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Endogenous non-retroviral RNA virus elements in mammalian genomes

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Abstract

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 elements1,2. Although many other viruses, including non-retroviral RNA viruses, are known to generate DNA forms of their own genomes during replication3,4,5, 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 nucleus6,7,8. 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.

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Figure 1: Bornavirus N-like elements in mammalian genomes.
Figure 2: Phylogenetic tree of exogenous bornaviruses and mammalian EBLNs.
Figure 3: Reverse transcription and integration of BDV RNA in mammalian cells.
Figure 4: Structures of BDV N integration events in OL cells.

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Data deposits

The TLS EBLN and RBV sequences reported here have been deposited in the DDBJ/EMBL/GenBank and the accession numbers are shown in Figure 2.

References

  1. Jern, P. & Coffin, J. M. Effects of retroviruses on host genome function. Annu. Rev. Genet. 42, 709–732 (2008)

    Article  CAS  PubMed  Google Scholar 

  2. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001)

  3. Zhdanov, V. M. Integration of viral genomes. Nature 256, 471–473 (1975)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Klenerman, P., Hengartner, H. & Zinkernagel, R. M. A non-retroviral RNA virus persists in DNA form. Nature 390, 298–301 (1997)

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Geuking, M. B. et al. Recombination of retrotransposon and exogenous RNA virus results in nonretroviral cDNA integration. Science 323, 393–396 (2009)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Tomonaga, K., Kobayashi, T. & Ikuta, K. Molecular and cellular biology of Borna disease virus infection. Microbes Infect. 4, 491–500 (2002)

    Article  CAS  PubMed  Google Scholar 

  7. de la Torre, J. C. Molecular biology of Borna disease virus and persistence. Front. Biosci. 7, d569–d579 (2002)

    Article  PubMed  Google Scholar 

  8. Lipkin, W. I. & Briese, T. in Fields Virology 5th edn (eds Knipe, D. M. & Howley, P. M.) 1829–1851 (Lippincott Williams & Wilkins, 2007)

    Google Scholar 

  9. Chase, G. et al. Borna disease virus matrix protein is an integral component of the viral ribonucleoprotein complex that does not interfere with polymerase activity. J. Virol. 81, 743–749 (2007)

    Article  CAS  PubMed  Google Scholar 

  10. Ewing, R. M. et al. Large-scale mapping of human protein–protein interactions by mass spectrometry. Mol. Syst. Biol. 3, 89 (2007)

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mercer, J. M. & Roth, V. L. The effects of Cenozoic global change on squirrel phylogeny. Science 299, 1568–1572 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Kistler, A. L. et al. Recovery of divergent avian bornaviruses from cases of proventricular dilatation disease: identification of a candidate etiologic agent. Virol. J. 5, 88 (2008)

    Article  PubMed  PubMed Central  Google Scholar 

  13. Francischetti, I. M., My-Pham, V., Harrison, J., Garfield, M. K. & Ribeiro, J. M. Bitis gabonica (Gaboon viper) snake venom gland: toward a catalog for the full-length transcripts (cDNA) and proteins. Gene 337, 55–69 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hui, E. K., Wang, P. C. & Lo, S. J. Strategies for cloning unknown cellular flanking DNA sequences from foreign integrants. Cell. Mol. Life Sci. 54, 1403–1411 (1998)

    Article  CAS  PubMed  Google Scholar 

  15. Holmes, E. C. Molecular clocks and the puzzle of RNA virus origins. J. Virol. 77, 3893–3897 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Duffy, S., Shackelton, L. A. & Holmes, E. C. Rates of evolutionary change in viruses: patterns and determinants. Nature Rev. Genet. 9, 267–276 (2008)

    Article  CAS  PubMed  Google Scholar 

  17. Korber, B., Theiler, J. & Wolinsky, S. Limitations of a molecular clock applied to considerations of the origin of HIV-1. Science 280, 1868–1871 (1998)

