MER65, MER89 and MER34 were related to each other, and to the HEPSIs sensu stricto. Leib-Msch C, Seifarth W, Schn U. Simages. The concordance of PBS determination between ReTe PBS motifs scoring>0 and Leipzig perfect and imperfect hits with two mismatches, was 1108 of 1401 chains (79%). A third bias, towards increased T frequency, occurred in LTR46, HERVFB, HERVFC and HERVH. Viruses. 1976;261(5556):1018. All frames without stops for at least 130 amino acids (up to 15frames per retrotransposon DNA) were BLASTed against the Gag, Pro, Pol and Env puteins found by ReTe. A complete list of HERV groups and their copy number remains to be published. In case a putein is reconstructed, ReTe estimates the number of shifts and stops for each of the four major genes. doi:10.1093/nar/gkm515. Magiorkinis G, Gifford RJ, Katzourakis A, De Ranter J, Belshaw R. Env-less endogenous retroviruses are genomic superspreaders. 
D3: a complex HML3 chain where the RepeatMasker based Simage indicates contributions from six different HMLs. While no replication-competent HERVs have been recognized, some retain up to three of four intact ORFs. HERV4 is highly similar to HERVFRD. Barbulescu M, Turner G, Seaman MI, Deinard AS, Kidd KK, Lenz J. New Env (n=94) consensuses were calculated based on these subgroups (Additional file 4: List S4). Hence we wanted to identify and characterize the HERV proviruses found in the GRCh37/hg19. A few (227) chains had flanks which were>70% similar to a flank of another chain (with respect to the BLAST score towards their own flanks), indicating that a minor portion (7%) of the chains were the result of a duplication of a sequence encompassing both the provirus and its flanks (cf. JB received a 1 month visiting professorship from the University of Cagliari for working on this paper. 4, 5,6), but also clustered with MER4 chains (termed MER4I in RepBase). All had a discernible Gag putein, 34 had a Pro, 28 a Pol, and 17 an Env. 
2d). As described below, each of the remainder (canonical chains, see Methods) could be unequivocally assigned to one specific group. Mobile DNA. Article All authors read and approved the final manuscript.
A group appearing close to the most basal branches of the Class I gamma-like group clustered with Pol and Gag of the exogenous epsilonretrovirus, walleye dermal sarcoma virus (WDSV). These features are described in Tables2 and 3, and are detailed in Additional file 5: Table S5 and Additional files 2: List S2. Acquisition of a new envelope can give access to new host cells. Experian offers a wide range ofproducts and services. D5: a complex chain which contains undetermined HML sequences in the end of pol, and whole of env. 1, 2c, 5). Constructing primate phylogenies from ancient retrovirus sequences. Even defective recombinants can be packaged and reintegrated by a more complete retrovirus, so-called midwife elements [36, 57]. 1c, 2c and Additional file 1: Table S1). 1992;73(Pt 5):108797. Chichester: Wiley. Others were widely separated from the main HERV group. 2002;62(19):55106. Smit AF. Georgetown, Texas: Landes Bioscience; 2005. p. 186239. Mosaic is Experian's comprehensive cross-channel classification system. They probably derive from retroviruses which invaded both primates and artiodactyls. J Gen Virol. 2003;100(22):130138. This Env was highly similar to HERVE Env. PubMed None shared flanks with the other 37. 2005;2:50. doi:10.1186/1742-4690-2-50. APOBEC-mediated editing of viral RNA. Current Opin Genet Develop. When PBS motifs with perfect Leipzig matches were compared against ReTe matches scoring>0, nearly all (748 of 844 chains, 89%) gave the same result. Fei C, Atterby C, Edqvist PH, Ponten F, Zhang WW, Larsson E et al. Google Scholar. However, the patterns of putative recombination are so consistent and clearly different from the canonical HMLs that we favour that they are the result of recombination. Translational frame shifts were estimated from the reading frames recorded in ReTe for motif hits occurring near the gag/pro and pro/pol borders, respectively. 