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Journal of Virology, September 2007, p. 10188-10194, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00337-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Evidence of Intragenic Recombination in G1 Rotavirus VP7 Genes

Tung Gia Phan,¹ Shoko Okitsu,¹ Niwat Maneekarn,² and Hiroshi Ushijima^1*

Department of Developmental Medical Sciences, Institute of International Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,¹ Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand²

Received 15 February 2007/ Accepted 25 June 2007

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The G1 rotavirus is the most widespread genotype causing acute gastroenteritis in children. In an attempt to investigate the occurrence of intragenic recombination, 131 complete coding region sequences of VP7 genes of the G1 rotaviruses in GenBank were examined. Three hitherto-unreported intragenic recombinant rotaviruses were identified. It was noteworthy that two different types (interlineage and intersublineage) of intragenic recombination in rotaviruses were also found. This is the first report to demonstrate the existence of intragenic recombinations between interlineage and intersublineage in G1 rotaviruses.

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Acute gastroenteritis is a significant cause of morbidity and mortality of children in both developed and developing countries. Despite much progress in the understanding of the pathogenesis of the disease and its management with the widespread use of oral rehydration therapies, acute gastroenteritis consistently ranks as one of the top causes of death worldwide (9, 10, 20). The rotaviruses, which comprise a genus in the family Reoviridae, are icosahedral in appearance. With VP4 spikes, the rotavirus is about 110 nm in diameter. The virion of this virus is a nonenveloped, triple-layered capsid containing 11 segments of double-stranded RNA genome. The rotavirus genome encodes six structural and six nonstructural proteins (3). This virus is estimated to be responsible for 111 million episodes of diarrhea requiring only home care, 25 million clinic visits, 2 million hospitalizations, and 325,000 to 592,000 deaths every year in children under five years old (12). Over past decades, G1 rotaviruses have been the most widespread genotype causing acute gastroenteritis in children from many countries covering all continents of the world (18). Nucleotide substitution and genomic reassortment have been proposed to be the most important mechanisms of rotavirus evolution in nature (3, 4, 18). The rapidly increasing detection of G1 rotavirus, in association with the genetic heterogeneity, raises intriguing questions such as whether rotavirus evolution is driven by intragenic recombination. Thus, the objective of this study was to assess the occurrence of intragenic recombination in the VP7 genes of the G1 rotaviruses.

A total of 131 sequences of the G1 rotaviruses, including our 36 sequence data from China, Japan, and Vietnam (15, 22, 26), which did not include any gaps in the alignment for the entire coding region of VP7 genes, were collected from GenBank. Sequence alignment was performed using CLUSTAL X (21). Phylogenetic trees with 100 bootstrap replicates of the nucleotide alignment datasets were generated using the neighbor-joining method (17). Genetic distance was calculated using Kimura's two-parameter method (PHYLIP) (6). SimPlot was used to detect recombinant rotavirus sequences as well as the breakpoints (7).

All 131 sequences of the G1 rotaviruses in this study were classified into different lineages and sublineages (Fig. 1) according to the recent G1 rotavirus classification scheme in which the nucleotide homology of rotavirus strains within each sublineage ranged from 98% to 100%, indicating a genetic difference of only less than 2% among them; the nucleotide sequence divergence between sublineages within the same lineage was from 3% to 4%; and sequence variation among strains between lineages was considerably higher, ranging from 5% to 16% (15). Interestingly, by using SimPlot, we found the VP7 genes of three G1 rotavirus strains to have intragenic recombinations between interlineage and intersublineage.

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FIG. 1. Lineages and sublineages of 131 VP7 gene nucleotide sequences of G1 rotavirus used in the study. Our strains from China, Japan, and Vietnam are highlighted in boldface. The scale indicates nucleotide substitutions per position. The numbers in the branches indicate the bootstrap values. Bootstrap values of 70% or higher are considered significant for the grouping.