    Article  CAS  PubMed  Google Scholar 

  18. Morrish, T. A. et al. DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nature Genet. 31, 159–165 (2002)

    Article  CAS  PubMed  Google Scholar 

  19. Maestre, J., Tchenio, T., Dhellin, O. & Heidmann, T. mRNA retroposition in human cells: processed pseudogene formation. EMBO J. 14, 6333–6338 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Esnault, C., Maestre, J. & Heidmann, T. Human LINE retrotransposons generate processed pseudogenes. Nature Genet. 24, 363–367 (2000)

    Article  CAS  PubMed  Google Scholar 

  21. Kazazian, H. H. Mobile elements: drivers of genome evolution. Science 303, 1626–1632 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Zhang, Z., Carriero, N. & Gerstein, M. Comparative analysis of processed pseudogenes in the mouse and human genomes. Trends Genet. 20, 62–67 (2004)

    Article  PubMed  Google Scholar 

  23. Pavlicek, A. & Jurka, J. in Genomic disorders (eds Lupski, J. R. & Stankiewicz, P.) 57–72 (Humana Press, 2006)

    Book  Google Scholar 

  24. Saitou, N. & Nei, M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4, 406–425 (1987)

    CAS  PubMed  Google Scholar 

  25. Tamura, K., Dudley, J., Nei, M. & Kumar, S. MEGA4: molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol. Biol. Evol. 24, 1596–1599 (2007)

    Article  CAS  PubMed  Google Scholar 

  26. Lovatt, A. et al. High throughput detection of retrovirus-associated reverse transcriptase using an improved fluorescent product enhanced reverse transcriptase assay and its comparison to conventional detection methods. J. Virol. Methods 82, 185–200 (1999)

    Article  CAS  PubMed  Google Scholar 

  27. Ohtaki, N. et al. Downregulation of an astrocyte-derived inflammatory protein, S100B, reduces vascular inflammatory responses in brains persistently infected with Borna disease virus. J. Virol. 81, 5940–5948 (2007)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Minami, M., Poussin, K., Brechot, C. & Paterlini, P. A novel PCR technique using Alu-specific primers to identify unknown flanking sequences from the human genome. Genomics 29, 403–408 (1995)

    Article  CAS  PubMed  Google Scholar 

  29. Wo, Y. Y., Peng, S. H. & Pan, F. M. Enrichment of circularized target DNA by inverse polymerase chain reaction. Anal. Biochem. 358, 149–151 (2006)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Kawahara for helping the capture of the wild shrews (Sorex unguiculatus and Sorex gracillimus) at Kiritappu wetland, Hokkaido, Japan. We thank I. Francischetti for provision of Gaboon viper (Bitis gabonica) venom gland tissue and a cDNA library, D. Vaughan for thirteen-lined ground squirrel (Spermophilus tridecemlineatus) brain and liver tissues, and K. Maeda, T. Miyazawa and N. Ohtaki for providing culture cell lines from several mammalian species. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) Grants-in-aid for Scientific Research on Priority Areas (Infection and Host Responses; Matrix of Infection Phenomena) (K.T.), PRESTO (RNA and Biofunctions) from Japan Science and Technology Agency (JST) (K.T.), a Health Labour Sciences Research Grants for Research on Measures for Intractable Diseases (H20 nanchi ippan 035) from the Ministry of Health, Labor and Welfare of Japan (K.T.), research grant R37 CA 089441 from the National Cancer Institute (J.M.C.) and a fellowship from the Wenner-Gren Foundation (P.J.). J.M.C. was a Research Professor of the American Cancer Society with support from the George Kirby Foundation.

Author Contributions K.T. designed research; M.H., T.H., T.D. and K.T. conducted experiments using virus and culture systems; T.O. collected samples; Y.S., Y.K. and T.G. performed phylogenetic analysis; M.H., T.H., Y.S., K.I., P.J., T.G., J.M.C. and K.T. analysed data; and M.H., Y.S., P.J., J.M.C. and K.T. wrote the manuscript. All authors discussed the results.

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Correspondence to Keizo Tomonaga.

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Horie, M., Honda, T., Suzuki, Y. et al. Endogenous non-retroviral RNA virus elements in mammalian genomes. Nature 463, 84–87 (2010). https://doi.org/10.1038/nature08695

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