COMPUTATIONAL MODELS OF FUNCTION AND EVOLUTION OF CIS-REGULATORY SEQUENCES BY

Gene expression is controlled by regulatory DNA sequences, often called cis-regulatory modules or CRMs in higher organisms. Even though complete genomes are available in many species, a catalog of CRMs is far from complete. Meanwhile, how basic building blocks of CRMs, called transcription factor binding sites (TFBSs), coordinate to drive gene expression is unclear. My thesis is focused on predicting the location of CRMs in genomes and understanding their function and evolution through computational methods. The first part of my thesis developed a comparative genomic method of CRM prediction. This method is based on a probabilistic model of CRM evolution, capturing the constraint as well as turnover of TFBSs during evolution. Through a statistical approach that marginal-izes hidden variables, the method is able to deal with the uncertainty of sequence alignment and prediction of individual TFBSs, two primary technical hurdles of existing methods. In a related work, I collaborated with a graduate colleague to study the empirical evolutionary pattern of TFBSs, taking advantage of the recently available 12 Drosophila genomes. We found, among other things, that the evolution of binding sites is constrained by the affinitie