Ban-59. The G1 rotavirus strain Ban-59 (U26366) was isolated from an infant with acute gastroenteritis in Bangladesh during 1988, and only this strain was assigned into lineage VII (15). Figure 2A shows evidence of the novel recombinant G1 rotavirus bearing different lineage sequence when the nucleotide sequence of strain Ban-59 was compared with that of strain JP421 belonging to lineage IV using SimPlot. The recombination breakpoints were estimated at positions 469 and 649. Before position 469 and after position 649, the identities of Ban-59 and JP421 were distinctly different, ranging from 90% to 93%. From positions 469 to 649, their identities were extremely high (100%). In contrast, the examination of the sequences for nucleotides 469 to 649 among G1 rotavirus lineages revealed the low identities, ranging from 82% to 96%. Of note, this region contained antigenic regions B (nucleotides 474 to 506) and E (nucleotides 615 to 620). Figure 2B also revealed that Ban-59 clustered into different lineages when the different part of VP7 gene-based grouping was performed. From nucleotides 49 to 468 and from nucleotides 650 to 1029, the lineage VII of Ban-59 remained. However, Ban-59 was classified into lineage IV. This kind of phenomenon was recognized as intragenic recombination between interlineage.

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FIG. 2. Identification of novel recombinant G1 rotavirus strain Ban-59. (A) Nucleotide identity comparison of the complete coding regions of VP7 genes of Ban-59 (belonging to lineage VII as a query strain) with that of JP421 (belonging to lineage IV as a reference strain). (B) Observation of changes of genotypes of the Ban-59 on the basis of phylogenetic trees of nucleotide sequences. The scale indicates nucleotide substitutions per position. Numbers in the branches indicate bootstrap values. Bootstrap values of 70% or higher are considered significant for the grouping.

Strain D. More than 10 years before the isolation of strain Ban-59, strain D (AB118022) was identified in the United States in 1974. Strain D, together with three Brazilian strains isolated in 1991 and 1992 (Brazil-4, Brazil-5, and Brazil-6), formed sublineage IIIa (15). Using SimPlot, we determined the recombination event and the breakpoint at position 449 in the VP7 gene when strain D was compared with the reference strain Brazil-5, belonging to sublineage IIIa, and with the reference strain Egypt-8, belonging to sublineage IIIb (Fig. 3A). In comparison with Egypt-8, strain D shared a high level of nucleotide identity (98%) in the region from nucleotide 49 to nucleotide 448 and a lower level of the nucleotide identity (97%) in the region from nucleotides 449 to 1029. In contrast, strain D shared a low level of nucleotide identity (96%) in the region from nucleotides 49 to 448 and a high level of the nucleotide identity (98%) in the region from nucleotides 449 to 1029 with Brazil-5. Figure 3B demonstrated that strain D clustered into different sublineages when the different part of VP7 gene-based grouping was performed. Obviously, strain D was recognized as the intragenic recombinant between intersublineage IIIa and intersublineage IIb. It was found that the recombinant region (nucleotides 49 to 448) contained antigenic region A (nucleotides 309 to 353).

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FIG. 3. Identification of novel recombinant G1 rotavirus strain D. (A) Nucleotide identity comparison of the complete coding regions of VP7 genes of strain D (belonging to lineage IIIb as a query strain) with those of the Egypt-8 (belonging to lineage IIIb) and Brazil-5 (belonging to lineage IIIa as reference strains). (B) Observation of changes of genotypes of D on the basis of phylogenetic trees of nucleotide sequences. The scale indicates nucleotide substitutions per position. Numbers in the branches indicate bootstrap values. Bootstrap values of 70% or higher are considered significant for the grouping.

