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  • 1.
    Alsmark, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Foster, Peter G.
    Sicheritz-Ponten, Thomas
    Nakjang, Sirintra
    Embley, T. Martin
    Hirt, Robert P.
    Patterns of prokaryotic lateral gene transfers affecting parasitic microbial eukaryotes2013Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, nr 2, s. R19-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The influence of lateral gene transfer on gene origins and biology in eukaryotes is poorly understood compared with those of prokaryotes. A number of independent investigations focusing on specific genes, individual genomes, or specific functional categories from various eukaryotes have indicated that lateral gene transfer does indeed affect eukaryotic genomes. However, the lack of common methodology and criteria in these studies makes it difficult to assess the general importance and influence of lateral gene transfer on eukaryotic genome evolution. Results: We used a phylogenomic approach to systematically investigate lateral gene transfer affecting the proteomes of thirteen, mainly parasitic, microbial eukaryotes, representing four of the six eukaryotic super-groups. All of the genomes investigated have been significantly affected by prokaryote-to-eukaryote lateral gene transfers, dramatically affecting the enzymes of core pathways, particularly amino acid and sugar metabolism, but also providing new genes of potential adaptive significance in the life of parasites. A broad range of prokaryotic donors is involved in such transfers, but there is clear and significant enrichment for bacterial groups that share the same habitats, including the human microbiota, as the parasites investigated. Conclusions: Our data show that ecology and lifestyle strongly influence gene origins and opportunities for gene transfer and reveal that, although the outlines of the core eukaryotic metabolism are conserved among lineages, the genes making up those pathways can have very different origins in different eukaryotes. Thus, from the perspective of the effects of lateral gene transfer on individual gene ancestries in different lineages, eukaryotic metabolism appears to be chimeric.

  • 2. Andersson, Anders F.
    et al.
    Lundgren, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Eriksson, Stefan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Rosenlund, Magnus
    Bernander, Rolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Nilsson, Peter
    Global analysis of mRNA stability in the archaeon Sulfolobus2006Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 7, nr 10, s. R99-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Transcript half-lives differ between organisms, and between groups of genes within the same organism. The mechanisms underlying these differences are not clear, nor are the biochemical properties that determine the stability of a transcript. To address these issues, genome-wide mRNA decay studies have been conducted in eukaryotes and bacteria. In contrast, relatively little is known about RNA stability in the third domain of life, Archaea. Here, we present a microarray-based analysis of mRNA half-lives in the hyperthermophilic crenarchaea Sulfolobus solfatoricus and Sulfolobus acidocaldarius, constituting the first genome-wide study of RNA decay in archaea. Results: The two transcriptomes displayed similar half-life distributions, with medians of about five minutes. Growth-related genes, such as those involved in transcription, translation and energy production, were over-represented among unstable transcripts, whereas uncharacterized genes were over-represented among the most stable. Half-life was negatively correlated with transcript abundance and, unlike the situation in other organisms, also negatively correlated with transcript length. Conclusion: The mRNA half-life distribution of Sulfolobus species is similar to those of much faster growing bacteria, contrasting with the earlier observation that median mRNA half-life is proportional to the minimal length of the cell cycle. Instead, short half-lives may be a general feature of prokaryotic transcriptomes, possibly related to the absence of a nucleus and/or more limited post-transcriptional regulatory mechanisms. The pattern of growth-related transcripts being among the least stable in Sulfolobus may also indicate that the short half-lives reflect a necessity to rapidly reprogram gene expression upon sudden changes in environmental conditions.

  • 3.
    Andersson, Anders
    et al.
    KTH, Tidigare Institutioner, Bioteknologi.
    Keskitalo, J.
    Sjödin, A.
    Bhalerao, Rupali
    KTH, Tidigare Institutioner, Bioteknologi.
    Sterky, Fredrik
    KTH, Tidigare Institutioner, Bioteknologi.
    Wissel, K.
    Tandre, K.
    Aspeborg, Henrik
    KTH, Tidigare Institutioner, Bioteknologi.
    Moyle, R.
    Ohmiya, Y.
    Brunner, A.
    Gustafsson, P.
    Karlsson, J.
    Lundeberg, Joakim
    KTH, Tidigare Institutioner, Bioteknologi.
    Nilsson, O.
    Sandberg, G.
    Strauss, S.
    Sundberg, B.
    Uhlén, Mathias
    KTH, Tidigare Institutioner, Bioteknologi.
    Jansson, S.
    Nilsson, Peter
    KTH, Tidigare Institutioner, Bioteknologi.
    A transcriptional timetable of autumn senescence2004Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 5, nr 4, s. R24-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: We have developed genomic tools to allow the genus Populus ( aspens and cottonwoods) to be exploited as a full-featured model for investigating fundamental aspects of tree biology. We have undertaken large-scale expressed sequence tag ( EST) sequencing programs and created Populus microarrays with significant gene coverage. One of the important aspects of plant biology that cannot be studied in annual plants is the gene activity involved in the induction of autumn leaf senescence. Results: On the basis of 36,354 Populus ESTs, obtained from seven cDNA libraries, we have created a DNA microarray consisting of 13,490 clones, spotted in duplicate. Of these clones, 12,376 (92%) were confirmed by resequencing and all sequences were annotated and functionally classified. Here we have used the microarray to study transcript abundance in leaves of a free-growing aspen tree ( Populus tremula) in northern Sweden during natural autumn senescence. Of the 13,490 spotted clones, 3,792 represented genes with significant expression in all leaf samples from the seven studied dates. Conclusions: We observed a major shift in gene expression, coinciding with massive chlorophyll degradation, that reflected a shift from photosynthetic competence to energy generation by mitochondrial respiration, oxidation of fatty acids and nutrient mobilization. Autumn senescence had much in common with senescence in annual plants; for example many proteases were induced. We also found evidence for increased transcriptional activity before the appearance of visible signs of senescence, presumably preparing the leaf for degradation of its components.

  • 4. Andersson, Anders
    et al.
    Keskitalo, Johanna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Sjödin, Andreas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Bhalerao, Rupali
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Sterky, Fredrik
    Wissel, Kirsten
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Tandre, Karolina
    Aspeborg, Henrik
    Moyle, Richard
    Ohmiya, Yasunori
    Bhalerao, Rishikesh
    Brunner, Amy
    Gustafsson, Petter
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Karlsson, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Lundeberg, Joakim
    Nilsson, Ove
    Sandberg, Göran
    Strauss, Steven
    Sundberg, Björn
    Uhlen, Mathias
    Jansson, Stefan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Nilsson, Peter
    A transcriptional timetable of autumn senescence2004Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 5, nr 4, s. R24-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background We have developed genomic tools to allow the genus Populus (aspens and cottonwoods) to be exploited as a full-featured model for investigating fundamental aspects of tree biology. We have undertaken large-scale expressed sequence tag (EST) sequencing programs and created Populus microarrays with significant gene coverage. One of the important aspects of plant biology that cannot be studied in annual plants is the gene activity involved in the induction of autumn leaf senescence. Results On the basis of 36,354 Populus ESTs, obtained from seven cDNA libraries, we have created a DNA microarray consisting of 13,490 clones, spotted in duplicate. Of these clones, 12,376 (92%) were confirmed by resequencing and all sequences were annotated and functionally classified. Here we have used the microarray to study transcript abundance in leaves of a free-growing aspen tree (Populus tremula) in northern Sweden during natural autumn senescence. Of the 13,490 spotted clones, 3,792 represented genes with significant expression in all leaf samples from the seven studied dates. Conclusions We observed a major shift in gene expression, coinciding with massive chlorophyll degradation, that reflected a shift from photosynthetic competence to energy generation by mitochondrial respiration, oxidation of fatty acids and nutrient mobilization. Autumn senescence had much in common with senescence in annual plants; for example many proteases were induced. We also found evidence for increased transcriptional activity before the appearance of visible signs of senescence, presumably preparing the leaf for degradation of its components.

  • 5.
    Andersson, Anders
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi.
    Lundgren, Magnus
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University.
    Eriksson, Stefan
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University.
    Rosenlund, Magnus
    KTH, Skolan för teknikvetenskap (SCI), Matematik (Inst.).
    Bernander, Rolf
    Department of Molecular Evolution, Evolutionary Biology Center, Uppsala University.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Genteknologi.
    Global analysis of mRNA stability in the archaeon Sulfolobus2006Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 7, nr 10, s. R99-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Transcript half-lives differ between organisms, and between groups of genes within the same organism. The mechanisms underlying these differences are not clear, nor are the biochemical properties that determine the stability of a transcript. To address these issues, genome-wide mRNA decay studies have been conducted in eukaryotes and bacteria. In contrast, relatively little is known about RNA stability in the third domain of life, Archaea. Here, we present a microarray-based analysis of mRNA half-lives in the hyperthermophilic crenarchaea Sulfolobus solfataricus and Sulfolobus acidocaldarius, constituting the first genome-wide study of RNA decay in archaea. Results: The two transcriptomes displayed similar half-life distributions, with medians of about five minutes. Growth-related genes, such as those involved in transcription, translation and energy production, were over-represented among unstable transcripts, whereas uncharacterized genes were over-represented among the most stable. Half-life was negatively correlated with transcript abundance and, unlike the situation in other organisms, also negatively correlated with transcript length. Conclusion: The mRNA half-life distribution of Sulfolobus species is similar to those of much faster growing bacteria, contrasting with the earlier observation that median mRNA half-life is proportional to the minimal length of the cell cycle. Instead, short half-lives may be a general feature of prokaryotic transcriptomes, possibly related to the absence of a nucleus and/or more limited post-transcriptional regulatory mechanisms. The pattern of growth-related transcripts being among the least stable in Sulfolobus may also indicate that the short half-lives reflect a necessity to rapidly reprogram gene expression upon sudden changes in environmental conditions.

