| The intersection between chemistry and biology has always been important for understanding the molecular processes of life. One of the key challenges today is to determine how chemicals regulate biological systems which has implications for how chemicals may be used for research as well as the development of therapeutics. Genomic technologies have great strides in this area and continue to do so. In this dissertation, I describe four areas of work that sought to advance this field: (1) Development of a cost-effective and extensible platform that integrates three distinct assays with the goal of improving the characterization of the bioactivity of small-molecules and making the technology accessible. This platform is built on the robust TAG4 barcode microarray and simultaneously resolves the fitness of strains derived from pools of (a) homozygous deletion mutants, (b) heterozygous deletion mutants, and (c) genomic library transformants; (2) Development of methods to screen drug combinations systematically and to identify genetic mutants that modify the cellular response to drug combinations thereby allowing the mechanistic basis for the interaction to be inferred; (3) Glyoxal and methyglyoxal are reactive carbonyls, formed as by-products of metabolism and found in a large number of environmental sources such as cigarette smoke, automobile exhaust and thermal processing of food. This dissertation describes the results of using multiple genomewide assays to identify the genetic basis for carbonyl stress resistance; (4) Gain-of-function (GOF) genetic screens are a powerful way of generating phenotypes and have been used with great success in multiple biological systems. I describe the generation of a yeast pool expressing 12,000 different human genes and demonstrate that toxic human genes can be identified via a competitive growth assay. |
