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  • 1.
    Barrio, Alvaro Martinez
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ekerljung, Marie
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Benachenhou, Farid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Sperber, Göran O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bongcam-Rudloff, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Andersson, Göran
    The First Sequenced Carnivore Genome Shows Complex Host-Endogenous Retrovirus Relationships2011In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 5, p. e19832-Article in journal (Refereed)
    Abstract [en]

    Host-retrovirus interactions influence the genomic landscape and have contributed substantially to mammalian genome evolution. To gain further insights, we analyzed a female boxer (Canis familiaris) genome for complexity and integration pattern of canine endogenous retroviruses (CfERV). Intriguingly, the first such in-depth analysis of a carnivore species identified 407 CfERV proviruses that represent only 0.15% of the dog genome. In comparison, the same detection criteria identified about six times more HERV proviruses in the human genome that has been estimated to contain a total of 8% retroviral DNA including solitary LTRs. These observed differences in man and dog are likely due to different mechanisms to purge, restrict and protect their genomes against retroviruses. A novel group of gammaretrovirus-like CfERV with high similarity to HERV-Fc1 was found to have potential for active retrotransposition and possibly lateral transmissions between dog and human as a result of close interactions during at least 10.000 years. The CfERV integration landscape showed a non-uniform intra-and inter-chromosomal distribution. Like in other species, different densities of ERVs were observed. Some chromosomal regions were essentially devoid of CfERVs whereas other regions had large numbers of integrations in agreement with distinct selective pressures at different loci. Most CfERVs were integrated in antisense orientation within 100 kb from annotated protein-coding genes. This integration pattern provides evidence for selection against CfERVs in sense orientation relative to chromosomal genes. In conclusion, this ERV analysis of the first carnivorous species supports the notion that different mammals interact distinctively with endogenous retroviruses and suggests that retroviral lateral transmissions between dog and human may have occurred.

  • 2.
    Benachenhou, Farid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Oja, Merja
    Helsinki University of Technology.
    Sperber, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Blikstad, Vidar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Somervuo, Panu
    Helsinki Institute for Information Technology, Department of Computer Science, University of Helsinki.
    Kaski, Samuel
    Helsinki Institute for Information Technology, Department of Computer Science, University of Helsinki.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Evolutionary Conservation of Orthoretroviral Long Terminal Repeats (LTRs) and ab initio Detection of Single LTRs in Genomic Data2009In: PLos ONE, ISSN 1932-6203, Vol. 4, no 4, p. e5179-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Retroviral LTRs, paired or single, influence the transcription of both retroviral and non-retroviral genomic sequences. Vertebrate genomes contain many thousand endogenous retroviruses (ERVs) and their LTRs. Single LTRs are difficult to detect from genomic sequences without recourse to repetitiveness or presence in a proviral structure. Understanding of LTR structure increases understanding of LTR function, and of functional genomics. Here we develop models of orthoretroviral LTRs useful for detection in genomes and for structural analysis. PRINCIPAL FINDINGS: Although mutated, ERV LTRs are more numerous and diverse than exogenous retroviral (XRV) LTRs. Hidden Markov models (HMMs), and alignments based on them, were created for HML- (human MMTV-like), general-beta-, gamma- and lentiretroviruslike LTRs, plus a general-vertebrate LTR model. Training sets were XRV LTRs and RepBase LTR consensuses. The HML HMM was most sensitive and detected 87% of the HML LTRs in human chromosome 19 at 96% specificity. By combining all HMMs with a low cutoff, for screening, 71% of all LTRs found by RepeatMasker in chromosome 19 were found. HMM consensus sequences had a conserved modular LTR structure. Target site duplications (TG-CA), TATA (occasionally absent), an AATAAA box and a T-rich region were prominent features. Most of the conservation was located in, or adjacent to, R and U5, with evidence for stem loops. Several of the long HML LTRs contained long ORFs inserted after the second A rich module. HMM consensus alignment allowed comparison of functional features like transcriptional start sites (sense and antisense) between XRVs and ERVs. CONCLUSION: The modular conserved and redundant orthoretroviral LTR structure with three A-rich regions is reminiscent of structurally relaxed Giardia promoters. The five HMMs provided a novel broad range, repeat-independent, ab initio LTR detection, with prospects for greater generalisation, and insight into LTR structure, which may aid development of LTR-targeted pharmaceuticals.

  • 3.
    Blomberg, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Sperber, Göran. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Benachenhou, Farid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Towards a retrovirus database, RetroBank2010In: Centennial Retrovirus Meeting / [ed] Rene Daniel, Jiri Hejnar, Anna Marie Skalka, Jan Svoboda, Bologna, Italy: Medimond , 2010, p. 19-22Conference paper (Other academic)
  • 4. Blomberg, Jonas
    et al.
    Ushameckis, Dimitrijs
    Jern, Patric
    Evolutionary Aspects of Human Endogenous Retroviral Sequences (HERVs) and Disease2005In: Retroviruses and Primate Genome Evolution, Georgetown, TX, USA: Eurekah.com / Landes Bioscience , 2005Chapter in book (Refereed)
  • 5. Brattås, Per Ludvik
    et al.
    Jönsson, Marie E.
    Fasching, Liana
    Nelander Wahlestedt, Jenny
    Shahsavani, Mansoureh
    Falk, Ronny
    Falk, Anna
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Parmar, Malin
    Jakobsson, Johan
    TRIM28 Controls a Gene Regulatory Network Based on Endogenous Retroviruses in Human Neural Progenitor Cells2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Endogenous retroviruses (ERVs), which make up 8% of the human genome, have been proposed to participate in the control of gene regulatory networks. In this study, we find a region- and developmental stage-specific expression pattern of ERVs in the developing human brain, which is linked to a transcriptional network based on ERVs. We demonstrate that almost 10,000, primarily primate-specific, ERVs act as docking platforms for the co-repressor protein TRIM28 in human neural progenitor cells, which results in the establishment of local heterochromatin. Thereby, TRIM28 represses ERVs and consequently regulates the expression of neighboring genes. These results uncover a gene regulatory network based on ERVs that participates in control of gene expression of protein-coding transcripts important for brain development.

