PT  - JOURNAL ARTICLE
AU  - Esteban Finol
AU  - Eng Eong Ooi
TI  - Evolution of subgenomic RNA shapes dengue virus adaptation and epidemiological fitness
AID  - 10.1101/267922
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 267922
4099  - http://biorxiv.org/content/early/2018/02/19/267922.short
4100  - http://biorxiv.org/content/early/2018/02/19/267922.full
AB  - Changes in dengue viruses (DENV) genome could give rise to fitter strains that spread epidemically. Mutations in the 3’ untranslated region (3’UTR) of DENV-2 genome were recently shown to result in increased subgenomic flavivirus RNA (sfRNA) production. sfRNA inhibited host TRIM25 protein activity and reduced interferon (IFN) expression. It may thus enable DENV to reach higher viremia and higher infection rates of blood-feeding Aedes mosquitoes. Whether differences in 3’UTRs shaped DENV evolution remains incompletely understood. Herein, we applied a ‘bigdata’ approach - we retrieved 3544 dengue virus genomes from NBCI database - and combined RNA sequence covariation, RNA phylogenetics and site specific ncRNA natural selection estimation to gain insights into sfRNA evolution. We found that the second nuclease resistant (NR2) structure of DENV-2 sfRNA has undergone strong positive selection. Conversely, other sfRNA structures are under purifying selection and highly conserved despite sequence divergence. Epidemiological reports also suggest that nucleotide substitutions in NR2 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.HighlightsDengue viruses (DENV) preserve RNA elements in their 3’ untranslated region (UTR).Using RNA phylogeny and phylogenetics, we quantified natural selection on this ncRNA.Nuclease resistant (NR) structures in DENV 3’UTRs contributed to DENV speciation.A highly evolving NR structure appears to increase DENV-2 epidemiological fitness.