  • 6.
    Andersson, Leif
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Swedish University of Agricultural Sciences.
    Archibald, Alan L.
    Bottema, Cynthia D.
    Brauning, Rudiger
    Burgess, Shane C.
    Burt, Dave W.
    Casas, Eduardo
    Cheng, Hans H.
    Clarke, Laura
    Couldrey, Christine
    Dalrymple, Brian P.
    Elsik, Christine G.
    Foissac, Sylvain
    Giuffra, Elisabetta
    Groenen, Martien A.
    Hayes, Ben J.
    Huang, LuSheng S.
    Khatib, Hassan
    Kijas, James W.
    Kim, Heebal
    Lunney, Joan K.
    McCarthy, Fiona M.
    McEwan, John C.
    Moore, Stephen
    Nanduri, Bindu
    Notredame, Cedric
    Palti, Yniv
    Plastow, Graham S.
    Reecy, James M.
    Rohrer, Gary A.
    Sarropoulou, Elena
    Schmidt, Carl J.
    Silverstein, Jeffrey
    Tellam, Ross L.
    Tixier-Boichard, Michele
    Tosser-Klopp, Gwenola
    Tuggle, Christopher K.
    Vilkki, Johanna
    White, Stephen N.
    Zhao, Shuhong
    Zhou, Huaijun
    Coordinated international action to accelerate genome-to-phenome with FAANG, the Functional Annotation of Animal Genomes project2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe the organization of a nascent international effort, the Functional Annotation of Animal Genomes (FAANG) project, whose aim is to produce comprehensive maps of functional elements in the genomes of domesticated animal species.

  • 7.
    Ashelford, Kevin
    et al.
    School of Biological Sciences, University of Liverpool, Liverpool, UK.
    Eriksson, Maria E
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Allen, Christopher M
    Applied Biosystems, part of Life Technologies, Warrington, UK.
    D’Amore, Linda
    School of Biological Sciences, University of Liverpool, Liverpool, UK.
    Johansson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Gould, Peter
    School of Biological Sciences, University of Liverpool, Liverpool, UK.
    Kay, Susanne
    School of Biological Sciences, University of Liverpool, Liverpool, UK.
    Millar, Andrew J.
    Institute of Molecular Plant Sciences, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
    Hall, Neil
    School of Biological Sciences, University of Liverpool, Liverpool, UK.
    Hall, Anthony
    School of Biological Sciences, University of Liverpool, Liverpool, UK.
    Full genome re-sequencing reveals a novel circadian clock mutationin Arabidopsis2011Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, s. R28-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Map based cloning in Arabidopsis thaliana can be a difficult and time-consuming process,specifically if the phenotype is subtle and scoring labour intensive. An alternative to map basedcloning would be to directly sequence the whole genome of a mutant to uncover the mutationresponsible for the phenotype.

    Results: Here, we have re-sequenced the 120 Mb genome of a novel Arabidopsis clock mutant earlybird (ebi-1), using massively parallel sequencing by ligation. This process was further complicated by the fact that ebi-1 is in Wassilewskija (Ws-2), not the reference accession ofArabidopsis. The approach reveals evidence of DNA strand bias in the ethyl methanesulfonate(EMS) mutation process. We have demonstrated the utility of sequencing a backcrossed line andusing gene expression data to limit the number of SNP considered. Using new SNP informationwe have excluded a previously identified clock gene, PRR7. Finally, we have identified a SNPin the gene AtNFXL-2 as the likely cause of the ebi-1 phenotype and validated this bycharacterising a further allele.

    Conclusion: In Arabidopsis, as in other organisms, the (EMS) mutation load can be high. Here wedescribe how sequencing a backcrossed line, using functional genomics and analysing new SNPinformation can be used to reduce the number EMS mutations for consideration. Moreover, theapproach we describe here does not require out-crossing and scoring F2 mapping populations, anapproach which can be compromised by background effects. The strategy has broad utility andwill be an extremely useful tool to identify causative SNP in other organisms.

  • 8.
    Balliu, Brunilda
    et al.
    Stanford Univ, Dept Pathol, Sch Med, Stanford, CA USA.
    Durrant, Matthew
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA USA.
    de Goede, Olivia
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA USA.
    Abell, Nathan
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA USA.
    Li, Xin
    Stanford Univ, Dept Pathol, Sch Med, Stanford, CA USA.
    Liu, Boxiang
    Stanford Univ, Dept Biol, Sch Med, Stanford, CA USA.
    Gloudemans, Michael J.
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA USA.
    Cook, Naomi L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala Univ, Dept Med Sci, Uppsala, Sweden.
    Smith, Kevin S.
    Stanford Univ, Dept Pathol, Sch Med, Stanford, CA USA.
    Knowles, David A.
    New York Genome Ctr, New York, NY USA.
    Pala, Mauro
    Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Cucca, Francesco
    Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Schlessinger, David
    NIA, Lab Genet, Bethesda, MD USA.
    Jaiswal, Siddhartha
    Stanford Univ, Dept Pathol, Sch Med, Stanford, CA USA.
    Sabatti, Chiara
    Stanford Univ, Dept Biomed Data Sci, Sch Med, Stanford, CA USA.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Ingelsson, Erik
    Stanford Univ, Sch Med, Div Cardiovasc Med, Dep Med, Stanford, CA USA; Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA USA; Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA USA.
    Montgomery, Stephen B.
    Stanford Univ, Dept Pathol, Sch Med, Stanford, CA USA; Stanford Univ, Dept Genet, Sch Med, Stanford, CA USA.
    Genetic regulation of gene expression and splicing during a 10-year period of human aging2019Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 20, nr 1, artikel-id 230Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age.

    Results: We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age.

    Conclusions: These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.

  • 9.
    Barrenäs, Fredrik
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Chavali, Sreenivas
    MRC-Laboratory of Molecular Biology, University of Cambridge, Hills Road, Cambridge, CB2 0QH, UK.
    Alves, Alexessander Couto
    Department of Genomics of Common Disease, School of Public Health, Imperial College, UK.
    Coin, Lachlan
    Department of Genomics of Common Disease, School of Public Health, Imperial College, UK.
    Jarvelin, Marjo-Riitta
    Department of Genomics of Common Disease, School of Public Health, Imperial College, UK.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, University of Gothenburg, Gothenburg, Sweden.
    Langston, Michael A
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, USA .
    Ramasamy, Adaikalavan
    Department of Genomics of Common Disease, School of Public Health, Imperial College, London, UK .
    Rogers, Gary
    Department of Electrical Engineering and Computer Science, University of Tennessee, Knoxville, USA .
    Wang, Hui
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Benson, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Highly interconnected genes in disease-specific networks are enriched for disease-associated polymorphisms2012Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, nr 6, s. R46-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Complex diseases are associated with altered interactions between thousands of genes. We developed a novel method to identify and prioritize disease genes, which was generally applicable to complex diseases.

    RESULTS: We identified modules of highly interconnected genes in disease-specific networks derived from integrating gene-expression and protein interaction data. We examined if those modules were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies. First, we analyzed publicly available gene expression microarray and genome-wide association study (GWAS) data from 13, highly diverse, complex diseases. In each disease, highly interconnected genes formed modules, which were significantly enriched for genes harboring disease-associated SNPs. To test if such modules could be used to find novel genes for functional studies, we repeated the analyses using our own gene expression microarray and GWAS data from seasonal allergic rhinitis. We identified a novel gene, FGF2, whose relevance was supported by functional studies using combined small interfering RNA-mediated knock-down and gene expression microarrays. The modules in the 13 complex diseases analyzed here tended to overlap and were enriched for pathways related to oncological, metabolic and inflammatory diseases. This suggested that this union of the modules would be associated with a general increase in susceptibility for complex diseases. Indeed, we found that this union was enriched with GWAS genes for 145 other complex diseases.

    CONCLUSIONS: Modules of highly interconnected complex disease genes were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies.

  • 10. Barribeau, Seth M.
    et al.
    Sadd, Ben M.
    du Plessis, Louis
    Brown, Mark J. F.
    Buechel, Severine D.
    Institute of Integrative Biology, Switzerland.
    Cappelle, Kaat
    Carolan, James C.
    Christiaens, Olivier
    Colgan, Thomas J.
    Erler, Silvio
    Evans, Jay
    Helbing, Sophie
    Karaus, Elke
    Lattorff, H. Michael G.
    Marxer, Monika
    Meeus, Ivan
    Näpflin, Kathrin
    Niu, Jinzhi
    Schmid-Hempel, Regula
    Smagghe, Guy
    Waterhouse, Robert M.
    Yu, Na
    Zdobnov, Evgeny M.
    Schmid-Hempel, Paul
    A depauperate immune repertoire precedes evolution of sociality in bees2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, nr 83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Sociality has many rewards, but can also be dangerous, as high population density and low genetic diversity, common in social insects, is ideal for parasite transmission. Despite this risk, honeybees and other sequenced social insects have far fewer canonical immune genes relative to solitary insects. Social protection from infection, including behavioral responses, may explain this depauperate immune repertoire. Here, based on full genome sequences, we describe the immune repertoire of two ecologically and commercially important bumblebee species that diverged approximately 18 million years ago, the North American Bombus impatiens and European Bombus terrestris.

    RESULTS: We find that the immune systems of these bumblebees, two species of honeybee, and a solitary leafcutting bee, are strikingly similar. Transcriptional assays confirm the expression of many of these genes in an immunological context and more strongly in young queens than males, affirming Bateman's principle of greater investment in female immunity. We find evidence of positive selection in genes encoding antiviral responses, components of the Toll and JAK/STAT pathways, and serine protease inhibitors in both social and solitary bees. Finally, we detect many genes across pathways that differ in selection between bumblebees and honeybees, or between the social and solitary clades.

    CONCLUSIONS: The similarity in immune complement across a gradient of sociality suggests that a reduced immune repertoire predates the evolution of sociality in bees. The differences in selection on immune genes likely reflect divergent pressures exerted by parasites across social contexts.

  • 11.
    Berglund, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nevalainen, Elisa M
    Molin, Anna-Maja
    Perloski, Michele
    André, Catherine
    Zody, Michael C
    Sharpe, Ted
    Hitte, Christophe
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lohi, Hannes
    Webster, Matthew T
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Novel origins of copy number variation in the dog genome2012Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 13, nr 8, s. R73-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution.

  • 12.
    Bolivar, Paulina
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Gueguen, Laurent
    Univ Claude Bernard Lyon 1, CNRS, UMR 5558, Lab Biol & Biometrie Evolut, Lyon, France.
    Duret, Laurent
    Univ Claude Bernard Lyon 1, CNRS, UMR 5558, Lab Biol & Biometrie Evolut, Lyon, France.
    Ellegren, Hans
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    Mugal, Carina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi.
    GC-biased gene conversion conceals the prediction of the nearly neutral theory in avian genomes2019Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 20, artikel-id 5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The nearly neutral theory of molecular evolution predicts that the efficacy of natural selection increases with the effective population size. This prediction has been verified by independent observations in diverse taxa, which show that life-history traits are strongly correlated with measures of the efficacy of selection, such as the d(N)/d(S) ratio. Surprisingly, avian taxa are an exception to this theory because correlations between life-history traits and d(N)/d(S) are apparently absent. Here we explore the role of GC-biased gene conversion on estimates of substitution rates as a potential driver of these unexpected observations.

