Selective pressures on DNA sequences often result in signatures of departures from neutral evolution that can be captured by statistical tests, such as the McDonald-Kreitman test. However, the nature of such selective forces often remains unknown to the experimentalists. A striking example of this is seen in the Drosophila protein coding bag of marbles (bam) gene, which plays a key role in early male and female reproduction. Like another germline gene, Sex lethal, bam genetically interacts with the endosymbiont Wolbachia, as Wolbachia rescues the reduced fertility of a bam mutant. Wolbachia has been proposed to drive the rapid evolution at bam, which motivates careful studies to better understand the relationship between the two entities. Here, I present both functional and computational work that examine different aspects of the bam-Wolbachia relationship. In the first project, I explored the specificity of the bam Wolbachia interaction by generating 22 new bam mutants. I find that there is no specificity between the rescue of mutants and the known binding regions of bam, suggesting Wolbachia does not interact with one singular bam partner to rescue fertility. Additionally, I find that Wolbachia rescue is specific to functionally mutant bam alleles and there is no substantial evidence of Wolbachia interaction with germline stem cells in bam mutants. Ultimately, I return to the commonality of bam and Sxl, posing the possibility that Wolbachia is rescuing the bam and Sxl hypomorphs through targeting restoration of their shared protein complex’s function. In the second project, I designed a model to investigate an evolutionary process of “buffering” by Wolbachia for bam mutants. I propose that amino acid changes can be correlated with a return to the original function after a period of relaxed selective constraint due, i.e., Wolbachia “buffering.” I use simulations to implement this model, informing selective constraint with measures of amino acid affinity based on the Miyata (1979) and BLOSUM62 matrices. I find that a return-to-function model results in amino acid fixations, but our ability to detect them with the McDonald-Kreitman test is limited. Lastly, I present preliminary work on several additional projects, including questions on the Wolbachia interaction with bam in male D. melanogaster, Wolbachia horizontal gene transfers to Drosophila hosts, characterization of a low titer Wolbachia variant, and a brief analysis on details of sequence variation in bam of D. melanogaster and D. simulans.