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November 4, 2016

Two Wrong Genes Can Make a Right, but When? Rules Emerge

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    In a global study of genetic suppression, harmful mutations were seen to slow the growth of yeast cells. In some yeast cells, growth rate improvements were attributed to a suppressive mutation in a second gene. Ultimately, experiments revealed hundreds of suppressor mutations. In this image, the faster the cells grow, the bigger the size of colonies (dots). [J. Drinjakovic]

    The enemy of my enemy is my friend—this ancient concept explains many peculiar and even unsavory alliances. And it applies not just to affairs of state, but to the genome, where a potentially deleterious mutation can be effectively neutralized by a second mutation, a suppressor mutation. Until recently, suppressor mutations were all but unknown. Recruiting them to fight disease-causing mutations was hardly a possibility. Now, however, systematic genomic surveys are giving us hints as to why some lucky people remain healthy despite carrying mutations that are known to cause debilitating disorders such as cystic fibrosis or Fanconi anemia.

    A new study has even compiled the first comprehensive set of suppressive mutations in a cell. What’s more, it has succeeded in revealing a set of general properties that can be used to predict suppressive interactions.

    The study, entitled "Exploring Genetic Suppression Interactions on a Global Scale," appeared November 4 in the journal Science. It was led by scientists from the University of Toronto and the University of Minnesota-Twin Cities, who examined both literature-curated and unbiased experimental data, which was based on both systematic genetic mapping and whole-genome sequencing.

    Although they compiled large-scale suppression networks in yeast, the scientists indicated that their work could provide a template for extending suppression studies to more complex organisms. This would be a significant development. If it were possible to identify human genes in which suppressive mutations occurred, it would be possible to understand how they relate to disease-causing genes, with implications for drug development.

    “Most suppression pairs identified novel relationships among functionally related genes, providing new insights into the functional wiring diagram of the cell,” wrote the authors of the Science paper. “In addition to suppressor mutations, we identified frequent secondary mutations, in a subset of genes, that likely cause a delay in the onset of stationary phase, which appears to promote their enrichment within a propagating population.”

    Finding suppressor mutations is not easy. In humans, it would be like looking for a needle in the haystack. A suppressive mutation could, in theory, be any one of the hundreds of thousands of misspellings in the DNA, scattered across the 20,000 human genes, which make every genome unique. To test them all would be impractical.

    "A study like this has never been done on a global scale,” said Jolanda van Leeuwen, a postdoctoral fellow at the University of Toronto and the first author of the Nature paper. “And since it is not possible to do these experiments in humans, we used yeast as a model organism, in which we can know exactly how mutations affect the cell's health.”

    With only 6000 genes, yeast cells are a simpler version of our own, yet the same basic rules of genetics apply to both. Also, it's relatively easy to remove any gene from yeast cells to study the most severe case of a mutation, where the gene function is completely gone.

    In the unbiased analysis, the scientists measured how well the yeast cells grew when they carried a damaging mutation on its own, or in combination with another mutation. Because harmful mutations slow down cell growth, any improvement in growth rate was thanks to the suppressive mutation in a second gene. These experiments revealed hundreds of suppressor mutations for the known damaging mutations.

    This analysis and the literature review both pointed to the same conclusion. To find suppressor genes, we often don't need to look far from the genes with damaging mutations. These genes tend to have similar roles in the cell—either because their protein products are physically located in the same place, or because they work in the same molecular pathway.

    "We've uncovered fundamental principles of genetic suppression and show that damaging mutations and their suppressors are generally found in genes that are functionally related,” stated Charles Boone, Ph.D., one of the corresponding authors of the study and a researcher at the University of Toronto’s Donnelly Centre and the Department of Molecular Genetics. “Instead of looking for a needle in the haystack, we can now narrow down our focus when searching for suppressors of genetic disorders in humans. We've gone from a search area spanning 20,000 genes to hundreds, or even dozens. That's a big step forward."

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