It is increasingly clear that the evolution of gene regulation plays an important role in determining morphological, behavioral and physiological diversity between and within species. Understanding the evolutionary mode of gene regulation is critical for expanding fundamental knowledge about living systems. Although it is well known that gene regulation is an intricate process that can occur at multiple levels, the question remains to as to how gene regulation has evolved at these levels leading to the same regulatory consequences. It is also important to illustrate whether and how phenotypically robust regulation of the same orthologous genes in different species can be achieved using different mechanisms. The latter issue is particularly pivotal in addressing how robustness in gene regulation evolved in nature. Yeasts provide unique model systems to study the evolution of gene regulation because of the advanced knowledge on their biology and exceptionally powerful genetics and genomics tools. With ample glucose and sufficient oxygen, most eukaryotic organisms catabolize glucose via mitochondrial respiration. In contrast, baker's yeast, Saccharomyces cerevisiae, and its close relatives, have evolved to conduct fermentation even in the presence of oxygen (aerobic fermentation) after whole genome duplication (WGD). Regulation of mitochondrial functions plays a critical role in aerobic fermentation. Hundreds of nuclear genes that function in mitochondria have evolved to be repressed by glucose only in the post-WGD yeast species through several regulatory mechanisms.
Our aim i s to use yeasts as models to elucidate how these novel gene regulatory mechanisms evolved. To continue our previous contribution on functional redundancy and evolution, we will further establish a novel conceptual framework for gene regulation evolution that can be readily tested in other research systems, i.e. the same orthologous genes could achieve robust regulation in different species by evolutionary drift among functionally overlapping mechanisms. New knowledge that can be learned uniquely from the proposed studies will lead to a much broader appreciation for the importance of gene regulatory evolution. This research can also reveal new insights into regulatory changes of mitochondrial functions in cancers, due to the metabolic similarity between yeasts and tumor cells. We believe that even though this application is specific to an inherent phenomenon in yeast, it asks general questions about the evolution of gene regulation, and thus will have a significant impact on evolutionary and medical research.
A deeper understanding of how gene regulation evolves will have profound impacts on both basic and biomedical research. Due to the metabolic similarity between yeast and tumor cells, and the conservation of central carbon metabolism between them, illustrating the evolutionary processes leading to unique features of yeast metabolism will also shed light on the regulatory changes in mitochondrial function that occur during tumorigenesis, a direction that has been underappreciated in cancer biology. Our research may open up very unique areas at the intersection of evolution and medicine for further exploration.