Genomic stratification and differential natural selection signatures among human norovirus genogroup II isolates

Noroviruses (NoVs), which are members of the family Caliciviridae, are the most common cause of gastroenteritis in humans. Ten NoV genogroups have been reported so far. Of these, genogroup II (GII) is the most prevalent, and it causes serious infections worldwide. The complete genome sequences of NoV GII isolates from different geographical regions were retrieved from the public database. The model-based clustering approach, implemented in the STRUCTURE resource, was employed for assessment of genetic composition. The MEGA X and IQ Tree tools were used for phylogenetic analysis. Genome-wide natural selection analysis was performed using maximum-likelihood-based methods. The demographic features of NoV GII genome sequences were assessed using the BEAST package. All of the NoV GII sequences initially clustered into two main subpopulations at significant K = 2, where the genotype GII.4 samples clearly split from the rest of the genotypes. This indicates a marked genetic distinction between norovirus GII.4 and non-GII.4 samples. Phylogenetic analysis showed the presence of five distinct subclades for genotype GII.2 and seven subclades for GII.4 samples. Several isolates with admixed ancestry were identified that constituted distinct subclusters in the phylogenetic tree. No continental-specific genetic distinctions were observed among the NoV GII samples. Significant genomic signatures of both positive and negative natural selection were identified across the NoV GII genes. A differential pattern of positive selection signals was inferred between the GII.4 and non-GII.4 genotypes. The demographic analysis revealed an increase in the effective population size of NoV GII during 2009-2010, followed by a rapid fall in 2015.