Evolutionary Dynamics of Human Rotaviruses: Balancing Reassortment with Preferred Genome Constellations

Abstract

Group A human rotaviruses (RVs) are a major cause of severe gastroenteritis in infants and young children. Yet, aside from the genes encoding serotype antigens (VP7; G-type and VP4; P-type), little is known about the genetic make-up of emerging and endemic human RV strains. To gain insight into the diversity and evolution of RVs circulating at a single location over a period of time, we sequenced the eleven-segmented, double-stranded RNA genomes of fifty-one G3P[8] strains collected from 1974 to 1991 at Children's Hospital National Medical Center, Washington, D. C. During this period, G1P[8] strains typically dominated, comprising on average 56% of RV infections each year in hospitalized children. A notable exception was in the 1976 and 1991 winter seasons when the incidence of G1P[8] infections decreased dramatically, a trend that correlated with a significant increase in G3P[8] infections. Our sequence analysis indicates that the 1976 season was characterized by the presence of several genetically distinct, co-circulating clades of G3P[8] viruses, which contained minor but significant differences in their encoded proteins. These 1976 lineages did not readily exchange gene segments with each other, but instead remained stable over the course of the season. In contrast, the 1991 season contained a single major clade, whose genome constellation was similar to one of the 1976 clades. The 1991 clade may have gained a fitness advantage after reassorting with as of yet unidentified RV strain(s). This study reveals for the first time that genetically distinct RV clades of the same G/P-type can co-circulate and cause disease. The findings from this study also suggest that, although gene segment exchange occurs, most reassortant strains are replaced over time by lineages with preferred genome constellations. Elucidation of the selective pressures that favor maintenance of RVs with certain sets of genes may be necessary to anticipate future vaccine needs. Rotaviruses are the most important cause of severe diarrhea in infants and young children. Due to the segmented nature of their genomes, rotaviruses can exchange (reassort) genes during co-infections, a feature that is predicted to generate new, possibly more dangerous virus strains. However, the amount of gene reassortment occurring in nature is not known, as very few rotavirus genomes have been sequenced. To better understand the genetic make-up of rotaviruses circulating at a single location over a period of time, we sequenced the genomes of fifty-one isolates recovered from sick children from 1974 to 1991 at Children's Hospital National Medical Center, Washington, D. C. By analyzing these sequences, we found that several distinct groups (clades) of rotaviruses co-circulated and caused disease in a single epidemic season. In contrast to what was previously thought, very few rotaviruses exchanged gene segments with each other; instead, the genome constellations of the viruses remained relatively stable. We also discovered that these distinct rotavirus clades encode different viral proteins, which may be important in the development of effective vaccines. Together, the findings from this first large-scale rotavirus genomics project provide unparalleled insight into how these pathogens evolve during their spread through the human population.