find that this LGT is underrepresented in third instar larvae indicative of being heterochromatic. Fluorescence in situ hybridization of mitotic chromosomes confirms that the LGT in the Hawaii line is heterochromatic and represents similar to 20% of the sequence on chromosome 4 (dot chromosome, Muller element F). Conclusions: This collection of related lines contain large lateral gene transfers composed of multiple Wolbachia genomes that constitute >2% of the D. ananassae genome (similar to 5 Mbp) and partially explain the abnormally large size of chromosome 4 in D. ananassae.

  • 37. Kumar, Vikas
    et al.
    Kutschera, Verena E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Nilsson, Maria A.
    Janke, Axel
    Genetic signatures of adaptation revealed from transcriptome sequencing of Arctic and red foxes2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 585Article in journal (Refereed)
    Abstract [en]

    Background: The genus Vulpes (true foxes) comprises numerous species that inhabit a wide range of habitats and climatic conditions, including one species, the Arctic fox (Vulpes lagopus) which is adapted to the arctic region. A close relative to the Arctic fox, the red fox (Vulpes vulpes), occurs in subarctic to subtropical habitats. To study the genetic basis of their adaptations to different environments, transcriptome sequences from two Arctic foxes and one red fox individual were generated and analyzed for signatures of positive selection. In addition, the data allowed for a phylogenetic analysis and divergence time estimate between the two fox species. Results: The de novo assembly of reads resulted in more than 160,000 contigs/transcripts per individual. Approximately 17,000 homologous genes were identified using human and the non-redundant databases. Positive selection analyses revealed several genes involved in various metabolic and molecular processes such as energy metabolism, cardiac gene regulation, apoptosis and blood coagulation to be under positive selection in foxes. Branch site tests identified four genes to be under positive selection in the Arctic fox transcriptome, two of which are fat metabolism genes. In the red fox transcriptome eight genes are under positive selection, including molecular process genes, notably genes involved in ATP metabolism. Analysis of the three transcriptomes and five Sanger re-sequenced genes in additional individuals identified a lower genetic variability within Arctic foxes compared to red foxes, which is consistent with distribution range differences and demographic responses to past climatic fluctuations. A phylogenomic analysis estimated that the Arctic and red fox lineages diverged about three million years ago. Conclusions: Transcriptome data are an economic way to generate genomic resources for evolutionary studies. Despite not representing an entire genome, this transcriptome analysis identified numerous genes that are relevant to arctic adaptation in foxes. Similar to polar bears, fat metabolism seems to play a central role in adaptation of Arctic foxes to the cold climate, as has been identified in the polar bear, another arctic specialist.

  • 38. Kutsenko, Alexey
    et al.
    Svensson, Thomas
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Lundeberg, Joakim
    Bjork, Petra
    Sonnhammer, Erik
    Giacomello, Stefania
    Visa, Neus
    Wieslander, Lars
    The Chironomus tentans genome sequence and the organization of the Balbiani ring genes2014In: BMC Genomics, ISSN 1471-2164, 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.

  • 39.
    Lillie, Mette
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sheng, Zheya
    Huazhong Agr Univ, Coll Anim Sci & Technol, Key Lab Agr Anim Genet Breeding & Reprod, Minist Educ, Wuhan 430070, Peoples R China..
    Honaker, Christa F.
    Virginia Polytech Inst & State Univ, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Dorshorst, Ben J.
    Virginia Polytech Inst & State Univ, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA..
    Ashwell, Christopher M.
    North Carolina State Univ, Prestage Dept Poultry Sci, Raleigh, NC 27695 USA..
    Siegel, Paul B.
    Virginia Polytech Inst & State Univ, Dept Anim & Poultry Sci, Blacksburg, VA 24061 USA.
    Carlborg, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Genome-wide standing variation facilitates long-term response to bidirectional selection for antibody response in chickens2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 99Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Long-term selection experiments provide a powerful approach to gain empirical insights into adaptation, allowing researchers to uncover the targets of selection and infer their contributions to the mode and tempo of adaptation. Here we implement a pooled genome re-sequencing approach to investigate the consequences of 39 generations of bidirectional selection in White Leghorn chickens on a humoral immune trait: antibody response to sheep red blood cells.

