Multi-well plate loaded with colonies of yeast cells with a known damaging mutation, paired with other randomized mutations; colonies carrying protective mutations are larger because the cells grow faster.

Credit: Jovana Drinjakovic/University of Toronto

Mutations that Serve to Protect

We tend to think of genetic mutations as the "bad guys," but some mutations can actually help mitigate the impact of disease.

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It’s easy to think of all genetic mutations as being bad. After all, they are errors: typos in the letters that make up the genetic code. Collect up enough harmful mutations in a single cell and you could wind up with cancer. Mutations in particular genes can even spell certain diseases, such as one called CFTR that causes cystic fibrosis, a genetic disease affecting the lungs and digestive tract.

Mutations happen all the time. But the truth is, many mutations are neutral. Genes code for sequences of amino acids, the building blocks for proteins that drive all of a cell’s activities. Each amino acid is spelled using a sequence of three letters, and so some mutations simply change the spelling, but code for the same amino acid.

In fact, even when mutations impact the proteins they code for, they may provide unexpected benefits. This is the driver behind evolution.

Researchers at the University of Toronto are intrigued by this idea of beneficial or protective mutations.

For instance, Andrew Fraser, professor of molecular genetics at the University of Toronto, studies cystic fibrosis. The onset and severity of cystic fibrosis varies dramatically, even though all patients share a mutation in the same gene. However, some patients will be diagnosed as newborns, and others will not notice any symptoms until adulthood.

Starting in worms, Fraser looked beyond the one disease-causing gene. He surveyed all the other genes that might change the severity of its impact. He found that many other genes act like dimmer switches, affecting how much of the faulty protein gets made.

Because the faulty protein doesn’t function as well as the original, its impact is amplified even more when its concentration gets too low. This effect was also validated in human cells.

The nature of the disease-causing mutation itself is only one factor in how severe the symptoms will be. Having this information can give patients a better sense of what to anticipate as they make healthcare decisions.

Running with the same idea, co-authors Brenda Andrews, Charles Boone and Frederick Roth are looking for genes that suppress disease-causing mutations. Also professors of molecular genetics at the University of Toronto and members of the Canadian Institute for Advanced Research, they collaborated with Professor Chad Myers of the University of Minnesota-Twin Cities to systematically look for protective genes in yeast.

Yeast have fewer genes than human cells, making them a simpler model to study. Colonies of yeast cells were grown with a known damaging mutation that slows growth. When paired with other randomized mutations, colonies carrying protective mutations are larger because the cells grow faster.

This rapid method to screen for effects of many genes at once allowed the researchers to look beyond the most popular genes in the literature, revealing hundreds of suppressor genes. The researchers could then look for general patterns and relationships between the damaging mutations and the protective ones.

It turns out that the resulting proteins from these pairs of genes tended to be related. They often shared a usual physical location in the cell, or were both players in a the same molecular pathway. Knowing this narrows the search for suppressor genes in human cells, and could even guide future drug development by mimicking their role in the cell.

Research on genes beyond the disease-causing mutation expands the view of genetic diseases to capture a bigger picture. Understanding how mutations can be protective helps patients better manage their health.

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Karyn Ho is a science animator and engineer who thrives at the interface between science, engineering, medicine, and art. She earned her MScBMC (biomedical communications) and PhD (chemical engineering and biomedical engineering) at the University of Toronto. Karyn is passionate about using cutting edge discoveries to create dynamic stories as a way of supporting innovation, collaboration, education, and informed decision making. By translating knowledge into narratives, her vision is to captivate people, spark their curiosity, and motivate them to share what they learned.