| Description |
Viruses undergo rapid genetic changes in response to selective forces imposed by host immune defenses. All organisms are at risk of virus infections, and the ancient and ongoing coevolution between viruses and their hosts have shaped genome evolution for both biological partners. One family of viruses, the poxviruses, share a long history with humans, and pose a current threat for emerging and re-emerging diseases. Despite the extensive history of mammalian poxvirus infections, little is known about the ways in which poxviruses adapt to their hosts. In this thesis, I use the model poxvirus, vaccinia virus (VACV), in various experimental evolution systems to investigate mechanisms of poxvirus evolution. These studies reveal new mechanisms of poxvirus adaptation involving recombination-mediated gene amplification events that provide multiple benefits to viral fitness. We first identify adaptive copy number variation (CNV) of a VACV gene encoding a weak virulence factor that promotes fitness in response to host innate immune defenses. Additional gene copies lead to both increased protein expression and an increased chance of gaining beneficial point mutations within the expanded gene locus. I then show that the presence of CNV can also promote the accumulation of a single nucleotide variant in a distant gene. These results establish a direct role for recombination in mediating adaptive genetic changes, while simultaneously promoting additional adaptations in the form of intragenic and extragenic point mutations. To more fully understand the effects of recombination on single nucleotide variant dynamics, I then analyze evolving VACV populations containing a beneficial point mutation within expanded gene arrays. New sequencing technologies permit detailed analyses of these complex genetic regions, and reveal shared features of genome evolution between VACV and a wide array of organisms that highlight the utility of poxviruses as a model system to investigate mechanisms of rapid gene conversion. These studies collectively reveal new facets of virus adaptation, and add substantially to our understanding of poxvirus evolution with potentially broad applications ranging from devising new therapeutic strategies to predicting and combating future pandemics. |
