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Left-hand column: Wild-Type refers to normal, unmodified genes. Right-hand column: Mutant gene refers to those gene mutations expressed or generated . Far Right: Disease severity reflected by degree of gene mutation via the volume of faulty protein produced by any particular individual.

Bad genes don't always lead to same outcomes

New research has uncovered how DNA influences the potential severity of any genetic disease. Two people with the same disease-causing gene mutation do not always become ill to the same extent — an end result that has puzzled scientists for decades.

Andrew Fraser PhD, professor in the University of Toronto's Donnelly Centre Department of Molecular Genetics, along with his team has uncovered a key to what makes each person's response unique to a gene mutation.

"We have shown how your genetic background — that is, the unique set of DNA letters present in a person's genome — influences the severity of their genetic disease."

Andrew Fraser PhD, professor, University of Toronto Donnelly Centre, Department of Molecular Genetics, Toronto, Ontario.

This finding advances the ability of scientists to predict how severely an inherited genetic disease will affect an individual. This is a key insight for managing disease. Study results are published in Cell, a leading biomedical journal.

The onset and severity of genetic diseases can vary widely. For example, people who carry mutations in a gene called CFTR will go on to develop cystic fibrosis (CF), a lung disease where mucus build-up makes breathing difficult and leads to life-threatening infections. But while some patients are diagnosed as newborns, others do not show any signs until adulthood.

Predicting disease severity is critical as the uncertainty surrounding disease performance expectations can be almost as frightening as the original diagnosis.

"At present we can tell little more than someone will get a genetic disease, but cannot tell them how bad it might be. This is a bit like telling someone that they will have a car crash but not whether they will receive a mild bump or a major injury. Changing this uncertainty helps patients greatly and also lets doctors focus on those likely to be most severely affected," says Fraser.

Disease-causing mutations mainly strike at a gene's function - they change the order of DNA letters so that the gene's product, a protein, ends up faulty and unable to do its job in a cell.

However, our genetic background influences how much protein is made in each of our cells. The amount of proteins produced is finely tuned by our genes — much as a dimmer switch adjusts electrical output. Each person, therefore, has a unique amount of different proteins as a result of our own DNA structure.

If a person carries a mutation that results in a disease, Fraser's team found the quantity of that faulty protein being made by an individual's DNA affects if the mutation becomes severe — or not.

This important insight into human disease came from a powerful experimental organism - a lowly worm. "Worms are the only animals in which we could do this massive scale of experimentation to investigate how genetic background affects the severity of genetic disorders," adds Fraser.

Following initial experiments scrutinizing a quarter of a million worms for the effects of one genetic mutation, the data validated the same message: the severity of a disorder is a combination of the mutation in the protein and the amount of that protein found within an individual.

Of the three billion DNA letters that make up the human genome, an astonishing three million are different between any two people.

This genetic variation has a great affect on our lives, underpinning our looks, talents and social interactions. But there is also a more sinister side, it also determines what diseases we get and how badly they might turn out to be.

Fraser: "Now for the first time we can begin to predict disease severity for each affected person by measuring their unique personal gene activity. We hope that this will eventually lead to new therapies aimed at turning down the severity of genetic diseases and a new way to tackle any life-threatening conditions."

Abstract Highlights
• Comparison of loss-of-function phenotypes of 1,400 genes in two C. elegans isolates
• ∼20% of genes have different loss-of-function phenotypes in two individuals
• Differences in severity of mutant phenotypes predictable from expression

Summary
Many mutations cause genetic disorders. However, two people inheriting the same mutation often have different severity of symptoms, and this is partly genetic. The effects of genetic background on mutant phenotypes are poorly understood, but predicting them is critical for personalized medicine. To study this phenomenon comprehensively and systematically, we used RNAi to compare loss-of-function phenotypes for ∼1,400 genes in two isolates of C. elegans and find that ∼20% of genes differ in the severity of phenotypes in these two genetic backgrounds. Crucially, this effect of genetic background on the severity of both RNAi and mutant phenotypes can be predicted from variation in the expression levels of the affected gene. This is also true in mammalian cells, suggesting it is a general property of genetic networks. We suggest that differences in the manifestation of mutant phenotypes between individuals are largely the result of natural variation in gene expression.

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