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BIOGRAPHY:
In 1989 Dr. Boone received his Ph.D. in molecular biology from
McGill University in Montreal, Canada. He then did postdoctoral
research in genetics at the University of Oregon in Eugene, and in 1993
began work at the Institute of Molecular Biology and Biochemistry in
Burnaby, Canada. In 1999 he received the Premier's Research Excellence
Award from the Province of Ontario government. He is also a recipient
of the William E. Rawls Award for Research Excellence of the National
Cancer Institute of Canada and the 2003 Merck Frosst Award of the
Canadian Society of Biochemistry. He is currently Professor at the
University of Toronto's Banting and Best Department of Medical
Research. His research focuses on clarifying the molecular mechanisms
by which fungal MAP kinase signal transduction cascades regulate
polarized morphogenesis, the process by which fungal cells switch from
the unicellular to the filamentous form, and on the topology of genetic
networks for eukaryotic cells, using the budding yeast Saccharomyces
cerevisiae as a model system.
RESEARCH ABSTRACT SUMMARY:
Global Mapping of the Yeast Genetic Interaction Network: Discovering Gene and Drug Function
In the budding yeast Saccharomyces cerevisiae, about 80
percent of the approximately 6000 genes are nonessential, indicating
that many biological processes are buffered from the phenotypic
consequences of genetic perturbation. To examine these functional
relationships, we developed a method called synthetic genetic array
(SGA) analysis, which automates yeast genetics and enables a systematic
and high-throughput construction of double mutants from an ordered
array of about 4700 viable gene deletion mutants. In particular, double
mutants showing reduced fitness (a synthetic sick phenotype) or
lethality (a synthetic lethal phenotype) define functional
relationships between genes and their corresponding pathways. We have
undertaken a project to generate a synthetic genetic interaction
network for the yeast cell with the expectation that it will represent
a global map of functional relationships amongst most genes. We found
that synthetic genetic interactions are more common than anticipated
previously, with an average query gene displaying about 30 different
interactions. Cluster analysis of a compendium of about 132 SGA screens
revealed that genes displaying similar patterns of genetic interactions
often encode proteins within the same pathway or complex; therefore,
the yeast genetic interaction network predicts precise molecular roles
of previously uncharacterized genes. Moreover, because a gene deletion
mutation provides a model for the effect of a compound that inhibits
its corresponding gene product, our compendium of synthetic genetic
profiles provides a key for determining the cellular targets of small
molecules and thus provides a tool for antifungal drug discovery. In
another application of this technology, we have backcrossed the set of
yeast deletion alleles to a wild-type S. cerevisiae strain that
is capable of filamentous growth, and we are attempting to identify a
comprehensive set of genes required for polarized morphogenesis. These
genes are of particular interest because the transition from budding to
filamentous growth is a component of Candida albicans
pathogenesis.
Photo: Courtesy of Charles Boone
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