| The past few decades have witnessed an array of advances in DNA science including the introduction of genomics and bioinformatics. The quest for complete genome sequences has driven the development of microarray and massively parallel sequencing technologies at a rapid pace, yielding numerous scientific discoveries. My thesis applies several of these genome-scale technologies to understand genomic response to perturbation as well as chromatin structure, and it is divided into three major studies. The first study describes a method I developed to identify drug targets by overexpressing human genes in yeast. This chemical genomic assay makes use of the human ORFeome collection and oligonucleotide microarrays to identify potential novel human drug targets. My second study applies genome resequencing of yeast that have evolved resistance to antifungal drug combinations. Using massively parallel genomic sequencing, I identified novel genomic variations that were responsible for this resistance and it was confirmed in vivo. Lastly, I report the characterization of chromatin structure in a non-eukaryotic species, an archaeon. The conservation of the nucleosomal landscape in archaea suggests that chromatin is not solely a hallmark of eukaryotes, and that its role in transcriptional regulation is ancient. Together, these 3 studies illustrate how maturation of genomic technology for research applications has great utility for the identification of potential human and antifungal drug targets and offers an encompassing glance at the structure of genomes. |
