The genetic and evolutionary mechanisms underlying the origins of new molecularfunctions - SUMMARY The molecular basis by which a new function emerges in evolution sets the mechanisms by which it can break down – ultimately contributing to disease. Unfortunately, our understanding of the genetic, molecular, and evolutionary mechanisms responsible for the origins of new functions is limited because most functions evolved only once in the distant past and have been modified by subsequent evolutionary processes. In particular, changes in gene regulation are a common route by which new molecular functions occur, account for much of the variation in complex traits, and play important roles in human health and disease. However, fundamental questions about the evolution of gene regulation remain unknown. First, we often do not know the genes responsible for regulatory changes. This is in large part because we lack systems and tools where the genetic basis of regulatory differences can be determined between species. Second, while transcription factors play key roles in gene regulation and changes in them can be sources of disease, we lack approaches for determining whether they play key roles in the evolution of gene regulation. Furthermore, if transcription factors are important sources of regulatory variation, the molecular mechanisms by which pleiotropic consequences are avoided are poorly understood. Third, correct gene regulation is essential, yet differences in regulation are quite common. Despite this, the rate of regulatory change and the evolutionary mechanisms responsible are not known because we lack systems where these can be dissected into the individual molecular changes that occurred. Over the next five years, my research group will address these knowledge gaps using high- throughput approaches in the Saccharomyces yeast. Despite being as genetically distinct as humans and birds, species in the Saccharomyces genus naturally produce viable hybrids and can be genetically crossed after precise genome engineering. We will use this ability to develop a system for mapping the genetic basis of regulatory differences on long evolutionary timescales. This will reveal common genetic sources of regulatory divergence, as well as the broad molecular basis by which regulatory evolution occurs. Saccharomyces yeast also contain all common mechanisms of transcription factor binding found among eukaryotes. We will develop high- throughput and unbiased approaches for determining how important changes in these transcription factors have been in regulatory evolution. Finally, we will determine the rate of regulatory change and the molecular basis for compensatory changes in gene regulation. The long-term goal of this work is to improve our understanding of how gene regulation functions and evolves to improve our ability to predict the effects of regulatory variation in health and disease.
