The Giddings lab is developing computational and experimental methods to understand the relationship of an organism’s genome to its proteome. They use mass spectrometry to make high-throughput mass measurements of proteins, which are mapped back to elucidate their relationship to the genome, using computational tools. They have developed a computational tool called Genome Fingerprint Scanning (GFS) that performs an in-silico translation and proteolytic digestion of an entire genome sequence. Since only raw genome sequence is used, there is no bias in determining where genes are located or what their products might be. A peptide mass list from mass spectrometry data is then matched to the predicted proteolytic digest to look for clusters where a relatively high number of peptide masses match with a particular DNA sequence, indicating the likelihood of identifying the corresponding gene. This approach has the potential to address a variety of interesting biological questions. One is understanding the mechanisms of antibiotic resistance. Bacterial resistance to antibiotics often occurs in a two-stage process. The first stage is when the primary mutation is incurred, conferring initial drug resistance. The second stage consists of several additional mutations that allow the bacteria to thrive with the “handicap” of sustaining the intial mutation. These compensatory mutations can be pinpointed using the proteomic methods and informatics tools developed by the Giddings group, to understand their functional implications and perhaps design improved antibiotics. Another application for these methods is the basic question of how many genes there are in a sequenced genome. It is clear that DNA sequence alone is not sufficient to answer this question. The Giddings lab is taking an unbiased approach by directly identifying which part of the genome encodes proteins that are extracted from cells in the laboratory. This is the most definitive evidence possible for the presence of protein coding genes. The lab is applying this approach to the recently sequenced Francisella tularensis and Tetrahymena thermophila genomes.