What can worms tell us about variable consequences of mutation?

A lot of research effort is directed towards identifying disease causing mutations, but have you ever wondered why some mutations have little or variable effect from one individual to another? Even when the mutation would be predicted to impair or completely eliminate gene function?

It has long been recognized in model systems such as the yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans that genetic interactions between closely related genes can mitigate the effect of a mutation in one of the members of the interacting pair, leading to a completely suppressed or partially penetrant phenotype. Recent work by Burga et al, published in the December 8, 2011 issue of Nature, provides the latest example of such a genetic interaction network in C. elegans. Their investigation of the tbx-8 and tbx-9 T-box transcription factor genes provides a clear demonstration of two genes which functionally compensate for each other, such that when the tbx-8 gene is rendered completely non-functional increased expression of the tbx-9 gene naturally compensates for its loss in a significant percentage of affected individuals.

Going a step further, the authors work demonstrates that a general chaperone buffering system, in this case measured by the expression of the daf-21 Hsp90 gene, can additionally mitigate the effects of the tbx-8 mutation. Most interesting is the author’s observation that when the genetic interaction network mechanism and the chaperone buffering mechanism are both active, the effect of the tbx-8 mutation is nearly completely suppressed – providing intriguing clues to the variable consequences of mutation in other species, including human disease.

What’s your favorite example of compensatory genes?