  • 6. Delhomme, N.
    et al.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zamani, Neda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lantz, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lin, Y. C.
    Hvidsten, T. R.
    Höppner, Marc P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Van de Peer, Y.
    Lundeberg, J.
    Grabherr, Manfred G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Street, N. R.
    Serendipitous Meta-Transcriptomics: The Fungal Community of Norway Spruce (Picea abies)2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0139080Article in journal (Refereed)
    Abstract [en]

    After performing de novo transcript assembly of >1 billion RNA-Sequencing reads obtained from 22 samples of different Norway spruce (Picea abies) tissues that were not surface sterilized, we found that assembled sequences captured a mix of plant, lichen, and fungal transcripts. The latter were likely expressed by endophytic and epiphytic symbionts, indicating that these organisms were present, alive, and metabolically active. Here, we show that these serendipitously sequenced transcripts need not be considered merely as contamination, as is common, but that they provide insight into the plant's phyllosphere. Notably, we could classify these transcripts as originating predominantly from Dothideomycetes and Leotiomycetes species, with functional annotation of gene families indicating active growth and metabolism, with particular regards to glucose intake and processing, as well as gene regulation.

  • 7. Fasching, L.
    et al.
    Kapopoulou, A.
    Sachdeva, R.
    Petri, R.
    Jönsson, M. E.
    Männe, C.
    Turelli, P.
    Jern, Patric
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cammas, F.
    Trono, D.
    Jakobsson, J.
    TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, no 1, p. 20-28Article in journal (Refereed)
    Abstract [en]

    TRIM28 is a corepressor that mediates transcriptional silencing by establishing local heterochromatin. Here, we show that deletion of TRIM28 in neural progenitor cells (NPCs) results in high-level expression of two groups of endogenous retroviruses (ERVs): IAP1 and MMERVK10C. We find that NPCs use TRIM28-mediated histone modifications to dynamically regulate transcription and silencing of ERVs, which is in contrast to other somatic cell types using DNA methylation. We also show that derepression of ERVs influences transcriptional dynamics in NPCs through the activation of nearby genes and the expression of long noncoding RNAs. These findings demonstrate a unique dynamic transcriptional regulation of ERVs in NPCs. Our results warrant future studies on the role of ERVs in the healthy and diseased brain.

  • 8.
    Forsman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Yun, Zhihong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Hu, Lijuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Uzhameckis, Dmitrijs
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Development of broadly targeted human endogenous gammaretroviralpol-based real time PCRs Quantitation of RNA expression in human tissues2005In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 129, no 1, p. 16-30Article in journal (Refereed)
    Abstract [en]

    Endogenous retroviral sequences (ERVs) are dynamic genomic components with profound influences on gene expression and genomic structure. Their extent of expression is not well known. Several broadly targeted real-time reverse transcription PCR (QPCRs) systems for surveillance of RNA expression of the major groups of human gammaretroviral ERVs were constructed. The highly conserved reverse transcriptase (RT) and integrase (IN) domains of the pol gene were used as targets for the PCRs, which were both probe-based (TaqMan) and probe-less (SYBR Green). Different levels of primer and probe degeneracy, with or without inosine, were tested. Several of the PCRs had sensitivities of a few HERV nucleic acid copies per PCR reaction. Specificities were approximately as expected from the fit of primers and probes. Gammaretroviral HERV RNA expression was studied in different human tissues. Each HERV group had a specific pattern of expression. HERV-E was highly expressed in testis, HERV-I/T in brain and testis, HERV-H in brain and testis, while HERV-W was highly expressed in placenta. Gammaretroviral RNA was not detected in plasma from 50 blood donors in saliva from 20 persons. In conclusion, a set of tools for investigation of gammaretroviral HERV RNA expression was created.

  • 9. Groenen, M. A.
    et al.
    Archibald, A. L.
    Uenishi, H.
    Tuggle, C. K.
    Takeuchi, Y.
    Rothschild, M. F.
    Rogel-Gaillard, C.
    Park, C.
    Milan, D.
    Megens, H. J.
    Li, S.
    Larkin, D. M.
    Kim, H.
    Frantz, L. A.
    Caccamo, M.
    Ahn, H.
    Aken, B. L.
    Anselmo, A.
    Anthon, C.
    Auvil, L.
    Badaoui, B.
    Beattie, C. W.
    Bendixen, C.
    Berman, D.
    Blecha, F.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Bolund, L.
    Bosse, M.
    Botti, S.
    Bujie, Z.
    Byström, M.
    Capitanu, B.
    Carvalho-Silva, D.
    Chardon, P.
    Chen, C.
    Cheng, R.
    Choi, S. H.
    Chow, W.
    Clark, R. C.
    Clee, C.
    Crooijmans, R. P.
    Dawson, H. D.
    Dehais, P.
    De Sapio, F.
    Dibbits, B.
    Drou, N.
    Du, Z. Q.
    Eversole, K.
    Fadista, J.
    Fairley, S.
    Faraut, T.
    Faulkner, G. J.
    Fowler, K. E.
    Fredholm, M.
    Fritz, E.
    Gilbert, J. G.
    Giuffra, E.
    Gorodkin, J.
    Griffin, D. K.
    Harrow, J. L.
    Hayward, Alexander
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Howe, K.
    Hu, Z. L.
    Humphray, S. J.
    Hunt, T.
    Hornshoj, H.
    Jeon, J. T.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jones, M.
    Jurka, J.
    Kanamori, H.
    Kapetanovic, R.
    Kim, J.
    Kim, J. H.
    Kim, K. W.
    Kim, T. H.
    Larson, G.
    Lee, K.
    Lee, K. T.
    Leggett, R.
    Lewin, H. A.
    Li, Y.
    Liu, W.
    Loveland, J. E.
    Lu, Y.
    Lunney, J. K.
    Ma, J.
    Madsen, O.
    Mann, K.
    Matthews, L.
    McLaren, S.
    Morozumi, T.
    Murtaugh, M. P.
    Narayan, J.
    Nguyen, D. T.
    Ni, P.
    Oh, S. J.
    Onteru, S.
    Panitz, F.
    Park, E. W.
    Park, H. S.
    Pascal, G.
    Paudel, Y.
    Perez-Enciso, M.
    Ramirez-Gonzalez, R.
    Reecy, J. M.
    Rodriguez-Zas, S.
    Rohrer, G. A.
    Rund, L.
    Sang, Y.
    Schachtschneider, K.
    Schraiber, J. G.
    Schwartz, J.
    Scobie, L.
    Scott, C.
    Searle, S.
    Servin, B.
    Southey, B. R.
    Sperber, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Stadler, P.
    Sweedler, J. V.
    Tafer, H.
    Thomsen, B.
    Wali, R.
    Wang, J.
    White, S.
    Xu, X.
    Yerle, M.
    Zhang, G.
    Zhang, J.
    Zhao, S.
    Rogers, J.
    Churcher, C.
    Schook, L. B.
    Analyses of pig genomes provide insight into porcine demography and evolution2012In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7424, p. 393-398Article in journal (Refereed)
    Abstract [en]

