Project 450839

Genome sequencing has provided an unprecedented view into the extent of human genetic variation. However, our ability to understand and interpret this genetic information remains rudimentary. This knowledge void represents the central challenge facing geneticists today, one that must be addressed to realize the promise of precision medicine. Our research has shown that a major component of the inability to interpret information in our genomes likely stems from complex genetic interactions. While all humans have essentially the same set of genes, we each carry millions of subtle variants in most of our genes, some of which modulate gene activity. Because genes work in concert with one another, the effect of one genetic variant can depend greatly on its interaction(s) with other variants present in the same genome. For example, if two genes work together to control an important cellular function, then an individual can usually tolerate a genetic variant that inactivates one or the other gene alone, but not variation in both genes, simultaneously. Thus, to understand the differences between any two human genomes, we must understand how millions of genetic differences affect gene function individually and how they interact with one another. To address this challenge, we will use state-of-the-art gene editing technology to systematically explore genetic interactions in human cells. We will map a global network of genetic interactions that will define the roles of genes and reveal how specific subsets of genes work together to coordinate essential cellular functions.