    Results: We analyze the relationship between d(N)/d(S) estimated from alignments of 47 avian genomes and several proxies for effective population size. To distinguish the impact of GC-biased gene conversion from selection, we use an approach that accounts for non-stationary base composition and estimate d(N)/d(S) separately for changes affected or unaffected by GC-biased gene conversion. This analysis shows that the impact of GC-biased gene conversion on substitution rates can explain the lack of correlations between life-history traits and d(N)/d(S). Strong correlations between life-history traits and d(N)/d(S) are recovered after accounting for GC-biased gene conversion. The correlations are robust to variation in base composition and genomic location.

    Conclusions: Our study shows that gene sequence evolution across a wide range of avian lineages meets the prediction of the nearly neutral theory,the efficacy of selection increases with effective population size. Moreover, our study illustrates that accounting for GC-biased gene conversion is important to correctly estimate the strength of selection.

  • 13.
    Bornelöv, Susanne
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Cambridge CB2 1QR, England..
    Seroussi, Eyal
    Agr Res Org, Volcani Ctr, Rishon Leziyyon, Israel..
    Yosefi, Sara
    Agr Res Org, Volcani Ctr, Rishon Leziyyon, Israel..
    Pendavis, Ken
    Univ Arizona, Coll Agr & Life Sci, Tucson, AZ 85721 USA..
    Burgess, Shane C.
    Univ Arizona, Coll Agr & Life Sci, Tucson, AZ 85721 USA..
    Grabherr, Manfred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Friedman-Einat, Miriam
    Agr Res Org, Volcani Ctr, Rishon Leziyyon, Israel..
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA..
    Correspondence on Lovell et al.: identification of chicken genes previously assumed to be evolutionarily lost2017Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 18, artikel-id 112Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Through RNA-Seq analyses, we identified 137 genes that are missing in chicken, including the long-sought-after nephrin and tumor necrosis factor genes. These genes tended to cluster in GC-rich regions that have poor coverage in genome sequence databases. Hence, the occurrence of syntenic groups of vertebrate genes that have not been observed in Aves does not prove the evolutionary loss of such genes.

  • 14. Brolin, M
    et al.
    Ribacke, Ulf
    Nilsson, Sandra
    Ankarklev, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Moll, Kirsten
    Wahlgren, Mats
    Chen, Qijun
    Simultaneous transcription of duplicated var2csa gene copies in individual Plasmodium falciparum parasites2009Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 10, nr 10, s. R117-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Single nucleotide polymorphisms are common in duplicated genes, causing functional preservation, alteration or silencing. The Plasmodium falciparum genes var2csa and Pf332 are duplicated in the haploid genome of the HB3 parasite line. Whereas the molecular function of Pf332 remains to be elucidated, VAR2CSA is known to be the main adhesin in placental parasite sequestration. Sequence variations introduced upon duplication of these genes provide discriminative possibilities to analyze allele-specific transcription with a bearing towards understanding gene dosage impact on parasite biology. Results: We demonstrate an approach combining real-time PCR allelic discrimination and discriminative RNA-FISH to distinguish between highly similar gene copies in P. falciparum parasites. The duplicated var2csa variants are simultaneously transcribed, both on a population level and intriguingly also in individual cells, with nuclear co-localization of the active genes and corresponding transcripts. This indicates transcriptional functionality of duplicated genes, challenges the dogma of mutually exclusive var gene transcription and suggests mechanisms behind antigenic variation, at least in respect to the duplicated and highly similar var2csa genes. Conclusions: Allelic discrimination assays have traditionally been applied to study zygosity in diploid genomes. The assays presented here are instead successfully applied to the identification and evaluation of transcriptional activity of duplicated genes in the haploid genome of the P. falciparum parasite. Allelic discrimination and gene or transcript localization by FISH not only provide insights into transcriptional regulation of genes such as the virulence associated var genes, but also suggest that this sensitive and precise approach could be used for further investigation of genome dynamics and gene regulation.

  • 15. Brownstein, Catherine A.
    et al.
    Beggs, Alan H.
    Homer, Nils
    Merriman, Barry
    Yu, Timothy W.
    Flannery, Katherine C.
    DeChene, Elizabeth T.
    Towne, Meghan C.
    Savage, Sarah K.
    Price, Emily N.
    Holm, Ingrid A.
    Luquette, Lovelace J.
    Lyon, Elaine
    Majzoub, Joseph
    Neupert, Peter
    McCallie, David, Jr.
    Szolovits, Peter
    Willard, Huntington F.
    Mendelsohn, Nancy J.
    Temme, Renee
    Finkel, Richard S.
    Yum, Sabrina W.
    Medne, Livija
    Sunyaev, Shamil R.
    Adzhubey, Ivan
    Cassa, Christopher A.
    de Bakker, Paul I. W.
    Duzkale, Hatice
    Dworzynski, Piotr
    Fairbrother, William
    Francioli, Laurent
    Funke, Birgit H.
    Giovanni, Monica A.
    Handsaker, Robert E.
    Lage, Kasper
    Lebo, Matthew S.
    Lek, Monkol
    Leshchiner, Ignaty
    MacArthur, Daniel G.
    McLaughlin, Heather M.
    Murray, Michael F.
    Pers, Tune H.
    Polak, Paz P.
    Raychaudhuri, Soumya
    Rehm, Heidi L.
    Soemedi, Rachel
    Stitziel, Nathan O.
    Vestecka, Sara
    Supper, Jochen
    Gugenmus, Claudia
    Klocke, Bernward
    Hahn, Alexander
    Schubach, Max
    Menzel, Mortiz
    Biskup, Saskia
    Freisinger, Peter
    Deng, Mario
    Braun, Martin
    Perner, Sven
    Smith, Richard J. H.
    Andorf, Janeen L.
    Huang, Jian
    Ryckman, Kelli
    Sheffield, Val C.
    Stone, Edwin M.
    Bair, Thomas
    Black-Ziegelbein, E. Ann
    Braun, Terry A.
    Darbro, Benjamin
    DeLuca, Adam P.
    Kolbe, Diana L.
    Scheetz, Todd E.
    Shearer, Aiden E.
    Sompallae, Rama
    Wang, Kai
    Bassuk, Alexander G.
    Edens, Erik
    Mathews, Katherine
    Moore, Steven A.
    Shchelochkov, Oleg A.
    Trapane, Pamela
    Bossler, Aaron
    Campbell, Colleen A.
    Heusel, Jonathan W.
    Kwitek, Anne
    Maga, Tara
    Panzer, Karin
    Wassink, Thomas
    Van Daele, Douglas
    Azaiez, Hela
    Booth, Kevin
    Meyer, Nic
    Segal, Michael M.
    Williams, Marc S.
    Tromp, Gerard
    White, Peter
    Corsmeier, Donald
    Fitzgerald-Butt, Sara
    Herman, Gail
    Lamb-Thrush, Devon
    McBride, Kim L.
    Newsom, David
    Pierson, Christopher R.
    Rakowsky, Alexander T.
    Maver, Ales
    Lovrecic, Luca
    Palandacic, Anja
    Peterlin, Borut
    Torkamani, Ali
    Wedell, Anna
    Huss, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Alexeyenko, Andrey
    Lindvall, Jessica M.
    Magnusson, Mans
    Nilsson, Daniel
    Stranneheim, Henrik
    Taylan, Fulya
    Gilissen, Christian
    Hoischen, Alexander
    van Bon, Bregje
    Yntema, Helger
    Nelen, Marcel
    Zhang, Weidong
    Sager, Jason
    Zhang, Lu
    Blair, Kathryn
    Kural, Deniz
    Cariaso, Michael
    Lennon, Greg G.
    Javed, Asif
    Agrawal, Saloni
    Ng, Pauline C.
    Sandhu, Komal S.
    Krishna, Shuba
    Veeramachaneni, Vamsi
    Isakov, Ofer
    Halperin, Eran
    Friedman, Eitan
    Shomron, Noam
    Glusman, Gustavo
    Roach, Jared C.
    Caballero, Juan
    Cox, Hannah C.
    Mauldin, Denise
    Ament, Seth A.
    Rowen, Lee
    Richards, Daniel R.
    San Lucas, F. Anthony
    Gonzalez-Garay, Manuel L.
    Caskey, C. Thomas
    Bai, Yu
    Huang, Ying
    Fang, Fang
    Zhang, Yan
    Wang, Zhengyuan
    Barrera, Jorge
    Garcia-Lobo, Juan M.
    Gonzalez-Lamuno, Domingo
    Llorca, Javier
    Rodriguez, Maria C.
    Varela, Ignacio
    Reese, Martin G.
    De la Vega, Francisco M.
    Kiruluta, Edward
    Cargill, Michele
    Hart, Reece K.
    Sorenson, Jon M.
    Lyon, Gholson J.
    Stevenson, David A.
    Bray, Bruce E.
    Moore, Barry M.
    Eilbeck, Karen
    Yandell, Mark
    Zhao, Hongyu
    Hou, Lin
    Chen, Xiaowei
    Yan, Xiting
    Chen, Mengjie
    Li, Cong
    Yang, Can
    Gunel, Murat
    Li, Peining
    Kong, Yong
    Alexander, Austin C.
    Albertyn, Zayed I.
    Boycott, Kym M.
    Bulman, Dennis E.
    Gordon, Paul M. K.
    Innes, A. Micheil
    Knoppers, Bartha M.
    Majewski, Jacek
    Marshall, Christian R.
    Parboosingh, Jillian S.
    Sawyer, Sarah L.
    Samuels, Mark E.
    Schwartzentruber, Jeremy
    Kohane, Isaac S.
    Margulies, David M.
    An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge2014Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, nr 3, artikel-id R53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

