Grant: Foundation Grant

<html> <body> <p>The long-term goal of my research program is to provide a foundation for interpreting personal genomes and facilitating personalized medicine. We are pioneering the field of systems-level genetic network analysis. Genetic interactions may underlie a significant proportion of inherited phenotypes, including those associated with human disease. Thus, to properly interpret our genomes and predict phenotype, we must understand the general rules of genetic interactions, and their landscape with respect to genome architecture. My group automated yeast genetics such that we could map genetic interactions globally. Genetic interactions identify functional relationships between genes and their pathways, offering the potential to outline a functional wiring diagram and generate the first computational model of the cell. The projects described here are designed to develop trainees with expertise in the general fields of Molecular Genetics, Bioinformatics, and Systems Biology.<br> <b>Aim 1. Completing the Global Genetic Interaction Network for Yeast.</b> <br> We will complete tests of all 5000 nonessential genes and all 1,100 essential genes for genetic interactions in a 6000 x 6000 matrix, producing the first complete genetic interaction map for any organism. The set of essential genes is key because they represent hubs on the global network. To complete essential gene analysis, we will construct 600 new conditional temperature-sensitive alleles of essential genes.<br> The yeast genome also contains 300 pairs of nonessential paralog pairs that were retained evolutionarily following a whole genome duplication event and, thus these genes require special analysis. To quantify their functional redundancy and place these genes on the global genetic interaction map we will map triple mutant interactions for each paralog double mutant. More generally, we will expand this triple mutant analysis to singleton genes to assess the potential scope of triple mutant genetic interaction space for the whole genome.<br> <b>Aim 2. Large-scale Mapping of Mechanistically Diverse Genetic Interactions.</b> <br> Because diverse types of genetic interactions are possible, we are also expanding our investigation beyond interactions associated with double mutant loss-of-function phenotypes. We will map a global set of dosage suppressors for the set of 1,100 essential genes and carry out the first systematic analysis of genetic suppression. We will also assess the potential for genetic interactions to occur within a heterozygous diploid context. General systems-level rules associated with these genetic interactions will be particularly critical for understanding the genotype to phenotype problem.<br> <b>Aim 3. Chemical Genomics.</b> <br> We&rsquo;ve shown previously that our global genetic interaction network provides a key for interpreting chemical-genetic interaction profiles. We are now developing a new high-throughput, chemical-genomic screening system in which entire chemical libraries, composed of thousands of compounds, can be tested for chemical-genetic interactions to predict their cellular target. We will utilize this system to functionally annotate several chemical libraries and link bioactive compounds to their targets.<br> <b>Aim 4. Human Cancer Cell Genetic Interaction Maps.</b> <br> Finally, CRISPR-Cas9 gene editing technology enables genome-scale genetic interaction analysis in mammalian cells and thus we will generate a large-scale genetic interaction map in human cancer cells.</p> </body> </html>