Avian reovirus L2 genome segment sequences and predicted structure/function of the encoded RNA-dependent RNA polymerase protein
© Xu and Coombs; licensee BioMed Central Ltd. 2008
Received: 02 December 2008
Accepted: 17 December 2008
Published: 17 December 2008
The orthoreoviruses are infectious agents that possess a genome comprised of 10 double-stranded RNA segments encased in two concentric protein capsids. Like virtually all RNA viruses, an RNA-dependent RNA polymerase (RdRp) enzyme is required for viral propagation. RdRp sequences have been determined for the prototype mammalian orthoreoviruses and for several other closely-related reoviruses, including aquareoviruses, but have not yet been reported for any avian orthoreoviruses.
We determined the L2 genome segment nucleotide sequences, which encode the RdRp proteins, of two different avian reoviruses, strains ARV138 and ARV176 in order to define conserved and variable regions within reovirus RdRp proteins and to better delineate structure/function of this important enzyme. The ARV138 L2 genome segment was 3829 base pairs long, whereas the ARV176 L2 segment was 3830 nucleotides long. Both segments were predicted to encode λB RdRp proteins 1259 amino acids in length. Alignments of these newly-determined ARV genome segments, and their corresponding proteins, were performed with all currently available homologous mammalian reovirus (MRV) and aquareovirus (AqRV) genome segment and protein sequences. There was ~55% amino acid identity between ARV λB and MRV λ3 proteins, making the RdRp protein the most highly conserved of currently known orthoreovirus proteins, and there was ~28% identity between ARV λB and homologous MRV and AqRV RdRp proteins. Predictive structure/function mapping of identical and conserved residues within the known MRV λ3 atomic structure indicated most identical amino acids and conservative substitutions were located near and within predicted catalytic domains and lining RdRp channels, whereas non-identical amino acids were generally located on the molecule's surfaces.
The ARV λB and MRV λ3 proteins showed the highest ARV:MRV identity values (~55%) amongst all currently known ARV and MRV proteins. This implies significant evolutionary constraints are placed on dsRNA RdRp molecules, particularly in regions comprising the canonical polymerase motifs and residues thought to interact directly with template and nascent mRNA. This may point the way to improved design of anti-viral agents specifically targeting this enzyme.
The avian reoviruses (ARVs) are members of the family Reoviridae, the only group of dsRNA viruses (out of seven dsRNA virus families) that infect mammals [1, 2]. The ARVs are the prototypic members of syncytia-inducing, non-enveloped viruses within the Orthoreovirus genus. This genus is divided into 3 subgroups: non-syncytia-inducing mammalian reovirus (MRV; subgroup 1; the prototype of the whole genus), avian reovirus and Nelson Bay virus (subgroup 2), and baboon reovirus (subgroup 3) . In contrast to the MRV, which are rarely associated with human pathology [2, 4–6], the ARV are significant pathogens of poultry, and cause a variety of diseases, including infectious enteritis in turkeys , viral arthritis/tenosynovitis , "pale bird" and runting-stunting syndromes , and gastroenteritis, hepatitis, myocarditis, and respiratory illness in chickens [2, 8, 10].
Like MRV, ARV is a non-enveloped virus with 10 linear double-stranded RNA gene segments surrounded by a double concentric icosahedral capsid shell (inner shell [also called core] and outer shell) of 70–80 nm diameter [11, 12]. The ARV genomic segments can be resolved into three size classes based on their electrophoretic mobilities, designated L (large), M (medium), and S (small) [11, 12]. In total, the genomic composition includes 3 large segments (Ll, L2, L3), 3 medium sized segments (Ml, M2, M3), and 4 small segments (S1, S2, S3, S4). Nine of the segments are monocistronic and encode a single different protein [11–13] while S1 is tricistronic with partially overlapping open reading frames (ORFs) that encode for three proteins [14, 15]. Although ARVs share many features with the prototypic MRVs, several notable differences exist including host range, pathogenicity, hemagglutination properties, and syncytium formation [11, 12, 16–21].
Genomic coding differences also exist between MRV and ARV. For example, although the ARV and MRV S1 genome segments encode homologous receptor-binding proteins [19, 22, 23], the ARV S1 genome segment encodes two additional ARV-specific gene products, one of which is responsible for ARV's unusual cell-cell fusion ability [14, 15, 24], whereas the MRV S1 segment encodes only one additional protein . In addition, available data [12, 26] suggest each of the homologous orthoreovirus λ-class proteins are encoded by different ARV and MRV L-class genome segments. Differences in the functional properties of homologous ARV and MRV proteins have also been reported. For example, two non-homologous dsRNA-binding proteins (the ARV σA core protein and the MRV σ3 major outer capsid protein) are predicted to regulate PKR activation [27, 28] while the ARV σA core protein displays nucleoside triphosphate phosphohydrolase (NTPase) activity , ascribed to the non-homologous MRV μ2  and λ1  core proteins. Based on these early comparative studies, it seems likely that additional analysis of ARV will continue to broaden our understanding of the Reoviridae family, possibly leading to the identification of novel features that impact on the distinct biological and pathogenic properties of ARV.
Recent advances have allowed sequence determinations of a growing number of virus isolates. Many ARV and MRV genome segment sequences have been reported. In addition, the complete genomic sequences of three prototype strains of MRV have been completed [32–34]. In contrast, sequence information from ARV isolates is more limited. While the entire complement of S-class genome segments (for example, [14, 15, 35–39]) and M-class genome segments (for example, [40, 41]) have been determined for some ARV clones, and sequence information is available for some ARV L1 and L3 genome segments [42, 43], there is, at present, no sequence information for the ARV L2 genome segment. This segment is presumed to encode for the viral RNA-dependent RNA polymerase (RdRp) protein, an essential enzyme for RNA virus replication. Thus, we determined the genomic sequences of the ARV L2 genome segments from two different strains of ARV (ARV138 and ARV176) in order to expand the available ARV sequence database, determine sequences of the ARV RdRp protein, and to delineate conserved structure/function features of this key viral-encoded enzyme.
