The mode and tempo of hepatitis C virus evolution within and among hosts

Abstract

BackgroundHepatitis C virus (HCV) is a rapidly-evolving RNA virus that establishes chronic infections in humans. Despite the virus' public health importance and a wealth of sequence data, basic aspects of HCV molecular evolution remain poorly understood. Here we investigate three sets of whole HCV genomes in order to directly compare the evolution of whole HCV genomes at different biological levels: within- and among-hosts. We use a powerful Bayesian inference framework that incorporates both among-lineage rate heterogeneity and phylogenetic uncertainty into estimates of evolutionary parameters.ResultsMost of the HCV genome evolves at ~0.001 substitutions/site/year, a rate typical of RNA viruses. The antigenically-important E1/E2 genome region evolves particularly quickly, with correspondingly high rates of positive selection, as inferred using two related measures. Crucially, in this region an exceptionally higher rate was observed for within-host evolution compared to among-host evolution. Conversely, higher rates of evolution were seen among-hosts for functionally relevant parts of the NS5A gene. There was also evidence for slightly higher evolutionary rate for HCV subtype 1a compared to subtype 1b.ConclusionsUsing new statistical methods and comparable whole genome datasets we have quantified, for the first time, the variation in HCV evolutionary dynamics at different scales of organisation. This confirms that differences in molecular evolution between biological scales are not restricted to HIV and may represent a common feature of chronic RNA viral infection. We conclude that the elevated rate observed in the E1/E2 region during within-host evolution more likely results from the reversion of host-specific adaptations (resulting in slower long-term among-host evolution) than from the preferential transmission of slowly-evolving lineages.

Historical Trends in the Hepatitis C Virus Epidemics in North America and Australia

“…not likely to vary significantly from the estimates used in the previous study [17]. The tMRCA estimates for both North American and Australian 1a sequences were in the early 20th century, suggesting the virus was present in both continents at the beginning of the century.…”

“…Because the HCV genome features widely varied evolutionary rates, within infected hosts, across infected populations, and between different regions within the genome, assumptions regarding these rates have the potential to influence the outcome of the complex statistical methods applied in the coalescent analysis described here. Accordingly, for the present analysis, the substitution rates for the full genome estimated by Gray et al [17] were used as priors. It should be noted that because most sequences used in our study were from acute infections, they could plausibly have a higher substitution rate in the envelope region, given that the virus is recognized to mutate frequently in this region as it adapts for efficient entry and to the immune responses within the new host.…”

“…The log-normal relaxed clock was selected as the best model from marginal likelihood analysis conducted by calculating posterior simulation-based analogue of Akaike information criterion (data not shown) [15,16]. substitution rates for the full genome, previously estimated by Gray et al [17] and Choudhary et al [15] for subtypes 1a and 3a, respectively, were used as external priors in this analysis. The SRD06 model was used to estimate relative substitution rates, the α parameter, and the proportion of invariant sites for the first 2 codon positions and the third codon position separately.…”

Evolutionary analysis of hepatitis C virus gene sequences from 1953

“…Despite a high variation in estimated rootto-tip distances for the 1953 isolates, there is a tendency for these strains to be closer to the root than the sequences sampled after 1988 (figure 1c). The gradient of this plot, which represents evolutionary rate, was 0.00107 substitutions per site per year, which is marginally lower than the rate estimated previously for subtype 1b whole genomes using a Bayesian relaxed molecular clock approach (0.00118 -0.00125 substitutions per site per year) [26]. The x-intercept, which represents an estimate of the date of the phylogeny root, was 1894.…”

“…¼ 23 years) on the date of the phylogeny root. This information on root age was obtained from the most comprehensive molecular clock analysis of HCV subtype 1b undertaken to date [26].…”