Harvesting the Genome's Bounty: Integrative Genomics

In this post-genomic era, we face the daunting challengeof assigning function to tens of thousands of uncharacterized open reading frames. Furthermore, the physical andfunctional connections between gene products must beelucidated if we are to understand how the linear DNA sequence encodes dynamic cellular function. An unexpectedresult of the Human Genome Project is the low number ofpredicted human genes, roughly fivefold more than in single-celled yeasts and approximately double that in flies orworms (Lander et al. 2001; Venter et al. 2001). Increasedconnectivity between this relatively constant number ofgenes may underlie the massive increase in system-levelcomplexity that distinguishes yeast from humans.Genome-wide approaches to discovery of gene functionnow include systematic analysis of genetic interactions,protein interactions, genome-wide expression profiles, andmutant phenotypes. More than any single approach, eachof which is subject to caveats in interpretation and reproducibility, the intersection of orthogonal genome-scaledata sets provides a robust means to interrogate gene function. Here, we summarize advanced genome-scale methods for biological discovery in the budding yeast Saccharomyces cerevisiae, many of which will be transportable tointerrogation of human gene function...