Cells and viruses
Avian reovirus strain 138 (ARV138) and strain 176 (ARV176) are laboratory stocks. Virus clones were amplified in the continuous quail cell line QM5 in Medium 199 (Gibco) supplemented to contain 7.5% fetal calf serum (Hyclone), 2 mM glutamine, 100 U/ml penicillin, 100 μg/ml streptomycin, and 1 μg/ml amphotericin B, essentially as previously described .
Sequencing the L2 genome segment
Genomic dsRNA was extracted from amplified virus P2 stocks with phenol/chloroform . The extracted dsRNA were resolved in 10% SDS-PAGE and resolved L1, L2, and L3 segments separately excised. Individual segment gel bands were collected into microcentrifuge tubes, macerated, and incubated in 1–2 volumes of diffusion buffer (0.5 M ammonium acetate; 10 mM magnesium acetate; 1 mM EDTA, pH 8.0; 0.1% SDS) at 50°C for 30 minutes. The macerated gel pieces were pelleted by centrifugation at 10,000 × g for 1 min, supernatants were collected and dsRNA precipitated by ethanol. Each pellet was dried and resuspended in ddH2O for 3' ligation-based RT-PCR. All primers used for ligation, RT-PCR, and sequencing were synthesized by Invitrogen. An anchor primer, P-5' CTTATTTATTTGCGAGATGGTTATCATTTTAATTATCTCCATG 3'-Bio (5'-end phosphorylated and 3'-end biotin-blocked) was ligated to the 3' end of each genome segment, using T4 RNA ligase according to the manufacturer's instructions (Promega Inc., Madison, USA). Ligated products were precipitated by mixing with 1/2 volume of (30% PEG 8000 in 30 mM MgCl2), and centrifuged immediately at 10,000 × g for 30 minutes. The supernatants were removed and pellets were dried and dissolved in ddH2O for cDNA synthesis. Full-length cDNA copies of each L2 genome segment were synthesized using a primer (24-mer) complementary to the anchor primer by SuperScript™ II reverse transcriptase according to the manufacturer's instructions (Invitrogen). PCR amplification was performed using cDNA, a forward primer (i.e. primer used for RT), and a reverse primer, 5' ACCGAGGAGAGGgatgaataa 3', designed against highly conserved 3'-end nucleotide sequences of currently known consensus ARV L1 and L3 segment plus strands (shown in lower case) by Expand Long Template PCR System (Roche). PCR products used for DNA sequencing were gel purified using QIAquick® gel extraction kit according to the manufacturer's instructions (Qiagen).
DNA sequencing was performed in both directions by use of an ABI Prism BigDye Terminator v3.1 Cycle Sequencing Ready Reaction Kit (Applied Biosystems) and an Applied Biosystems Genetic Analyzer DNA Model 3100. The first two sequencing reactions were performed with the primers used for PCR amplification. Primers for subsequent reactions were designed from newly obtained sequences to completely sequence each full-length PCR product in both directions. Sequences nearer the ends of each segment were determined from PCR products that were amplified with a primer complementary to the anchor primer and an internal gene-specific primer. Sequences obtained from both directions were assembled and checked for accuracy with SeqMan® (Lasergene®, Version 7.1.0; DNASTAR, Inc.).
Sequences were compiled and analyzed using the Lasergene® software suite (Version 7.1.0; DNASTAR, Inc.) Pairwise sequence alignments were performed using the Wilbur-Lipman method  for highly divergent nucleotide sequences, the Martinez-NW method  for closely related nucleotide sequences, and the Lipman-Pearson method  for protein alignments in MegAlign® (Lasergene®). Multiple sequence alignments were performed using Clustal-W  and T-Coffee , and alignment adjustments were manually performed as needed in MegAlign®. Amino acid alignment images were adjusted in Adobe Photoshop 7.0 (Adobe®). Nucleotide compositions and protein molecular weights were calculated by DNA statistics and protein statistics, respectively, in EditSeq® (Lasergene®). Phylogenetic trees were constructed using Neighbor-Joining and tested with 1000 bootstrap replicates in MEGA version 4 .
3-D structural analyses
Molecular graphics coordinates of the mammalian reovirus (MRV) λ3 crystal structure (PDB # 1MUK; ), were manipulated with the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (; supported by NIH P41 RR-01081). Resulting images were imported into Adobe Photoshop and assembled with Adobe Illustrator (Adobe).
Nucleotide sequences used in this study
GenBank Accession Number
Genome-segment lengths, non-translated regions, and encoded proteins of ARV138 and ARV176
Molecular weight (kDa)e
(no. of bases)
(no. of bases)
Percent identities of the ARV L2 genome segments and homologous encoded proteins of MRV and Aquareovirusesa
In conclusion, we report the first sequence analysis of the avian reovirus RdRp gene and protein. The ARV λB and MRV λ3 proteins showed the highest ARV:MRV identity values (~55%) amongst currently known ARV and MRV proteins, suggesting significant evolutionary constraints are placed on dsRNA RdRp molecules, particularly in regions comprising the canonical polymerase motifs and residues thought to interact directly with template and nascent mRNA.
We thank members of our laboratory for critical reviews of this manuscript and Kolawole Opanubi for expert technical assistance. This research was supported by grant FRN-11630 from the Canadian Institutes of Health Research.
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