Evolution of Subgenomic RNA Shapes Dengue Virus Adaptation and Epidemiological Fitness
34 Pages Posted: 4 Dec 2018 Publication Status: Published
More...Abstract
Genetic changes in the dengue virus (DENV) genome affects viral fitness both clinically and epidemiologically. Even in the 3’ untranslated region (3’UTR), mutations could impact the formation of subgenomic flaviviral RNA (sfRNA) and the specificity of sfRNA in inhibiting host proteins necessary for successful viral replication. Indeed, we have recently shown that mutations in the 3’UTR of DENV2 affected its ability to inhibit TRIM25 E3 ligase activity to reduce interferon (IFN) expression, which potentially contributed to the emergence of a new viral clade during the 1994 dengue epidemic in Puerto Rico. However, whether differences in 3’UTRs shaped DENV evolution on a larger scale remains incompletely understood. Herein, we combined RNA phylogeny with phylogenetics to gain insights on sfRNA evolution. We found that sfRNA structures are under purifying selection and highly conserved despite sequence divergence. Interestingly, only the second flaviviral Nuclease-resistant RNA (fNR2) structure of DENV-2 has undergone strong positive selection. Epidemiological reports also suggest that nucleotide substitutions in fNR2 may drive DENV-2 epidemiological fitness, possibly through sfRNA-protein interactions. Collectively, our findings indicate that 3’UTRs are important determinants of DENV fitness in human-mosquito cycles.
Keywords: dengue virus; sfRNA; epidemiological fitness; ncRNA evolution
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