Academic journal article Genetics

The Yeast Deletion Collection: A Decade of Functional Genomics

Academic journal article Genetics

The Yeast Deletion Collection: A Decade of Functional Genomics

Article excerpt

Yeast as a Model for Molecular Genetics

The yeast Saccharomyces cerevisiae has a long, illustrious history as the first domesticated organism. In the 1970s, many voices argued that yeast, specifically S. cerevisae,is well suited as a model eukaryote to expand the discoveries derived from phage and prokaryotic studies (for review see Hall and Linder 1993). The success of S. cerevisae as a model eukaryotic organism speaks for itself and has been well documented in several inspiring chapters published in GENETICS as YeastBook (Hinnebusch and Johnston 2011). In addition to providing the first complete eukaryotic ge- nome sequence, S. cerevisiae is the only organism for which a complete deletion mutant strain collection exists. This col- lection has been used in a wide array of screens, and the individual strains have proved to be invaluable tools. One of the most powerful arguments for the utility of yeast as a use- ful model in these and other systems biology studies has come directly from the use and application of the yeast de- letion collection to understand gene function, genetic inter- actions, and gene-environment transactions.

The concept of a yeast deletion project was inspired by the sequencing of the S. cerevisiae genome. The yeast se- quencing project, one of the earliest genome consortia, served as a model for many sequencing projects that fol- lowed. Andre Goffeau, had the vision (and audacity) to sug- gest a sequencing project 60 times larger than any prior effort. In 1986, Goffeau, together with Steve Oliver, set up the infrastructure required to accomplish this milestone (Goffeau 2000). By the time it was completed, the network included 35 laboratories worldwide.

Two results from the yeast sequencing project had an immediate impact on the scientific community. First, despite decades of effort, most of the protein-coding genes predicted from the DNA sequence were new discoveries (i.e.,not previously identified by homology or experiment) (Dujon 1996). This surprising result reinforced the ambitions of the Human Genome Project (HGP) by putting to rest many concerns over the project's value. Second, the fact that so many yeast genes were found to be conserved across evolu- tion validated the idea that comparative analysis of model organism genomes would help to annotate the human ge- nome. Indeed, the evolutionary conservation of yeast genes extends to ^1000 human disease genes, many of which exhibit "functional conservation" by their ability to comple- ment the S. cerevisiae ortholog (Heinicke et al. 2007)

A Brief History of the Saccharomyces Genome Deletion Project

As the yeast sequencing project neared completion, assigning function to newly discovered gene sequences became a prior- ity. As geneticists have long appreciated, an effective way to probe gene function is via mutation. Even before the yeast sequencing project was complete, creation of a genome-wide yeast mutant collection was underway in several laboratories. One effort to create a large-scale mutant collection was by transposon tagging (Burns et al. 1994; Ross-Macdonald et al. 1999). These studies included the construction of .11,000 mutants affecting nearly 2000 annotated genes that enabled large-scale systematic studies of gene expression, protein lo- calization, and disruption phenotypes on an unprecedented scale. Importantly, the data from screens of ^8000 strains performed in 20 different growth conditions were made widely available and established, early on, the importance of distribution of annotated screening data (Kumar et al. 2002). This pioneering study laid a foundation for all future large-scale yeast genome-wide analysis methods. It was one of the first (DeRisi et al. 1997) to introduce the concept of identifying functionally related genes by cluster analysis (Ross-Macdonald et al. 1999).

A similar large-scale mutant strategy, " genetic footprint- ing," was used to generate a collection of Ty1 transposon mutants covering most of yeast chromosome V (Smith et al. …

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