    RESULTS: We observed wide genome involvement in response to this selection regime. Many genomic regions were highly differentiated resulting from this experimental selection regime, an involvement of up to 20% of the chicken genome (208.8 Mb). While genetic drift has certainly contributed to this, we implement gene ontology, association analysis and population simulations to increase our confidence in candidate selective sweeps. Three strong candidate genes, MHC, SEMA5A and TGFBR2, are also presented.

    CONCLUSIONS: The extensive genomic changes highlight the polygenic genetic architecture of antibody response in these chicken populations, which are derived from a common founder population, demonstrating the extent of standing immunogenetic variation available at the onset of selection.

  • 40.
    Lindskog, Cecilia
    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.
    Linné, Jerker
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fagerberg, Linn
    Hallstrom, Bjorn M.
    Sundberg, Carl Johan
    Lindholm, Malene
    Huss, Mikael
    Kampf, Caroline
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Choi, Howard
    Liem, David A.
    Ping, Peipei
    Varemo, Leif
    Mardinoglu, Adil
    Nielsen, Jens
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Uhlen, Mathias
    The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling2015In: BMC Genomics, ISSN 1471-2164, 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.

  • 41.
    Llano-Diez, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Gustafson, Ann-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Olsson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model2011In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 12, p. 602-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. To elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness associated with AQM, a gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals.

    RESULTS:

    During the observation period, 1583 genes were significantly up- or down-regulated by factors of two or greater. A significant temporal gene expression pattern was constructed at short (6h-4 days), intermediate (5-8 days) and long (9-14 days) durations. A striking early and maintained up-regulation (6h-14d) of muscle atrogenes (muscle ring-finger 1/tripartite motif-containing 63 and F-box protein 32/atrogin-1) was observed, followed by an upregulation of the proteolytic systems at intermediate and long durations (5-14d). Oxidative stress response genes and genes that take part in amino acid catabolism, cell cycle arrest, apoptosis, muscle development, and protein synthesis together with myogenic factors were significantly up-regulated from 5 to 14 days. At 9-14 d, genes involved in immune response and the caspase cascade were up-regulated. At 5-14d, genes related to contractile (myosin heavy chain and myosin binding protein C), regulatory (troponin, tropomyosin), developmental, caveolin-3, extracellular matrix, glycolysis/gluconeogenesis, cytoskeleton/sarcomere regulation and mitochondrial proteins were down-regulated. An activation of genes related to muscle growth and new muscle fiber formation (increase of 3 myogenic factors and JunB and down-regulation of myostatin) and up-regulation of genes that code protein synthesis and translation factors were found from 5 to 14 days.

    CONCLUSIONS:

    Novel temporal patterns of gene expression have been uncovered, suggesting a unique, coordinated and highly complex mechanism underlying the muscle wasting associated with AQM in ICU patients and providing new target genes and avenues for intervention studies.

  • 42.
    Lovmar, Lovisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ahlford, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Jonsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Silhouette scores for assessment of SNP genotype clusters2005In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 6, article id 35Article in journal (Refereed)
    Abstract [en]

    Background: High-throughput genotyping of single nucleotide polymorphisms ( SNPs) generates large amounts of data. In many SNP genotyping assays, the genotype assignment is based on scatter plots of signals corresponding to the two SNP alleles. In a robust assay the three clusters that define the genotypes are well separated and the distances between the data points within a cluster are short. "Silhouettes" is a graphical aid for interpretation and validation of data clusters that provides a measure of how well a data point was classified when it was assigned to a cluster. Thus "Silhouettes" can potentially be used as a quality measure for SNP genotyping results and for objective comparison of the performance of SNP assays at different circumstances. Results: We created a program (ClusterA) for calculating "Silhouette scores", and applied it to assess the quality of SNP genotype clusters obtained by single nucleotide primer extension ("minisequencing") in the Tag-microarray format. A Silhouette score condenses the quality of the genotype assignment for each SNP assay into a single numeric value, which ranges from 1.0, when the genotype assignment is unequivocal, down to -1.0, when the genotype assignment has been arbitrary. In the present study we applied Silhouette scores to compare the performance of four DNA polymerases in our minisequencing system by analyzing 26 SNPs in both DNA polarities in 16 DNA samples. We found Silhouettes to provide a relevant measure for the quality of SNP assays at different reaction conditions, illustrated by the four DNA polymerases here. According to our result, the genotypes can be unequivocally assigned without manual inspection when the Silhouette score for a SNP assay is > 0.65. All four DNA polymerases performed satisfactorily in our Tag-array minisequencing system. Conclusion: "Silhouette scores" for assessing the quality of SNP genotyping clusters is convenient for evaluating the quality of SNP genotype assignment, and provides an objective, numeric measure for comparing the performance of SNP assays. The program we created for calculating Silhouette scores is freely available, and can be used for quality assessment of the results from all genotyping systems, where the genotypes are assigned by cluster analysis using scatter plots.

