GENOMICS
How Many Genes Do Cells Need? Maybe Almost All of Them
An ambitious study in yeast shows that the health of cells depends on the highly intertwined effects of many genes, few of which can be deleted together without consequence.
The activities of genes in complex organisms, including humans, may be deeply interrelated.
Olena Shmahalo/Quanta Magazine; Model by: TheEmptyRoom
By knocking out genes three at a time, scientists have painstakingly deduced the web of genetic interactions that keeps a cell alive. Researchers long ago identified essential genes that yeast cells can’t live without, but new work, which appears today in Science, shows that looking only at those gives a skewed picture of what makes cells tick: Many genes that are inessential on their own become crucial as others disappear. The result implies that the true minimum number of genes that yeast — and perhaps, by extension, other complex organisms — need to survive and thrive may be surprisingly large.
About 20 years ago, Charles Boone and Brenda Andrews decided to do something slightly nuts. The yeast biologists, both professors at the University of Toronto, set out to systematically destroy or impair the genes in yeast, two by two, to get a sense of how the genes functionally connected to one another. Only about 1,000 of the 6,000 genes in the yeast genome, or roughly 17 percent, are considered essential for life: If a single one of them is missing, the organism dies. But it seemed that many other genes whose individual absence was not enough to spell the end might, if destroyed in tandem, sicken or kill the yeast. Those genes were likely to do the same kind of job in the cell, the biologists reasoned, or to be involved in the same process; losing both meant the yeast could no longer compensate.
Ignorant as science may still be about certain happenings in yeast, it’s dwarfed by our ignorance of what is going on in our own cells
Boone and Andrews realized they could use this idea to figure out what various genes were doing. They and their collaborators went about it deliberately, by first generating more than 20 million strains of yeast that were each missing two genes — almost all of the unique combinations of knockouts among those 6,000 genes. The researchers then scored how healthy each of the double mutant strains was and investigated how the missing genes could be related. The results let the researchers sketch a map of the shadowy web of interactions that underlie life. Two years ago, they reported the details of the map and revealed that it had already allowed researchers to discover previously unknown roles for genes.
Along the way, however, they realized that a surprising number of genes in the experiment didn’t have any obvious interactions with others. “Maybe, in some cases, deleting two genes isn’t enough,” Andrews said, reflecting on their thoughts at the time. Elena Kuzmin, a graduate student in the lab who is now a postdoc at McGill University, decided to go one step further by knocking out a third gene.
In the paper out today in Science, Kuzmin, Boone, Andrews and their collaborators at the University of Toronto, the University of Minnesota and elsewhere report that effort has yielded a deeper and more detailed map of the cell’s inner workings. Unlike in the double mutant experiments, the researchers did not make every possible combination of mutations — there are about 36 billion different ways to knock out three genes in yeast. Instead, they looked at the pairs of genes they’d already knocked out and ranked their interactions according to severity. They took a number of those pairs, whose effects ranged from making cells grow a little slower to making them significantly impaired, and matched them up one by one with knockouts of other genes, generating about 200,000 triple mutant strains. They monitored how quickly colonies of the mutant yeast grew, and after noting which mutants were struggling, they checked databases to see what the disabled genes were thought to do.
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READ MORE HERE: Quanta Magazine
