The trade-off effect on arboviruses including DENV obligated to adapt alternatively into the invertebrate vector and vertebrate host is believed to be associated with reduced rate of mutations.

Thus, DENV evolution is also subjected to trade-off effects by the vector wherein fitness of the virus improves when it replicates in one cell line compared to alternative passages in both Akt inhibitor mosquito and human cells [45]. It has been suggested that the trade-off effect may be responsible for evolution of distinct lineages within DENV serotype as seen in the case of serotype 1 in Columbia [46]. According to this study [46], hyperendemic infections of dengue in humans contributed to relaxing the trade-off effect on the virus from the mosquito vector population in the region. Although elevated mutational rate in LY3039478 chemical structure viruses is primarily due to the lack of proof-reading activity of RNA-dependent RNA-polymerases, relaxation of vector associated trade-off effects on virus may also lead to increased rate of substitutions in dengue virus [46]. Based on these studies and the studies suggesting that Vadimezan mw nucleotide substitution patterns may have co-evolutionary

links between mosquito and virus [39], it is thus likely that evolution of dengue virus is intricately dependent upon selective pressure resulting from both host (relating to immune status) and mosquito (relating to vectorial capacity) [47]. Thus, why spatial

population and phylogenetic analyses of DENV are essential for better understanding the history and epidemiology of the disease [48]. According to the selection-mutation-drift theory [49], some codons are used preferentially over alternate synonymous codons for better efficiency of translation of a gene, while mutation and drift balances the selection force on that gene. In this context, the results from our investigation indicated an excess of non-preferred codons over preferred codons suggesting that synonymous sites are under relaxed selection in DENV. Thus, the balance between selection and mutation likely contributes to the widespread prevalence of silent sites which are weakly selected in the DENV genome. While GC percentage can have a significant influence on codon bias, the DENV genome shows ~ 50% GC content in the coding sequences, wherein the effective number of codons within each serotype typically varies from 48 to 51. At the same time, it is known that changes in the 1st and 2nd positions can have an effect on compositional bias of amino acids of proteins in insects [50–52]. In the DENV genome, we found that the fixed mutations leading to differential usage of codons are primarily associated with four specific amino acids: Gly, Pro, Ser and Thr.