  • 43.
    Mank, Judith E.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    The unique genomic properties of sex-biased genes: insights from avian microarray data2008In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 9, p. 148-Article in journal (Refereed)
    Abstract [en]

    Background: In order to develop a framework for the analysis of sex-biased genes, we present a characterization of microarray data comparing male and female gene expression in 18 day chicken embryos for brain, gonad, and heart tissue. Results: From the 15982 significantly expressed coding regions that have been assigned to either the autosomes or the Z chromosome ( 12979 in brain, 13301 in gonad, and 12372 in heart), roughly 18% were significantly sex- biased in any one tissue, though only 4 gene targets were biased in all tissues. The gonad was the most sex- biased tissue, followed by the brain. Sex- biased autosomal genes tended to be expressed at lower levels and in fewer tissues than unbiased gene targets, and autosomal somatic sex- biased genes had more expression noise than similar unbiased genes. Sex-biased genes linked to the Z- chromosome showed reduced expression in females, but not in males, when compared to unbiased Z- linked genes, and sex- biased Z- linked genes were also expressed in fewer tissues than unbiased Z coding regions. Third position GC content, and codon usage bias showed some sex- biased effects, primarily for autosomal genes expressed in the gonad. Finally, there were several over-represented Gene Ontology terms in the sex- biased gene sets. Conclusion: On the whole, this analysis suggests that sex- biased genes have unique genomic and organismal properties that delineate them from genes that are expressed equally in males and females.

  • 44. Marklund, Stefan
    et al.
    Carlborg, Örjan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    SNP detection and prediction of variability between chicken lines using genome resequencing of DNA pools2010In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, no 1, p. 665-Article in journal (Refereed)
    Abstract [en]

    Background: Next-generation sequencing technologies are widely used for detection of millions of Single Nucleotide Polymorphisms (SNPs) and also provide a means of assessing their variation. This information is useful for composing subsets of highly informative SNPs for region-specific or genome-wide analysis and to identify mutations regulating phenotypic differences within or between populations. In this study, we investigated the sensitivity of SNP detection and introduced the flanking SNPs value (FSV) as a novel measure for predicting SNP-variability using similar to 5X genome resequencing with ABI SOLID and DNA pools from two chicken lines divergently selected for juvenile bodyweight. Results: Genotyping with a 60 K SNP chip revealed polymorphisms within or between two divergently selected chicken lines for 31 363 SNPs, 48% of which were also detected using resequencing of DNA pools. SNP detection using resequencing was more powerful for positions with larger differences in allele frequency between the lines. About 50% of the SNPs with non-reference allele frequencies in the range 0.5-0.6 and 67% of those with frequencies > 0.9 could be detected. On average, similar to 3.7 SNPs/kb were detected by resequencing, with about 5% lower density on microchromosomes than on macrochromosomes. There was a positive correlation between the observed between-line SNP variation from the 60 K chip analysis and our proposed FSV score computed from the genome resequencing data. The strongest correlations on macrochromosomes and microchromosomes were observed when the FSV was calculated with total flanking regions of 62 kb (correlation 0.55) and 38 kb (correlation 0.45), respectively. Conclusions: Genome resequencing with limited coverage (similar to 5X) using pooled DNA samples and three non-reference reads as a threshold for SNP detection, identified 50 - 67% of the 60 K SNPs with a non-reference allele frequency larger than 0.5. The SNP density was around 5% lower on the microchromosomes, most likely because of their higher gene content. Our proposed method to estimate the SNP variation (FSV) uses additional sequence information to better predict SNP informativity. The FSV scores showed higher correlations for SNPs with a larger difference in allele frequency between the populations. The correlation was strongest on macrochromosomes, probably due to a lower recombination rate.