    For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars approximately 1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.

  • 10.
    Hayward, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cornwallis, Charlie K.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pan-vertebrate comparative genomics unmasks retrovirus macroevolution2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 2, p. 464-469Article in journal (Refereed)
    Abstract [en]

    Although extensive research has demonstrated host-retrovirus microevolutionary dynamics, it has been difficult to gain a deeper understanding of the macroevolutionary patterns of host-retrovirus interactions. Here we use recent technological advances to infer broad patterns in retroviral diversity, evolution, and host-virus relationships by using a large-scale phylogenomic approach using endogenous retroviruses (ERVs). Retroviruses insert a proviral DNA copy into the host cell genome to produce new viruses. ERVs are provirus insertions in germline cells that are inherited down the host lineage and consequently present a record of past host-viral associations. By mining ERVs from 65 host genomes sampled across vertebrate diversity, we uncover a great diversity of ERVs, indicating that retroviral sequences are much more prevalent and widespread across vertebrates than previously appreciated. The majority of ERV clades that we recover do not contain known retroviruses, implying either that retroviral lineages are highly transient over evolutionary time or that a considerable number of retroviruses remain to be identified. By characterizing the distribution of ERVs, we show that no major vertebrate lineage has escaped retroviral activity and that retroviruses are extreme host generalists, having an unprecedented ability for rampant host switching among distantly related vertebrates. In addition, we examine whether the distribution of ERVs can be explained by host factors predicted to influence viral transmission and find that internal fertilization has a pronounced effect on retroviral colonization of host genomes. By capturing the mode and pattern of retroviral evolution and contrasting ERV diversity with known retroviral diversity, our study provides a cohesive framework to understand host-virus coevolution better.

  • 11.
    Hayward, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghazal, Awaisa
    Andersson, Göran
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    ZBED Evolution: Repeated Utilization of DNA Transposons as Regulators of Diverse Host Functions2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e59940-Article in journal (Refereed)
    Abstract [en]

    ZBED genes originate from domesticated hAT DNA transposons and encode regulatory proteins of diverse function in vertebrates. Here we reveal the evolutionary relationship between ZBED genes and demonstrate that they are derived from at least two independent domestication events in jawed vertebrate ancestors. We show that ZBEDs form two monophyletic clades, one of which has expanded through several independent duplications in host lineages. Subsequent diversification of ZBED genes has facilitated regulation of multiple diverse fundamental functions. In contrast to known examples of transposable element exaptation, our results demonstrate a novel unprecedented capacity for the repeated utilization of a family of transposable element-derived protein domains sequestered as regulators during the evolution of diverse host gene functions in vertebrates. Specifically, ZBEDs have contributed to vertebrate regulatory innovation through the donation of modular DNA and protein interacting domains. We identify that C7ORF29, ZBED2, 3, 4, and ZBEDX form a monophyletic group together with ZBED6, that is distinct from ZBED1 genes. Furthermore, we show that ZBED5 is related to Buster DNA transposons and is phylogenetically separate from other ZBEDs. Our results offer new insights into the evolution of regulatory pathways, and suggest that DNA transposons have contributed to regulatory complexity during genome evolution in vertebrates.

  • 12.
    Hayward, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Broad-scale phylogenomics provides insights into retrovirus–host evolution2013In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 50, p. 20146-20151Article in journal (Refereed)
    Abstract [en]

    Genomic data provide an excellent resource to improve understanding of retrovirus evolution and the complex relationships among viruses and their hosts. In conjunction with broad-scale in silico screening of vertebrate genomes, this resource offers an opportunity to complement data on the evolution and frequency of past retroviral spread and so evaluate future risks and limitations for horizontal transmission between different host species. Here, we develop a methodology for extracting phylogenetic signal from large endogenous retrovirus (ERV) datasets by collapsing information to facilitate broad-scale phylogenomics across a wide sample of hosts. Starting with nearly 90,000 ERVs from 60 vertebrate host genomes, we construct phylogenetic hypotheses and draw inferences regarding the designation, host distribution, origin, and transmission of the Gammaretrovirus genus and associated class I ERVs. Our results uncover remarkable depths in retroviral sequence diversity, supported within a phylogenetic context. This finding suggests that current infectious exogenous retrovirus diversity may be underestimated, adding credence to the possibility that many additional exogenous retroviruses may remain to be discovered in vertebrate taxa. We demonstrate a history of frequent horizontal interorder transmissions from a rodent reservoir and suggest that rats may have acted as important overlooked facilitators of gammaretrovirus spread across diverse mammalian hosts. Together, these results demonstrate the promise of the methodology used here to analyze large ERV datasets and improve understanding of retroviral evolution and diversity for utilization in wider applications.