  • 16. Brownstein, Catherine A.
    et al.
    Beggs, Alan H.
    Homer, Nils
    Merriman, Barry
    Yu, Timothy W.
    Flannery, Katherine C.
    DeChene, Elizabeth T.
    Towne, Meghan C.
    Savage, Sarah K.
    Price, Emily N.
    Holm, Ingrid A.
    Luquette, Lovelace J.
    Lyon, Elaine
    Majzoub, Joseph
    Neupert, Peter
    McCallie, David, Jr.
    Szolovits, Peter
    Willard, Huntington F.
    Mendelsohn, Nancy J.
    Temme, Renee
    Finkel, Richard S.
    Yum, Sabrina W.
    Medne, Livija
    Sunyaev, Shamil R.
    Adzhubey, Ivan
    Cassa, Christopher A.
    de Bakker, Paul I. W.
    Duzkale, Hatice
    Dworzynski, Piotr
    Fairbrother, William
    Francioli, Laurent
    Funke, Birgit H.
    Giovanni, Monica A.
    Handsaker, Robert E.
    Lage, Kasper
    Lebo, Matthew S.
    Lek, Monkol
    Leshchiner, Ignaty
    MacArthur, Daniel G.
    McLaughlin, Heather M.
    Murray, Michael F.
    Pers, Tune H.
    Polak, Paz P.
    Raychaudhuri, Soumya
    Rehm, Heidi L.
    Soemedi, Rachel
    Stitziel, Nathan O.
    Vestecka, Sara
    Supper, Jochen
    Gugenmus, Claudia
    Klocke, Bernward
    Hahn, Alexander
    Schubach, Max
    Menzel, Mortiz
    Biskup, Saskia
    Freisinger, Peter
    Deng, Mario
    Braun, Martin
    Perner, Sven
    Smith, Richard J. H.
    Andorf, Janeen L.
    Huang, Jian
    Ryckman, Kelli
    Sheffield, Val C.
    Stone, Edwin M.
    Bair, Thomas
    Black-Ziegelbein, E. Ann
    Braun, Terry A.
    Darbro, Benjamin
    DeLuca, Adam P.
    Kolbe, Diana L.
    Scheetz, Todd E.
    Shearer, Aiden E.
    Sompallae, Rama
    Wang, Kai
    Bassuk, Alexander G.
    Edens, Erik
    Mathews, Katherine
    Moore, Steven A.
    Shchelochkov, Oleg A.
    Trapane, Pamela
    Bossler, Aaron
    Campbell, Colleen A.
    Heusel, Jonathan W.
    Kwitek, Anne
    Maga, Tara
    Panzer, Karin
    Wassink, Thomas
    Van Daele, Douglas
    Azaiez, Hela
    Booth, Kevin
    Meyer, Nic
    Segal, Michael M.
    Williams, Marc S.
    Tromp, Gerard
    White, Peter
    Corsmeier, Donald
    Fitzgerald-Butt, Sara
    Herman, Gail
    Lamb-Thrush, Devon
    McBride, Kim L.
    Newsom, David
    Pierson, Christopher R.
    Rakowsky, Alexander T.
    Maver, Ales
    Lovrecic, Luca
    Palandacic, Anja
    Peterlin, Borut
    Torkamani, Ali
    Wedell, Anna
    Huss, Mikael
    Alexeyenko, Andrey
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab. Stockholm Bioinformatics Centre, Science for Life Laboratory, Solna, Sweden .
    Lindvall, Jessica M.
    Magnusson, Mans
    Nilsson, Daniel
    Stranneheim, Henrik
    Taylan, Fulya
    Gilissen, Christian
    Hoischen, Alexander
    van Bon, Bregje
    Yntema, Helger
    Nelen, Marcel
    Zhang, Weidong
    Sager, Jason
    Zhang, Lu
    Blair, Kathryn
    Kural, Deniz
    Cariaso, Michael
    Lennon, Greg G.
    Javed, Asif
    Agrawal, Saloni
    Ng, Pauline C.
    Sandhu, Komal S.
    Krishna, Shuba
    Veeramachaneni, Vamsi
    Isakov, Ofer
    Halperin, Eran
    Friedman, Eitan
    Shomron, Noam
    Glusman, Gustavo
    Roach, Jared C.
    Caballero, Juan
    Cox, Hannah C.
    Mauldin, Denise
    Ament, Seth A.
    Rowen, Lee
    Richards, Daniel R.
    San Lucas, F. Anthony
    Gonzalez-Garay, Manuel L.
    Caskey, C. Thomas
    Bai, Yu
    Huang, Ying
    Fang, Fang
    Zhang, Yan
    Wang, Zhengyuan
    Barrera, Jorge
    Garcia-Lobo, Juan M.
    Gonzalez-Lamuno, Domingo
    Llorca, Javier
    Rodriguez, Maria C.
    Varela, Ignacio
    Reese, Martin G.
    De la Vega, Francisco M.
    Kiruluta, Edward
    Cargill, Michele
    Hart, Reece K.
    Sorenson, Jon M.
    Lyon, Gholson J.
    Stevenson, David A.
    Bray, Bruce E.
    Moore, Barry M.
    Eilbeck, Karen
    Yandell, Mark
    Zhao, Hongyu
    Hou, Lin
    Chen, Xiaowei
    Yan, Xiting
    Chen, Mengjie
    Li, Cong
    Yang, Can
    Gunel, Murat
    Li, Peining
    Kong, Yong
    Alexander, Austin C.
    Albertyn, Zayed I.
    Boycott, Kym M.
    Bulman, Dennis E.
    Gordon, Paul M. K.
    Innes, A. Micheil
    Knoppers, Bartha M.
    Majewski, Jacek
    Marshall, Christian R.
    Parboosingh, Jillian S.
    Sawyer, Sarah L.
    Samuels, Mark E.
    Schwartzentruber, Jeremy
    Kohane, Isaac S.
    Margulies, David M.
    An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge2014Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, nr 3, s. R53-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

  • 17.
    Bürglin, Thomas R.
    Södertörns högskola, Institutionen för livsvetenskaper.
    The Hedgehog protein family2008Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 9, nr 11, s. 241-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Hedgehog (Hh) pathway is one of the fundamental signal transduction pathways in animal development and is also involved in stem-cell maintenance and carcinogenesis. The hedgehog (hh) gene was first discovered in Drosophila, and members of the family have since been found in most metazoa. Hh proteins are composed of two domains, an amino-terminal domain HhN, which has the biological signal activity, and a carboxy-terminal autocatalytic domain HhC, which cleaves Hh into two parts in an intramolecular reaction and adds a cholesterol moiety to HhN. HhC has sequence similarity to the self-splicing inteins, and the shared region is termed Hint. New classes of proteins containing the Hint domain have been discovered recently in bacteria and eukaryotes, and the Hog class, of which Hh proteins comprise one family, is widespread throughout eukaryotes. The non-Hh Hog proteins have carboxy-terminal domains ( the Hog domain) highly similar to HhC, although they lack the HhN domain, and instead have other amino-terminal domains. Hog proteins are found in many protists, but the Hh family emerged only in early metazoan evolution. HhN is modified by cholesterol at its carboxyl terminus and by palmitate at its amino terminus in both flies and mammals. The modified HhN is released from the cell and travels through the extracellular space. On binding its receptor Patched, it relieves the inhibition that Patched exerts on Smoothened, a G-protein-coupled receptor. The resulting signaling cascade converges on the transcription factor Cubitus interruptus (Ci), or its mammalian counterparts, the Gli proteins, which activate or repress target genes.

  • 18. Ceron, Julian
    et al.
    Swoboda, Peter
    Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institute.
    Caenorhabditis elegans comes of age2008Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 9, nr 6, s. 312-Artikel i tidskrift (Övrigt vetenskapligt)
  • 19. Chen, Nansheng
    et al.
    Mah, Allan
    Blacque, Oliver E.
    Chu, Jeffrey
    Phgora, Kiran
    Bakhoum, Mathieu W.
    Newbury, C. Rebecca Hunt
    Khattra, Jaswinder
    Chan, Susanna
    Go, Anne
    Efimenko, Evgeni
    Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institute.
    Johnsen, Robert
    Phirke, Prasad
    Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institute.
    Swoboda, Peter
    Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institute.
    Marra, Marco
    Moerman, Donald G.
    Leroux, Michel R.
    Baillie, David L.
    Stein, Lincoln D.
    Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics2006Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 7, nr 12, s. R126-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The recent availability of genome sequences of multiple related Caenorhabditis species has made it possible to identify, using comparative genomics, similarly transcribed genes in Caenorhabditis elegans and its sister species. Taking this approach, we have identified numerous novel ciliary genes in C. elegans, some of which may be orthologs of unidentified human ciliopathy genes. Results: By screening for genes possessing canonical X-box sequences in promoters of three Caenorhabditis species, namely C. elegans, C. briggsae and C. remanei, we identified 93 genes ( including known X-box regulated genes) that encode putative components of ciliated neurons in C. elegans and are subject to the same regulatory control. For many of these genes, restricted anatomical expression in ciliated cells was confirmed, and control of transcription by the ciliogenic DAF-19 RFX transcription factor was demonstrated by comparative transcriptional profiling of different tissue types and of daf-19(+) and daf-19(-) animals. Finally, we demonstrate that the dye-filling defect of dyf-5( mn400) animals, which is indicative of compromised exposure of cilia to the environment, is caused by a nonsense mutation in the serine/threonine protein kinase gene M04C9.5. Conclusion: Our comparative genomics-based predictions may be useful for identifying genes involved in human ciliopathies, including Bardet-Biedl Syndrome ( BBS), since the C. elegans orthologs of known human BBS genes contain X-box motifs and are required for normal dye filling in C. elegans ciliated neurons.

  • 20.
    Daniel, Chammiran
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Silberberg, Gilad
    Behm, Mikaela
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Öhman, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Alu elements shape the primate transcriptome by cis-regulation of RNA editing2014Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, nr 2, artikel-id R28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 21.
    Daniel, Chammiran
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Widmark, Albin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Rigardt, Ditte
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Öhman, Marie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Editing inducer elements increases A-to-I editing efficiency in the mammalian transcriptome2017Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 18, artikel-id 195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Adenosine to inosine (A-to-I) RNA editing has been shown to be an essential event that plays a significant role in neuronal function, as well as innate immunity, in mammals. It requires a structure that is largely double-stranded for catalysis but little is known about what determines editing efficiency and specificity in vivo. We have previously shown that some editing sites require adjacent long stem loop structures acting as editing inducer elements (EIEs) for efficient editing. Results: The glutamate receptor subunit A2 is edited at the Q/R site in almost 100% of all transcripts. We show that efficient editing at the Q/R site requires an EIE in the downstream intron, separated by an internal loop. Also, other efficiently edited sites are flanked by conserved, highly structured EIEs and we propose that this is a general requisite for efficient editing, while sites with low levels of editing lack EIEs. This phenomenon is not limited to mRNA, as non-coding primary miRNAs also use EIEs to recruit ADAR to specific sites. Conclusions: We propose a model where two regions of dsRNA are required for efficient editing: first, an RNA stem that recruits ADAR and increases the local concentration of the enzyme, then a shorter, less stable duplex that is ideal for efficient and specific catalysis. This discovery changes the way we define and determine a substrate for A-to-I editing. This will be important in the discovery of novel editing sites, as well as explaining cases of altered editing in relation to disease.

