Genomic and phenotypic characterization of myxoma virus from Great Britain reveals multiple evolutionary pathways distinct from those in Australia

Abstract

The co-evolution of myxoma virus (MYXV) and the European rabbit occurred independently in Australia and Europe from different progenitor viruses. Although this is the canonical study of the evolution of virulence, whether the genomic and phenotypic outcomes of MYXV evolution in Europe mirror those observed in Australia is unknown. We addressed this question using viruses isolated in the United Kingdom early in the MYXV epizootic (1954–1955) and between 2008–2013. The later UK viruses fell into three distinct lineages indicative of a long period of separation and independent evolution. Although rates of evolutionary change were almost identical to those previously described for MYXV in Australia and strongly clock-like, genome evolution in the UK and Australia showed little convergence. The phenotypes of eight UK viruses from three lineages were characterized in laboratory rabbits and compared to the progenitor (release) Lausanne strain. Inferred virulence ranged from highly virulent (grade 1) to highly attenuated (grade 5). Two broad disease types were seen: cutaneous nodular myxomatosis characterized by multiple raised secondary cutaneous lesions, or an amyxomatous phenotype with few or no secondary lesions. A novel clinical outcome was acute death with pulmonary oedema and haemorrhage, often associated with bacteria in many tissues but an absence of inflammatory cells. Notably, reading frame disruptions in genes defined as essential for virulence in the progenitor Lausanne strain were compatible with the acquisition of high virulence. Combined, these data support a model of ongoing host-pathogen co-evolution in which multiple genetic pathways can produce successful outcomes in the field that involve both different virulence grades and disease phenotypes, with alterations in tissue tropism and disease mechanisms.

A phylogenomic analysis of Marek's disease virus reveals independent paths to virulence in Eurasia and North America

“…The mean evolutionary rate for the selected evolutionary model was 1.58 × 10 −5 substitutions per site per year (95% HPD values = 1.19 × 10 −5 –2.00 × 10 −5 ). This was similar to rates inferred from a range of implemented models (Figure b) and is slightly higher than the rate of ~1 × 10 −5 subs per site per year reported for a distantly related dsDNA virus Myxoma virus (MYXV, family Poxviridae) (Kerr et al., , ).…”

“…For example, of the genes associated with virulence, only 10% were shared by both virulent Eurasian and North American strains, with the majority of genes either containing no variation (>50%) or harboring variants that were specific to one but not both lineages (10%–20%). This is not surprising given the size and complexity of the MDV genome, and it supports findings from recent studies of virulence evolution in the distantly related dsDNA virus MYXV, where similar patterns of genotypic evolution were observed during the processes of attenuation and virulence adaptation (Kerr et al., , ). This contrasts with smaller RNA viruses such as HIV‐1 and influenza (Baigent & McCauley, ; Kimata, Kuller, Anderson, Dailey, & Overbaugh, ), where the limited repertoire of genes is thought to restrict the mutational landscape and therefore the available routes to adaptive evolution.…”

“…Our use of MDV samples collected between 1968 and 2015 enables a first insight into the origin and tempo of MDV evolution, representing the first alphaherpesvirus affecting agricultural animals to have undergone such a detailed genome‐scale phylogenetic analysis. Our temporal phylogeny of MDV yielded an evolutionary rate of ~1.6 × 10 −5 , which is in line with a range of rates that have been recorded for similarly sized dsDNA viruses such as variola virus (~9 × 10 −6 ) (Duggan et al., ; Firth et al., ) and MYXV (~1 × 10 −5 ) (Kerr et al., , ). Overall, such rates are generally higher than typically expected for dsDNA viruses and imply higher rates of nucleotide substitution than those inferred by host–virus codivergence analysis (Firth et al., ).…”

Myxoma virusjumps species to the Iberian hare

“…DNA extracted from infected tissue was directly analysed to prevent the accumulation of mutations during culture on rabbit cells. Agarose gel electrophoresis and Sanger sequencing of the amplified products identified an insertion (termed Ins‐H1, Figure b, Lane M009 H) of 2,863 nt located within the MYXV gene M009L , between genome positions 12,336 and 12,337 (MYXV Accession numbers AF170726 (Cameron et al, ) and KY548791 (Kerr, Cattadori, Liu, et al, ; Kerr, Cattadori, Rogers, et al, ). To determine if the insertion was present in further samples, 20 hare samples (originating from 18 provinces) were analysed in the M009L region.…”

“…Humans facilitated this well‐documented jump by bringing the European rabbit into proximity with the natural MYXV reservoir. The use of MYXV as a biological control agent in Australia and Europe contributed to its widespread distribution, and the MYXV/rabbit system has become a model for host–virus evolution (Fenner, ; Di Giallonardo & Holmes, ; Kerr, ; Kerr, Cattadori, Liu, et al, ; Kerr, Cattadori, Rogers, et al, ). MYXV is a poxvirus with a double‐stranded DNA genome of 161.8 kb for the reference strain Lausanne.…”