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. 2016 May 13:6:25873.
doi: 10.1038/srep25873.

An RNA-dependent RNA polymerase gene in bat genomes derived from an ancient negative-strand RNA virus

Masayuki Horie  1   2 , Yuki Kobayashi  3 , Tomoyuki Honda  4 , Kan Fujino  5 , Takumi Akasaka  6 , Claudia Kohl  7 , Gudrun Wibbelt  8 , Kristin Mühldorfer  8 , Andreas Kurth  7 , Marcel A Müller  9 , Victor M Corman  9   10 , Nadine Gillich  2 , Yoshiyuki Suzuki  11 , Martin Schwemmle  2 , Keizo Tomonaga  4   12   13
Affiliations

An RNA-dependent RNA polymerase gene in bat genomes derived from an ancient negative-strand RNA virus

Masayuki Horie et al. Sci Rep. .

Abstract

Endogenous bornavirus-like L (EBLL) elements are inheritable sequences derived from ancient bornavirus L genes that encode a viral RNA-dependent RNA polymerase (RdRp) in many eukaryotic genomes. Here, we demonstrate that bats of the genus Eptesicus have preserved for more than 11.8 million years an EBLL element named eEBLL-1, which has an intact open reading frame of 1,718 codons. The eEBLL-1 coding sequence revealed that functional motifs essential for mononegaviral RdRp activity are well conserved in the EBLL-1 genes. Genetic analyses showed that natural selection operated on eEBLL-1 during the evolution of Eptesicus. Notably, we detected efficient transcription of eEBLL-1 in tissues from Eptesicus bats. To the best of our knowledge, this study is the first report showing that the eukaryotic genome has gained a riboviral polymerase gene from an ancient virus that has the potential to encode a functional RdRp.

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Figures

Figure 1
Figure 1. EBLL element in Eptesicus fuscus.
(a) Schematic figures of the BDV genome, spliced BDV L mRNA and efEBLL-1. The numbers above the boxes indicate the positions of amino acid residues in BDV L or efEBLL-1. White and black circles represent splicing donors and acceptors in the BDV genome, respectively. Red and blue circles indicate the S3 transcription initiation and T4 transcription termination signals, respectively. Yellow boxes indicate target site duplication (TSD). The efEBLL-1 N-terminal region coloured in red does not have homology with BDV L. (b) Nucleotide sequence alignment of BDV L and efEBLL-1. The blue boxed areas indicate the ORFs of BDV L or efEBLL-1. Red and underlined blue letters indicate the S3 transcription start and T4 transcription termination signals (or T4-like sequences), respectively. The poly-A sequences are indicated with blue letters. Yellow boxes indicate the TSD. nt, nucleotides.
Figure 2
Figure 2. Endogenization of eEBLL-1 in the Eptesicus species.
Schematic phylogenetic tree of the Eptesicus bat species. The tree topology was adopted from a previous report. The arrows indicate the integration events of eEBLL-1 or EBLLs in Myotis bats. The red circle indicates the divergent point of the Eptesicus species. Red boxes show the species analyzed in this study.
Figure 3
Figure 3. Amino acid sequence alignment between BDV L and efEBLL-1.
(a) Schematic figure of the BDV L protein. The numbers above the box indicate the amino acid residue positions. The pink boxes show conserved blocks I-V of the mononegaviral RdRp. The highly conserved stretches “a” and A–D and the PRNTase domain are shown. The regions of the possible functional domains in eEBLL-1 predicted by the Pfam search (PF00946, Mononegavirales RNA-dependent RNA polymerase domain and PF14318, Mononegavirales mRNA-capping region V domain) are shown. (b,c) Amino acid sequence alignments spanning blocks II and III (b) and block V (c) between BDV L and efEBLL-1. “a”, A, B, C and D show the conserved stretches among the mononegaviral RdRps. Orange boxes indicate strictly invariant amino acid residues among the mononegaviral RdRps. Red and green letters show functional motifs and highly conserved amino acid residues among the mononegaviral RdRps, respectively.
Figure 4
Figure 4. Expression of EBLL-1 RNA in the Eptesicus species.
(a) Schematic figure of eEBLL-1. Primer pairs used for RT-PCR analysis are indicated. Blue circle, T4-like sequence; yellow box, target site duplication (TSD). (b) Detection of the expression of eEBLL-1 RNAs with different primer pairs. Primer pairs are indicated at the left. Lanes 1-5. E. serotinus; 6-10. E. nilssonii; 11. M. daubentonii. These gel images were cropped, and full-length gels are available in Supp. Fig. 9.
Figure 5
Figure 5. Detection of natural selection in eEBLL-1.
(a) The distribution of the number of premature termination codons that efEBLL-1 acquired during 11.8 million years under neutral evolution from 100,000 simulation replicates. The frequency of zero stop codons is indicated with a red bar (0.0105). (b) The dN/dS ratios at each branch of the eEBLL-1 phylogenetic tree. The branches where purifying selection was detected are indicated with red letters. *p < 0.05; **p < 0.01.
Figure 6
Figure 6. A phylogenetic tree of bat EBLLs with bornaviral and nyamiviral L genes.
The JTT + G model of amino acid substitution was used in the construction of the maximum likelihood tree. The bootstrap value is indicated for each interior branch. The scale bar shows the number of amino acid substitutions per site. eEBLL-1s are indicated in dark blue. Other EBLL elements in bat genomes and their accession numbers are shown in light blue. ml, M. lucifugus; md, M. daubentonii, ef, E. fuscus, LGSV-1, Loveridge’s garter snake virus 1; CnBV-1 and CnBV-2, canary bornaviruses; BoDV-1 (BDV), Borna disease virus; PaBV-1, -2, and -4, parrot bornaviruses; NYMV, Nyamanini nyavirus; SbCNV, Soybean cyst nematode virus.
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