  • 22. Dick, G J
    et al.
    Andersson, Anders
    KTH, Skolan för bioteknologi (BIO), Genteknologi.
    Baker, B J
    Simmons, S L
    Thomas, B C
    Yelton, A P
    Banfield, J F
    Community-wide analysis of microbial genome sequence signatures2009Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 10, nr 8, s. R85-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Analyses of DNA sequences from cultivated microorganisms have revealed genome-wide, taxa-specific nucleotide compositional characteristics, referred to as genome signatures. These signatures have far-reaching implications for understanding genome evolution and potential application in classification of metagenomic sequence fragments. However, little is known regarding the distribution of genome signatures in natural microbial communities or the extent to which environmental factors shape them. RESULTS: We analyzed metagenomic sequence data from two acidophilic biofilm communities, including composite genomes reconstructed for nine archaea, three bacteria, and numerous associated viruses, as well as thousands of unassigned fragments from strain variants and low-abundance organisms. Genome signatures, in the form of tetranucleotide frequencies analyzed by emergent self-organizing maps, segregated sequences from all known populations sharing < 50 to 60% average amino acid identity and revealed previously unknown genomic clusters corresponding to low-abundance organisms and a putative plasmid. Signatures were pervasive genome-wide. Clusters were resolved because intra-genome differences resulting from translational selection or protein adaptation to the intracellular (pH approximately 5) versus extracellular (pH approximately 1) environment were small relative to inter-genome differences. We found that these genome signatures stem from multiple influences but are primarily manifested through codon composition, which we propose is the result of genome-specific mutational biases. CONCLUSIONS: An important conclusion is that shared environmental pressures and interactions among coevolving organisms do not obscure genome signatures in acid mine drainage communities. Thus, genome signatures can be used to assign sequence fragments to populations, an essential prerequisite if metagenomics is to provide ecological and biochemical insights into the functioning of microbial communities.

  • 23. Dyke, Stephanie O M
    et al.
    Cheung, Warren A
    Joly, Yann
    Ammerpohl, Ole
    Lutsik, Pavlo
    Rothstein, Mark A
    Caron, Maxime
    Busche, Stephan
    Bourque, Guillaume
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Flicek, Paul
    Beck, Stephan
    Hirst, Martin
    Stunnenberg, Henk
    Siebert, Reiner
    Walter, Jörn
    Pastinen, Tomi
    Epigenome data release: a participant-centered approach to privacy protection2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, artikel-id 142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Large-scale epigenome mapping by the NIH Roadmap Epigenomics Project, the ENCODE Consortium and the International Human Epigenome Consortium (IHEC) produces genome-wide DNA methylation data at one base-pair resolution. We examine how such data can be made open-access while balancing appropriate interpretation and genomic privacy. We propose guidelines for data release that both reduce ambiguity in the interpretation of open-access data and limit immediate access to genetic variation data that are made available through controlled access.

  • 24. Fairfield, Heather
    et al.
    Gilbert, Griffith J
    Barter, Mary
    Corrigan, Rebecca R
    Curtain, Michelle
    Ding, Yueming
    D'Ascenzo, Mark
    Gerhardt, Daniel J
    He, Chao
    Huang, Wenhui
    Richmond, Todd
    Rowe, Lucy
    Probst, Frank J
    Bergström, David E
    Murray, Stephen A
    Bult, Carol
    Richardson, Joel
    Kile, Benjamin T
    Gut, Ivo
    Hager, Jorg
    Sigurdsson, Snaevar
    Mauceli, Evan
    Di Palma, Federica
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Cunningham, Michael L
    Cox, Timothy C
    Justice, Monica J
    Spector, Mona S
    Lowe, Scott W
    Albert, Thomas
    Donahue, Leah Rae
    Jeddeloh, Jeffrey
    Shendure, Jay
    Reinholdt, Laura G
    Mutation discovery in mice by whole exome sequencing2011Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, nr 9, s. R86-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report the development and optimization of reagents for in-solution, hybridization-based capture of the mouse exome. By validating this approach in a multiple inbred strains and in novel mutant strains, we show that whole exome sequencing is a robust approach for discovery of putative mutations, irrespective of strain background. We found strong candidate mutations for the majority of mutant exomes sequenced, including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis.

  • 25. Faurby, Søren
    et al.
    Werdelin, Lars
    Naturhistoriska riksmuseet, Enheten för paleobiologi.
    Svenning, Jens-Christian
    The difference between trivial and scientific names: There were never any true cheetahs in North America2016Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760XArtikel i tidskrift (Övrigt vetenskapligt)
  • 26. Fleischer, Thomas
    et al.
    Frigessi, Arnoldo
    Johnson, Kevin C.
    Edvardsen, Hege
    Touleimat, Nizar
    Klajic, Jovana
    Riis, Margit L. H.
    Haakensen, Vilde D.
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Naume, Bjorn
    Helland, Aslaug
    Borresen-Dale, Anne-Lise
    Tost, Jorg
    Christensen, Brock C.
    Kristensen, Vessela N.
    Genome-wide DNA methylation profiles in progression to in situ and invasive carcinoma of the breast with impact on gene transcription and prognosis2014Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, nr 8, s. 435-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Ductal carcinoma in situ (DCIS) of the breast is a precursor of invasive breast carcinoma. DNA methylation alterations are thought to be an early event in progression of cancer, and may prove valuable as a tool in clinical decision making and for understanding neoplastic development. Results: We generate genome-wide DNA methylation profiles of 285 breast tissue samples representing progression of cancer, and validate methylation changes between normal and DCIS in an independent dataset of 15 normal and 40 DCIS samples. We also validate a prognostic signature on 583 breast cancer samples from The Cancer Genome Atlas. Our analysis reveals that DNA methylation profiles of DCIS are radically altered compared to normal breast tissue, involving more than 5,000 genes. Changes between DCIS and invasive breast carcinoma involve around 1,000 genes. In tumors, DNA methylation is associated with gene expression of almost 3,000 genes, including both negative and positive correlations. A prognostic signature based on methylation level of 18 CpGs is associated with survival of breast cancer patients with invasive tumors, as well as with survival of patients with DCIS and mixed lesions of DCIS and invasive breast carcinoma. Conclusions: This work demonstrates that changes in the epigenome occur early in the neoplastic progression, provides evidence for the possible utilization of DNA methylation-based markers of progression in the clinic, and highlights the importance of epigenetic changes in carcinogenesis.

  • 27.
    Fuxelius, Hans-Henrik
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Darby, Alistair C.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Cho, N. H.
    Andersson, Siv G. E.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Visualization of pseudogenes in intracellular bacteria reveals the different tracks to gene destruction2008Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 9, nr 2, s. R42-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Pseudogenes reveal ancestral gene functions. Some obligate intracellular bacteria, such as Mycobacterium leprae and Rickettsia spp., carry substantial fractions of pseudogenes. Until recently, horizontal gene transfers were considered to be rare events in obligate host-associated bacteria. Results: We present a visualization tool that displays the relationships and positions of degraded and partially overlapping gene sequences in multiple genomes. With this tool we explore the origin and deterioration patterns of the Rickettsia pseudogenes and find that variably present genes and pseudogenes tend to have been acquired more recently, are more divergent in sequence, and exhibit a different functional profile compared with genes conserved across all species. Overall, the origin of only one-quarter of the variable genes and pseudogenes can be traced back to the common ancestor of Rickettsia and the outgroup genera Orientia and Wolbachia. These sequences contain only a few disruptive mutations and show a broad functional distribution profile, much like the core genes. The remaining genes and pseudogenes are extensively degraded or solely present in a single species. Their functional profile was heavily biased toward the mobile gene pool and genes for components of the cell wall and the lipopolysaccharide. Conclusion: Reductive evolution of the vertically inherited genomic core accounts for 25% of the predicted genes in the variable segments of the Rickettsia genomes, whereas 75% stems from the flux of the mobile gene pool along with genes for cell surface structures. Thus, most of the variably present genes and pseudogenes in Rickettsia have arisen from recent acquisitions.

  • 28.
    Genshaft, Alex S.
    et al.
    MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;MIT, Dept Chem, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Ragon Inst Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
    Li, Shuqiang
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    Gallant, Caroline J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Darmanis, Spyros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Uppsala, Sweden.;Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA.;Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA.;Howard Hughes Med Inst, Stanford, CA USA..
    Prakadan, Sanjay M.
    MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;MIT, Dept Chem, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Ragon Inst Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
    Ziegler, Carly G. K.
    MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Ragon Inst Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Harvard Univ, Div Hlth Sci & Technol, Cambridge, MA 02138 USA.;MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA..
    Lundberg, Martin
    Olink Prote, Uppsala, Sweden..
    Fredriksson, Simon
    Olink Prote, Uppsala, Sweden..
    Hong, Joyce
    MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA..
    Regev, Aviv
    Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Dept Biol, Boston, MA 02142 USA.;MIT, Koch Inst, Boston, MA 02142 USA.;Howard Hughes Med Inst, Chevy Chase, MD 20815 USA..
    Livak, Kenneth J.
    Fluidigm Corp, San Francisco, CA 94080 USA..
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Shalek, Alex K.
    MIT, Inst Med Engn & Sci, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;MIT, Dept Chem, Cambridge, MA 02139 USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;MIT, Ragon Inst Massachusetts Gen Hosp, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Harvard Univ, Div Hlth Sci & Technol, Cambridge, MA 02138 USA.;MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA..
    Multiplexed, targeted profiling of single-cell proteomes and transcriptomes in a single reaction2016Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 17, artikel-id 188Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present a scalable, integrated strategy for coupled protein and RNA detection from single cells. Our approach leverages the DNA polymerase activity of reverse transcriptase to simultaneously perform proximity extension assays and complementary DNA synthesis in the same reaction. Using the Fluidigm C1 (TM) system, we profile the transcriptomic and proteomic response of a human breast adenocarcinoma cell line to a chemical perturbation, benchmarking against in situ hybridizations and immunofluorescence staining, as well as recombinant proteins, ERCC Spike-Ins, and population lysate dilutions. Through supervised and unsupervised analyses, we demonstrate synergies enabled by simultaneous measurement of single-cell protein and RNA abundances. Collectively, our generalizable approach highlights the potential for molecular metadata to inform highly-multiplexed single-cell analyses.

