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Punctuated Evolution of Myxoma Virus: Rapid and Disjunct

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Punctuated Evolution of Myxoma Virus: Rapid and Disjunct bioRxiv preprint doi: https://doi.org/10.1101/465583; this version posted November 8, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Punctuated evolution of myxoma virus: rapid and disjunct 2 evolution of a recent viral lineage in Australia 3 4 5 Peter J. Kerr1, John-Sebastian Eden2,3, Francesca Di Giallonardo4, David Peacock5,6, June 6 Liu1,7, Tanja Strive1,8, Andrew F. Read9,10, Edward C. Holmes2* 7 8 9 1CSIRO Health and Biosecurity, Canberra, Australian Capital Territory 2601, Australia. 10 2Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Life and 11 Environmental Sciences and Sydney Medical School, Charles Perkins Centre, University of 12 Sydney, Sydney, New South Wales 2006, Australia. 13 3Centre for Virus Research, Westmead Institute for Medical Research, Westmead, NSW 14 2145, Australia. 15 4The Kirby Institute, University of New South Wales, Randwick, NSW 2052, Australia. 16 5Biosecurity SA, Adelaide 5001, South Australia. 17 6School of Animal and Veterinary Sciences, the University of Adelaide, Roseworthy, SA 18 5371, Australia. 19 7Department of Agriculture and Water Resources, 7 London Circuit, Canberra, Australian 20 Capital Territory 2601, Australia. 21 8Centre for Invasive Species Solutions, Bruce, Australian Capital Territory 2617, Australia. 22 9Center for Infectious Disease Dynamics and Department of Biology, The Pennsylvania 23 State University, University Park, Pennsylvania 16802, USA. 24 10Department of Entomology, The Pennsylvania State University, University Park, 25 Pennsylvania 16802, USA. 26 27 *Author for correspondence: 28 Email: [email protected] 29 Tel: +61 2 9351 5591 30 31 Word count: Abstract - 247 words, Importance - 140 words, Main text - 5930 words 32 33 Running title: Punctuated evolution of myxoma virus. 1 bioRxiv preprint doi: https://doi.org/10.1101/465583; this version posted November 8, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 34 ABSTRACT 35 Myxoma virus (MYXV) has been evolving in a novel host species – European rabbits – in 36 Australia since 1950. Previous studies of viruses sampled from 1950 to 1999 revealed a 37 remarkably clock-like evolutionary process across all Australian lineages of MYXV. Through 38 an analysis of 49 newly generated MYXV genome sequences isolated in Australia between 39 2008 and 2017 we show that MYXV evolution in Australia can be characterized by three 40 lineages, one of which exhibited a greatly elevated rate of evolutionary change and a 41 dramatic break-down of temporal structure. Phylogenetic analysis revealed that this 42 apparently punctuated evolutionary event occurred between 1996 and 2012. The branch 43 leading to the rapidly evolving lineage contained a relatively high number of non- 44 synonymous substitutions, and viruses in this lineage reversed a mutation found in the 45 progenitor standard laboratory strain (SLS) and all previous sequences that disrupts the 46 reading frame of the M005L/R gene. Analysis of genes encoding proteins involved in DNA 47 synthesis or RNA transcription did not reveal any mutations likely to cause rapid evolution. 48 Although there was some evidence for recombination across the MYXV phylogeny, this was 49 not associated with the increase in evolutionary rate. The period from 1996 to 2012 saw 50 significant declines in wild rabbit numbers, due to the introduction of rabbit hemorrhagic 51 disease and prolonged drought in south-eastern Australia, followed by the partial recovery 52 of populations. We therefore suggest that a rapidly changing environment for virus 53 transmission changed the selection pressures faced by MYXV and altered the course of 54 virus evolution. 55 56 IMPORTANCE 57 The co-evolution of myxoma virus (MYXV) and European rabbits in Australia is one of the 58 most important natural 'experiments' in evolutionary biology, providing insights into virus 59 adaptation to new hosts and the evolution of virulence. Previous studies of MYXV evolution 60 have also shown that the virus evolves both relatively rapidly and in a strongly clock-like 61 manner. Using newly acquired MYXV genome sequences from Australia we show that the 62 virus has experienced a dramatic change in evolutionary behavior over the last 20 years, 63 with a break-down in clock-like structure, the appearance of a rapidly evolving virus 64 lineage, and the accumulation of multiple non-synonymous and indel mutations. We 65 suggest that this punctuated evolutionary event likely reflects a change in selection 66 pressures as rabbit numbers declined following the introduction of rabbit hemorrhagic 67 disease virus and drought in the geographic regions inhabited by rabbits. 