J Virol. 2014 Oct 1. pii: JVI.02494-14. [Epub ahead of print]
RNA Populations in Immunocompromised Patients as Reservoirs for Novel Norovirus Variants.
Noroviruses are the leading cause of acute gastroenteritis outbreaks worldwide. The majority of norovirus outbreaks are caused by genogroup II.4 (GII.4) noroviruses. Novel GII.4 noroviruses emerge every 2-4 years and replace older variants as the dominant norovirus. The process of the emergence of novel variants is believed to be caused by a combination of recombination, genetic drift, and selection driven by population immunity, but how or where these novel variants emerge is not known. We detected two previously unknown novel GII.4 variants, termed GII.4 UNK1 and GII.4 UNK2, and a diverse norovirus population in fecal specimens from immunocompromised individuals with diarrhea after they had undergone bone-marrow transplantation. We hypothesized that immunocompromised individuals can serve as reservoirs for novel norovirus variants. To test our hypothesis, metagenomic analysis of viral RNA populations was combined with a full genome bioinformatic analysis of publicly available GII.4 noroviruses sequences from 1974 - 2014 to identify converging sites. Localization analysis indicated that variable sites were more likely to be within two amino acids (P< 0.05) of positively selected sites. Further analysis indicated polymorphic site distribution was random and its proximity to positively selected sites was dependent on the size of the norovirus genome and the number of positively selected sites. The results indicate that random mutations can have a positive impact on driving norovirus evolution and that immunocompromised individuals have the ability to serve as a potential reservoirs for novel GII.4 strains.
Norovirus is the most common cause of viral gastroenteritis in the US. Every two to three years novel norovirus variants emerge and rapidly disseminate throughout the world. The continual emergence of novel noroviruses is believed to be caused by a combination of genetic drift, population immunity, and recombination, but exactly how this emergence occurs remains unknown. In this study we identified two novel GII.4 variants in immunocompromised bone marrow transplant patients. Using metagenomic and bioinformatics analysis, we show that most genetic polymorphisms in the novel variants occur near, 0-2 amino acids, of positively selected sites, but the distribution of mutations was random; clustering of polymorphisms with positively selected sites was a result of genome size, number of mutations and positively selected sites. This study shows that immunocompromised patients can harbor infectious novel norovirus variants and although mutations in viruses are random they can have a positive effect in viral evolution.
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