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Sperber, Göran
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Publications (10 of 18) Show all publications
Vargiu, L., Rodriguez-Tome, P., Sperber, G. O., Cadeddu, M., Grandi, N., Blikstad, V., . . . Blomberg, J. (2016). Classification and characterization of human endogenous retroviruses: mosaic forms are common. Retrovirology, 13, Article ID 7.
Open this publication in new window or tab >>Classification and characterization of human endogenous retroviruses: mosaic forms are common
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2016 (English)In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 13, article id 7Article in journal (Refereed) Published
Abstract [en]

Background: Human endogenous retroviruses (HERVs) represent the inheritance of ancient germ-line cell infections by exogenous retroviruses and the subsequent transmission of the integrated proviruses to the descendants. ERVs have the same internal structure as exogenous retroviruses. While no replication-competent HERVs have been recognized, some retain up to three of four intact ORFs. HERVs have been classified before, with varying scope and depth, notably in the RepBase/RepeatMasker system. However, existing classifications are bewildering. There is a need for a systematic, unifying and simple classification. We strived for a classification which is traceable to previous classifications and which encompasses HERV variation within a limited number of clades. Results: The human genome assembly GRCh 37/hg19 was analyzed with RetroTector, which primarily detects relatively complete Class I and II proviruses. A total of 3173 HERV sequences were identified. The structure of and relations between these proviruses was resolved through a multi-step classification procedure that involved a novel type of similarity image analysis ("Simage") which allowed discrimination of heterogeneous (noncanonical) from homogeneous (canonical) HERVs. Of the 3173 HERVs, 1214 were canonical and segregated into 39 canonical clades (groups), belonging to class I (Gamma-and Epsilon-like), II (Beta-like) and III (Spuma-like). The groups were chosen based on (1) sequence (nucleotide and Pol amino acid), similarity, (2) degree of fit to previously published clades, often from RepBase, and (3) taxonomic markers. The groups fell into 11 supergroups. The 1959 noncanonical HERVs contained 31 additional, less well-defined groups. Simage analysis revealed several types of mosaicism, notably recombination and secondary integration. By comparing flanking sequences, LTRs and completeness of gene structure, we deduced that some noncanonical HERVs proliferated after the recombination event. Groups were further divided into envelope subgroups (altogether 94) based on sequence similarity and characteristic "immunosuppressive domain" motifs. Intra and inter(super) group, as well as intraclass, recombination involving envelope genes ("env snatching") was a common event. LTR divergence indicated that HERV-K(HML2) and HERVFC had the most recent integrations, HERVL and HUERSP3 the oldest. Conclusions: A comprehensive HERV classification and characterization approach was undertaken. It should be applicable for classification of all ERVs. Recombination was common among HERV ancestors.

Keywords
Human endogenous retrovirus, Classification, Simage, Bioinformatics, RetroTector, Phylogeny, Recombination
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-277788 (URN)10.1186/s12977-015-0232-y (DOI)000368759100001 ()26800882 (PubMedID)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2017-11-30Bibliographically approved
Benachenhou, F., Sperber, G. O., Bongcam-Rudloff, E., Andersson, G., Boeke, J. D. & Blomberg, J. (2013). Conserved structure and inferred evolutionary history of long terminal repeats (LTRs). Mobile DNA, 4, 5
Open this publication in new window or tab >>Conserved structure and inferred evolutionary history of long terminal repeats (LTRs)
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2013 (English)In: Mobile DNA, ISSN 1759-8753, E-ISSN 1759-8753, Vol. 4, p. 5-Article in journal (Refereed) Published
Abstract [en]

