We usually think of mutations as errors in our genes that will make us sick.
But not all errors are bad, and some can even cancel out, or suppress, the fallout of those mutations known to cause disease.
Little is known about this process–called genetic suppression–but that’s about to change as University of Toronto researchers begin to lay out the general rules behind it.
Researchers have compiled the first comprehensive set of suppressive mutations in a cell, to be published in Science on November 4.
Their findings could help explain how suppressive mutations combine with disease-causing mutations to soften the blow of a disease, or even completely protect against it.
It’s a curious bit of biology that’s only come to light as more healthy people have had their genomes sequenced.
Among them are a few, and extremely lucky folks, who dodge the bullet and remain healthy, displaying disease resilience, despite carrying catastrophic mutations that cause debilitating disorders, such as Cystic Fibrosis or Fanconi anemia.
How could this be?
According to the researchers, 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.
Imagine being stuck in a room with a broken thermostat and it’s getting too hot. To cool down, you could fix the thermostat–or you could just break a window.
This is how genetic suppression works to keep cells healthy despite damaging mutations. And it opens a new way of understanding, and maybe even treating, genetic disorders.
But finding these mutations is not easy. In humans, it’s 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.
To solve the problem, they used yeast as a model organism, in which they can know exactly how mutations affect the cell’s health.
With only 6,000 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 in order to study the most severe case of a mutation, where the gene function is completely gone.
The teams 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 those scientists have already studied in detail.
Which is why the researchers also carried out an unbiased analysis, by 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 thanks 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, they 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.
The study has 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, the researchers can now narrow down our focus when searching for suppressors of genetic disorders in humans.
Citation: van Leeuwen J, et al. (2016). Exploring genetic suppression interactions on a global scale. Science, published online. DOI: 10.1126/science.aag0839.
Figure legend: This Knowridge.com image is credited to J. Drinjakovic.