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.
Highlights
Hepatitis C virus (HCV) is a rapidly-evolving RNA virus that establishes chronic infections in humans
Rapidly-evolving RNA viruses that establish chronic infections, such as the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV), appear to exhibit qualitatively different evolutionary dynamics when their genetic diversity is studied at different organisational scales [1,2]
Within-host evolutionary dynamics can be observed by comparing sequences that represent different virions sampled from a single infected individual over several years, whereas among-host evolution is revealed by collating sequences that each represent a
Summary
Hepatitis 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. Rapidly-evolving RNA viruses that establish chronic infections, such as the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV), appear to exhibit qualitatively different evolutionary dynamics when their genetic diversity is studied at different organisational scales [1,2]. Despite the wealth of HCV sequence data and the relevance of HCV genetic diversity to public health, many aspects of HCV molecular evolution are poorly understood, in comparison to HIV, despite HCV having a higher overall global prevalence that HIV. Many previous studies used non-phylogenetic methods (such as the relative-rates test) to estimate the HCV evolutionary rate, which are known to be less efficient and potentially more biased than phylogenetic approaches [17]
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