  • 13. Horie, Masayuki
    et al.
    Honda, Tomoyuki
    Suzuki, Yoshiyuki
    Kobayashi, Yuki
    Daito, Takuji
    Oshida, Tatsuo
    Ikuta, Kazuyoshi
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gojobori, Takashi
    Coffin, John M
    Tomonaga, Keizo
    Endogenous non-retroviral RNA virus elements in mammalian genomes.2010In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 463, no 7277, p. 84-87Article in journal (Refereed)
    Abstract [en]

    Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements. Although many other viruses, including non-retroviral RNA viruses, are known to generate DNA forms of their own genomes during replication, none has been found as DNA in the germline of animals. Bornaviruses, a genus of non-segmented, negative-sense RNA virus, are unique among RNA viruses in that they establish persistent infection in the cell nucleus. Here we show that elements homologous to the nucleoprotein (N) gene of bornavirus exist in the genomes of several mammalian species, including humans, non-human primates, rodents and elephants. These sequences have been designated endogenous Borna-like N (EBLN) elements. Some of the primate EBLNs contain an intact open reading frame (ORF) and are expressed as mRNA. Phylogenetic analyses showed that EBLNs seem to have been generated by different insertional events in each specific animal family. Furthermore, the EBLN of a ground squirrel was formed by a recent integration event, whereas those in primates must have been formed more than 40 million years ago. We also show that the N mRNA of a current mammalian bornavirus, Borna disease virus (BDV), can form EBLN-like elements in the genomes of persistently infected cultured cells. Our results provide the first evidence for endogenization of non-retroviral virus-derived elements in mammalian genomes and give novel insights not only into generation of endogenous elements, but also into a role of bornavirus as a source of genetic novelty in its host.

  • 14.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genomic Variation and Evolution of HERV-H and other Endogenous Retroviruses (ERVs)2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    An exogenous retrovirus (XRV) that integrates into a germ cell may be inherited as a Mendelian gene; it becomes an endogenous retrovirus (ERV). The human genome consists of up to 8% HERVs.

    The gammaretroviral (ERV class I) HERV-H, with 926 members, is the largest ERV group. Despite millions of years since integration, it has polymorphic envelope open reading frames in at least three loci. Selections for functional envelopes are indicated on chromosomes 1 and 2. However, envelopes were present only in a fraction of the total HERV-H. Mutated polymerases, indicating old ERVs, contradicted relatively intact long terminal repeats. To explain this, we formulated a “Midwife” element theory where proteins are complemented in trans.

    A phylogenetic analysis did not support separate HERV-H and -F groups. The new taxonomy included HERV-H like (RGH2-like and RTVLH2-like subgroups) and Adjacent HERV-H like. A bioinformatic reconstruction of a putative ancestral HERV-H exposed novel traits. Two nucleocapsid zinc fingers and a pronounced nucleotide bias for C in the HERV-H like were unique among the gammaretroviruses.

    Two recently integrated gammaretroviral groups (PtNeo-I[PTERV1] and -II) were found in chimpanzees but not in humans. The PtNeo groups were most similar to baboon ERVs and a macaque sequence, but neither to other chimpanzee nor to any human gammaretroviruses. The pattern was consistent with cross-species transfer via predation.

    To advance the retroviral taxonomy, we projected structural markers over sequence phylogenetic trees. A number of markers were useful to distinguish between genera and to delineate groups.

    Basic retroviral knowledge is vital to understand emerging infections. Phylogenetic analyses of taxonomically improved sequences, facilitates the search for common retroviral denominators to target. This thesis provided new insights in retroviral evolution and taxonomy using the ERVs, with special focus on the large gammaretroviral HERV-H group, as an additional source of information next to that of XRVs.

    List of papers
    1. Full-length HERV-H elements with env SU open reading frames in the human genome.
    Open this publication in new window or tab >>Full-length HERV-H elements with env SU open reading frames in the human genome.
    2002 (English)In: AIDS Res Hum Retroviruses, ISSN 0889-2229, Vol. 18, no 9, p. 671-6Article in journal (Refereed) Published
    Keywords
    Amino Acid Sequence, Chromosomes; Human; Pair 1, Chromosomes; Human; Pair 2, Endogenous Retroviruses/*genetics, Gene Products; env/*genetics, Genome; Human, Humans, Molecular Sequence Data, Multigene Family, Mutation, Open Reading Frames/genetics, Retroviridae Proteins/*genetics, Sequence Homology; Amino Acid
    Identifiers
    urn:nbn:se:uu:diva-74374 (URN)12079564 (PubMedID)
    Available from: 2005-09-22 Created: 2005-09-22 Last updated: 2011-01-13
    2. Definition and variation of human endogenous retrovirus H.
    Open this publication in new window or tab >>Definition and variation of human endogenous retrovirus H.
    2004 (English)In: Virology, ISSN 0042-6822, Vol. 327, no 1, p. 93-110Article in journal (Refereed) Published
    Keywords
    Amino Acid Sequence, Base Sequence, Computational Biology, DNA Transposable Elements, Electrophoresis/methods, Endogenous Retroviruses/classification/*genetics, Evolution; Molecular, Genes; pol, Humans, Molecular Sequence Data, Phylogeny, Polymerase Chain Reaction, Polymorphism; Single Nucleotide, Research Support; Non-U.S. Gov't, Temperature, Variation (Genetics)
    Identifiers
    urn:nbn:se:uu:diva-74369 (URN)15327901 (PubMedID)
    Available from: 2005-09-22 Created: 2005-09-22 Last updated: 2011-01-12
    3. Sequence variability, gene structure, and expression of full-length human endogenous
    Open this publication in new window or tab >>Sequence variability, gene structure, and expression of full-length human endogenous
    2005 (English)In: J Virol, ISSN 0022-538X, Vol. 79, no 10, p. 6325-37Article in journal (Refereed) Published
    Keywords
    Amino Acid Sequence, Base Sequence, Comparative Study, Endogenous Retroviruses/*genetics, Gene Expression, Gene Products; gag/genetics, Genes; Viral/*genetics, Molecular Sequence Data, Open Reading Frames/genetics, Proviruses/*genetics, Research Support; Non-U.S. Gov't, Sequence Alignment, Terminal Repeat Sequences, Variation (Genetics)
    Identifiers
    urn:nbn:se:uu:diva-74368 (URN)15858016 (PubMedID)
    Available from: 2005-09-22 Created: 2005-09-22 Last updated: 2011-01-11
    4. Divergent patterns of recent retroviral integrations in the human and chimpanzee genomes: probable transmissions between other primates and chimpanzees
    Open this publication in new window or tab >>Divergent patterns of recent retroviral integrations in the human and chimpanzee genomes: probable transmissions between other primates and chimpanzees
    2006 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 80, no 3, p. 1367-1375Article in journal (Refereed) Published
    Abstract [en]

