Comparative evolutionary epidemiology of dengue virus serotypes

► Evolutionary rates are statistically identical in all DENV serotypes. ► The E gene codon sites are under strong purifying selection. ► No evidence of adaptive molecular evolution was found on the basal branches of DENV. ► DENV genetic diversity presents a strong geographic structure on a global scale. ► Effective population sizes of DENV-1, 2 and 3 have increased since the early 2000s. Evolutionary studies on dengue virus have frequently focused on intra-serotype diversity or on specific epidemics. In this study, we compiled a comprehensive data set of the envelope gene of dengue virus serotypes and conducted an extensive comparative study of evolutionary molecular epidemiology. We found that substitution rates are homogeneous among dengue serotypes, although their population dynamics have differed over the past few years as inferred by Bayesian coalescent methods. On a global scale, DENV-2 is the serotype with the highest effective population size. The genealogies also showed geographical structure within the serotypes. Finally, we also explored the causes of dengue virus serotype diversification by investigating the plausibility that it was driven by adaptive changes. Our results suggest that the envelope gene is under significant purifying selection and the hypothesis that dengue virus serotype diversification was the result of stochastic events cannot be ruled out.