Background: Long terminal repeats (LTRs, consisting of U3-R-U5 portions) are important elements of retroviruses and related retrotransposons. They are difficult to analyse due to their variability. The aim was to obtain a more comprehensive view of structure, diversity and phylogeny of LTRs than hitherto possible. Results: Hidden Markov models (HMM) were created for 11 clades of LTRs belonging to Retroviridae (class III retroviruses), animal Metaviridae (Gypsy/Ty3) elements and plant Pseudoviridae (Copia/Ty1) elements, complementing our work with Orthoretrovirus HMMs. The great variation in LTR length of plant Metaviridae and the few divergent animal Pseudoviridae prevented building HMMs from both of these groups. Animal Metaviridae LTRs had the same conserved motifs as retroviral LTRs, confirming that the two groups are closely related. The conserved motifs were the short inverted repeats (SIRs), integrase recognition signals (5' TGTTRNR ... YNYAACA 3'); the polyadenylation signal or AATAAA motif; a GT-rich stretch downstream of the polyadenylation signal; and a less conserved AT-rich stretch corresponding to the core promoter element, the TATA box. Plant Pseudoviridae LTRs differed slightly in having a conserved TATA-box, TATATA, but no conserved polyadenylation signal, plus a much shorter R region. The sensitivity of the HMMs for detection in genomic sequences was around 50% for most models, at a relatively high specificity, suitable for genome screening. The HMMs yielded consensus sequences, which were aligned by creating an HMM model (a 'Superviterbi' alignment). This yielded a phylogenetic tree that was compared with a Pol-based tree. Both LTR and Pol trees supported monophyly of retroviruses. In both, Pseudoviridae was ancestral to all other LTR retrotransposons. However, the LTR trees showed the chromovirus portion of Metaviridae clustering together with Pseudoviridae, dividing Metaviridae into two portions with distinct phylogeny. Conclusion: The HMMs clearly demonstrated a unitary conserved structure of LTRs, supporting that they arose once during evolution. We attempted to follow the evolution of LTRs by tracing their functional foundations, that is, acquisition of RNAse H, a combined promoter/polyadenylation site, integrase, hairpin priming and the primer binding site (PBS). Available information did not support a simple evolutionary chain of events.

Keywords
LTR, Long terminal repeat, Retrotransposon, Retrovirus, Phylogeny, Genome evolution
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-200830 (URN)10.1186/1759-8753-4-5 (DOI)000318308200001 ()
Available from: 2013-06-04 Created: 2013-06-04 Last updated: 2017-12-06Bibliographically approved
Cadeddu, M., Vargiu, L., Rodriguez-Tome, P., Sperber, G. O., Blomberg, J. & Tramontano, E. (2013). Identification and analysis of HML2 sequences in human genome assembly GRCh37/hg19. Paper presented at Frontiers of Retrovirology: Complex retorviruses, retroelements and their hosts, 16-18 September, 2013, Cambridge, UK. Retrovirology, 10(S1), P9
Open this publication in new window or tab >>Identification and analysis of HML2 sequences in human genome assembly GRCh37/hg19
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2013 (English)In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 10, no S1, p. P9-Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211134 (URN)10.1186/1742-4690-10-S1-P9 (DOI)000326099100042 ()
Conference
Frontiers of Retrovirology: Complex retorviruses, retroelements and their hosts, 16-18 September, 2013, Cambridge, UK
Available from: 2013-11-20 Created: 2013-11-20 Last updated: 2017-12-06Bibliographically approved
Vargiu, L., Rodriguez-Tome, P., Sperber, G. O., Tramontano, E. & Blomberg, J. (2013). Overview of human endogenous retroviruses found in human genome assembly GRCh37/hg19. Paper presented at Frontiers of Retrovirology: Complex retorviruses, retroelements and their hosts, 16-18 September, 2013, Cambridge, UK. Retrovirology, 10(S1), P6
Open this publication in new window or tab >>Overview of human endogenous retroviruses found in human genome assembly GRCh37/hg19
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2013 (English)In: Retrovirology, ISSN 1742-4690, E-ISSN 1742-4690, Vol. 10, no S1, p. P6-Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-211135 (URN)10.1186/1742-4690-10-S1-P6 (DOI)000326099100040 ()
Conference
Frontiers of Retrovirology: Complex retorviruses, retroelements and their hosts, 16-18 September, 2013, Cambridge, UK
Available from: 2013-11-20 Created: 2013-11-20 Last updated: 2017-12-06Bibliographically approved
Groenen, M. A., Archibald, A. L., Uenishi, H., Tuggle, C. K., Takeuchi, Y., Rothschild, M. F., . . . Schook, L. B. (2012). Analyses of pig genomes provide insight into porcine demography and evolution. Nature, 491(7424), 393-398
Open this publication in new window or tab >>Analyses of pig genomes provide insight into porcine demography and evolution
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2012 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 491, no 7424, p. 393-398Article in journal (Refereed) Published
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.

National Category
Genetics Evolutionary Biology Animal and Dairy Science
Research subject
Biology with specialization in Evolutionary Genetics; Biology with specialization in Evolutionary Functional Genomics
Identifiers
urn:nbn:se:uu:diva-185085 (URN)10.1038/nature11622 (DOI)000311031600036 ()
Available from: 2012-11-20 Created: 2012-11-20 Last updated: 2017-12-07Bibliographically approved
Bolisetty, M., Blomberg, J., Benachenhou, F., Sperber, G. & Beemon, K. (2012). Unexpected diversity and expression of avian endogenous retroviruses. mBio, 3(5), e00344-12
Open this publication in new window or tab >>Unexpected diversity and expression of avian endogenous retroviruses
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2012 (English)In: mBio, ISSN 2161-2129, Vol. 3, no 5, p. e00344-12Article in journal (Refereed) Published
Abstract [en]