    The human genome is littered by endogenous retrovirus sequences (HERVs), which constitute up to 8% of the total genomic sequence. The sequencing of the human (Homo sapiens) and chimpanzee (Pan troglodytes) genomes has facilitated the evolutionary study of ERVs and related sequences. We screened both the human genome (version hg16) and the chimpanzee genome (version PanTro1) for ERVs and conducted a phylogenetic analysis of recent integrations. We found a number of recent integrations within both genomes. They segregated into four groups. Two larger gammaretrovirus-like groups (PtG1 and PtG2) occurred in chimpanzees but not in humans. The PtG sequences were most similar to two baboon ERVs and a macaque sequence but neither to other chimpanzee ERVs nor to any human gammaretrovirus-like ERVs. The pattern was consistent with cross-species transfer via predation. This appears to be an example of horizontal transfer of retroviruses with occasional fixation in the germ line.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-82748 (URN)10.1128/JVI.80.3.1367-1375.2006. (DOI)16415014 (PubMedID)
    Available from: 2006-09-30 Created: 2006-09-30 Last updated: 2017-12-14Bibliographically approved
    5. Use of Endogenous Retroviral Sequences (ERVs) and structural markers for retroviral
    Open this publication in new window or tab >>Use of Endogenous Retroviral Sequences (ERVs) and structural markers for retroviral
    2005 (English)In: Retrovirology, ISSN 1742-4690, Vol. 2, no 1, p. 50-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-74362 (URN)16092962 (PubMedID)
    Available from: 2005-09-22 Created: 2005-09-22 Last updated: 2011-01-11
  • 15. Jern, Patric
    et al.
    Coffin, John M
    Effects of retroviruses on host genome function.2008In: Annual Review of Genetics, ISSN 0066-4197, E-ISSN 1545-2948, Vol. 42, p. 709-32Article in journal (Refereed)
    Abstract [en]

    For millions of years, retroviral infections have challenged vertebrates, occasionally leading to germline integration and inheritance as ERVs, genetic parasites whose remnants today constitute some 7% to 8% of the human genome. Although they have had significant evolutionary side effects, it is useful to view ERVs as fossil representatives of retroviruses extant at the time of their insertion into the germline and not as direct players in the evolutionary process itself. Expression of particular ERVs is associated with several positive physiological functions as well as certain diseases, although their roles in human disease as etiological agents, possible contributing factors, or disease markers-well demonstrated in animal models-remain to be established. Here we discuss ERV contributions to host genome structure and function, including their ability to mediate recombination, and physiological effects on the host transcriptome resulting from their integration, expression, and other events.

  • 16. Jern, Patric
    et al.
    Coffin, John M
    Host-retrovirus arms race: trimming the budget.2008In: Cell host & microbe, ISSN 1934-6069, Vol. 4, no 3, p. 196-7Article in journal (Refereed)
    Abstract [en]

    In this issue of Cell Host & Microbe, OhAinle et al., 2008 report that APOBEC3H, a potent innate retroviral restriction factor in primates, lost its function twice independently during recent evolution in humans, stressing an ever present trade-off between benefit and cost of protection against pathogens.

  • 17.
    Jern, Patric
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindeskog, Mats
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Damita
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Blomberg, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Full-length HERV-H elements with env SU open reading frames in the human genome.2002In: AIDS Res Hum Retroviruses, ISSN 0889-2229, Vol. 18, no 9, p. 671-6Article in journal (Refereed)
  • 18. Jern, Patric
    et al.
    Russell, Rebecca A
    Pathak, Vinay K
    Coffin, John M
    Likely role of APOBEC3G-mediated G-to-A mutations in HIV-1 evolution and drug resistance.2009In: PLoS pathogens, ISSN 1553-7374, Vol. 5, no 4, p. e1000367-Article in journal (Refereed)
    Abstract [en]

    The role of APOBEC3 (A3) protein family members in inhibiting retrovirus infection and mobile element retrotransposition is well established. However, the evolutionary effects these restriction factors may have had on active retroviruses such as HIV-1 are less well understood. An HIV-1 variant that has been highly G-to-A mutated is unlikely to be transmitted due to accumulation of deleterious mutations. However, G-to-A mutated hA3G target sequences within which the mutations are the least deleterious are more likely to survive selection pressure. Thus, among hA3G targets in HIV-1, the ratio of nonsynonymous to synonymous changes will increase with virus generations, leaving a footprint of past activity. To study such footprints in HIV-1 evolution, we developed an in silico model based on calculated hA3G target probabilities derived from G-to-A mutation sequence contexts in the literature. We simulated G-to-A changes iteratively in independent sequential HIV-1 infections until a stop codon was introduced into any gene. In addition to our simulation results, we observed higher ratios of nonsynonymous to synonymous mutation at hA3G targets in extant HIV-1 genomes than in their putative ancestral genomes, compared to random controls, implying that moderate levels of A3G-mediated G-to-A mutation have been a factor in HIV-1 evolution. Results from in vitro passaging experiments of HIV-1 modified to be highly susceptible to hA3G mutagenesis verified our simulation accuracy. We also used our simulation to examine the possible role of A3G-induced mutations in the origin of drug resistance. We found that hA3G activity could have been responsible for only a small increase in mutations at known drug resistance sites and propose that concerns for increased resistance to other antiviral drugs should not prevent Vif from being considered a suitable target for development of new drugs.

