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Using genomic sequencing to explore vaccinia virus diversity, recombination and evolution Open Access


Other title
vaccinia virus
next generation sequencing (NGS)
Type of item
Degree grantor
University of Alberta
Author or creator
Qin, Li
Supervisor and department
Evans, David (MMI)
Examining committee member and department
Brunetti, Craig (Trent University, Department of Biology)
Mason, Andrew (Department of Medicine, Division of Gastroenterology)
Hazes, Bart (MMI)
Houghton, Michael (MMI)
Department of Medical Microbiology and Immunology
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Smallpox was eradicated using vaccinia viruses (VACV) as vaccines, including Dryvax, a calf-lymph vaccine derived from the New York City Board of Health (NYCBH) strain, and TianTan, a chicken egg cultured vaccine used exclusively in China. To take advantage of the next generation sequencing technology, this thesis examined the genetic diversity of the population of viruses present in a sample of Dryvax and TianTan stocks. In Dryvax stock, any two clones differ by approximately 570 SNPs (single nucleotide polymophism), exhibiting a patchy pattern of polymorphic sites across the whole genome due to recombination. In addition, 110 small indels (insertion and deletion) were observed in the Dryvax stock. Over 85% of indels are associated with repeats and a rare naturally attenuated virus bearing a large deletion in the right telomere (DPP17) was also identified. In contrast, there are barely any SNPs and indels detected in the TianTan clones, suggesting that this stock has been cloned previously. Two different subclones were detected; TP03 encoding large deletions in the terminal repeats that extend into both VEGF (vaccinia epithelial growth factor) genes and create a small plaque variant, and TP05 having the longest genome in all TianTan clones. To further study the mechanism of poxvirus recombination, I coinfected two of my sequenced viruses (TP05 and DPP17) and used the different SNPs to track the origin of progeny recombinants. My studies showed that recombinants contain a patchwork of DNA fragments, with the number of exchanges increasing with passage. Further passage also selected for TianTan DNA and correlated with increased plaque size. The recombinants produced through a single round of co-infection exhibited a bias towards the short conversion tracks (<1 kbp) and exhibited 1 exchange per 12 kbp, close to the ~1 per 8 kbp in the literature. Finally, I explored the possible origin of VACVs and evolutionary relationship among extant VACVs. My study showed that VACV is probably derived from a horsepox-like virus by reductive evolution. An intermediate virus has been suggested to originate from horsepox virus and serve as an ancestral strain for all other extant VACVs. A model of illegitimate recombination is proposed to help explain this evolutionary process.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Genome scale patterns of recombination between coinfecting vaccinia viruses. Qin L, Evans DH. J Virol. 2014 May;88(10):5277-86. doi: 10.1128/JVI.00022-14. Epub 2014 Feb 26.Genomic analysis of vaccinia virus strain TianTan provides new insights into the evolution and evolutionary relationships between Orthopoxviruses. Qin L, Liang M, Evans DH. Virology. 2013 Jul 20;442(1):59-66. doi: 10.1016/j.virol.2013.03.025. Epub 2013 Apr 19.Genomic analysis of the vaccinia virus strain variants found in Dryvax vaccine. Qin L, Upton C, Hazes B, Evans DH. J Virol. 2011 Dec;85(24):13049-60. doi: 10.1128/JVI.05779-11. Epub 2011 Oct 5.

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