It Took 15 Years to Map Every Gene Interaction in a Yeast Cell

Understanding how thousands of individual yeast genes interact in pairs could expose the underlying genetic bases of human diseases.

After 15 years of research, scientists from the University of Toronto and University of Minnesota have completed the first complete genetic network map of a yeast cell, which details how thousands of individual genes interact with one another to give rise to cellular life. Their research, published last Thursday in Science, could prove instrumental in finding the genetic mechanisms for a host of human diseases and lead to individually tailored therapies.

The human genome is comprised of some 20,000 individual genes which are organized in hierarchical networks to regulate cellular function. The way individual genes are paired can lead to drastically different results and can mean the difference between life and death. But analyzing the hundreds of millions of unique gene pairs that can be derived from the human genome is a gargantuan task, so the researchers started with something a little smaller—a yeast cell.

A yeast cell may seem like a far cry from a human cell, but genetically speaking we've got quite a bit in common. Yeast cells also only have about 6,000 genes, many of which are also found in humans, which makes the analysis relatively simpler. Still, when everything was said and done, the researchers analyzed almost all of the possible 18 million gene pairs that can be generated from the yeast genome.

The process began around 2000, when an international team of researchers began deleting every single yeast gene one at a time to see the effects. What they found was surprising: only one in five genes in yeast appeared to be necessary for the organism's survival. With drastic improvements in gene editing technology like CRISPR in the last few years, researchers found that the same was true of human genes: the vast majority of human genetic material appeared to be superfluous for survival.

In short, it appeared as though most genes—in both yeast and humans—were acting as buffers, protecting essential genetic material from mutations and environmental stressors.

Intrigued by this observation, Brenda Andrews and Charlie Boone, professors of molecular genetics at the University of Toronto, led a team of researchers on a mission to discover whether a cell would survive after losing a pair of genes. If most genetic material just acted as a buffer, did it matter which genes did the buffering?

After some 15 years of research on this question and nearly 18 million pairs of yeast genes analyzed, Andrews and her colleagues have completed a map which shows how all the genes in a yeast cell interact. What they found was that if one particular yeast gene loses its function, there is another gene in the cell capable of fulfilling the role of the lost gene.

Moreover, some of the gene pairs were discovered to be "synthetic lethal," which means that losing both of the genes results in cell death, but only losing one gene in the pair does not. Fortunately, such pairings are relatively rare in the yeast genome, which is a good thing—it means that in most cases genes have a functional backup somewhere else in the genome which can replace a damaged gene without causing cell death.

According to the researchers, this means that when looking for the genetic origins of a disease, it is probably more useful to look for this origin in gene pairs rather than individual genes since the way genes interact seems to largely determine cellular health. In cancer, for example, the notion of synthetic lethality is already paving the way for effective new treatments. Compared with a healthy cell, cancer cells have genomes awash in mutations—the ability to identify the back-up genes for cancerous genomes could lead to drugs which specifically target cancerous cells while leaving healthy cells unscathed.

Identifying gene pairings that underlie human disease will require mapping the interactions of some 200 million gene pairs. It's a huge task, but because of the overlap between the yeast genome and human genome, the yeast map developed by Andrews and her colleagues provides a huge initial boost in this direction.

"Without our many years of genetic network analysis with yeast, [we] wouldn't have known the extent to which genetic interactions drive cellular life or how to begin mapping a global genetic network in human cells," said Charles Boone, a professor of molecular genetics at the University of Toronto. "We have tested the method to completion in a model system to provide the proof of principle for how to approach this problem in human cells. There's no doubt it will work and generate a wealth of new information."