  • 19.
    Jern, Patric
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sperber, Göran
    Department of Neuroscience.
    Ahlsén, Göran
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Blomberg, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sequence variability, gene structure, and expression of full-length human endogenous2005In: J Virol, ISSN 0022-538X, Vol. 79, no 10, p. 6325-37Article in journal (Refereed)
  • 20.
    Jern, Patric
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sperber, Göran
    Department of Neuroscience.
    Blomberg, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Definition and variation of human endogenous retrovirus H.2004In: Virology, ISSN 0042-6822, Vol. 327, no 1, p. 93-110Article in journal (Refereed)
  • 21.
    Jern, Patric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sperber, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Divergent patterns of recent retroviral integrations in the human and chimpanzee genomes: probable transmissions between other primates and chimpanzees2006In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 80, no 3, p. 1367-1375Article in journal (Refereed)
    Abstract [en]

    The human genome is littered by endogenous retrovirus sequences (HERVs), which constitute up to 8% of the total genomic sequence. The sequencing of the human (Homo sapiens) and chimpanzee (Pan troglodytes) genomes has facilitated the evolutionary study of ERVs and related sequences. We screened both the human genome (version hg16) and the chimpanzee genome (version PanTro1) for ERVs and conducted a phylogenetic analysis of recent integrations. We found a number of recent integrations within both genomes. They segregated into four groups. Two larger gammaretrovirus-like groups (PtG1 and PtG2) occurred in chimpanzees but not in humans. The PtG sequences were most similar to two baboon ERVs and a macaque sequence but neither to other chimpanzee ERVs nor to any human gammaretrovirus-like ERVs. The pattern was consistent with cross-species transfer via predation. This appears to be an example of horizontal transfer of retroviruses with occasional fixation in the germ line.

  • 22.
    Jern, Patric
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sperber, Göran
    Department of Neuroscience. fysiologi.
    Blomberg, Jonas
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Use of Endogenous Retroviral Sequences (ERVs) and structural markers for retroviral2005In: Retrovirology, ISSN 1742-4690, Vol. 2, no 1, p. 50-Article in journal (Refereed)
  • 23. Jern, Patric
    et al.
    Stoye, Jonathan P
    Coffin, John M
    Role of APOBEC3 in genetic diversity among endogenous murine leukemia viruses.2007In: PLoS genetics, ISSN 1553-7404, Vol. 3, no 10, p. 2014-22Article in journal (Refereed)
    Abstract [en]

    The ability of human and murine APOBECs (specifically, APOBEC3) to inhibit infecting retroviruses and retrotransposition of some mobile elements is becoming established. Less clear is the effect that they have had on the establishment of the endogenous proviruses resident in the human and mouse genomes. We used the mouse genome sequence to study diversity and genetic traits of nonecotropic murine leukemia viruses (polytropic [Pmv], modified polytropic [Mpmv], and xenotropic [Xmv] subgroups), the best-characterized large set of recently integrated proviruses. We identified 49 proviruses. In phylogenetic analyses, Pmvs and Mpmvs were monophyletic, whereas Xmvs were divided into several clades, implying a greater number of replication cycles between the integration events. Four distinct primer binding site types (Pro, Gln1, Gln2 and Thr) were dispersed within the phylogeny, indicating frequent mispriming. We analyzed the frequency and context of G-to-A mutations for the role of mA3 in formation of these proviruses. In the Pmv and Mpmv (but not Xmv) groups, mutations attributable to mA3 constituted a large fraction of the total. A significant number of nonsense mutations suggests the absence of purifying selection following mutation. A strong bias of G-to-A relative to C-to-T changes was seen, implying a strand specificity that can only have occurred prior to integration. The optimal sequence context of G-to-A mutations, TTC, was consistent with mA3. At least in the Pmv group, a significant 5' to 3' gradient of G-to-A mutations was consistent with mA3 editing. Altogether, our results for the first time suggest mA3 editing immediately preceding the integration event that led to retroviral endogenization, contributing to inactivation of infectivity.

  • 24.
    Kierczak, Marcin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jablonska, Jagoda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Forsberg, S. K.
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tengvall, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Scholz, Veronica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Meadows, Jennifer R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    cgmisc: Enhanced Genome-wide Association Analyses and Visualisation2015In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 31, no 23, p. 3830-3831Article in journal (Refereed)
    Abstract [en]

    SUMMARY:

    High-throughput genotyping and sequencing technologies facilitate studies of complex genetic traits and provide new research opportunities. The increasing popularity of genome-wide association studies (GWAS) leads to the discovery of new associated loci and a better understanding of the genetic architecture underlying not only diseases, but also other monogenic and complex phenotypes. Several softwares are available for performing GWAS analyses, R environment being one of them.

    RESULTS: We present cgmisc, an R package that enables enhanced data analysis and visualisation of results from GWAS. The package contains several utilities and modules that complement and enhance the functionality of the existing software. It also provides several tools for advanced visualisation of genomic data and utilises the power of the R language to aid in preparation of publication-quality figures. Some of the package functions are specific for the domestic dog (Canis familiaris) data.

    AVAILABILITY: The package is operating system-independent and is available from: https://github.com/cgmisc-team/cgmisc CONTACT: cgmisc@imbim.uu.se.

