BookDavid Stuart Lawrie.
During my graduate career, my research has focused on studying signals of purifying selection, using the tools of population genomics and molecular evolution to elucidate the underlying function of sites across the genome. In this thesis, I first focus on the theoretical implications of the interplay between weak constraint and mutational biases for divergence data between species. By explicitly incorporating the selective fitness of nucleotides into DNA substitution models, weak selection and mutational biases under this model can together have unexpected effects on the pattern of DNA sequence evolution over a phylogeny. In the next chapter, I investigate the selective forces acting on the synonymous sites of D. melanogaster, taking advantage of the high quality, deep population sequencing data available for that species. Within-species polymorphism data can allow for the detection of strong purifying selection using a combination of SNP density and allele frequency. Synonymous sites are generally assumed to be subject to weak selective constraint. However, contrary to this expectation, I demonstrate in Chapter 2 that a substantial proportion of synonymous sites in D. melanogaster are evolving under very strong selective constraint while few, if any are evolving under weak or moderate constraint. I conclude by examining the power and properties of using divergence and polymorphism to search for functional elements in a genome. There is a large potential gain in power from having deep samples of population variation in multiple related species, which, combined with divergence data, should allow for the estimation of selection coefficients on relatively few sites. Comparative population genomics, the analysis of large-scale population data within and between species, represents a powerful extension to current approaches using the evolutionary signatures of purifying selection to detect functional elements and ascertain their functional importance.