  • 29. Gerardo, Nicole M
    et al.
    Altincicek, Boran
    Anselme, Caroline
    Atamian, Hagop
    Barribeau, Seth M
    de Vos, Martin
    Duncan, Elizabeth J
    Evans, Jay D
    Gabaldón, Toni
    Ghanim, Murad
    Heddi, Adelaziz
    Kaloshian, Isgouhi
    Latorre, Amparo
    Moya, Andres
    Nakabachi, Atsushi
    Parker, Benjamin J
    Pérez-Brocal, Vincente
    Pignatelli, Miguel
    Rahbé, Yvan
    Ramsey, John S
    Spragg, Chelsea J
    Tamames, Javier
    Tamarit, Daniel
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Tamborindeguy, Cecilia
    Vincent-Monegat, Caroline
    Vilcinskas, Andreas
    Immunity and other defenses in pea aphids, Acyrthosiphon pisum.2010Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 11, nr 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Recent genomic analyses of arthropod defense mechanisms suggest conservation of key elements underlying responses to pathogens, parasites and stresses. At the center of pathogen-induced immune responses are signaling pathways triggered by the recognition of fungal, bacterial and viral signatures. These pathways result in the production of response molecules, such as antimicrobial peptides and lysozymes, which degrade or destroy invaders. Using the recently sequenced genome of the pea aphid (Acyrthosiphon pisum), we conducted the first extensive annotation of the immune and stress gene repertoire of a hemipterous insect, which is phylogenetically distantly related to previously characterized insects models.

    RESULTS: Strikingly, pea aphids appear to be missing genes present in insect genomes characterized to date and thought critical for recognition, signaling and killing of microbes. In line with results of gene annotation, experimental analyses designed to characterize immune response through the isolation of RNA transcripts and proteins from immune-challenged pea aphids uncovered few immune-related products. Gene expression studies, however, indicated some expression of immune and stress-related genes.

    CONCLUSIONS: The absence of genes suspected to be essential for the insect immune response suggests that the traditional view of insect immunity may not be as broadly applicable as once thought. The limitations of the aphid immune system may be representative of a broad range of insects, or may be aphid specific. We suggest that several aspects of the aphid life style, such as their association with microbial symbionts, could facilitate survival without strong immune protection.

  • 30. Glass, Daniel
    et al.
    Viñuela, Ana
    Davies, Matthew N
    Ramasamy, Adaikalavan
    Parts, Leopold
    Knowles, David
    Brown, Andrew A
    Hedman, Åsa K
    Small, Kerrin S
    Buil, Alfonso
    Grundberg, Elin
    Nica, Alexandra C
    Di Meglio, Paola
    Nestle, Frank O
    Ryten, Mina
    Durbin, Richard
    McCarthy, Mark I
    Deloukas, Panagiotis
    Dermitzakis, Emmanouil T
    Weale, Michael E
    Bataille, Veronique
    Spector, Tim D
    Gene expression changes with age in skin, adipose tissue, blood and brain.2013Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, nr 7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age.

    RESULTS: Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues.

    CONCLUSIONS: Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.

  • 31. Gnerre, Sante
    et al.
    Lander, Eric S
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Jaffe, David B
    Assisted assembly: how to improve a de novo genome assembly by using related species2009Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 10, nr 8, s. R88-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe a new assembly algorithm, where a genome assembly with low sequence coverage, either throughout the genome or locally, due to cloning bias, is considerably improved through an assisting process via a related genome. We show that the information provided by aligning the whole-genome shotgun reads of the target against a reference genome can be used to substantially improve the quality of the resulting assembly.

  • 32.
    Guerrero-Bosagna, Carlos
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biologi. Linköpings universitet, Tekniska fakulteten.
    High type II error and interpretation inconsistencies when attempting to refute transgenerational epigenetic inheritance2016Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 17, nr 1, artikel-id 153Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A recently published article in Genome Biology attempts to refute important aspects of the phenomenon of transgenerational epigenetic inheritance (TEI). An alternative explanation of the data is offered here, showing that TEI is indeed not contradicted.Please see related Correspondence article: www.dx.doi.org/10.1186/s13059-016-0981-5 and related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-015-0619-z.

  • 33. Götz, Dorothee
    et al.
    Paytubi, Sonia
    Munro, Stacey
    Lundgren, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Bernander, Rolf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    White, Malcolm F.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Molekylär evolution.
    Responses of hyperthermophilic crenarchaea to UV irradiation2007Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 8, nr 10, s. R220-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:

    DNA damage leads to cellular responses that include the increased expression of DNA repair genes, repression of DNA replication and alterations in cellular metabolism. Archaeal information processing pathways resemble those in eukaryotes, but archaeal damage response pathways remain poorly understood.

    Results:

    We analyzed the transcriptional response to UV irradiation in two related crenarchaea, Sulfolobus solfataricus and Sulfolobus acidocaldarius. Sulfolobus species encounter high levels of DNA damage in nature, as they inhabit high temperature, aerobic environments and are exposed to sunlight. No increase in expression of DNA repair genes following UV irradiation was observed. There was, however, a clear transcriptional response, including repression of DNA replication and chromatin proteins. Differential effects on the expression of the three transcription factor B ( tfb) genes hint at a mechanism for the modulation of transcriptional patterns in response to DNA damage. TFB3, which is strongly induced following UV irradiation, competes with TFB1 for binding to RNA polymerase in vitro, and may act as a repressor of transcription or an alternative transcription factor for certain promoters.

    Conclusion:

    A clear response to DNA damage was observed, with down-regulation of the DNA replication machinery, changes in transcriptional regulatory proteins, and up-regulation of the biosynthetic enzymes for beta-carotene, which has UV protective properties, and proteins that detoxify reactive oxygen species. However, unlike eukaryotes and bacteria, there was no induction of DNA repair proteins in response to DNA damage, probably because these are expressed constitutively to deal with increased damage arising due to high growth temperatures.

  • 34.
    Hard, Joanna
    et al.
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Al Hakim, Ezeddin
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Kindblom, Marie
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Bjorklund, Asa K.
    Uppsala Univ, Dept Cell & Mol Biol, Natl Bioinformat Infrastruct Sweden, Scilifelab, Uppsala, Sweden..
    Sennblad, Bengt
    Uppsala Univ, Dept Cell & Mol Biol, Natl Bioinformat Infrastruct Sweden, Scilifelab, Uppsala, Sweden..
    Demirci, Ilke
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Paterlini, Marta
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Reu, Pedro
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Borgström, Erik
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Genteknologi.
    Stahl, Patrik L.
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Michaelsson, Jakob
    Karolinska Inst, Dept Med, Ctr Infect Med, Huddinge, Sweden..
    Mold, Jeff E.
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Frisen, Jonas
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden..
    Conbase: a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing2019Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 20, artikel-id 68Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Accurate variant calling and genotyping represent major limiting factors for downstream applications of single-cell genomics. Here, we report Conbase for the identification of somatic mutations in single-cell DNA sequencing data. Conbase leverages phased read data from multiple samples in a dataset to achieve increased confidence in somatic variant calls and genotype predictions. Comparing the performance of Conbase to three other methods, we find that Conbase performs best in terms of false discovery rate and specificity and provides superior robustness on simulated data, in vitro expanded fibroblasts and clonal lymphocyte populations isolated directly from a healthy human donor.

  • 35. Herman, Jonathan D.
    et al.
    Rice, Daniel P.
    Ribacke, Ulf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Silterra, Jacob
    Deik, Amy A.
    Moss, Eli L.
    Broadbent, Kate M.
    Neafsey, Daniel E.
    Desai, Michael M.
    Clish, Clary B.
    Mazitschek, Ralph
    Wirth, Dyann F.
    A genomic and evolutionary approach reveals non-genetic drug resistance in malaria2014Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, nr 11, s. 511-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use.

  • 36.
    Holland, Linda Z.
    et al.
    Univ Calif San Diego, Scripps Inst Oceanog, Marine Biol Res Div, La Jolla, CA 92093 USA.
    Ocampo Daza, Daniel
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi. Univ Calif Merced, Sch Nat Sci, Merced, CA 95343 USA.
    A new look at an old question: when did the second whole genome duplication occur in vertebrate evolution?2018Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 19, artikel-id 209Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A recent study used 61 extant animal genomes to reconstruct the chromosomes of the hypothetical amniote ancestor. Comparison of this karyotype to the 17 chordate linkage groups previously inferred in the ancestral chordate indicated that two whole genome duplications probably occurred in the lineage preceding the ancestral vertebrate.

  • 37.
    Hugerth, Luisa W.
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi.
    Larsson, John
    Alneberg, Johannes
    KTH, Skolan för bioteknologi (BIO), Genteknologi.
    Lindh, Markus V.
    Legrand, Catherine
    Pinhassi, Jarone
    Andersson, Anders F.
    KTH, Skolan för bioteknologi (BIO), Genteknologi.
    Metagenome-assembled genomes uncover a global brackish microbiome2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, artikel-id 279Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Microbes are main drivers of biogeochemical cycles in oceans and lakes. Although the genome is a foundation for understanding the metabolism, ecology and evolution of an organism, few bacterioplankton genomes have been sequenced, partly due to difficulties in cultivating them. Results: We use automatic binning to reconstruct a large number of bacterioplankton genomes from a metagenomic time-series from the Baltic Sea, one of world's largest brackish water bodies. These genomes represent novel species within typical freshwater and marine clades, including clades not previously sequenced. The genomes' seasonal dynamics follow phylogenetic patterns, but with fine-grained lineage-specific variations, reflected in gene-content. Signs of streamlining are evident in most genomes, and estimated genome sizes correlate with abundance variation across filter size fractions. Comparing the genomes with globally distributed metagenomes reveals significant fragment recruitment at high sequence identity from brackish waters in North America, but little from lakes or oceans. This suggests the existence of a global brackish metacommunity whose populations diverged from freshwater and marine relatives over 100,000 years ago, long before the Baltic Sea was formed (8000 years ago). This markedly contrasts to most Baltic Sea multicellular organisms, which are locally adapted populations of freshwater or marine counterparts. Conclusions: We describe the gene content, temporal dynamics and biogeography of a large set of new bacterioplankton genomes assembled from metagenomes. We propose that brackish environments exert such strong selection that lineages adapted to them flourish globally with limited influence from surrounding aquatic communities.