  • 45.
    Molin, Anna-Maja
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berglund, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Webster, Matthew T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide copy number variant discovery in dogs using the CanineHD genotyping array2014In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, p. 210-Article in journal (Refereed)
    Abstract [en]

    Background: Substantial contribution to phenotypic diversity is accounted for by copy number variants (CNV). In human, as well as other species, the effect of CNVs range from benign to directly disease-causing which motivates the continued investigations of CNVs. Previous canine genome-wide screenings for CNVs have been performed using high-resolution comparative genomic hybridisation arrays which have contributed with a detailed catalogue of CNVs. Here, we present the first CNV investigation in dogs based on the recently reported CanineHD 170 K genotyping array. The hitherto largest dataset in canine CNV discovery was assessed, 351 dogs from 30 different breeds, enabling identification of novel CNVs and a thorough characterisation of breed-specific CNVs. Results: A stringent procedure identified 72 CNV regions with the smallest size of 38 kb and of the 72 CNV regions, 38 overlapped 148 annotated genes. A total of 29 novel CNV regions were found containing 44 genes. Furthermore, 15 breed specific CNV regions were identified of which 14 were novel and some of them overlapped putative disease susceptibility genes. In addition, the human ortholog of 23 canine copy number variable genes identified herein has been previously suggested to be dosage-sensitive in human. Conclusions: The present study evaluated the performance of the CanineHD in detecting CNVs and extends the current catalogue of canine CNV regions with several dozens of novel CNV regions. These novel CNV regions, which harbour candidate genes that possibly contribute to phenotypic variation in dogs or to disease-susceptibility, are a rich resource for future investigations.

  • 46.
    Mugal, Carina F.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Nabholz, Benoit
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Ellegren, Hans
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Genome-wide analysis in chicken reveals that local levels of genetic diversity are mainly governed by the rate of recombination2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 86-Article in journal (Refereed)
    Abstract [en]

    Background: Polymorphism is key to the evolutionary potential of populations. Understanding which factors shape levels of genetic diversity within genomes forms a central question in evolutionary genomics and is of importance for the possibility to infer episodes of adaptive evolution from signs of reduced diversity. There is an on-going debate on the relative role of mutation and selection in governing diversity levels. This question is also related to the role of recombination because recombination is expected to indirectly affect polymorphism via the efficacy of selection. Moreover, recombination might itself be mutagenic and thereby assert a direct effect on diversity levels. Results: We used whole-genome re-sequencing data from domestic chicken (broiler and layer breeds) and its wild ancestor (the red jungle fowl) to study the relationship between genetic diversity and several genomic parameters. We found that recombination rate had the largest effect on local levels of nucleotide diversity. The fact that divergence (a proxy for mutation rate) and recombination rate were negatively correlated argues against a mutagenic role of recombination. Furthermore, divergence had limited influence on polymorphism. Conclusions: Overall, our results are consistent with a selection model, in which regions within a short distance from loci under selection show reduced polymorphism levels. This conclusion lends further support from the observations of strong correlations between intergenic levels of diversity and diversity at synonymous as well as non-synonymous sites. Our results also demonstrate differences between the two domestic breeds and red jungle fowl, where the domestic breeds show a stronger relationship between intergenic diversity levels and diversity at synonymous and non-synonymous sites. This finding, together with overall lower diversity levels in domesticates compared to red jungle fowl, seem attributable to artificial selection during domestication.

  • 47.
    Naidoo, Thijessen
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Sjödin, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Schlebusch, Carina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Jakobsson, Mattias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution.
    Patterns of variation in cis-regulatory regions: examining evidence of purifying selection2018In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 19, article id 95Article in journal (Refereed)
    Abstract [en]

    Background: With only 2 % of the human genome consisting of protein coding genes, functionality across the rest of the genome has been the subject of much debate. This has gained further impetus in recent years due to a rapidly growing catalogue of genomic elements, based primarily on biochemical signatures (e.g. the ENCODE project). While the assessment of functionality is a complex task, the presence of selection acting on a genomic region is a strong indicator of importance. In this study, we apply population genetic methods to investigate signals overlaying several classes of regulatory elements.