Endogenous retroviruses (ERVs) were identified and characterized in three avian genomes to gain insight into early retroviral evolution. Using the computer program RetroTector to detect relatively intact ERVs, we identified 500 ERVs in the chicken genome, 150 in the turkey genome, and 1,200 in the zebra finch genome. Previous studies suggested that endogenous alpharetroviruses were present in chicken genomes. In this analysis, a small number of alpharetroviruses were seen in the chicken and turkey genomes; however, these were greatly outnumbered by beta-like, gamma-like, and alphabeta proviruses. While the avian ERVs belonged to the same major groups as mammalian ERVs, they were more heterogeneous. In particular, the beta-like viruses revealed an evolutionary continuum with the gradual acquisition and loss of betaretroviral markers and a transition from beta to alphabeta and then to alpharetroviruses. Thus, it appears that birds may resemble a melting pot for early ERV evolution. Many of the ERVs were integrated in clusters on chromosomes, often near centromeres. About 25% of the chicken ERVs were in or near cellular transcription units; this is nearly random. The majority of these integrations were in the sense orientation in introns. A higher-than-random number of integrations were >100 kb from the nearest gene. Deep-sequencing studies of chicken embryo fibroblasts revealed that about 20% of the 500 ERVs were transcribed and translated. A subset of these were also transcribed in vivo in chickens, showing tissue-specific patterns of expression.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-184909 (URN)10.1128/mBio.00344-12 (DOI)000310585000036 ()
Available from: 2012-11-20 Created: 2012-11-15 Last updated: 2012-12-10Bibliographically approved
Blomberg, J., Sheikholvaezin, A., Elfaitouri, A., Blomberg, F., Sjösten, A., Mattson Ulfstedt, J., . . . Sperber, G. (2011). Phylogeny-directed search for murine leukemia virus-like retroviruses in vertebrate genomes and in patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome and prostate cancer [Review]. Advances in Virology, 2011, 341294
Open this publication in new window or tab >>Phylogeny-directed search for murine leukemia virus-like retroviruses in vertebrate genomes and in patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome and prostate cancer
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2011 (English)In: Advances in Virology, ISSN 1687-8639, E-ISSN 1687-8647, Vol. 2011, p. 341294-Article, book review (Refereed) Published
Abstract [en]

Gammaretrovirus-like sequences occur in most vertebrate genomes. Murine Leukemia Virus (MLV) like retroviruses (MLLVs) are a subset, which may be pathogenic and spread cross-species. Retroviruses highly similar to MLLVs (xenotropic murine retrovirus related virus (XMRV) and Human Mouse retrovirus-like RetroViruses (HMRVs)) reported from patients suffering from prostate cancer (PC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) raise the possibility that also humans have been infected. Structurally intact, potentially infectious MLLVs occur in the genomes of some mammals, especially mouse. Mouse MLLVs contain three major groups. One, MERV G3, contained MLVs and XMRV/HMRV. Its presence in mouse DNA, and the abundance of xenotropic MLVs in biologicals, is a source of false positivity. Theoretically, XMRV/HMRV could be one of several MLLV transspecies infections. MLLV pathobiology and diversity indicate optimal strategies for investigating XMRV/HMRV in humans and raise ethical concerns. The alternatives that XMRV/HMRV may give a hard-to-detect "stealth" infection, or that XMRV/HMRV never reached humans, have to be considered.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-294407 (URN)
Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2017-11-30
Blomberg, J., Sheikholvaezin, A., Elfaitouri, A., Blomberg, F., Sjösten, A., Mattson Ulfstedt, J., . . . Sperber, G. (2011). Phylogeny-directed search for murine leukemia virus-like retroviruses in vertebrate genomes and in patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome and prostate cancer [Review]. Advances in Virology, 2011, 341294
Open this publication in new window or tab >>Phylogeny-directed search for murine leukemia virus-like retroviruses in vertebrate genomes and in patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome and prostate cancer
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2011 (English)In: Advances in Virology, ISSN 1687-8639, E-ISSN 1687-8647, Vol. 2011, p. 341294-Article, book review (Refereed) Published
Abstract [en]

