Yeast Mutations Offer Window Into Human Disease

Drs Brenda Andrews and Charles Boone of University of Toronto, as well as Howard Bussey of McGill used simple yeast cells to demonstrate that there are many different combinations of genetic mutations that can lead to cell death or reduced cell fitness. The research team will now focus on mapping gene interactions for those yeast genes that are similar to human genes. Their study appears in the Feb. 6 issue of the journal Science.

The researchers crossed a yeast strain carrying a mutation in a particular gene of interest with a collection or "array" of other yeast strains to determine which gene pairs were lethal. The team studied more than 4,000 of these interactions involving gene pairs and were able to provide a large scale "genetic interaction network" that provokes new ideas about how genes interact to produce different traits.

For example, they determined that genes arrange themselves in "neighbourhoods" or small networks. A gene is more likely to interact with its "neighbour," they discovered, than with more distant genes. Each yeast gene has on average about 30 of these interactions over the life of a cell, many more than had been predicted by previous experiments. By understanding the composition of these genetic "neighbourhoods," it is possible to predict which genes will interact and which traits will result when two genes combine.

"Constructing these networks will help human geneticists to focus their research on the culprits of disease," says Andrews, chair of U of T's medical genetics and microbiology department. "If we can begin to construct these kinds of networks in an intelligent way, we might directly accelerate the discovery of those genes that are lethal when combined."

The study has sparked interest among other researchers in developing techniques for mapping the genetic "neighbourhoods" of more complex organisms. "Because our global genetic network studies map out how cells work, they have implications that may help in our understanding of the bases of complex inherited diseases such as glaucoma, type II diabetes and schizophrenia" says Howard Bussey, a Professor at McGill's Dept of Biology. "We're grateful that Genome Canada and Genome Quebec had the foresight to provide $2.6 million in critical funding to enable us to undertake this pioneering work."

The study's lead authors are Amy Hin Yan Tong, a U of T graduate student in the molecular and medical genetics department, and Guillaume Lesage, a post-doctoral student at McGill. The international team included researchers at Harvard Medical School, Cornell University, the University of Pennsylvania, the University of California, the Institute of Biochemistry in Zurich, Switzerland, MRC Laboratory in Cambridge, England, and Memorial Sloan-Kettering Cancer Center in New York.

The study received funding from the Canadian Institutes of Health Research, the Canadian Foundation for Innovation and Genome Canada through the Ontario Genomics Institute and Genome Quebec.

Howard Bussey can be reached through Anie Perrault, Genome Canada. To reach University of Toronto researchers, please contact Elaine Smith, University of Toronto.