Origin and phylodynamics of rabbit hemorrhagic disease virus

Abstract

To determine the origin, phylogenetic relationships, and evolutionary dynamics of rabbit hemorrhagic disease virus (RHDV), we examined 210 partial and complete capsid gene nucleotide sequences. Using a Bayesian Markov chain Monte Carlo approach, we estimated that these sequences evolved at a rate of 3.9 x 10(-4) to 11.9 x 10(-4) nucleotide substitutions per site per year. This rate was consistent across subsets of data, was robust in response to recombination, and casts doubt on the provenance of viral strains isolated from the 1950s to the 1970s, which share strong sequence similarity to modern isolates. Using the same analysis, we inferred that the time to the most recent common ancestor for a joint group of RHDV and rabbit calicivirus sequences was <550 years ago and was <150 years ago for the RHDV isolates that have spread around the world since 1984. Importantly, multiple lineages of RHDV were clearly circulating before the major Chinese outbreak of 1984, a finding indicative of an early evolution of RHDV virulence. Four phylogenetic groups within RHDV were defined and analyzed separately. Each group shared a common ancestor in the mid-1960s or earlier, and each showed an expansion of populations starting before 1984. Notably, the group characterized by the antigenic variant RHDVa harbors the greatest genetic diversity, compatible with an elevated fitness. Overall, we contend that the high virulence of RHDV likely evolved once in the early part of the 20th century, well before the documented emergence of rabbit hemorrhagic disease in 1984.

FIG. 1.

ML tree of 217 sequences of the capsid gene of RHDV and RCV. The tree is drawn to a scale of nucleotide substitutions per site and is midpoint rooted for purposes of clarity. The magnified portions of the tree show the positions of the seven United Kingdom isolates sampled before 1984. Note their close relationship to more contemporaneous isolates. A more comprehensive analysis of these data is presented in Fig. 2.

FIG. 2.

MCC tree of the “total” data set of 210 capsid gene sequences of RHDV and RCV. The time-scale (x axis) is given in years since the most recent sample. The four phylogenetic groups used in the subsequent analysis of RHDV population dynamics are indicated. Node numbers depict posterior probability values (a measure of node support), while node bars the depict the 95% HPD values on node height (age). The year 1984, indicating the year of the Chinese outbreak, is marked with a dotted line.

FIG. 3.

MCC tree of RHDV group 3 which contains the earliest Chinese isolate from 1984 (shaded). The time-scale (x axis) is given in years since the most recent sample. Node numbers depict posterior probability values, while node bars the depict the 95% HPD values on node height. The year 1984, indicating the year of the Chinese outbreak, is marked with a dotted line.

FIG. 4.

Bayesian skyline plots depicting the changing levels of relative genetic diversity through time (N_eτ, where N_e is the effective population size and τ the generation time between subsequent transmission events). Note that because the date of the most recent sample differs between groups, the skyline plots for each group are on slightly different absolute time-scales. The year 1984, indicating the year of the Chinese outbreak, is marked with a dotted line.