Archives of Virology

, Volume 161, Issue 8, pp 2133–2148 | Cite as

Population genomics of dengue virus serotype 4: insights into genetic structure and evolution

  • Vaishali P. Waman
  • Sunitha Manjari Kasibhatla
  • Mohan M. Kale
  • Urmila Kulkarni-Kale
Original Article


The spread of dengue disease has become a global public health concern. Dengue is caused by dengue virus, which is a mosquito-borne arbovirus of the genus Flavivirus, family Flaviviridae. There are four dengue virus serotypes (1-4), each of which is known to trigger mild to severe disease. Dengue virus serotype 4 (DENV-4) has four genotypes and is increasingly being reported to be re-emerging in various parts of the world. Therefore, the population structure and factors shaping the evolution of DENV-4 strains across the world were studied using genome-based population genetic, phylogenetic and selection pressure analysis methods. The population genomics study helped to reveal the spatiotemporal structure of the DENV-4 population and its primary division into two spatially distinct clusters: American and Asian. These spatial clusters show further time-dependent subdivisions within genotypes I and II. Thus, the DENV-4 population is observed to be stratified into eight genetically distinct lineages, two of which are formed by American strains and six of which are formed by Asian strains. Episodic positive selection was observed in the structural (E) and non-structural (NS2A and NS3) genes, which appears to be responsible for diversification of Asian lineages in general and that of modern lineages of genotype I and II in particular. In summary, the global DENV-4 population is stratified into eight genetically distinct lineages, in a spatiotemporal manner with limited recombination. The significant role of adaptive evolution in causing diversification of DENV-4 lineages is discussed. The evolution of DENV-4 appears to be governed by interplay between spatiotemporal distribution, episodic positive selection and intra/inter-genotype recombination.


Markov Chain Monte Carlo Dengue Virus Envelope Gene Dengue Virus Serotypes Brazilian Strain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by a Center of Excellence (CoE) grant from the Department of Biotechnology (DBT), Government of India, New Delhi. UKK acknowledges DBT CoE for financial assistance. VPW acknowledges DBT fellowship. SMK acknowledges the Bioinformatics Resources and Applications Facility (BRAF), C-DAC, Pune.

Compliance with ethical standards


This work was supported by a Center of Excellence (CoE) grant from the Department of Biotechnology (DBT), Government of India, New Delhi, India.

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

705_2016_2886_MOESM1_ESM.doc (218 kb)
Online resource 1: Table S1. Dataset of 134 strains of DENV-4. Table enlists serial number, GenBank accession number, name, country, collection date, genotype and subpopulation (assigned using STRUCTURE program). Serial numbers are used to represent the corresponding strain in bar plot given in Fig. 2 (DOC 217 kb)
705_2016_2886_MOESM2_ESM.tif (423 kb)
Online resource 2: Figure S1. Complete genome-based phylogenetic tree of DENV-4 obtained using Maximum-likelihood method. 134 DENV-4 genomes were used to generate tree using ML with 1000 bootstrap replicates. OTU is labelled as: ‘DENV4| (genotype)| (GenBank accession number)’ for every DENV-4 strain. Branches in tree are color-coded as per the eight subpopulations obtained using STRUCTURE program. They are GS (red) GIII (green), GI-A (blue), GI-B (magenta), GII-A1 (yellow), older GII-A2 (orange), modern GII-A3 (purple) and an admixed GII-A4 (cyan) (TIFF 423 kb)
705_2016_2886_MOESM3_ESM.tif (252 kb)
Online resource 3: Figure S2. Complete genome-based tree of DENV-4 obtained using Maximum-parsimony method. 134 DENV-4 genomes were used to generate tree using MP with 1000 bootstrap replicates. OTU is labelled as: ‘DENV4|(genotype)|(GenBank accession number)’ for every strain. Branches in tree are color-coded as per eight subpopulations obtained using STRUCTURE program: GS (red) GIII (green), GI-A (blue), GI-B (magenta), GII-A1 (yellow), GII-A2 (orange), GII-A3 (purple) and an GII-A4 (cyan) (TIFF 251 kb)
705_2016_2886_MOESM4_ESM.tif (283 kb)
Online resource 4: Figure S3. Envelope gene-based tree of DENV-4 obtained using Neighbor-joining method. Tree is generated using NJ with 1000 bootstrap replicates. OTU is labelled as: ‘DENV4|(genotype)|(GenBank accession number)’ for every strain. Branches are color-coded as per eight subpopulations obtained using STRUCTURE program: GS (red), GIII (green), GI-A (blue), GI-B (magenta), GII-A1 (yellow), older GII-A2 (orange), modern GII-A3 (purple) and GII-A4 (cyan) (TIFF 282 kb)
705_2016_2886_MOESM5_ESM.tif (412 kb)
Online resource 5: Figure S4. Envelope gene-based time-scaled tree of DENV-4 obtained using BEAST v18.2. Envelope-gene sequences were extracted from DENV-4 genomic entries having year information. Time-scale tree using uncorrelated lognormal relaxed clock model with constant population size, was generated. OTU is labelled as: ‘D4|(genotype)|(GenBank accession number)|(year)|(country)’ for every strain. Few country fields were labelled as ‘NA’ to indicate their non-availability. Nodes and branches are labelled with posterior probability values. Branches are color-coded as per eight subpopulations obtained using STRUCTURE program: GS (red), GIII (green), GI-A (blue), GI-B (magenta), GII-A1 (yellow), GII-A2 (orange), GII-A3 (purple) and GII-A4 (cyan) (TIFF 411 kb)
705_2016_2886_MOESM6_ESM.pdf (52 kb)
Online resource 6: Figure S5. Episodic positive selection on codon-90 in NS2A, obtained using MEME. Selection on NS2A codon-90 was observed to be stronger on branch (red) leading to modern GI-A lineage (PDF 51 kb)
705_2016_2886_MOESM7_ESM.pdf (58 kb)
Online resource 7: Figure S6. Episodic positive selection on codon-142 in NS3, obtained using MEME. Selection on NS3 codon-142 was observed to be stronger on branch (red) leading to cluster of Asian DENV-4 subpopulations (PDF 58 kb)
705_2016_2886_MOESM8_ESM.meg (1.6 mb)
Online resource 8. Complete-genome alignment (mega format) of 134 DENV-4 strains (MEG 1596 kb)


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Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Vaishali P. Waman
    • 1
  • Sunitha Manjari Kasibhatla
    • 1
    • 2
  • Mohan M. Kale
    • 3
  • Urmila Kulkarni-Kale
    • 1
  1. 1.Bioinformatics CentreSavitribai Phule Pune University (formerly University of Pune)PuneIndia
  2. 2.Bioinformatics GroupCentre for Development of Advanced ComputingPuneIndia
  3. 3.Department of StatisticsSavitribai Phule Pune University (formerly University of Pune)PuneIndia

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