For the past 20 years, researchers have been trying to link human disease to single mutations in genes. However, just as most of our physical traits arise from the combined effort of a number of genes, human diseases are often the result of an interaction between multiple genes. And from the thousands of genes known today, deciphering multigenic interactions can quickly become a mission (nearly) impossible.

Charles Boone, a geneticist in the Banting and Best department of medical research, has dug into this huge task with a very small organism: single-celled yeast. Many yeast genes are conserved, or have close copies of themselves, in higher organisms such as humans. This means a map of genetic interactions in yeast would make a very good model of what human genetic networks may look like. The problem lies in the huge number of interactions waiting to be studied, even among yeast’s 6000-odd genes. “We have to think of new, smart ways of doing that,” said Boone.

After completing his graduate studies at McGill University, Boone came to teach at U of T in 2000. In 2001, his research team developed a system to uncover gene interactions quickly and robotically: a synthetic genetic array (SGA). “Eighty percent of genes are non-essential,” said Boone. So the mutation or deletion of many yeast genes does not lead to the death of the cell.

This points to the presence of so-called buffering pathways-genetic rescue teams-that take up a missing function when a gene is knocked out of order. “Even though you compromise a pathway by deleting a gene,” Boone explained, “another steps up and backs it up.” But what happens if you also delete the back-up gene? The term for this is “synthetic lethality.” It means the cell cannot survive without the specific gene combination you have knocked out. When this occurs, it means you have stumbled upon a buffering relationship among the 5,000 non-essential yeast genes. By systematically crossing mutant with mutant, Boone’s lab uses synthetic lethality to find which gene-pair interactions are important to the survival of the yeast, and to what measure the genes are buffering each other.

With the robotic arm of the SGA screening thousands of genes at a time, Boone and his team have mapped four per cent of yeast-gene interactions to date. “This [yeast] is a little machine,” Boone said. “We can figure out how the machine works.”

With the yeast gene interaction map started, Boone’s primary focus is on completing the map and finding new ways to screen genetic networks in higher organisms. In identifying genetic interactions in organisms like yeast, flies, and worms, Boone ultimately hopes his research will help to model gene networks in human disease.

Already, his research has sparked discoveries from all reaches of the scientific community. “That’s one of the fun things about doing large-scale stuff,” Boone commented. “You cover many different topics that you’re not an expert in.”