Russia-1407. The G1 rotavirus strain Russia-1407 (S83903) was originally detected in Russia, and it was assigned to sublineage IIe (15). When the nucleotide sequence of Russia-1407 was compared with that of Oh-64 by using SimPlot, an apparent site of genetic recombination was found at position 549 in the VP7 gene (Fig. 4A). Before this site, the identities of Russia-1407 and Oh-64 were rather low (only 96%). After this site, however, they were highly similar (99%). The results demonstrated that the nucleotide sequences of regions from positions 49 to 548 in these two strains were rather different, but their sequences from positions 549 to 1029 were identical. The phylogenetic trees also supported the SimPlot results. Figure 4B showed that Russia-1407 was grouped into two distinct sublineages, IIa and IIe, according to its low and high identities of nucleotide sequences to Oh-64. Taken together, the results clearly indicated that Russia-1407 was the novel intragenic recombinant of intersublineage. It was found that the recombinant region (nucleotides 549 to 1029) contained antigenic regions C (nucleotides 672 to 713), D (nucleotides 921 to 925), E (nucleotides 615 to 920), and F (nucleotides 747 to 776).

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FIG. 4. Identification of novel recombinant G1 rotavirus strain Russia-1407. (A) Nucleotide identity comparison of the complete coding regions of VP7 genes of Russia-1407 (belonging to lineage IIe as a query strain) with that of OH-64 (belonging to lineage IIa as a reference strain). (B) Observation of changes of genotypes of Russia-1407 on the basis of phylogenetic trees of nucleotide sequences. The scale indicates nucleotide substitutions per position. Numbers in the branches indicate bootstrap values. Bootstrap values of 70% or higher are considered significant for the grouping.

G1 rotaviruses have been reported as the most common genotype in many countries (8, 11, 18). Even though many studies have conducted surveillance on rotavirus infection in various countries, reports documenting intragenic recombination in rotaviruses are limited. To date, only three intragenic recombinant rotaviruses, CHW17 and CH55 from China (recombination between G1 and G3) and ArgRes1723 from Argentina (recombination between sublineages Ib and Ic within G4), were detected (14, 19). Remarkably, we found three novel intragenic recombinant rotaviruses, accounting for 2.3% (3 of 131). This seems to be a high frequency for rotaviruses, which are not generally thought to undergo intragenic recombination. Three novel intragenic recombinants were found in three different continents, including Asia (Ban-59), Europe (Russia-1407), and North America (D), where the prevalence of G1 rotavirus infection was very high, ranging from 60.3% to 73.7% (18). However, among three previously reported intragenic recombinants, two were found in Asia (CHW17 and CH55) and one was found in South America, where the prevalence of G3 and G4 rotavirus infection was low (only 6.5% and 8.8.3%, respectively) (18). Obviously, the prevalence of intragenic recombinants in G3 and G4 rotaviruses is higher than that in G1 rotavirus.

Phylogenetic analysis showed that these rotavirus strains clustered into different lineages and sublineages within the G1 genotype when gene-based grouping was performed for a different region of VP7. These observations suggested that there are two distinct kinds of intragenic recombination, interlineages and intersublineages. These results are noteworthy because this is the first report, to the best of our knowledge, showing intragenic recombination in interlineages and intersublineages of G1 rotaviruses. These phenomenons improve our current knowledge of the G1 rotavirus evolution as well as of the origin of genetic heterogeneity. Altogether, the recombination in rotaviruses could greatly affect phylogenetic groupings and confuse molecular epidemiological studies. Among three previously described intragenic recombinants, strains CHW17 and CH55 appeared to result from a double-crossover event (19) and strain ArgRes1723 appeared to result from a single-crossover event (14). Consistent with these findings, the single and double crossovers were also found in two novel intragenic recombinants (strain D and strain Russia-1407) and in one novel intragenic recombinant (strain Ban-59) detected in the study, respectively.

