Bridging Functional Genomics and Toxicogenomics Through DNA Microarrays in a Fish Model

In a case study of finding gene expression signatures for environmental stressors in Cyprinodon variegatus, this dissertation examines several important issues of applying DNA microarray technology to fish toxicogenomics. The most relevant disciplines, fish toxicogenomics and computational systems biology are reviewed in Chapter 1. Chapter 2 reviews major aspects of DNA microarray technology. On DNA microarrays, even for probes that target the same transcript, large variations are seen in the probe signals. These variations are partly dependent and partly independent on probe sequences. Chapter 3 estimates the sequence independent variation by combining experimental and computational approaches. Chapter 4 and 5 take on the central problem of sequence dependent variations, that is, modeling the physiochemistry of microarray hybridization. I propose a new competitive hybridization model, which demonstrates good success on publically available benchmark data. This new model leads the way to quantification of absolute target concentration, and brings critical insights into probe design and data interpretation on DNA microarrays. Our model relies on the accuracy of computing duplexing energy, which does yet not take into account secondary structures of probes and targets. I further explore the structural effects in Chapter 6. In order to see the complete Abstract, please download the dissertation