  • 38.
    Hugerth, Luisa W.
    et al.
    KTH Royal Institute of Technology.
    Larsson, John
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Alneberg, Johannes
    KTH Royal Institute of Technology.
    Lindh, Markus V.
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Legrand, Catherine
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Pinhassi, Jarone
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Andersson, Anders F.
    KTH Royal Institute of Technology.
    Metagenome-assembled genomes uncover a global brackish microbiome2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, artikel-id 279Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Microbes are main drivers of biogeochemical cycles in oceans and lakes. Although the genome is a foundation for understanding the metabolism, ecology and evolution of an organism, few bacterioplankton genomes have been sequenced, partly due to difficulties in cultivating them. Results: We use automatic binning to reconstruct a large number of bacterioplankton genomes from a metagenomic time-series from the Baltic Sea, one of world's largest brackish water bodies. These genomes represent novel species within typical freshwater and marine clades, including clades not previously sequenced. The genomes' seasonal dynamics follow phylogenetic patterns, but with fine-grained lineage-specific variations, reflected in gene-content. Signs of streamlining are evident in most genomes, and estimated genome sizes correlate with abundance variation across filter size fractions. Comparing thegenomes with globally distributed metagenomes reveals significant fragment recruitment at high sequence identity from brackish waters in North America, but little from lakes or oceans. This suggests the existence of a global brackish metacommunity whose populations diverged from freshwater and marine relatives over 100,000 years ago, long before the Baltic Sea was formed (8000 years ago). This markedly contrasts to most Baltic Sea multicellular organisms, which are locally adapted populations of freshwater or marine counterparts. Conclusions: We describe the gene content, temporal dynamics and biogeography of a large set of new bacterioplankton genomes assembled from metagenomes. We propose that brackish environments exert such strong selection that lineages adapted to them flourish globally with limited influence from surrounding aquatic communities.

  • 39.
    Hugerth, Luisa W.
    et al.
    KTH Royal Institute of Technology.
    Larsson, John
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Alneberg, Johannes
    KTH Royal Institute of Technology.
    Lindh, Markus V.
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Legrand, Catherine
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Pinhassi, Jarone
    Linnéuniversitetet, Fakulteten för Hälso- och livsvetenskap (FHL), Institutionen för biologi och miljö (BOM).
    Andersson, Anders F.
    KTH Royal Institute of Technology.
    Metagenome-assembled genomes uncover a global brackish microbiome2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, artikel-id 279Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Microbes are main drivers of biogeochemical cycles in oceans and lakes. Although the genome is a foundation for understanding the metabolism, ecology and evolution of an organism, few bacterioplankton genomes have been sequenced, partly due to difficulties in cultivating them. Results: We use automatic binning to reconstruct a large number of bacterioplankton genomes from a metagenomic time-series from the Baltic Sea, one of world's largest brackish water bodies. These genomes represent novel species within typical freshwater and marine clades, including clades not previously sequenced. The genomes' seasonal dynamics follow phylogenetic patterns, but with fine-grained lineage-specific variations, reflected in gene-content. Signs of streamlining are evident in most genomes, and estimated genome sizes correlate with abundance variation across filter size fractions. Comparing thegenomes with globally distributed metagenomes reveals significant fragment recruitment at high sequence identity from brackish waters in North America, but little from lakes or oceans. This suggests the existence of a global brackish metacommunity whose populations diverged from freshwater and marine relatives over 100,000 years ago, long before the Baltic Sea was formed (8000 years ago). This markedly contrasts to most Baltic Sea multicellular organisms, which are locally adapted populations of freshwater or marine counterparts. Conclusions: We describe the gene content, temporal dynamics and biogeography of a large set of new bacterioplankton genomes assembled from metagenomes. We propose that brackish environments exert such strong selection that lineages adapted to them flourish globally with limited influence from surrounding aquatic communities.

  • 40.
    Hughes, Diarmaid
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Evaluating genome dynamics: the constraints on rearrangements within bacterial genomes2000Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 1, nr 6, s. 0006.1-0006.8Artikel, forskningsöversikt (Övrigt vetenskapligt)
    Abstract [en]

    Inversions and translocations distinguish the genomes of closely related bacterial species, but most of these rearrangements preserve the relationship between the rearranged fragments and the axis of chromosome replication. Within species, such rearrangements are found less frequently, except in the case of clinical isolates of human pathogens, where rearrangements are very frequent.

  • 41. Hurst, Laurence D.
    et al.
    Sachenkova, Oxana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Daub, Carsten
    Forrest, Alistair R. R.
    Huminiecki, Lukasz
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Karolinska Institutet, Sweden; BILS bioinformatics infrastructure for life sciences, Sweden; Uppsala University, Sweden.
    A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators2014Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, nr 7, s. 413-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Conventional wisdom holds that, owing to the dominance of features such as chromatin level control, the expression of a gene cannot be readily predicted from knowledge of promoter architecture. This is reflected, for example, in a weak or absent correlation between promoter divergence and expression divergence between paralogs. However, an inability to predict may reflect an inability to accurately measure or employment of the wrong parameters. Here we address this issue through integration of two exceptional resources: ENCODE data on transcription factor binding and the FANTOM5 high-resolution expression atlas. Results: Consistent with the notion that in eukaryotes most transcription factors are activating, the number of transcription factors binding a promoter is a strong predictor of expression breadth. In addition, evolutionarily young duplicates have fewer transcription factor binders and narrower expression. Nonetheless, we find several binders and cooperative sets that are disproportionately associated with broad expression, indicating that models more complex than simple correlations should hold more predictive power. Indeed, a machine learning approach improves fit to the data compared with a simple correlation. Machine learning could at best moderately predict tissue of expression of tissue specific genes. Conclusions: We find robust evidence that some expression parameters and paralog expression divergence are strongly predictable with knowledge of transcription factor binding repertoire. While some cooperative complexes can be identified, consistent with the notion that most eukaryotic transcription factors are activating, a simple predictor, the number of binding transcription factors found on a promoter, is a robust predictor of expression breadth.

  • 42. Hurst, Laurence D.
    et al.
    Sachenkova, Oxana
    Daub, Carsten
    Forrest, Alistair R. R.
    Huminiecki, Lukasz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators2014Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, nr 7, s. 413-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Conventional wisdom holds that, owing to the dominance of features such as chromatin level control, the expression of a gene cannot be readily predicted from knowledge of promoter architecture. This is reflected, for example, in a weak or absent correlation between promoter divergence and expression divergence between paralogs. However, an inability to predict may reflect an inability to accurately measure or employment of the wrong parameters. Here we address this issue through integration of two exceptional resources: ENCODE data on transcription factor binding and the FANTOM5 high-resolution expression atlas. Results: Consistent with the notion that in eukaryotes most transcription factors are activating, the number of transcription factors binding a promoter is a strong predictor of expression breadth. In addition, evolutionarily young duplicates have fewer transcription factor binders and narrower expression. Nonetheless, we find several binders and cooperative sets that are disproportionately associated with broad expression, indicating that models more complex than simple correlations should hold more predictive power. Indeed, a machine learning approach improves fit to the data compared with a simple correlation. Machine learning could at best moderately predict tissue of expression of tissue specific genes. Conclusions: We find robust evidence that some expression parameters and paralog expression divergence are strongly predictable with knowledge of transcription factor binding repertoire. While some cooperative complexes can be identified, consistent with the notion that most eukaryotic transcription factors are activating, a simple predictor, the number of binding transcription factors found on a promoter, is a robust predictor of expression breadth.

  • 43.
    Hård, Joanna
    et al.
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Al Hakim, Ezeddin
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Kindblom, Marie
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Björklund, Åsa K.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sennblad, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Demirci, Ilke
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Paterlini, Marta
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Reu, Pedro
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Borgström, Erik
    KTH Royal Inst Technol, Div Gene Technol, Scilifelab, Solna, Sweden.
    Ståhl, Patrik L.
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Michaelsson, Jakob
    Karolinska Inst, Dept Med, Ctr Infect Med, Huddinge, Sweden.
    Mold, Jeff E.
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Frisen, Jonas
    Karolinska Inst, Dept Cell & Mol Biol, Solna, Sweden.
    Conbase: a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing2019Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 20, artikel-id 68Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Accurate variant calling and genotyping represent major limiting factors for downstream applications of single-cell genomics. Here, we report Conbase for the identification of somatic mutations in single-cell DNA sequencing data. Conbase leverages phased read data from multiple samples in a dataset to achieve increased confidence in somatic variant calls and genotype predictions. Comparing the performance of Conbase to three other methods, we find that Conbase performs best in terms of false discovery rate and specificity and provides superior robustness on simulated data, in vitro expanded fibroblasts and clonal lymphocyte populations isolated directly from a healthy human donor.