2005;13:4638. Thus, there is evidence that HERVE (the backbone of Harlequin), HERV9, HERVIP and HML2 were especially active in spawning infectious recombinant retroviruses. Nucleic Acids Res. 2014;88(5):2398405. Likewise, rvnr 4362, a relatively complete HML6 element at 16: 30635509, with multiple stops in all four major genes, was reported to encode a malignant melanoma antigen MLAVISCAV from its envelope [75]. A comprehensive HERV classification and characterization approach was undertaken. doi:10.1038/nrmicro1541. Tristem M. Identification and characterization of novel human endogenous retrovirus families by phylogenetic screening of the human genome mapping project database. View ourPrivacy Policyfor details on use and storage of your personal data. 6, 7). Clustering of Pol at the amino acid level minimized this problem. d Recombinant provirus with contributions from different ERVs, in this case a Harlequin element. Mayer J, Blomberg J, Seal RL. The frequent similarities between envelopes belonging to different groups, supergroups and classes show that acquisition of new envelope (env snatching) is a widespread phenomenon among the retroviruses which became endogenized in the human lineage. Endogenous retroviruses: still active after all these years? ORF-containing chains are also discussed in detail in Additional file 2: List S2. doi:10.1128/JVI.78.11.5784. aimed at pathogen discovery. PubMed Central You can change your mind at any time. However, the analysis with the RMRef system was performed simultaneously, so it was always possible to compare the two results. Among the two-zinc finger HERVs, HERVFA was most related to MER66 and LTR46, HERVFB most related to HERVH48 and HERVFC most related to ERV3-MacERV6 (rhesus), ERV3-1_CJal and ERV3-2_CJal (both from marmoset). LTR divergence indicated that HERV-K(HML2) and HERVFC had the most recent integrations, HERVL and HUERSP3 the oldest. 1406 totally. Pol sequences were aligned with Muscle. Features which then could be looked for were classification of 5 and 3 LTRs, and sense. Some of the noncanonical mosaic chains may have had replicative potential. As described in the text, this is a common pattern for chains labeled as Harlequin.
However, the LTR divergence ranged from 10 to 19%, compatible with integration 3040 MYA, Fig. A total of 39 canonical HERV groups are listed in Table4, in which both the number of the canonical and noncanonical classified sequences per each group is reported in comparison with the previously estimated proviral copy numbers [56]. PLoS One.
Benit L, De Parseval N, Casella JF, Callebaut I, Cordonnier A, Heidmann T. Cloning of a new murine endogenous retrovirus, MuERV-L, with strong similarity to the human HERV-L element and with a gag coding sequence closely related to the Fv1 restriction gene. Smith JG, Mothes W, Blacklow SC, Cunningham JM. Article Nucleic Acids Res. Google Scholar. Elfaitouri A, Shao X, Mattsson Ulfstedt J, Muradrasoli S, Blin Wiener A, Golbob S, et al.
C2: HERV9 LTR inside a HERVH. Selected envputeins were used for calculation of initial env and ISD consensuses. Experian Ltd is authorised and regulated by the Financial Conduct Authority (firm reference number 738097). Simplified new Env subgroup consensuses (labelled A, B, C, etc.) Young GR, Ploquin MJ, Eksmond U, Wadwa M, Stoye JP, Kassiotis G. Negative selection by an endogenous retrovirus promotes a higher-avidity CD4+T cell response to retroviral infection. The particle harbouring the recombinant genome then must infect a germ line cell and get genetically fixed in order to be registered as a HERV. It can be argued that ERV classification should be done at higher host taxonomic levels than in the human host, e.g. As reported previously, Gamma-like sequences (Class I) were more common than Beta-like (Class II). MaLR (Mammalian apparent LTR-retrotransposon) containing chains were also found. In general, the groups were judged to be homogeneous enough to be handled as discrete retroviral entities and their consensuses useful for detection and classification. The following results emerged: there were a large number of hits (539 chains). 2012;10:395406. The groups fell into 11 supergroups. Experian Ltd is registered in England and Wales (no. CAS The RepBase [32, 33] and RepeatMasker [34] systems are coordinated and comprehensive efforts to record and categorize all repeatable genetic elements. The Simages can be considered as magnifying glasses that allow a look inside the proviral sequences. PLoS One. Each twentieth was BLASTed against several sequence collections (RVref, RMref, HML and Consensus). Groups were further divided into envelope subgroups (altogether 94) based on sequence similarity and characteristic immunosuppressive domain motifs. Google Scholar. 2013;368(1626):20120493. doi:10.1098/rstb.2012.0493. 