The Boone-Andrews Lab looks back on the creation of the first-ever complete genetic interaction map
When researchers published the full genome sequence of the budding yeast Saccharomyces cerevisiae in 1996, the community raced to create mutants for a systematic interrogation of each gene’s role. Out of the approximately 6,000 identified genes, researchers found about 1,000 to be essential for fitness and survival. But as the years progressed, so did the demand for a comprehensive, holistic picture of how a yeast cell functions.
University of Toronto researchers Brenda Andrews and Charlie Boone saw the same finish line: a complete, global genetic interaction network map.
“Most labs wouldn’t consider taking such a large-scale project to completion—it's so expensive and it takes so much time.” says Boone. “But Brenda and I decided to see if we could. We would write grants saying a complete network was possible—even if we didn't have enough money or expertise at that point. But over 15 to 20 years, we managed to map the complete network.”
To test approximately 6,000 genes for genetic interactions, the group needed to create around 18 million double mutants. It was a marathon of persistence and an ongoing challenge to innovate faster and more efficient ways to perform the genome-wide genetic interactions screens.
“We had to develop better methods, more efficient robotics, and quantitative methods for scoring the data,” says Andrews.
Boone and Andrews collaborated to develop Synthetic Genetic Array (SGA) analysis in 2001, a robotics-based technology that allows for the systematic generation and analysis of double mutants. The group proved the technique can be used on a larger scale by 2004, and the following years involved bringing in computational experts like Gary Bader (Donnelly Centre) and Chad Myers (University of Minnesota) to help analyze the resultant piles of data following their technological advances.
“At the time it was hard to get computational biologists interested in that particular challenge,” Andrews recalled. “It was somewhat noisy data, and we had to figure out how to deal with it. That type of problem just didn't interest many people. Now it's a field of its own.”
Running this research marathon alongside Boone and Andrews is Michael Costanzo, a Senior Research Associate at the Donnelly and the lead author on the 2010 Science paper “The Genetic Landscape of a Cell”. The paper marked the 30% genome-scale milestone; focused primarily on non-essential gene interactions.
“In hindsight, we joke that if we’d had the courage to address the essential genes first, maybe we would've actually finished faster. Once we started screening these critical genes, they provided a highly structured scaffold,” explains Costanzo. “The essential genes ultimately produced about 5-fold more interactions. We quickly learned their importance as central hubs in these networks—how they define biological processes and the connections between them.”
Despite lacking the essential genes, the findings were striking: Figure 1 of the paper was a colour-coded gene network visualization, showing the correlations between genes with similar genetic interaction profiles.
“We visualized it—not by showing a million interactions but by showing how similar the profiles are,” says Boone. “We condensed it into a smaller dimension that revealed the functional information inherent in the data.”
The group’s work with yeast culminated in 2016, with the release of the first complete genome-scale genetic interaction map of a eukaryotic cell. The Science-published “A global genetic interaction network maps a wiring diagram of cellular function”, marked the end of an era for the Boone-Andrews lab.
While being interviewed, the three scientists provide over twenty names in a continuously expanding list of researchers; they include everyone—their lifelong collaborators, the 1970s yeast trailblazers, past and current Donnelly faculty, and former trainees who graduated decades ago. If there was a visualization of the labs and individuals needed to bring this project to fruition, the interconnected network might resemble a simplified version of the 2010 paper’s Figure 1.
“People were really happy to get involved, because they were seeing something new about their favorite gene or pathway,” says Andrews. “All this was coming together at the same time the Donnelly building opened—there was a good core of people with this collaborative attitude, who wanted to do team science and push the technology. Charlie and I started off in different departments and now we run one lab. It's a lot more fun and it's very fulfilling."
20th Anniversary Retrospective Series
This is the fifth instalment of a news series highlighting two decades of breakthroughs at the Donnelly Centre.
About the Donnelly Centre
The Donnelly Centre for Cellular and Biomolecular Research is a research hub at the University of Toronto’s Temerty Faculty of Medicine, where scientists from diverse fields work together to advance medicine and health. Founded in 2005, the Donnelly Centre is a global leader in research on systems biology, regenerative medicine and disease modelling.
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