UC San Diego

A central challenge to post-genomic biology is to elucidate the cellular networks that underlie biological form and function. Such networks of transcriptional, post- transcriptional and post-translation regulation form an essential part of the cellular repertoire. The recent explosion of high-throughput genome-wide technologies has allowed us to begin to elucidate the structure and function of such networks. Additionally, these technologies also allow direct comparisons of networks to be made across species -- a subject that has received comparatively less attention. Simultaneous study of multiple species at appropriate evolutionary distances allows us to make more general statements about the robustness, evolvability, modularity and evolutionary redundancy of cellular networks than can otherwise be made when studying a single species in isolation. In this thesis, I describe the generation and analysis of genome- wide mRNA expression and transcription factor localization data across four diverse species of yeast separated by hundreds of millions of years of evolution. In Chapter 3, I generate genome-wide transcription factor localization data for the budding yeasts S. cerevisiae, and C. glabrata discovering a system of tightly coupled compensatory trans and cis mutations in the AP-1 transcriptional network. These compensatory mutations allow for conserved transcriptional regulation despite continued genetic change. Such systems of tightly coupled compensatory mutations might serve to counter the widespread divergence observed in transcriptional networks, and may constitute a general evolutionary mechanism maintaining the regulation of transcriptional networks. In Chapter 4, I generate genome-wide transcription factor localization data for several cell-cycle transcription factors, but in the fission yeast S. pombe. Similarly to previous studies, I find relatively poor conservation of binding between orthologous transcription factors. However, further analysis of our data along with that of previous studies suggests that transcription factors while not being particularly well conserved at the level of the binding of target genes show stronger conservation in other ways such as DNA binding motif, the functional enrichment of target genes, transcription factor expression and transcription factor activity