Genetic characterization of dengue virus 4 complete genomes from East Java, Indonesia

Abstract

Dengue is an endemic arboviral disease with continuous transmission in Indonesia for more than five decades. A recent outbreak in Jember, East Java province, demonstrated the predominance of DENV-4, a serotype known for its low global spread and limited transmission. While epidemiological factors such as new serotype introduction and lacking herd immunity may explain its predominance, viral factors may also contribute. Using next-generation sequencing, we generated 13 representative complete genomes of DENV-4 responsible for the outbreak. Phylogenetic and evolutionary analyses on complete genomes were performed to understand the spatial and temporal dynamics of the viruses. Further analyses were done to study amino acid variations in DENV genes, as well as the potential events of recombination and selection pressure within the genomes. We revealed the DENV-4 genetic factors that may lead to its predominance in the 2019 Jember dengue outbreak. A combination of selection pressure and mutational genetic changes may contribute to the DENV-4 predominance in East Java, Indonesia. The possible intra-serotype recombination events involving the non-structural protein 5 (NS5) gene were also observed. Altogether, these genetic factors may act as additional factors behind the complex dengue outbreak mechanism.

Keywords: DENV-4; Dengue; Evolution; Genome; Phylogenetic; Recombination.

Fig. 1

Maximum likelihood tree of Jember complete genome sequences together with global DENV-4 reference strains available in public database (A). Jember DENV-4 is grouped into Clade IIa of DENV-4 Genotype II based on global Maximum Likelihood analysis of all DENV-4 complete genome sequences found in GenBank repository. Closely related sequences in Genotype IIa (within red square) were selected to generate a Maximum Clade Credibility (MCC) tree of Jember DENV-4 strains (red font) together with most closely related DENV-4 reference strains from Indonesia (blue font) and other countries (B). The number in each node represents the posterior probability of the particular node. The time to the most common recent ancestor (TMRCA) is shown as year [95% Highest Posterior Density (HPD)]. Arabic numbers show classification into Lineages

Fig. 2

Amino acid variation within Jember DENV-4 genome sequences compared to a reference strain. The positively selected amino acid site number 2772 within the NS5 gene is highlighted