Gammaretrovirus-like sequences occur in most vertebrate genomes. Murine Leukemia Virus (MLV) like retroviruses (MLLVs) are a subset, which may be pathogenic and spread cross-species. Retroviruses highly similar to MLLVs (xenotropic murine retrovirus related virus (XMRV) and Human Mouse retrovirus-like RetroViruses (HMRVs)) reported from patients suffering from prostate cancer (PC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) raise the possibility that also humans have been infected. Structurally intact, potentially infectious MLLVs occur in the genomes of some mammals, especially mouse. Mouse MLLVs contain three major groups. One, MERV G3, contained MLVs and XMRV/HMRV. Its presence in mouse DNA, and the abundance of xenotropic MLVs in biologicals, is a source of false positivity. Theoretically, XMRV/HMRV could be one of several MLLV transspecies infections. MLLV pathobiology and diversity indicate optimal strategies for investigating XMRV/HMRV in humans and raise ethical concerns. The alternatives that XMRV/HMRV may give a hard-to-detect "stealth" infection, or that XMRV/HMRV never reached humans, have to be considered.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-174999 (URN)10.1155/2011/341294 (DOI)22315600 (PubMedID)
Available from: 2012-05-31 Created: 2012-05-31 Last updated: 2017-12-07Bibliographically approved
Benachenhou, F., Jern, P., Oja, M., Sperber, G., Blikstad, V., Somervuo, P., . . . Blomberg, J. (2009). Evolutionary Conservation of Orthoretroviral Long Terminal Repeats (LTRs) and ab initio Detection of Single LTRs in Genomic Data. PLos ONE, 4(4), e5179
Open this publication in new window or tab >>Evolutionary Conservation of Orthoretroviral Long Terminal Repeats (LTRs) and ab initio Detection of Single LTRs in Genomic Data
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2009 (English)In: PLos ONE, ISSN 1932-6203, Vol. 4, no 4, p. e5179-Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2009
Keywords
Long terminal repeats, hidden markov models, virology, bioinformatics
National Category
Microbiology in the medical area
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-119767 (URN)10.1371/journal.pone.0005179 (DOI)000265509900009 ()19365549 (PubMedID)
Available from: 2010-03-02 Created: 2010-03-01 Last updated: 2018-01-12Bibliographically approved
Sperber, G., Lövgren, A., Eriksson, N.-E., Benachenhou, F. & Blomberg, J. (2009). RetroTector online, a rational tool for analysis of retroviral elements in small and medium size vertebrate genomic sequences. BMC Bioinformatics, 10 Suppl 6, S4
Open this publication in new window or tab >>RetroTector online, a rational tool for analysis of retroviral elements in small and medium size vertebrate genomic sequences
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2009 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 10 Suppl 6, p. S4-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The rapid accumulation of genomic information in databases necessitates rapid and specific algorithms for extracting biologically meaningful information. More or less complete retroviral sequences, also called proviral or endogenous retroviral sequences; ERVs, constitutes at least 5% of vertebrate genomes. After infecting the host, these retroviruses have integrated in germ line cells, and have then been carried in genomes for at least several 100 million years. A better understanding of structure and function of these sequences can have profound biological and medical consequences. METHODS: RetroTector (ReTe) is a platform-independent Java program for identification and characterization of proviral sequences in vertebrate genomes. The full ReTe requires a local installation with a MySQL database. Although not overly complicated, the installation may take some time. A "light" version of ReTe, (RetroTector online; ROL) which does not require specific installation procedures is provided, via the World Wide Web. RESULT: ROL http://www.fysiologi.neuro.uu.se/jbgs/ was implemented under the Batchelor web interface (A Lövgren et al). It allows both GenBank accession number, file and FASTA cut-and-paste admission of sequences (5 to 10,000 kilobases). Up to ten submissions can be done simultaneously, allowing batch analysis of <or= 100 Megabases. Jobs are shown in an IP-number specific list. Results are text files, and can be viewed with the program, RetroTectorViewer.jar (at the same site), which has the full graphical capabilities of the basic ReTe program. A detailed analysis of any retroviral sequences found in the submitted sequence is graphically presented, exportable in standard formats. With the current server, a complete analysis of a 1 Megabase sequence is complete in 10 minutes. It is possible to mask nonretroviral repetitive sequences in the submitted sequence, using host genome specific "brooms", which increase specificity. DISCUSSION: Proviral sequences can be hard to recognize, especially if the integration occurred many million years ago. Precise delineation of LTR, gag, pro, pol and env can be difficult, requiring manual work. ROL is a way of simplifying these tasks. CONCLUSION: ROL provides 1. annotation and presentation of known retroviral sequences, 2. detection of proviral chains in unknown genomic sequences, with up to 100 Mbase per submission.

Keywords
bioinformatics, retrovirus
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-106784 (URN)10.1186/1471-2105-10-S6-S4 (DOI)000267522200004 ()19534753 (PubMedID)
Available from: 2009-07-03 Created: 2009-07-02 Last updated: 2017-12-13Bibliographically approved
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