2 bioRxiv preprint doi: https://doi.org/10.1101/465583; this version posted November 8, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 68 An experimental field study in Australia in 1950 to test whether Myxoma virus (MYXV) could 69 be used as a biological control for European rabbits (Oryctolagus cuniculus) accidentally 70 initiated one of the largest and best known natural experiments in host-pathogen 71 coevolution. Detailed studies on the coevolution of the virus with its new host over the 72 subsequent 60 years have done much to inform thinking on pathogen evolution in general 73 and the evolution of virulence in particular (1-5). 74 75 MYXV is a poxvirus of the Leporipoxvirus genus (family Poxviridae; subfamily 76 Chordopoxvirinae). The natural host of the virus released in Australia is the South American 77 tapeti (forest rabbit: Sylvilagus minensis) (6), also called Sylvilagus brasiliensis (7, 8). In the 78 tapeti, MYXV causes a localized, cutaneous fibroma at the inoculation site (6). Virus is 79 passively transmitted on the mouthparts of biting insects such as mosquitoes or fleas 80 probing through the virus-rich fibroma. In general, MYXV does not appear to cause 81 significant clinical disease in the natural host. However, when European rabbits 82 (Oryctolagus cuniculus) are infected the virus spreads systemically, overwhelming the 83 immune system, to cause the lethal, disseminated disease myxomatosis (9). Related 84 viruses, Rabbit fibroma virus and Californian MYXV, occur in separate Sylvilagus spp in 85 North America. 86 87 Following its experimental release, MYXV unexpectedly spread across large swathes of 88 rabbit-infested south-eastern Australia (10). The released virus, originally isolated in Brazil 89 and later termed the Standard Laboratory Strain (SLS), had a case fatality rate (CFR) 90 estimated at 99.8% (11). However, there was rapid natural selection for slightly attenuated 91 viruses which, by allowing longer survival of the infected rabbit, were more efficiently 92 transmitted by the mosquito vectors (12-13). 93 94 To study the evolution of virulence field isolates of MYXV were classified into five virulence 95 grades based on CFR and average survival time (AST) in small groups of laboratory rabbits, 96 which are the same species and had essentially the same outcomes following infection as 97 wild European rabbits. Moderately attenuated grade 3 strains, with CFRs of 70-95%, 98 predominated in the field in the decades following the release. More attenuated grade 4 99 viruses were less common, while highly virulent grade 1 and 2 viruses became relatively 100 rare despite ongoing releases of virulent virus. Highly attenuated grade 5 viruses with CFRs 101 <50% were never common (2, 13-16). At the same time there was a strong selection for 102 resistance to myxomatosis in the wild rabbit population. The short generation interval of 3 bioRxiv preprint doi: https://doi.org/10.1101/465583; this version posted November 8, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 103 rabbits meant that this evolutionary process could be measured in real-time by challenging 104 successive generations of rabbits with virus of known virulence. At one study site, CFRs 105 dropped from 90% to 26% over a 7 year period (17-18). 106 107 The deliberate release in France of a separate Brazilian isolate of MYXV in 1952 led to the 108 establishment and spread of MYXV in Europe. Later termed the Lausanne strain (Lu), this 109 virus was more virulent than SLS (2, 19). However, although the starting virus, ecological 110 conditions and vectors were different, the evolutionary outcomes in Europe at the 111 phenotypic level were remarkably similar to those in Australia, with the emergence of 112 moderately attenuated strains of virus and selection for genetic resistance in the wild rabbit 113 population (16). The Lu sequence is the type sequence for MYXV. This virus was originally 114 isolated in 1949, and possesses a genome of 161,777 bp of linear double stranded DNA 115 with inverted terminal repeats (TIRs) of 11,577 bp and closed single strand hairpin loops at 116 the termini. The genome encodes 158 unique open reading frames (ORFs), 12 of which are 117 duplicated in the TIRs (20, 21). 118 119 The virus originally released in Australia, SLS, is believed to be derived from an isolate 120 made in Brazil around 1910 (22). A sample of this virus was later transferred to the 121 Rockefeller Institute (23) where it was maintained by passage in laboratory rabbits.
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