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The genetic wiring of cellular life

by CIFAR Oct 17 / 17

A landmark study reveals the genetic interactions that control the function of the yeast cell, and promises to provide insight into the workings of the human cell, including new insights into genetic diseases.

The paper published in Science magazine is the result of 15 years of work mapping out genetic interactions within the single-celled organism Saccharomyces cerevisiae, or brewer’s yeast. Although yeast cells have only 6,000 genes, compared to human’s 20,000, many of the most important cellular mechanisms and genetic networks are similar for both.

“This work creates a reference for figuring out similar genetic interactions in human cells. It’s going to help us in the search for genetic networks that play an important role in human disease,” says Charles Boone, co-director of CIFAR’s Genetic Networks program and a professor of molecular genetics at the University of Toronto. He is a senior author on the paper, along with Senior Fellow Brenda Andrews, also of the University of Toronto, and Fellow Chad L. Myers of the University of Minnesota.

The MTC pathway genetic interaction network shown here is an example of the networks described by the research. Nodes are grouped according to genetic interaction profile similarity and edges represent negative (blue) and positive (yellow) interactions. (Credit: Science)

The research stems from the fact that most cell functions don’t depend on only a single gene, but on multiple genes working together. To map out these interactions, they painstakingly generated millions of double mutants, creating all possible two-gene combinations, and scoring them for unusual phenotypes, including synthetic lethal negative genetic interactions, where the double mutant dies.

In total, they discovered 550,000 negative interactions, which had a negative effect on cell function, and another 350,000 with a positive effect, where the double mutant grows better than expected. They were able to use the information to create a map of groups of genes that fulfill similar roles, working together within the same general biological process, or playing a role in a particular protein complex or pathway. The result is what they call a “functional wiring diagram of the cell.”

Previous work had showed that a subset of about 1,000 of yeast’s approximately 6000 genes are essential for life, such that a deletion mutation in any one of these essential genes will prevent cell growth and division. The new work expands our understanding of cellular function, defining thousands of genetic conditions in which genes within the subset of approximately 5000 nonessential genes are also required for life.

Doing a similar analysis with the much larger human genome will be much more difficult. But the yeast map will provide important information about the genetic interactions within human cells as well, and could help researchers understand the complex genetics underlying a number of human diseases.