An experimental system is proposed for studying viral evolution in response to major changes in its genome: deletions, gene rearrangements, gene additions, and wholesale changes in regulation. Many of these genome changes will cause major drops in viral fitness. Can these modified viruses evolve back to high fitness, just as viruses have been extremely versatile in evolving resistance to drugs? The work will use the bacteriophage T7, which is amenable to a wide scope of genomic alterations and for which the supporting molecular genetics and biochemistry is extensive enough to develop a predictive framework for evolution and to interpret the evolutionary mechanisms. The three specific aims are: 1) Characterize regulatory evolution in viruses with modified, complete genomes; 2) Determine whether viruses with engineered deletions can evolve to recover original fitness levels; 3) Observe the evolution of viral genomes with new genes. Genome alterations will be performed, the altered viruses will be grown extensively to allow improvement through evolution, and the evolved genomes will be analyzed by sequencing, mapping beneficial changes, and site-directed mutation to test the effects of different mutations. The combined studies will yield an understanding of the mechanisms by which viral genomes evolve and maintain high fitness across a variety of genome modifications. The work developed here will have relevance to the development of live, attenuated vaccines, the improvement of phages as antibacterial agents (phage therapy), and to assess the long-term consequences of any viruses engineered to perform specific functions.
| Paff, Matthew L; Nuismer, Scott L; Ellington, Andrew et al. (2016) Virus wars: using one virus to block the spread of another. PeerJ 4:e2166 |
| Bull, James J (2016) Lethal gene drive selects inbreeding. Evol Med Public Health 2017:1-16 |
| Paff, Matthew L; Nuismer, Scott L; Ellington, Andrew D et al. (2016) Design and engineering of a transmissible antiviral defense. J Biol Eng 10:12 |
| Bull, J J (2015) Evolutionary decay and the prospects for long-term disease intervention using engineered insect vectors. Evol Med Public Health 2015:152-66 |
| Bull, J J (2015) Evolutionary reversion of live viral vaccines: Can genetic engineering subdue it? Virus Evol 1: |
| Bull, James J; Crandall, Cameron; Rodriguez, Anna et al. (2015) Models for the directed evolution of bacterial allelopathy: bacteriophage lysins. PeerJ 3:e879 |
| Paff, Matthew L; Stolte, Steven P; Bull, James J (2014) Lethal mutagenesis failure may augment viral adaptation. Mol Biol Evol 31:96-105 |
| Schmerer, Matthew; Molineux, Ian J; Bull, James J (2014) Synergy as a rationale for phage therapy using phage cocktails. PeerJ 2:e590 |
| Bull, James J; Lauring, Adam S (2014) Theory and empiricism in virulence evolution. PLoS Pathog 10:e1004387 |
| Schmerer, Matthew; Molineux, Ian J; Ally, Dilara et al. (2014) Challenges in predicting the evolutionary maintenance of a phage transgene. J Biol Eng 8:21 |
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