1995;23(21):422933. Additional file 1: Table S1). Article 2008;376(1):199204. It was marked MLLV* in Additional file 1: Table S1and Table 4. 1999;9(16):8618. 2013;13:4. doi:10.1186/1471-2407-13-4. An HERVH at chromosome 8:13309237 which is part of the gene HHLA1, an important regulator of stem cell differentiation, and is strongly upregulated during early embryogenesis [73] is colocalized with the provirus with rvnr 2965. Wet-lab and bioinformatics/computational approaches were both used to detect and enumerate HERV sequences, both proviral and solo-LTRs. By signing up to Experian business marketing communications you will receive the latest research, insight, news and invites to events and webinars. Scrutinizing the discrepancies (cf. Although most LINEs, SINEs and other nonretroviral repeats were removed by ReTe after sweeping with brooms optimized for primate genomes [35, 37] before attempted provirus detection, a few aberrant representatives were still present after this procedure. J Clin Investig. Cancer Res. Additional file 4: List S4. Thus, it is reasonable to include near-ORFs of significant length, with 1 shift or 1 stop, in a survey of HERV ORFs (Tables 5 and 6). A very approximate estimate of age since integration was calculated by multiplying percent divergence with 2.5. This approach has led to a number of identified HERV groups (also improperly named as families), often ranging between 26 and 31. There are no known replication competent HERVs. PubMed Central Young GR, Stoye JP, Kassiotis G. Are human endogenous retroviruses pathogenic? It allowed finding protein similarity with reference sequences which have not been formally translated into protein. Most (162) of these chains had an LTR2 (the HERVE LTR) in the 5 or 3 end. It covers a wide panel of species-specific variants of retroviral sequences from different vertebrates. Most HERVs integrated 10100 million years ago. Kamp C, Hirschmann P, Voss H, Huellen K, Vogt PH. For example, of 532 canonical HERVH chains 386 used H, 57 F and 19K. Of 87 canonical HERVL chains 35 used L, 33M and 2 S. A well known example of nucleotide bias is HIV, where copackaging of a cellular post-transcriptionally active cytidine deaminase, APOBEC, gives a bias for A [46, 47]. Not more than one unexplained twentieth (shown as a 0 in the Simage) per chain. Moreover, a HEPSI2 sequence (rvnr 4152) clustered with the avian errantiviruslike sequence Ovex1 (Pol tree, Fig. The Harlequin element Simages (see below) contained a prominent Env.
The issue of HERV characterization and phylogeny is large and calls for several publications. All 37 had at least one LTR12 (the HERV9 LTR) in 5 or 3 end. J Virol.
Nucleic Acids Res.
Several chains with similar internal mosaic structure, all in sense, but different flanks (degree of flank identity<70%). HERVK14=HML1, HERVK=HML2, LTR5=HML2 LTR, HERVK9=HML3, MER9=HML3 LTR, HERVK14C=HML9, HERVK11D=HML7, HERVK11=HML8. ISD variants with more than 5 amino acid mismatches to surrounding ISDs in the alignment were given sequential numbers; 1,2,3 etc. PubMed The authors declare that they have no competing interests. It is reasonable to assume that they had a common origin. For example, most of the copy numbers reported by [56] were estimated from BLAST searches of the human genome sequence available at the NCBI in August 2001. There are no apparent present-day HERV proviruses which tentatively can be ascribed this function. Some noncanonical chains were also classified into the supergroups. Roy-Burman P. Endogenous env elements: partners in generation of pathogenic feline leukemia viruses. Retrovirology. As described in Methods, the AutoFrame mechanism depended on the presence of reading frames of130 amino acids in the RepeatMasker library of 17500 LTR retrotransposons from a wide variety of hosts. An Env score based on this algorithm was stored in the field envhpoints of Additional file 1: Table S1. Long terminal repeats are used as alternative promoters for the endothelin B receptor and apolipoprotein C-I genes in humans. However, ReTe is not optimized for a complete identification of some class III sequences, such as Spumaretrovirus-like and mammalian apparent LTR-retrotransposon elements (MaLR), as well as for single-LTR detection. doi:10.1128/JVI.00966-14. The derivation and structure of this table is described in Methods. Cell Mol Life Sci CMLS. 2005;86(6):68591. 2012;109(19):738590.
