Identifying the molecular basis of complex traits is a major challenge to understanding phenotypic variation present in natural populations, including adaptations and human diseases. A longstanding hypothesis is that changes in gene regulation contribute as much or even more than changes in protein structure. While both population genetics and quantitative genetics approaches have been developed, both have had been biased towards the analysis of protein coding sequences. Recently, comparative genomics studies have shown that there are just as many functionally conserved noncoding as coding sequences, implying that many functional changes in gene regulation have yet to be discovered. The overall goal of our research program is to combine genome technologies with computational methods to investigate changes in gene regulation and their contribution to adaptation and disease. Leveraging the power of yeast genetics, we hope to generate and refine both methods and models for use in humans and other organisms.