Speaker
Description
Noroviruses are the leading cause of viral gastroenteritis, with most cases arising from genotype GII.4 infection. New GII.4 variants often emerge from long internal branches, a pattern similar to that observed for certain SARS-CoV-2 variants of concern, such as Omicron and Alpha. For SARS-CoV-2, diverse phylogenetic evidence suggests that prolonged infections are the source of these variants. Here, we evaluate whether prolonged infections may similarly give rise to new GII.4 variants by applying several analyses to population-level and within-host GII.4 sequence data, including phylogenetic analyses, root-to-tip divergence calculations, substitution rate estimation, and detailed sequence analyses. We first find that overall substitution rates for the GII.4 capsid gene exceed within-variant substitution rates. Analysis of prolonged GII.4 infections further shows that within-host evolutionary rates are often higher than those observed at the population level for matched variants. Many recurrent substitutions across prolonged infections occur in the P2 region of GII.4’s capsid gene, the dominant target of our immune response. This suggests that substantial antigenic change can arise within hosts experiencing prolonged infection. The majority of the identified recurrent substitutions in P2 are also ‘lineage-defining’ in that new GII.4 variants tend to carry substitutions in this region. Notably, and in contrast to SARS-CoV-2, most genetic differences between newly emerging GII.4 variants and earlier strains are synonymous rather than nonsynonymous. This pattern indicates strong purifying selection along these long branches, alongside positive selection acting on key antigenic sites. Consistent with this, capsid evolution within prolonged GII.4 infections also shows higher synonymous than nonsynonymous substitution rates. Together, these results are consistent with the hypothesis that prolonged infections may contribute to the emergence of new GII.4 variants. However, increased sampling at the population level will be necessary to more fully evaluate this hypothesis.
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