Research Project

Website: http://yeastgenomics.ca

Summary

Genome sequencing projects have revealed the massive catalogue of genes and the astounding genetic diversity in a variety of organisms, from yeast to man. Biomedical researchers are now faced with a formidable challenge as they confront this embarrassment of riches; how to assign functions to the thousands of uncharacterized genes, and how to use this information to understand how genes interact to determine cell function in health and disease. Despite amazing technical advances, our understanding of genetic interactions relevant to human disease remains remarkably rudimentary, and discovering relevant interactions demands an integrated, systematic approach. Our project focused on baker’s yeast (Saccharomyces cerevisiae), because this cell not only serves as a good model for human cells, but is also amazingly amenable to experimentation. Our team explored the connections between genes in yeast using a variety of experimental approaches and produced an integrated view of the cell and its functional sub-components.

Significant Outcomes to Date

• Rigorous investigation of yeast biology by the development of a protein-protein interaction network for yeast membrane-associated protein complexes, structural and functional characterization of unknown yeast proteins, determination of the DNA-binding specificities of all yeast transcription factors
• First comprehensive view of a global genetic interaction network for a eukaryotic cell, published in Science
• Development of an integrative bioinformatics platform for data analysis and dissemination
• Publication of over 50 peer reviewed manuscripts
• Contributed to the training of over 60 highly qualified personnel
• Raising of an additional $13M of funding as a consequence of this project

  Major databases maintained by the Integrative Biology project:

• CCBR Yeast Pathway Database consolidating publicly available yeast pathway data from SGD's (Saccharomyces Genome Database) Yeast Biochemical Pathways project
• CCBR Yeast Interaction Database, which contains data derived from Biogrid
• DRYGIN, a database of genetic interactions. Products available from Open Biosystems.
• Yeast GST-Tagged Collection for inducible overexpression of yeast ORFs
• Yeast Tet-Promoter Strains for control of transcriptional activity with a tetracycline rheostat

Notable Publications
Costanzo M, 2010. The genetic landscape of a cell. Science 327(5964): 425-31.

Berger, MF, 2008. Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences.  Cell 133(7): 1266-76

Badis, GA, et al. 2008. A library of yeast transcription factor motifs reveals a widespread function for Rsc3 in targeting nucleosome exclusion at promoters. Mol Cell. 32(6):878-87.

Collins SR, et al.  2007. Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map.  Nature  446: 806-10