The origins of DENV

As with most infectious diseases, inferring the origin of DENV from historical records alone is a difficult exercise. In particular, the clinical symptoms of DENV are often not sufficiently diagnostic to exclude other infectious agents. This withstanding, historical records reveal three key dates in the evolutionary history of DENV; (i) the earliest proposed description of DENV infection from a Chinese medical encyclopaedia dated to 992 AD, (ii) the first description of a large-scale DENV epidemics at the end of the 18th century, and (iii) the first

FIG. 1. The evolutionary history of DENV inferred through phylogenetic analysis. The phylogeny was reconstructed using a representative sample of 250 E gene sequences from all serotypes and subtypes of DENV under a maximum likelihood method and employing the HKY85+I+r4 model of nucleotide substitution. The subtype designation is shown next to the relevant groupings and estimates of the age of the most recent common ancestor (with confidence intervals in parenthesis) are shown for key nodes. All age estimates were taken from Twiddy et al (2003). The tree is mid-point rooted for purposes of clarity only and all horizontal branch lengths are drawn to a scale of the number of nucleotide substitutions per site.

FIG. 1. The evolutionary history of DENV inferred through phylogenetic analysis. The phylogeny was reconstructed using a representative sample of 250 E gene sequences from all serotypes and subtypes of DENV under a maximum likelihood method and employing the HKY85+I+r4 model of nucleotide substitution. The subtype designation is shown next to the relevant groupings and estimates of the age of the most recent common ancestor (with confidence intervals in parenthesis) are shown for key nodes. All age estimates were taken from Twiddy et al (2003). The tree is mid-point rooted for purposes of clarity only and all horizontal branch lengths are drawn to a scale of the number of nucleotide substitutions per site.

description of DHF/DSS epidemics following World War II (reviewed in Gubler 1997).

Luckily, viral gene sequence data offer an alternative means to infer the evolutionary history of DENV. Estimates for the age of DENV based on viral molecular clocks are relatively consistent (Twiddy et al 2003, Weaver & Barrett 2004, Zanotto et al 1996). For example, estimates for the date of the origin of DENV itself places this event within the last few thousand years, satisfactory adjacent to the earliest reports of dengue-like illness. Similarly, most molecular clock estimates for age of the genetic diversity within each serotype are similar, —100-300 years ago (Fig. 1). These dates most likely correspond to either the time of cross-species transmission from non-human primates to humans, or to the acquisition of Aedes aegypti as the principle vector for DENV transmission in humans (Moncayo et al 2004). However, one puzzle remains: why the genetic diversity within the four serotypes appears at approximately the same time? The most likely explanation is that the spill-over of DENV strains from non-human primates to humans has occurred throughout history but that only in the last few centuries have human populations been sufficiently large to ensure the development of sustained transmission networks (Zanotto et al 1996).

Could these molecular clock dates be grossly inaccurate? The biggest source of error will be if substitution rates vary dramatically between humans and other species, for example because rates of amino acid change increase as the virus adapts to new hosts. However, given that similar levels of genetic diversity have been observed in both humans and mosquito populations (Craig et al 2003, Lin et al 2004) as well as the relatively low rate of amino acid substitution in DENV (see below), any sporadic elevation in the rate of amino acid replacement is unlikely to greatly affect dating estimates.

There is also uncertainly as to where DENV originated. The most popular idea is that DENV has an African origin (Gaunt et al 2001) because many of the mosquito-borne flaviviruses related to DENV are found in Africa, implying that this clade as a whole originated here, and because A. aegypti is also believed to have originated in Africa. However, both these inferences are open to question in that the phylogeny of the flaviviruses is by no means certain, particularly as it is undoubtedly the case that many of the viruses most closely related to DENV have yet to be sampled, and because it is likely that A. aegypti has only recently been adopted as a DENV vector (Moncayo et al 2004). Indeed, because the four DENV serotypes are also present in both humans and monkeys in Asia (Wang et al 2002) it is also theoretically possible that DENV has an Asian origin. To resolve the question of the origin of DENV it will be necessary to undertake a wider sample of viruses in Africa, from where relatively little DENV has been sampled to date.

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