Image a game of Clue, the murder mystery board game, in which neither Miss Scarlet, Colonel Mustard, nor any of the other leading suspects did the deed. Instead, some intricate conspiracy, composed of an indeterminate number of lesser-known figures, was responsible. The task of unraveling such a conspiracy might seem familiar to genomic scientists, who happen to be grappling with a problem called “missing heritability.” Basically, these scientists are trying to work out why individual genes account for only a small portion of heritable diseases and other traits.

To date, most genetic analyses of heritable physical characteristics, including genome-wide association studies in human populations, have focused on so-called “additive” variants that have effects that occur regardless of the organism’s genetic background. Unfortunately, the additive variants don’t add up. To reconcile their genotypic/phenotypic sums, genomic scientists are spending more time investigating so-called higher-order interactions. In such interactions, multiple loci may influence a number of complex traits.

For example, a pair of scientists at the University of Southern California (USC) have definitively demonstrated that large sets of variations in the genetic code that do not individually appear to have much effect can collectively produce significant changes in an organism’s physical characteristics. The scientists—Ian M. Ehrenreich, Ph.D., an assistant professor of molecular biology, and Matthew B. Taylor, a Ph.D. student in molecular and computational biology—dissected a colony morphology trait that “segregates in a cross of two yeast strains and is caused by genetic interactions among five or more loci.”

Until now, most of our knowledge about genetic interactions in natural systems has come from studies focused on two-locus interactions where at least one of the loci exhibits a measurable effect on its own. The USC study, however, goes further, demonstrating that sets of five or more genetic variants can synthetically interact to produce major phenotypic effects.

The USC study appeared May 1 in PLOS Genetics, in an article entitled “Genetic Interactions Involving Five or More Genes Contribute to a Complex Trait in Yeast.” It promises to influence genetic mapping studies by encouraging other attempts to characterize higher-order interactions.

The authors caution, however, that “characterizing higher-order interactions using data from screens and annotations focused solely on reference genomes may be a challenge.” Yet they add that their work “highlights how genetic variation can serve as a tool for detecting previously unidentified functional relationships among genes.”

Specific results from the study include the following: “The causal genes have diverse functions in endocytosis (END3), oxidative stress response (TRR1), RAS-cAMP signaling (IRA2), and transcriptional regulation of multicellular growth (FLO8 and MSS11), and for the most part have not previously been shown to exhibit functional relationships. Further efforts uncovered two additional loci that together can complement the noncausal allele of END3.” This last finding suggests that multiple genotypes in the cross can specify the same phenotype.

“It’s exciting to provide a characterized example of how genetic background can influence the effects of mutations. We hope that this will open the door for future studies to tease apart how these complex interactions happen,” said Taylor.

One possibility raised by the study is that genetic variants that have the potential to cause major changes in an organism’s phenotype can be completely canceled out if they occur in the “wrong” genomic background. In any event, as the authors of the study concluded, “characterizing the larger-scale contribution of higher-order interactions to phenotypic variation is a necessary step in improving our basic understanding of the genotype-phenotype map.”

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