    Results: We disentangle signals of purifying selection acting directly on regulatory elements from the confounding factors of demography and purifying selection linked to e.g. nearby protein coding regions. We confirm the importance of regulatory regions proximal to coding sequence, while also finding differential levels of selection at distal regions. We note differences in purifying selection among transcription factor families. Signals of constraint at some genomic classes were also strongly dependent on their physical location relative to coding sequence. In addition, levels of selection efficacy across genomic classes differed between African and non-African populations.

    Conclusions: In order to assign a valid signal of selection to a particular class of genomic sequence, we show that it is crucial to isolate the signal by accounting for the effects of demography and linked-purifying selection. Our study highlights the intricate interplay of factors affecting signals of selection on functional elements.

  • 48. Natt, Daniel
    et al.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wright, Dominic
    Johnsson, Martin
    Belteky, Johan
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jensen, Per
    Heritable genome-wide variation of gene expression and promoter methylation between wild and domesticated chickens2012In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 59-Article in journal (Refereed)
    Abstract [en]

    Background: Variations in gene expression, mediated by epigenetic mechanisms, may cause broad phenotypic effects in animals. However, it has been debated to what extent expression variation and epigenetic modifications, such as patterns of DNA methylation, are transferred across generations, and therefore it is uncertain what role epigenetic variation may play in adaptation. Results: In Red Junglefowl, ancestor of domestic chickens, gene expression and methylation profiles in thalamus/hypothalamus differed substantially from that of a domesticated egg laying breed. Expression as well as methylation differences were largely maintained in the offspring, demonstrating reliable inheritance of epigenetic variation. Some of the inherited methylation differences were tissue-specific, and the differential methylation at specific loci were little changed after eight generations of intercrossing between Red Junglefowl and domesticated laying hens. There was an over-representation of differentially expressed and methylated genes in selective sweep regions associated with chicken domestication. Conclusions: Our results show that epigenetic variation is inherited in chickens, and we suggest that selection of favourable epigenomes, either by selection of genotypes affecting epigenetic states, or by selection of methylation states which are inherited independently of sequence differences, may have been an important aspect of chicken domestication.

  • 49.
    Olsson, M.
    et al.
    Karolinska Inst, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Kierczak, Marcin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Karlsson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jablonska, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leegwater, P.
    Univ Utrecht, Dept Clin Sci Compan Anim, Utrecht, Netherlands..
    Koltookian, M.
    Broad Inst MIT & Harvard, Boston, MA USA..
    Abadie, J.
    LUNAM Univ, Oniris, AMaROC Unit, F-44307 Nantes, France..
    De Citres, C. Dufaure
    ANTAGENE Anim Genet Lab, Lyon 69, France..
    Thomas, A.
    ANTAGENE Anim Genet Lab, Lyon 69, France..
    Hedhammar, A.
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Tintle, L.
    Wurtsboro Vet Clin, Wurtsboro, NY USA..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Boston, MA USA..
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Absolute quantification reveals the stable transmission of a high copy number variant linked to autoinflammatory disease2016In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, article id 299Article in journal (Refereed)
    Abstract [en]

    Background: Dissecting the role copy number variants (CNVs) play in disease pathogenesis is directly reliant on accurate methods for quantification. The Shar-Pei dog breed is predisposed to a complex autoinflammatory disease with numerous clinical manifestations. One such sign, recurrent fever, was previously shown to be significantly associated with a novel, but unstable CNV (CNV_16.1). Droplet digital PCR (ddPCR) offers a new mechanism for CNV detection via absolute quantification with the promise of added precision and reliability. The aim of this study was to evaluate ddPCR in relation to quantitative PCR (qPCR) and to assess the suitability of the favoured method as a genetic test for Shar-Pei Autoinflammatory Disease (SPAID). Results: One hundred and ninety-six individuals were assayed using both PCR methods at two CNV positions (CNV_14.3 and CNV_16.1). The digital method revealed a striking result. The CNVs did not follow a continuum of alleles as previously reported, rather the alleles were stable and pedigree analysis showed they adhered to Mendelian segregation. Subsequent analysis of ddPCR case/control data confirmed that both CNVs remained significantly associated with the subphenotype of fever, but also to the encompassing SPAID complex (p < 0.001). In addition, harbouring CNV_16.1 allele five (CNV_16.1 vertical bar 5) resulted in a four-fold increase in the odds for SPAID (p < 0.001). The inclusion of a genetic marker for CNV_16.1 in a genome-wide association test revealed that this variant explained 9.7 % of genetic variance and 25.8 % of the additive genetic heritability of this autoinflammatory disease. Conclusions: This data shows the utility of the ddPCR method to resolve cryptic copy number inheritance patterns and so open avenues of genetic testing. In its current form, the ddPCR test presented here could be used in canine breeding to reduce the number of homozygote CNV_16.1 broken vertical bar 5 individuals and thereby to reduce the prevalence of disease in this breed.

