In order to understand the evolution of complex traits such as fitness it is necessary to understand the distribution of mutational effects on the trait as well as the nature of the interactions between mutations. In this study, experimental manipulations of the RNA bacteriophage phi-6 will be used to: 1) Measure the distribution of mutational effects on fitness and determine how this distribution changes as genotypes approach an adaptive optimum, 2) Determine the form of interactions between many pairs of mutations, and 3) Measure the effects of dominance, the ability of a co-infecting virus to mask the defect of a mutated virus. Experiments will capitalize on the high mutation rate of RNA viruses and an automated, sensitive fitness assay to measure the effects of hundreds of naturally occurring mutations. Identified mutations will be combined into single phage to measure interaction effects, which will be characterized by their sign: positive if the fitness of individuals carrying multiple mutations is higher than expected from the individual effects of those mutations, and negative if the fitness of such individuals is lower than expected. In this manner, a library will be created of single mutants, and of double mutants for which the sign of the interaction is known. The ability to control aspects of the phi-6 lifestyle, such as co-infection and recombination, will allow the use of this library as a tool for testing evolutionary models whose outcomes depend critically on the sign of genetic interactions. In the current study, the library will be used to measure the costs and benefits associated with viral co-infection of a single host. In addition to its general relevance for evolutionary biology, this work has relevance specifically to the development of live attenuated vaccines, and to understanding the evolutionary responses of viruses to drug treatment.
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