Group A rotaviruses (RVs) are important pathogens that cause acute gastroenteritis in infants and young children (11
). In developing regions of the world with reduced access to medical care, RV infections lead to the deaths of ~450,000 children each year (50
). In industrialized countries, the burden of RV disease is mainly associated with the financial costs of treatment. Specifically, prior to the recent introduction of vaccines in the United States, it was estimated that RV-induced gastroenteritis caused more than 55,000 hospitalizations and 500,000 physician visits each year at a societal cost of ~$1 billion (40
). In 2006 and 2008, respectively, the U.S. Advisory Committee on Immunization Practices recommended the live-attenuated vaccines RotaTeq (Merck) and Rotarix (Glaxo-Smith Kline) for the routine immunization of infants (8
). RotaTeq is a pentavalent vaccine consisting of five human-bovine RV reassortants, each of which carries a separate human RV VP7 gene (G1, G2, G3, or G4) or a human RV P VP4 gene in the background of the bovine WC3 strain (G6P) (31
). In contrast, Rotarix is a monovalent vaccine derived from a human strain (89-12) with G1P specificity (53
). Postlicensure studies indicate that both RotaTeq and Rotarix prevent 85 to 100% of severe RV gastroenteritis in developed countries (15
). For reasons that remain unclear, the efficacy of the vaccines was found to be lower in developing regions of the world (2
). Surveillance networks have been established at various geographical locations (i) to obtain information on the prevalence and types of circulating RV strains, (ii) to determine whether human RVs are changing in the face of vaccine pressures, and (iii) to continue monitoring for the safety and efficacy of RotaTeq and Rotarix (5
). Importantly, the viral gene/genome sequences deduced via these epidemiological studies are illuminating the diversity and complex evolutionary dynamics of this common childhood pathogen.
RVs maintain their double-stranded RNA (dsRNA) genome as 11 separate segments, which can reassort when a host cell is infected with more than one strain (11
). These exchanges, described as genetic shift, have long been hypothesized to play an important role in generating viral diversity, allowing the virus to evolve rapidly in response to selection pressures (14
). In addition, the error-prone nature of the viral polymerase leads to the accumulation of point mutations in the viral genome, causing RV strains to drift antigenically (11
). However, because only limited numbers of complete genome sequences have been determined for naturally circulating human RVs, the frequency and significance of shift and drift are poorly understood. To aid in studies of RV diversity, a comprehensive classification system was developed that designates a genotype for each of the 11 viral genes (i.e., segments) based on established nucleotide identity cutoff values (28
). The acronym Gx-P[x]-Ix-Rx-Cx-Mx-Ax-Nx-Tx-Ex-Hx is used to describe a virus based on segments encoding each viral protein(s) (i.e., VP7-VP4-VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3-NSP4-NSP5/6). This system extends the well-known binomial classification of RVs that is based on the genes encoding outer capsid serotype antigens VP7 (G types) and VP4 (P types) to the other nine internal protein genes (encoding VP1 to VP3, VP6, and NSP1 to NSP5/6) (29
The complete genome classification approach provided data to support the existence of two dominant human RV genogroups (Wa-like and DS-1-like), originally identified using differential RNA-RNA hybridization (35
). Wa-like RVs almost invariably exhibit genotype 1 internal protein genes (i.e., I1-R1-C1-M1-A1-N1-T1-E1-H1) and tend to have G1P, G3P, G4P, and G9P specificities (29
). In contrast, DS-1-like RVs that have been fully sequenced are usually G2P strains with genotype 2 internal protein genes (i.e., I2-R2-C2-M2-A2-N2-T2-E2-H2) (29
). For the purposes of this paper, we will refer to the Wa-like genogroup as genogroup 1 (GG-1) and the DS-1-like genogroup as genogroup 2 (GG-2). Gene reassortment between GG-1 and GG-2 strains is possible, as evidenced by the isolation of human RVs containing both genotype 1 and genotype 2 genes from children suffering acute gastroenteritis (16
). However, based on the available sequence data, intergenogroup reassortants seem to be less prevalent in the human population than pure GG-1 or GG-2 strains (29
). It is possible that the genes (or the encoded proteins) of RVs belonging to the same genogroup have coevolved and operate best when kept together (3
). In this manner, it hypothesized that human RVs belonging to different genogroups create less fit reassortants which may not emerge in the human population. In contrast, segment exchange between RVs within a genogroup would be expected to occur more readily. Nevertheless, large-scale, complete genome sequence analyses of 62 archival GG-1 human RVs (51 G3P and 11 G4P strains) from Washington, DC, revealed that intragenogroup reassortants were less common than had been anticipated (32
). Comparative genomic studies of contemporary strains are needed to ascertain whether these previous results reflect the current status of RV diversity.
In this study, we report the complete genome sequence analysis of 58 GG-1 human RVs (36 G1P, 18 G3P, and 4 G12P strains) from children seeking medical attention for severe, acute gastroenteritis at Vanderbilt University Medical Center (VUMC) in Nashville, TN, from one prevaccine season (2005 to 2006) and two postvaccine seasons (2006 to 2007 and 2008 to 2009). Complete genome sequence analyses of modern human RVs are expected to enhance our understanding of the diversity and evolution of this important pediatric pathogen.