  • 50.
    Orsucci, Marion
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. INRA IRD CIRAD Montpellier SupAgro, CBGP UMR 1062, Montpellier, France; Univ Montpellier, DGIMI UMR 1333, INRA, Montpellier, France.
    Audiot, P.
    INRA IRD CIRAD Montpellier SupAgro, CBGP UMR 1062, Montpellier, France.
    Dorkeld, F.
    INRA IRD CIRAD Montpellier SupAgro, CBGP UMR 1062, Montpellier, France.
    Pommier, A.
    INRA IRD CIRAD Montpellier SupAgro, CBGP UMR 1062, Montpellier, France.
    Vabre, M.
    INRA, MELGUEIL DIASCOPE UE 0398, Mauguio, France.
    Gschloessl, B.
    INRA IRD CIRAD Montpellier SupAgro, CBGP UMR 1062, Montpellier, France.
    Rialle, S.
    Inst Genom Fonct, MGX Montpellier GenomiX, Montpellier, France.
    Severac, D.
    Inst Genom Fonct, MGX Montpellier GenomiX, Montpellier, France.
    Bourguet, D.
    INRA IRD CIRAD Montpellier SupAgro, CBGP UMR 1062, Montpellier, France.
    Streiff, R.
    INRA IRD CIRAD Montpellier SupAgro, CBGP UMR 1062, Montpellier, France; Univ Montpellier, DGIMI UMR 1333, INRA, Montpellier, France.
    Larval transcriptomic response to host plants in two related phytophagous lepidopteran species: implications for host specialization and species divergence2018In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 19, article id 265Article in journal (Refereed)
    Abstract [en]

    Background: Most phytophagous insects have morphological, behavioral and physiological adaptations allowing them to specialize on one or a few plant species. Identifying the mechanisms involved in host plant specialization is crucial to understand the role of divergent selection between different environments in species diversification, and to identify sustainable targets for the management of insect pest species. In the present study, we measured larval phenotypic and transcriptomic responses to host plants in two related phytophagous lepidopteran species: the European corn borer (ECB), a worldwide pest of maize, and the adzuki bean borer (ABB), which feeds of various dicotyledons. Our aim was to identify the genes and functions underlying host specialization and/or divergence between ECB and ABB.

    Results: At the phenotypic level, we observed contrasted patterns of survival, weight gain and developmental time between ECB and ABB, and within ECB and ABB reared on two different host plants. At the transcriptomic level, around 8% of the genes were differentially expressed (DE) between species and/or host plant. 70% of these DE genes displayed a divergent pattern of expression between ECB and ABB, regardless of the host, while the remaining 30% were involved in the plastic response between hosts. We further categorized plastic DE genes according to their parallel or opposite pattern between ECB and ABB to specifically identify candidate genes involved in the species divergence by host specialization. These candidates highlighted a comprehensive response, involving functions related to plant recognition, digestion, detoxification, immunity and development. Last, we detected viral, bacterial, and yeast genes whose incidence contrasted ECB and ABB samples, and maize and mugwort conditions. We suggest that these microorganism communities might influence the survival, metabolism and defense patterns observed in ECB and ABB larvae.

    Conclusions: The comprehensive approach developed in the present study allowed to identify phenotypic specialization patterns and underlying candidate molecular mechanisms, and highlighted the putative role of microorganisms in the insect-host plant interaction. These findings offer the opportunity to pinpoint specific and sustainable molecular or physiological targets for the regulation of ECB pest populations.

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