Disease Genes Effect May Be Overcome by Other Gene Mutations

A first-of-its-kind study, performed in the model yeast Saccharomyces cerevisiae, shows how “bad genes aren’t always bad news” in that the disease-causing effects of mutations in certain genes can be overcome by suppression-mutations in certain other genes. The study opens a new way for better understanding how some people naturally stay healthy despite having disease-causing mutations, and potentially a new path to better diagnostics and therapies of genetic disorders.

Though little has been known about the mechanisms of genetic suppression, researchers are uncovering the general rules behind it. An international team of researchers led by Professors Brenda Andrews, Charles Boone, and Frederick Roth of the University of Toronto School of Medicine (Toronto, Ontario, Canada) and Professor Chad Myers of the University of Minnesota-Twin Cities (Minneapolis, MN, USA) have compiled the first comprehensive set of suppressive mutations in a cell. Their findings could help explain how suppressive mutations combine with disease-causing mutations to reduce or even prevent a genetic disorder.

This curious bit of biology has come to light as increasing numbers of healthy people have had their genomes sequenced. Among them are a few who remain healthy despite carrying catastrophic mutations that usually cause debilitating disorders, such as Cystic Fibrosis or Fanconi anemia.

“We don’t really understand why some people with damaging mutations get the disease and some don’t. Some of this could be due to environment, but a lot of could be due to the presence of other mutations that are suppressing the effects of the first mutation,” said Prof. Roth. Certain suppression mutations can keep cells healthy despite otherwise damaging mutations. “If we know the genes in which these suppressive mutations occur, then we can understand how they relate to the disease-causing genes and that may guide future drug development,” said first author Dr. Jolanda van Leeuwen.

“A study like this has never been done on a global scale. 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,” said Dr. Van Leeuwen.

The researchers took a two-pronged approach. On the one hand, they analyzed all published data on known suppressive relationships between yeast genes. While informative, these results were inevitably skewed towards the most popular genes – the ones scientists have already studied in detail. So they also carried out an unbiased analysis by experimentally measuring how well the 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 due to the suppressive mutation in a second gene. These experiments revealed hundreds of suppressor mutations for the known damaging mutations. Importantly, regardless of the approach, the data point to the same conclusion: to find suppressor genes, there is often no need to look far from the genes with damaging mutations. The genes tend to have related roles in the cell – mainly either that their protein products are physically located in the same place, or that 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. 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,” said Prof. Boone.

The study, by van Leeuwen J, Pons C, et al, was published November 4, 2016, in the journal Science.

Related Links:
University of Toronto School of Medicine
University of Minnesota-Twin Cities