| Summary: | This thesis explores the limits of homology-based inference of protein function and evolution, where overall similarity between sequences can be a poor indicator of functional similarity or evolutionary relationships. Each case presented has undergone different patterns of evolutionary change due to differing selective pressures. Surface adaptations and regulatory (e.g., gene expression) divergence are examined as molecular determinants of novel functions whose patterns are easily missed by assessments of overall sequence similarity. Following this, internal repeats and mosaic sequences are investigated as cases in which key evolutionary events involving fragments of protein sequences are masked by overall comparison. Lastly, virulence factors, which cannot be unified based on sequence, are predicted by analysis of elevated host-mimicry patterns in pathogenic versus non-pathogenic bacterial genomes. These patterns have resulted from unique co-evolutionary pressures that apply to bacterial pathogens, but may be lacking in their close relatives. A recurring theme in the proteins/genes/genomes analyzed is an involvement in microbial pathogenesis or pathogen-defense. Due to the ongoing "evolutionary arms race" between hosts and pathogens, virulence and defense proteins have undergone—and will likely continue to generate—evolutionary novelties. Thus, they demonstrate the necessity to look beyond overall sequence comparison, and assess multiple dimensions of functional innovation in proteins.
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