Grant: Project Grant

Whole genome sequencing efforts continue to identify millions of genetic variants in individual genomes. While we can map genetic variation efficiently, current studies only explain a small fraction of trait heritability. While there are various explanations for this so-called "missing heritability", GIs between different variants may account for a significant component. We propose that a deep understanding of the basic principles of genetic interactions is required to accurately interpret individual genomes and to elucidate the genetic mechanisms underlying disease. Genetic suppression represents a particular type of genetic interaction where a mutation can improve the deleterious effects associated with a different genetic variant. Suppression interactions are important because they can provide mechanistic insights into how biological pathways relate to one another to modulate cellular functions. More generally, suppression interactions may play an important role in the genetics underlying human diseases. For example, a study identified adults harboring mutations for 8 severe conditions, with no reported clinical manifestation of the indicated disease. It is conceivable that this so-called genetic resiliency could be explained by individual-specific genetic interactions that result in suppression of the disease phenotype. However, we lack the expertise to identify suppressor mutations scattered across the complex genomes of these resilient individuals. Thus, we propose to map genetic suppression interactions on a large-scale in yeast and explore he conservation of these interactions in a model human cell line. The principles and characteristics that emerge from this study will contribute to our understanding of how genetic variance accumulates during evolution and more specifically how mutation of different genes can modify the severity of genetic traits, including human disease.