Abstract
Dengue virus (DENV) is the agent of the most widespread vector-borne viral disease of humans. To infer the timescale of DENV evolution with as much accuracy as possible, we compared, within a Bayesian Markov Chain Monte Carlo (MCMC) framework, estimates of phylogenetic tree length using both covarion and noncovarion models of molecular evolution, the latter also incorporating lineage-specific rate variation through a “relaxed” molecular clock. Using a data set of 32 complete genome sequences representing all four viral serotypes, we found evidence for covarion-like evolution at second codon positions in specific DENV genes, although rarely at the level of complete gene or genomes. Further, the covarion model had little effect on estimates of tree length and hence time to the Most Recent Common Ancestor (MRCA). We conclude that although covarion models can improve descriptions of the dynamics of amino acid substitution, they have little effect on estimates of the timescale of viral evolution, which in the case of DENV covers a period of no more than 2000 years.
Similar content being viewed by others
References
Bennett SN, Holmes EC, Chirivella M, Rodriguez DM, Beltran M, Vorndam V, Gubler DJ, McMillan WO (2006) Molecular evolution of dengue 2 virus in Puerto Rico: positive selection in the viral envelope accompanies clade reintroduction. J Gen Virol 87:885–893
Drummond AJ, Ho SYW, Phillips MJ, Rambaut A (2006) Relaxed phylogenetics and dating with confidence. PLoS Biol 4:e88
Drummond AJ, Rambaut A (2003) BEAST version 1.3. Available at: http://www.evolve.zoo.ox.ac.uk/beast/
Fitch WM, Markowitz E (1970) An improved method for determining codon variability in a gene and its application to the rate of fixation of mutations in evolution. Biochem Genet 4:579–593
Galtier N (2001) Maximum-likelihood phylogenetic analysis under a covarion-like model. Mol Biol Evol 18:866–873
Holmes EC (2003) Molecular clocks and the puzzle of RNA virus origins. J Virol 77:3893–3897
Huelsenbeck JP, Ronquist F (2001) MrBayes: Bayesian inference of phylogenetic trees. Bioinformatics 17:754–755
Huelsenbeck JP (2002) Testing a covariotide model of DNA substitution. Mol Biol Evol 19:698–707
Jenkins GM, Rambaut A, Pybus OG, Holmes EC (2002) Rates of molecular evolution in RNA viruses: a quantitative phylogenetic analysis. J Mol Evol 54:152–161
Klungthong C, Zhang C, Mammen Jr. MP, Ubol S, Holmes EC (2004) The molecular epidemiology of dengue virus serotype 4 in Bangkok, Thailand. Virology 329:168–179
Kuno G, Chang G-J, Tsuchiya KR, Karabatsos N, Cropp CB (1998) Phylogeny of the genus Flavivirus. J Virol 72:73–83
Lanciotti RS, Gubler DJ, Trent DW (1997) Molecular evolution and phylogeny of dengue-4 viruses. J Gen Virol 78:2279–2286
Nisalak A, Endy TP, Nimmannitya S, Kalayanarooj S, Thisayakorn U, Scott RM, Burke DS, Hoke CH, Innis BL, Vaughn DW (2003) Serotype-specific dengue virus circulation and dengue disease in Bangkok, Thailand from 1973–1999. Am J Trop Med Hyg 68:191–202
Rambaut A (1996) Se-Al: Sequence Alignment Editor. Available at: http://www.evolve.zoo.ox.ac.uk/
Twiddy SS, Woelk CH, Holmes EC (2002) Phylogenetic evidence for adaptive evolution of dengue viruses in nature. J Gen Virol 83:1679–1689
Twiddy SS, Holmes EC, Rambaut A (2003) Inferring the rate and time-scale of dengue virus evolution. Mol Biol Evol 20:122–129
Tuffley C, Steel M (1998) Modeling the covarion hypothesis of nucleotide substitution. Math Biosci 147:63–91
Wang E, Ni H, Xu R, Barrett ADT, Watowich SJ, Gubler DJ, Weaver SC (2000) Evolutionary relationships of endemic/epidemic and sylvatic dengue viruses. J Virol 74:3227–3234
Wang HC, Spencer M, Susko E, Roger AJ (2007) Testing for covarion-like evolution in protein sequences. Mol Biol Evol 24:294–305
Zanotto PM de A, Gould EA, Gao GF, Harvey PH, Holmes EC (1996) Population dynamics of flaviviruses revealed by molecular phylogenies. Proc Natl Acad Sci USA 93:548–553
Zhang C, Mammen MP Jr, Chinnawirotpisan P, Klungthong C, Rodpradit P, Monkongdee P, Nimmannitya S, Kalayanarooj S, Holmes EC (2005) Clade replacements in dengue virus serotypes 1 and 3 are associated with changing serotype prevalence. J Virol 79:15123–15130
Zhang C, Mammen MP Jr, Chinnawirotpisan P, Klungthong C, Rodpradit P, Nisalak A, Nimmannitya S, Kalayanarooj S, Vaughn DW, Holmes EC (2006) Structure and age of genetic diversity of dengue virus type 2 in Thailand. J Gen Virol 87:873–883
Acknowledgment
This work was supported by the Alfred P. Sloan Foundation Graduate Scholarship.
Author information
Authors and Affiliations
Corresponding author
Additional information
[Reviewing Editor: Dr. Nicolas Galtier]
Rights and permissions
About this article
Cite this article
Dunham, E.J., Holmes, E.C. Inferring the Timescale of Dengue Virus Evolution Under Realistic Models of DNA Substitution. J Mol Evol 64, 656–661 (2007). https://doi.org/10.1007/s00239-006-0278-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00239-006-0278-5