Sanchez-Martinez S, Aloia AL, Harvin D, Mirro J, Gorelick RJ, Jern P, et al. An Env quality control program (EnvQual, yielding envqpoints see Methods) was therefore written.
BMC Cancer. In the 1st million years post integration, gene conversion can diminish the degree of divergence. New York: Cold Spring Harbor; 1997. Nucleic Acids Res. Registered office: The Sir John Peace Building, Experian Way, NG2 Business Park, Nottingham NG80 1ZZ. If both are missed by ReTe, an entire provirus can be missed if it is defective. Simage analysis also contributed to determine the presence of a high number of mosaic HERV structures, some of which may be true recombinants, with a level of detail not previously appreciated. A maximum likelihood tree was calculated. A comprehensive (BLAST) search, with up to two mismatches, in the 3173 HERV chains, yielded 1407 matches. As shown in Additional file 1: Table S1, Simages from noncanonical HERVs demonstrated that a wide fraction of the mosaic sequences harbour MaLR (Class III; MST, MLT and THE fragments) on a Class I (n=51) or II (n=41) HERV backbone. Env subgroup consensuses (see Additional file 4: List S4) and reference envelope proteins were aligned by Muscle. No Alpha-, Deltaretrovirus- or Lentivirus-like elements were detectable. HERVs constitute 8% of the human genome [38]. doi:10.1093/nar/gkh075.
Present address: Nurideas S.r.l., Cagliari, Italy, Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy, Laura Vargiu,Marta Cadeddu,Nicole Grandi&Enzo Tramontano, Center for Advanced Studies, Research and Development in Sardinia, CRS4, Pula, Italy, Physiology Unit, Department of Neuroscience, Uppsala University, Uppsala, Sweden, Department of Medical Sciences, Uppsala University Hospital, Dag Hammarskjlds Vg 17, Uppsala, 751 85, Sweden, You can also search for this author in California Privacy Statement, Both HERVL and HERVS were homogeneous groups. ", "Even though we have a good general understanding of our customers, Experian is able to tell us who they are, what they are like and what they buy in far more detail than ever before.". The origin of the HML groups is uncertain, but we found that Pol from the MysTr betaretroviruslike sequences of marsh rice rats clustered close to HML5 and HML6, the two oldest HML groups [65], LTR divergence (823%, Additional file 5: Table S5-2). 2. A graphical overview is given in Fig. Only one HERVFC consensus sequence yielded a Pol putein, hence an average could not be computed. One (rvnr 5922) contained a MuERVL Pol-like putein, two (rvnr 4861 and 3058) vaguely Gag-like puteins. J Virol. Gpatch in Pro was detected by a program written by JB, using described features [93]. It led to a classification of 3045 (96%) of the 3173 HERVs. 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. But if the program continues beyond the natural stop codon, that codon will be counted as a stop. New Jersey: Wiley Online Library; 2009. HERV9 was related to MER41 and HERV30, more distantly to HERVW (Fig. Several hits covering longer sequence segments do however indicate a relationship worthy of further exploration. The PreXMRV1 and PreXMRV2 Simages precisely assigned each XMRV portion either to PreXMRV1 or PreXMRV2, validating the methodology. 
30 of them also had a twentieth most similar to HERVW just before this HERVI. Most of those are highly degenerate, giving a low chainscore of ReTe. Its envelope clustered with MER50LIKE Envelopes (Figs. We found evidence for frequent env snatching events. A few Errantiviruses and Pseudoviruses were also included; A set of 9 HML (HML) consensus sequences, generated for the HERVK (HML1-HML9) group [64]; The entire Repbase Update [33], a database of repetitive DNA elements was downloaded from: http://www.girinst.org/repbase/update/index.html; The LTR subset from the entire Repeatmasker (RMRef) collection of vertebrate repeats (release of May 2012) [34, 43] was downloaded from: http://www.repeatmasker.org. The final results from the analyses of Simages and taxonomic markers of the 3173 HERV sequences (Table1) showed that among them, 1214 (38%) could be unambiguously assigned to a specific group (canonical sequences) while 1959 (62%) could not be unequivocally classified to one group (noncanonical sequences). doi:10.1038/35057062. This was not confined to the 4 mentioned high-scoring chains. The LTR divergence ranged from 1732%. 4. HERVFC) up to the large HERVH group with roughly 1000 members and an even greater number of solo-LTRs. e Processed pseudogene, i.e. The list of all 3173 reconstructed retroviral sequences together with the main parameters that contributed to their characterization is reported in the supplementary material (Additional file 1: Table S1), and in a publically available.dbf table (see Methods). Interestingly, avian (Gallus gallus), crocodylian (Alligator mississippensis) and turtle (Chrysemis picta bellii) ERV Pols (some of which included dUTPase) intermingled with the Class III HERV Pols, here given the supergroup name HSERVIII (cf. Cohen M, Larsson E. Human endogenous retroviruses. 3.
