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Genetic Background Influences How Gene Mutations Interact

NEW YORK (GenomeWeb News) – Whether a gene mutation leads to a certain phenotype depends in part on how it interacts with other mutations and the genetic background in which those mutations are being expressed, researchers reported yesterday in PLOS Genetics.

By turning to the fruit fly model system, researchers at Michigan State University found that the wild-type genetic background affects the outcome of such genetic interactions some 75 percent of the time. This, Ian Dworkin, an associate professor of zoology at Michigan State, and his doctoral student Sudarschan Chari noted, could influence how gene networks should be constructed and, possibly, how some diseases should be treated.

"It's been known for a while that genetic mutations can modify each other," Dworkin said in a statement. "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. We wanted to know how common it was for wild-type genetic background to alter the way genetic mutations interact with each other. "

To calculate how often gene interactions are affected by the genetic background, Dworkin and Chari examined how a mutation in the fruit fly gene scalloped — which affects fly wing size and shape — was modified by other mutations in two wild-type fruit fly strains.

The sdE3 allele of scalloped had previously been shown to be susceptible to such background effects in its interactions with one other gene, and in this study, the researchers performed a genome-wide screen to search for dominant sdE3 modifiers in both the Oregon-R and Samarkand Drosophila melanogaster strains.

To do so, they crawled along the fruit fly genome, deleting segments one at a time to create 723 deletion strains — which covered about 90 percent of the autosomal genome — that were then crossed with lines containing the sdE3 allele. That way, they could determine how each stretch of the fruit fly genome interacted with the expression of sdE3. In addition, they created a second set of differently sized deletions to account for deletion size as an effect.

Of the deletion strains, 198 modified the sdE3 phenotype, the researchers said, and about 74 percent of those effects were dependent on the wild-type genetic background.

"We were surprised that the influence of wild-type genetic background on genetic interaction was so common," Dworkin added. "We knew it could happen, but no one had demonstrated that it was this prevalent."

Typically, the differences due to the background effect altered the magnitude of the phenotype. For example, through follow-up fine-mapping and candidate insertional mutations, the researchers noted that an allele of fly gene vg, or vestigial — whose gene product forms a heterodimer with sd gene product — acts as an enhancer, but that it is a strong enhancer in the Samarkand line and a weak enhancer in the Oregon-R line.

Still, the investigators noted instances in which the sd allele was modified in different directions in the two different backgrounds.

"This suggests that genetic interactions are often contingent on genetic background, with flexibility in genetic networks due to segregating variation in populations," Dworkin and Chari wrote. They added that these effects could influence conclusions scientists come to about genes' roles in certain processes and their spots in gene networks.

Dworkin further noted that "[t]he broader implication is that even for diseases with a simple genetic basis, variation in the genome may matter for both understanding and treatment," Dworkin added.

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