  • 25.
    Martinez Barrio, Alvaro
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Ekerljung, Marie
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Benachenhou, Farid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Sperber, Göran O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bongcam-Rudloff, Erik
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Andersson, Göran
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Data mining of the dog genome reveals novel Canine Endogenous Retroviruses(CfERVs)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Mining the dog genome for canine endogenous retroviruses (CfERV) using the program RetroTector© identified 407 CfERVs (0.15% of the total genome size). Phylogenetic analysis showed that the majority of these CfERVs belong to the gammaretroviridae (n=313) genus. In this group, we found 33 integrated CfERVs with similarity to the human HERV-Fc1. Eighteen of them had conserved open reading frames open and seven of the 18 were recent integrations (≤ 5% LTR divergence). Some of these CfERVs may have potential for active retrotransposition and could actively contribute to the plasticity of canine genomes. Similar to other vertebrates, betaretroviruses (n=28) was the second most common group. In addition, four spuma-like and four gypsy-like CfERVs were identified, the latter group being rare in vertebrate genomes. Moreover, we identified 55 CfERVs that could not be classified unambiguously to any known retroviral genera. The integration landscape shows that all dog chromosomes have CfERV integrations with non-uniform distribution both along and across chromosomes. Some regions were essentially devoid of CfERVs whereas other regions had large numbers. Notably, in a comparison between dog and human genomes, CfERV were approximately one fifth of the amount of HERVs found. Species-specific mechanisms for purging and protection against retroviral infections are suggested to act in the dog genome. The CfERV integration pattern showed that a substantial fraction of annotated genes were found within 100 kb distance from annotated proviruses. The majority of such integrations were placed in antisense orientation relative to the transcriptional direction of the neighboring chromosomal genes. In conclusion, our results from Canis familiaris genome analysis support the notion that different mammals may interact distinctively with endogenous retroviruses.

  • 26.
    Martínez Barrio, Álvaro
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lamichhaney, Sangeet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fan, Guangyi
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; BGI-Shenzhen, Shenzen, China; 5 College of Physics, Qingdao University, Qingdao, China .
    Rafati, Nima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pettersson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, He
    BGI-Shenzhen, Shenzen, China; College of Physics, Qingdao University, Qingdao, China.
    Dainat, Jacques
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University.
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martin, Marcel
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University.
    Nystedt, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Liu, Xin
    BGI-Shenzhen, Shenzen, China.
    Chen, Wenbin
    BGI-Shenzhen, Shenzhen, China.
    Liang, Xinming
    BGI-Shenzhen, Shenzhen, China.
    Shi, Chengcheng
    BGI-Shenzhen, Shenzhen, China.
    Fu, Yuanyuan
    BGI-Shenzhen, Shenzhen, China.
    Ma, Kailong
    BGI-Shenzhen, Shenzhen, China.
    Zhan, Xiao
    BGI-Shenzhen, Shenzhen, China.
    Feng, Chungang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gustafson, Ulla
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sällman Almén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Blass, Martina
    Department of Aquatic Resources, Institute of Coastal Research, Swedish University of Agricultural Sciences, Öregrund, Sweden.
    Casini, Michele
    Swedish University of Agricultural Sciences, Department of Aquatic Resources, Institute of Marine Research.
    Folkvord, Arild
    Department of Biology, University of Bergen, Bergen, Norway; Hjort Center of Marine Ecosystem Dynamics, Bergen, Norway; Institute of Marine Research, Bergen, Norway .
    Laikre, Linda
    Department of Zoology, Stockholm University.
    Ryman, Nils
    Department of Zoology, Stockholm University, Stockholm, Sweden.
    Lee, Simon Ming-Yuen Lee
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao.
    Xu, Xun
    BGI-Shenzhen, Shenzhen, China.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden; Department of Veterinary Integrative Biosciences, Texas A&M University, Texas, United States.
    The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing2016In: eLIFE, E-ISSN 2050-084X, Vol. 5, article id e12081Article in journal (Refereed)
    Abstract [en]

    Ecological adaptation is of major relevance to speciation and sustainable population management, but the underlying genetic factors are typically hard to study in natural populations due to genetic differentiation caused by natural selection being confounded with genetic drift in subdivided populations. Here, we use whole genome population sequencing of Atlantic and Baltic herring to reveal the underlying genetic architecture at an unprecedented detailed resolution for both adaptation to a new niche environment and timing of reproduction. We identify almost 500 independent loci associated with a recent niche expansion from marine (Atlantic Ocean) to brackish waters (Baltic Sea), and more than 100 independent loci showing genetic differentiation between spring- and autumn-spawning populations irrespective of geographic origin. Our results show that both coding and non-coding changes contribute to adaptation. Haplotype blocks, often spanning multiple genes and maintained by selection, are associated with genetic differentiation.

  • 27.
    Rubin, Carl-Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Megens, H. -J
    Barrio, Alvaro Martinez
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maqbool, K.
    Sayyab, S.
    Schwochow, D.
    Wang, Chao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlborg, Örjan
    SLU.
    Jørgensen, C. B.
    Archibald, A. L.
    Fredholm, M.
    Groenen, M. A. M.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strong signatures of selection in the domestic pig genome2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 48, p. 19529-19536Article in journal (Refereed)
    Abstract [en]

    Domestication of wild boar (Sus scrofa) and subsequent selection have resulted in dramatic phenotypic changes in domestic pigs for a number of traits, including behavior, body composition, reproduction, and coat color. Here we have used whole-genome resequencing to reveal some of the loci that underlie phenotypic evolution in European domestic pigs. Selective sweep analyses revealed strong signatures of selection at three loci harboring quantitative trait loci that explain a considerable part of one of the most characteristic morphological changes in the domestic pig - the elongation of the back and an increased number of vertebrae. The three loci were associated with the NR6A1, PLAG1, and LCORL genes. The latter two have repeatedly been associated with loci controlling stature in other domestic animals and in humans. Most European domestic pigs are homozygous for the same haplotype at these three loci. We found an excess of derived nonsynonymous substitutions in domestic pigs, most likely reflecting both positive selection and relaxed purifying selection after domestication. Our analysis of structural variation revealed four duplications at the KIT locus that were exclusively present in white or white-spotted pigs, carrying the Dominant white, Patch, or Belt alleles. This discovery illustrates how structural changes have contributed to rapid phenotypic evolution in domestic animals and how alleles in domestic animals may evolve by the accumulation of multiple causative mutations as a response to strong directional selection.