ReTe identified 1406 elements with PBS score>0. Modular evolution of the integrase domain in the Ty3/Gypsy class of LTR retrotransposons. It also contains 163 sequences collected from the HERV literature of the last 30 years. 2008;5:75. doi:10.1186/1742-4690-5-75. 1983;33:37987. Stoye JP. Among Class II, HML2 had 78% (70/89) while HML8 had 41% (24/58). The HEPSI supergroup is further discussed below, and in Additional file 2: List S2.5.2.2.8. Thus, distinction of an R PBS from a W PBS can be problematic. LTR10 (the HERVIP LTR) occurred in one terminal position in 23 chains, in 13 cases in two. in primates. 2009;448:1348. Identify and reach your customers via direct mail and ChannelView host mailing. HERVT is highly related to, but not formally part of, the MLLV supergroup. In: Coffin JM, Hughes SH, Varmus HE, editors. The most common hit for the HERV group was named a, the next most common b, etc. An advance in HERV knowledge must include a clear definition of the type, exact number and position of these retroviral sequences. Trends Biochem Sci. Google Scholar. Hum Mol Genet. Virus Genes. Endogenous retroviruses (ERVs) have a similar genetic organization as exogenous retroviruses, with two long terminal repeats (LTRs) encompassing the internal coding sequence of the four basic retroviral genes (gag, pro, pol and env), which thus are exposed to the vertebrate cellular environment [1]. As shown in Additional file 2: List S2, there exist RepBase HERV entities which were not detected in our ReTe-based search. Some retain the ability to produce virus-like particles [16, 17]. Moreover, ReTe detects proviruses a priori and is not dependent on repetition, giving the capacity to identify low-copy number retroviral sequences, like HERVFC, of which here two canonical elements are presented. HERV9 Env clustered with HERVHF Envs. Consensus statistics. The Autoframe hits for Env puteins sometimes varied within a HERV group. Some of them are shown in Fig.
Henzy JE, Johnson WE. These hits often occurred at the end of Gag, over the highly conserved zinc fingers, and do not necessarily indicate a recent evolutionary relationship. This mosaicism makes the classification of HERVI, HERVIP and HERV3 especially difficult. It is one of the oldest groups (Fig. 8. 4). A manual Gag reconstruction based on the HERVS and HERVL nucleotide consensuses was therefore made (cf. Nachman MW, Crowell SL. It is likely that an even more comprehensive analysis, maybe including other primate genomes, could clarify the classification of such elements. Aravind L, Koonin EV. ReTe PBS sequences were matched, accepting only exact matches, against the Leipzig derived tRNA sequences (second method). Relations shown indicate, but do not prove, an envelope transfer event. Some retroviral genetic structures encountered during this work. 4. This provided a credible PBS identification in over half of the PBS sequences detected by ReTe. 2011;333:97101. 4, 5), supported this relationship, which justified the classification of these sequences as separate HERV groups (here named HEPSI1-4) [50, 55]. LV participated in bioinformatics, checking of data and writing of the paper. doi:10.1186/1471-2105-10-S6-S4. Google Scholar. Benachenhou F, Blikstad V, Blomberg J. Cancer Immunol Immunother CII. Comparable results were obtained for the other measures of group heterogeneity. 2001;1(3):36592. The 01% divergence bin contained 13 HML2, 2 HERVH, 1 HERV9, 1 HERVIP, 1 HERV3 and 1 Harlequin. To resolve the complex genetic substructure of the identified HERV sequences and properly classify proviruses with heterogeneous content, we developed a novel methodology based on similarity image analysis (Fig.
mosaic classifications