  • 44.
    Ison, Jon
    et al.
    Tech Univ Denmark, Natl Life Sci Supercomp Ctr, Bldg 208, DK-2800 Lyngby, Denmark.
    Ienasescu, Hans
    Tech Univ Denmark, Natl Life Sci Supercomp Ctr, Bldg 208, DK-2800 Lyngby, Denmark.
    Chmura, Piotr
    Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark.
    Rydza, Emil
    Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark.
    Menager, Herve
    Inst Pasteur, Hub Bioinformat & Biostat, C3BI USR, 3756 IP CNRS, Paris, France.
    Kalas, Matus
    Univ Bergen, Computat Biol Unit, Dept Informat, N-5020 Bergen, Norway.
    Schwammle, Veit
    Univ Southern Denmark, Dept Biochem & Mol Biol, Campusvej 55, DK-5230 Odense, Denmark;Univ Southern Denmark, VILLUM Ctr Bioanalyt Sci, Campusvej 55, DK-5230 Odense, Denmark.
    Gruening, Bjoern
    Albert Ludwigs Univ Freiburg, Dept Comp Sci, Georges Kohler Allee 106, D-79110 Freiburg, Germany.
    Beard, Niall
    Univ Manchester, Sch Comp Sci, Oxford Rd, Manchester M13 9PL, Lancs, England.
    Lopez, Rodrigo
    EMBL European Bioinformat Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England.
    Duvaud, Severine
    SIB Swiss Inst Bioinformat, Quartier Sorge Batiment Amphipole, CH-1015 Lausanne, Switzerland.
    Stockinger, Heinz
    SIB Swiss Inst Bioinformat, Quartier Sorge Batiment Amphipole, CH-1015 Lausanne, Switzerland.
    Persson, Bengt
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Varekova, Radka Svobodova
    Masaryk Univ Brno, CEITEC Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic.
    Racek, Tomas
    Masaryk Univ Brno, CEITEC Cent European Inst Technol, Kamenice 5, Brno 62500, Czech Republic.
    Vondrasek, Jiri
    Czech Acad Sci, Inst Organ Chem & Biochem, Flemingovo Namesti 2, Prague 16000, Czech Republic.
    Peterson, Hedi
    Univ Tartu, Inst Comp Sci, ELIXIR EE, J Liivi 2, Tartu, Estonia.
    Salumets, Ahto
    Univ Tartu, Inst Comp Sci, ELIXIR EE, J Liivi 2, Tartu, Estonia.
    Jonassen, Inge
    Hooft, Rob
    Dutch Techcentre Life Sci, Jaarbeurspl 6, NL-3521 AL Utrecht, Netherlands.
    Nyronen, Tommi
    CSC IT Ctr Sci, POB 405, FI-02101 Espoo, Finland.
    Valencia, Alfonso
    BSC, Barcelona 08034, Spain;ICREA, Pg Lluis Co 23, Barcelona 08010, Spain.
    Capella, Salvador
    BSC, Barcelona 08034, Spain.
    Gelpi, Josep
    BSC, Barcelona 08034, Spain;Univ Barcelona, INB BSC CNS, Dept Biochem & Mol Biomed, Barcelona, Spain.
    Zambelli, Federico
    Natl Res Council CNR, Inst Biomembranes Bioenerget & Mol Biotechnol, Via Amendola 165-A, Bari, Italy;Univ Milan, Dept Biosci, Via Celoria 26, Milan, Italy.
    Savakis, Babis
    Biomed Sci Res Ctr, Alexander Fleming 34 Al Fleming Str, Vari 16672, Greece.
    Leskosek, Brane
    Univ Ljubljana, Fac Med, ELIXIR SI, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia.
    Rapacki, Kristoffer
    Blanchet, Christophe
    CNRS, UMS 3601, Inst Francais Bioinformat, IFB Core, 2 Rue Gaston Cremieux, F-91000 Evry, France.
    Jimenez, Rafael
    ELIXIR Hub, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England.
    Oliveira, Arlindo
    Inst Super Tecn, INESC ID, R Alves Redol 9, Lisbon, Portugal.
    Vriend, Gert
    Radboud Univ Nijmegen, Med Ctr, Postbus 9101, NL-6500 HB Nijmegen, Netherlands.
    Collin, Olivier
    Plateforme GenOuest Univ Rennes, INRIA, CNRS, IRISA, F-35000 Rennes, France.
    van Helden, Jacques
    Aix Marseille Univ, INSERM, Lab Theory & Approaches Genome Complex TAGC, Marseille, France.
    Longreen, Peter
    Tech Univ Denmark, Natl Life Sci Supercomp Ctr, Bldg 208, DK-2800 Lyngby, Denmark.
    Brunak, Soren
    Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark;Tech Univ Denmark, Dept Bio & Hlth Informat, Bldg 208, DK-2800 Lyngby, Denmark.
    The bio.tools registry of software tools and data resources for the life sciences2019Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 20, nr 1, artikel-id 164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bioinformaticians and biologists rely increasingly upon workflows for the flexible utilization of the many life science tools that are needed to optimally convert data into knowledge. We outline a pan-European enterprise to provide a catalogue () of tools and databases that can be used in these workflows. bio.tools not only lists where to find resources, but also provides a wide variety of practical information.

  • 45.
    Johansson, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Speck, Christian
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    A top-down view on DNA replication and recombination from 9,000 feet above sea level2011Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, nr 4, artikel-id 304Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A report of the Keystone Symposium 'DNA Replication and Recombination' held in Keystone, USA, 27 February to 4 March 2011.

  • 46.
    Kang, Wenjing
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Eldfjell, Yrin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Fromm, Bastian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Estivill, Xavier
    Biryukova, Inna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Friedländer, Marc R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    miRTrace reveals the organismal origins of microRNA sequencing data2018Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 19, artikel-id 213Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present here miRTrace, the first algorithm to trace microRNA sequencing data back to their taxonomic origins. This is a challenge with profound implications for forensics, parasitology, food control, and research settings where cross-contamination can compromise results. miRTrace accurately (> 99%) assigns real and simulated data to 14 important animal and plant groups, sensitively detects parasitic infection in mammals, and discovers the primate origin of single cells. Applying our algorithm to over 700 public datasets, we find evidence that over 7% are cross-contaminated and present a novel solution to clean these computationally, even after sequencing has occurred.

  • 47. Karlsson, Elinor K
    et al.
    Sigurdsson, Snaevar
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ivansson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Thomas, Rachael
    Elvers, Ingegerd
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wright, Jason
    Howald, Cedric
    Tonomura, Noriko
    Perloski, Michele
    Swofford, Ross
    Biagi, Tara
    Fryc, Sarah
    Anderson, Nathan
    Courtay-Cahen, Celine
    Youell, Lisa
    Ricketts, Sally L
    Mandlebaum, Sarah
    Rivera, Patricio
    von Euler, Henrik
    Kisseberth, William C
    London, Cheryl A
    Lander, Eric S
    Couto, Guillermo
    Comstock, Kenine
    Starkey, Mike P
    Modiano, Jaime F
    Breen, Matthew
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B2013Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, nr 12, artikel-id R132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.

    RESULTS: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors.

    CONCLUSIONS: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.

  • 48.
    Laurencon, Anne
    et al.
    Université de Lyon, France.
    Dubruille, Raphaelle
    Université de Lyon, France / University of Massachusetts Medical School, USA.
    Efimenko, Evgeni
    Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institute.
    Grenier, Guillaume
    Université de Lyon, France.
    Bissett, Ryan
    Université de Lyon, France / University of Glasgow, UK.
    Cortier, Elisabeth
    Université de Lyon, France.
    Rolland, Vivien
    Université de Lyon, France.
    Swoboda, Peter
    Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institute.
    Durand, Benedicte
    Université de Lyon, France.
    Identification of novel regulatory factor X (RFX) target genes by comparative genomics in Drosophila species2007Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 8, nr 9, s. R195-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Regulatory factor X (RFX) transcription factors play a key role in ciliary assembly in nematode, Drosophila and mouse. Using the tremendous advantages of comparative genomics in closely related species, we identified novel genes regulated by dRFX in Drosophila. Results: We first demonstrate that a subset of known ciliary genes in Caenorhabditis elegans and Drosophila are regulated by dRFX and have a conserved RFX binding site (X-box) in their promoters in two highly divergent Drosophila species. We then designed an X-box consensus sequence and carried out a genome wide computer screen to identify novel genes under RFX control. We found 412 genes that share a conserved X-box upstream of the ATG in both species, with 83 genes presenting a more restricted consensus. We analyzed 25 of these 83 genes, 16 of which are indeed RFX target genes. Two of them have never been described as involved in ciliogenesis. In addition, reporter construct expression analysis revealed that three of the identified genes encode proteins specifically localized in ciliated endings of Drosophila sensory neurons. Conclusion: Our X-box search strategy led to the identification of novel RFX target genes in Drosophila that are involved in sensory ciliogenesis. We also established a highly valuable Drosophila cilia and basal body dataset. These results demonstrate the accuracy of the X-box screen and will be useful for the identification of candidate genes for human ciliopathies, as several human homologs of RFX target genes are known to be involved in diseases, such as Bardet-BiedI syndrome.

  • 49.
    Le Duc, Diana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Renaud, Gabriel
    Krishnan, Arunkumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Almén, Markus Sällman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Huynen, Leon
    Prohaska, Sonja J.
    Ongyerth, Matthias
    Bitarello, Barbara D.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Hofreiter, Michael
    Stadler, Peter F.
    Pruefer, Kay
    Lambert, David
    Kelso, Janet
    Schoeneberg, Torsten
    Kiwi genome provides insights into evolution of a nocturnal lifestyle2015Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, artikel-id 147Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Kiwi, comprising five species from the genus Apteryx, are endangered, ground-dwelling bird species endemic to New Zealand. They are the smallest and only nocturnal representatives of the ratites. The timing of kiwi adaptation to a nocturnal niche and the genomic innovations, which shaped sensory systems and morphology to allow this adaptation, are not yet fully understood. Results: We sequenced and assembled the brown kiwi genome to 150-fold coverage and annotated the genome using kiwi transcript data and non-redundant protein information from multiple bird species. We identified evolutionary sequence changes that underlie adaptation to nocturnality and estimated the onset time of these adaptations. Several opsin genes involved in color vision are inactivated in the kiwi. We date this inactivation to the Oligocene epoch, likely after the arrival of the ancestor of modern kiwi in New Zealand. Genome comparisons between kiwi and representatives of ratites, Galloanserae, and Neoaves, including nocturnal and song birds, show diversification of kiwi's odorant receptors repertoire, which may reflect an increased reliance on olfaction rather than sight during foraging. Further, there is an enrichment of genes influencing mitochondrial function and energy expenditure among genes that are rapidly evolving specifically on the kiwi branch, which may also be linked to its nocturnal lifestyle. Conclusions: The genomic changes in kiwi vision and olfaction are consistent with changes that are hypothesized to occur during adaptation to nocturnal lifestyle in mammals. The kiwi genome provides a valuable genomic resource for future genome-wide comparative analyses to other extinct and extant diurnal ratites.

  • 50. Lokk, Kaie
    et al.
    Modhukur, Vijayachitra
    Rajashekar, Balaji
    Märtens, Kaspar
    Mägi, Reedik
    Kolde, Raivo
    Koltšina, Marina
    Nilsson, Torbjörn K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Vilo, Jaak
    Salumets, Andres
    Tõnisson, Neeme
    DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns2014Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 15, nr 4, s. r54-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: DNA epigenetic modifications, such as methylation, are important regulators of tissue differentiation, contributing to processes of both development and cancer. Profiling the tissue-specific DNA methylome patterns will provide novel insights into normal and pathogenic mechanisms, as well as help in future epigenetic therapies. In this study, 17 somatic tissues from four autopsied humans were subjected to functional genome analysis using the Illumina Infinium HumanMethylation450 BeadChip, covering 486 428 CpG sites. RESULTS: Only 2% of the CpGs analyzed are hypermethylated in all 17 tissue specimens; these permanently methylated CpG sites are located predominantly in gene-body regions. In contrast, 15% of the CpGs are hypomethylated in all specimens and are primarily located in regions proximal to transcription start sites. A vast number of tissue-specific differentially methylated regions are identified and considered likely mediators of tissue-specific gene regulatory mechanisms since the hypomethylated regions are closely related to known functions of the corresponding tissue. Finally, a clear inverse correlation is observed between promoter methylation within CpG islands and gene expression data obtained from publicly available databases. CONCLUSIONS: This genome-wide methylation profiling study identified tissue-specific differentially methylated regions in 17 human somatic tissues. Many of the genes corresponding to these differentially methylated regions contribute to tissue-specific functions. Future studies may use these data as a reference to identify markers of perturbed differentiation and disease-related pathogenic mechanisms.

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