  • 28. Sanchez-Martinez, Silvia
    et al.
    Aloia, Amanda L.
    Harvin, Demetria
    Mirro, Jane
    Gorelick, Robert J.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Coffin, John M.
    Rein, Alan
    Studies on the Restriction of Murine Leukemia Viruses by Mouse APOBEC32012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e38190-Article in journal (Refereed)
    Abstract [en]

    APOBEC3 proteins function to restrict the replication of retroviruses. One mechanism of this restriction is deamination of cytidines to uridines in (-) strand DNA, resulting in hypermutation of guanosines to adenosines in viral (+) strands. However, Moloney murine leukemia virus (MoMLV) is partially resistant to restriction by mouse APOBEC3 (mA3) and virtually completely resistant to mA3-induced hypermutation. In contrast, the sequences of MLV genomes that are in mouse DNA suggest that they were susceptible to mA3-induced deamination when they infected the mouse germline. We tested the possibility that sensitivity to mA3 restriction and to deamination resides in the viral gag gene. We generated a chimeric MLV in which the gag gene was from an endogenous MLV in the mouse germline, while the remainder of the viral genome was from MoMLV. This chimera was fully infectious but its response to mA3 was indistinguishable from that of MoMLV. Thus, the Gag protein does not seem to control the sensitivity of MLVs to mA3. We also found that MLVs inactivated by mA3 do not synthesize viral DNA upon infection; thus mA3 restriction of MLV occurs before or at reverse transcription. In contrast, HIV-1 restricted by mA3 and MLVs restricted by human APOBEC3G do synthesize DNA; these DNAs exhibit APOBEC3-induced hypermutation.

  • 29.
    Sperber, Göran O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Airola, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Automated recognition of retroviral sequences in genomic data - RetroTector©2007In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, no 15, p. 4964-4976Article in journal (Refereed)
    Abstract [en]

    Eukaryotic genomes contain many endogenous retroviral sequences(ERVs). ERVs are often severely mutated, therefore difficultto detect. A platform independent (Java) program package, RetroTector©(ReTe), was constructed. It has three basic modules: (i) detectionof candidate long terminal repeats (LTRs), (ii) detection ofchains of conserved retroviral motifs fulfilling distance constraintsand (iii) attempted reconstruction of original retroviral proteinsequences, combining alignment, codon statistics and propertiesof protein ends. Other features are prediction of additionalopen reading frames, automated database collection, graphicalpresentation and automatic classification. ReTe favors elements>1000-bp long due to its dependence on order of and distancesbetween retroviral fragments. It detects single or low-copy-numberelements. ReTe assigned a ‘retroviral’ score of890–2827 to 10 exogenous retroviruses from seven genera,and accurately predicted their genes. In a simulated model,ReTe was robust against mutational decay. The human genome wasanalyzed in 1–2 days on a LINUX cluster. Retroviral sequenceswere detected in divergent vertebrate genomes. Most ReTe detectedchains were coincident with Repeatmasker output and the HERVddatabase. ReTe did not report most of the evolutionary old HERV-Lrelated and MalR sequences, and is not yet tailored for singleLTR detection. Nevertheless, ReTe rationally detects and annotatesmany retroviral sequences.

  • 30. Yun, Zhihong
    et al.
    Hu, Lijuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Forsman, Anna
    Uzhameckis, Dmitrijs
    Jern, Patric
    Yolken, Robert
    Torrey, R Fuller
    Blomberg, Jonas
    Individual pattern of RNA expression of human endogenous gammaretrovirus-like sequences in the human brainManuscript (Other academic)
  • 31.
    Zamani, Neda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Russell, Pamela
    Lantz, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hoeppner, Marc
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Vijay, Nagarjun
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Mauceli, Evan
    di Palma, Federica
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Unsupervised genome-wide recognition of local relationship patterns2013In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, p. 347-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Phenomena such as incomplete lineage sorting, horizontal gene transfer, gene duplication and subsequent sub- and neo-functionalisation can result in distinct local phylogenetic relationships that are discordant with species phylogeny. In order to assess the possible biological roles for these subdivisions, they must first be identified and characterised, preferably on a large scale and in an automated fashion.

    RESULTS

    We developed Saguaro, a combination of a Hidden Markov Model (HMM) and a Self Organising Map (SOM), to characterise local phylogenetic relationships among aligned sequences using cacti, matrices of pair-wise distance measures. While the HMM determines the genomic boundaries from aligned sequences, the SOM hypothesises new cacti in an unsupervised and iterative fashion based on the regions that were modelled least well by existing cacti. After testing the software on simulated data, we demonstrate the utility of Saguaro by testing two different data sets: (i) 181 Dengue virus strains, and (ii) 5 primate genomes. Saguaro identifies regions under lineage-specific constraint for the first set, and genomic segments that we attribute to incomplete lineage sorting in the second dataset. Intriguingly for the primate data, Saguaro also classified an additional ~3% of the genome as most incompatible with the expected species phylogeny. A substantial fraction of these regions was found to overlap genes associated with both the innate and adaptive immune systems.

    CONCLUSIONS

    Saguaro detects distinct cacti describing local phylogenetic relationships without requiring any a priori hypotheses. We have successfully demonstrated Saguaro's utility with two contrasting data sets, one containing many members with short sequences (Dengue viral strains: n = 181, genome size = 10,700 nt), and the other with few members but complex genomes (related primate species: n = 5, genome size = 3 Gb), suggesting that the software is applicable to a wide variety of experimental populations. Saguaro is written in C++, runs on the Linux operating system, and can be downloaded from http://saguarogw.sourceforge.net/.

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