To date, two rotavirus vaccines, Rotarix and RotaTeq, have recently been released onto the market and licensed in more than 30 countries (1, 13, 16, 23, 24). Rotarix and RotaTeq have been proven to have significant clinical efficacies against G1 rotavirus gastroenteritis, with efficacy values of 96% and 95%, respectively (1, 23, 24). However, the occurrence of the G1 rotavirus gastroenteritis after immunization in children is possible. And these G1 rotavirus strains were different from the vaccine viruses (16, 23, 24). Therefore, the evidence of an intragenic recombination event in these cases should be investigated. Obviously, the intragenic recombination in the G1 rotaviruses in this study is important to aid the explanation of vaccine failure because it could produce immunity escape through exchanging antigenic regions between different G1 rotavirus strains with different antigenicities. Even antigenic regions were located in the recombinant regions of Ban-59, D, and Russia-1407; however, direct inspection of the alignment of the deduced sequences of antigenic regions of VP7 revealed that these antigenic regions are conserved among them and among the reference rotavirus strains used in the present study (15). It is likely that structural variation of the VP7 protein within a genotype develops by successive mutations in the gene (2). Therefore, the intragenic recombination in VP7 genes of three strains might induce the conformational changes of G1 rotavirus VP7 protein, which probably led to the changing antigenicity of these intragenic recombinant strains. To date, a study on localization of amino acids involved in conformational changes of rotavirus VP7 structure is not available (15). The identification of these amino acids is of significance and should be investigated by further studies.

Although the crucial contributions of genetic reassortment and nucleotide substitution in producing antigenic variants for rotaviruses (3, 4) have been recognized, the intragenic recombination events in a few rotavirus strains were reported. Several studies showed the mixed infections with two different serotypes or with different variants belonging to the same serotype in one individual, therefore increasing the probability of reassortment or intragenic recombination in the evolutionary pathway of rotaviruses (3-5). RNA intragenic recombination is a mechanism for virus evolution (25). The primary mechanism involved in intragenic recombination in RNA viruses is the copy-choice model in which intragenic recombination is known to depend on various immunological and intracellular constraints, such as (i) successful coinfection of the host and in a single cell by two parental strains, (ii) efficient replication of parental viral genomes with template switching, and (iii) adaptation to different environments to be transmitted (25). The observation of the rotavirus intragenic recombinant strains detected in the study probably underscored that these strains theoretically might fulfill all prerequisites for their intragenic recombination. However, it is unclear that a copy-choice mechanism could work in rotaviruses where all replication occurs in particles and the replication complexes are anchored and separated from each other. The predicted amino acid sequences, including regions adjacent to the suggested breakpoints, were further analyzed. No same amino acid breakpoints were identified since the nucleotide breakpoints at positions 469 and 649 in Ban-59 are involved in coding for the amino acids leucine (position 141) and glutamine (position 201), respectively, and the nucleotide breakpoints at positions 449 and 549 in D and Russia-1407 are involved in coding for the amino acids tyrosine (position 134) and proline (position 167), respectively. Interestingly, the alignment of complete VP7 protein using CLUSTAL X showed the highly conserved region from amino acid 124 to amino acid 210 in G1 rotaviruses (data not shown). More interestingly, all of four amino acid breakpoints of three recombinant G1 rotaviruses were located in this region. Altogether, this highly conserved region in the VP7 gene was a favorable condition for recombination in G1 rotaviruses. However, further research should be conducted to elucidate the molecular mechanism of intragenic recombination in rotaviruses.

In conclusion, our results have described the genetic characterization of novel intragenic recombinant rotaviruses and have increased the evidence of worldwide distribution of intragenic recombinant rotaviruses. Intragenic recombination events in rotaviruses are not completely understood; further research should be conducted to investigate whether intragenic recombination can be potentially dangerous for host species, and it likely limits the rotavirus control programs and has major implications for rotavirus vaccine design.

 
This study was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Sciences, and Technology, Japan, and the Ministry of Health, Labor, and Welfare, Japan.

 
* Corresponding author. Mailing address: Department of Developmental Medical Sciences, Institute of International Health, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033. Phone: 81-3-5841-3590. Fax: 81-3-5841-3629. E-mail: ushijima{at}m.u-tokyo.ac.jp

Published ahead of print on 3 July 2007.

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Journal of Virology, September 2007, p. 10188-10194, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00337-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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