It’s an intriguing question that needs to be asked: If two women have the same genetic mutation that puts them at higher-than-average risk for a disease such as breast cancer, why does only one develop the disease?

In the current issue of PLOS Genetics, Michigan State University’s(MSU) genetic scientists Ian Dworkin, associate professor of zoology and co-author of the paper and Sudarshan Chari, zoology doctoral student and the paper’s lead author, describe how the genome interacts with mutations that cause the differences we see among individuals.”It has been known for a while that genetic mutations can modify each other’s effects,” Dworkin noted. “And we also know that the subtle differences in an individual’s genome ? what scientists call wild type genetic background ? also affects how mutations are manifested.”


…Even for diseases with a simple genetic basis, variation in the genome may matter for both understanding and treatment…


A small number of recent studies have demonstrated that factors such as this wild-type background in which these mutations are studied can have a profound impact on the observed phenotype of both specific effects of the mutation and the interactions between mutations. However, Dworkin and Chari wanted to know how common it was for wild type genetic background to alter the way genetic mutations interact with each other. “This is the first time that it’s been examined in a systematic manner,” Dworkin explained.

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Drosophila melanogaster
The description of genetic networks – the maps of how genes interact with each other – is essential for much of biology, yet if, and how, the topologies of these networks are influenced by background is unknown. Using the genome of drosophila melanogaster, commonly know as fruit fly or vinegar fly, the researchers found that wild type genetic background affected the outcomes of interactions between genetic mutations about 75% of the time. They showed that this background-dependency was due, in part, to differential sensitivity to genetic perturbation. This outcome may have huge implications in how scientists construct these genetic networks.

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Missing networks?
“It may be that some crucial portions of genetic networks are missing,” he said. “It also seems that network descriptions are more fluid than we thought.”

Fruit flies have been called humans with wings, genetically speaking, due to their similarities. By focusing on wings and a genetic mutation that alters them, the researchers demonstrated the influence of wild type genetic background was actually quite common.

Implications for treatment
“The broader implication for humans is that even for diseases with a simple genetic basis, variation in the genome may matter for both understanding and treatment,” Dworkin explained.This new insight explains how, in an example like breast cancer, every woman’s genetic background is likely influencing how the mutation is expressed, causing different disease outcomes. The research also may help explain why some people benefit from a specific treatment for a disease, while others get no benefits or become resistant to a drug after a short time.

More sets of genes are involved
It’s likely that most diseases with a suspected genetic component, such as cancer, asthma or Parkinson’s, involve reactions between more than one set of genes. For Dworkin and Chari, the next step is to tease apart the intricacies of what’s happening.”Is it just the two pairs of genes that are interacting?” Dworkin asked. “Or is it that the two genes are interacting and then many other genes are modifying that reaction? This will help us understand how much complexity is involved.”

For more information:
[1] Chari S, Dworkin I. The Conditional Nature of Genetic Interactions: The Consequences of Wild-Type Backgrounds on Mutational Interactions in a Genome-Wide Modifier Screen. PLoS Genet (2013) 9(8): e1003661. doi:10.1371/journal.pgen.1003661.[Article]

Photo:By focusing on fruit fly wings and a genetic mutation that alters them, researchers atMichigan State Universitydemonstrated the influence of wild type genetic background was actually quite common.Photo Courtesy:Michigan State University.

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