Accurate quantification of within- and between-host HBV evolutionary rates requires explicit transmission chain modelling

Analyses of virus evolution in known transmission chains have the potential to elucidate the impact of transmission dynamics on the viral evolutionary rate and its difference within and between hosts. Lin et al. (2015, Journal of Virology, 89/7: 3512-22) recently investigated the evolutionary history of hepatitis B virus in a transmission chain and postulated that the 'colonization-adaptation-transmission' model can explain the differential impact of transmission on synonymous and non-synonymous substitution rates. Here, we revisit this dataset using a full probabilistic Bayesian phylogenetic framework that adequately accounts for the non-independence of sequence data when estimating evolutionary parameters. Examination of the transmission chain data under a flexible coalescent prior reveals a general inconsistency between the estimated timings and clustering patterns and the known transmission history, highlighting the need to incorporate host transmission information in the analysis. Using an explicit genealogical transmission chain model, we find strong support for a transmission-associated decrease of the overall evolutionary rate. However, in contrast to the initially reported larger transmission effect on non-synonymous substitution rate, we find a similar decrease in both non-synonymous and synonymous substitution rates that cannot be adequately explained by the colonization-adaptation-transmission model. An alternative explanation may involve a transmission/establishment advantage of hepatitis B virus variants that have accumulated fewer within-host substitutions, perhaps by spending more time in the covalently closed circular DNA state between each round of viral replication. More generally, this study illustrates that ignoring phylogenetic relationships can lead to misleading evolutionary estimates.