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.

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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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