Study reveals complex interactions between disease genes

A US study looking at the interaction between genes known to cause a rare genetic disease has shown that common and rare genetic variants interact to make symptoms more or less severe. These results may have major implications for how genetic studies are interpreted, according to the study authors, because it is highly likely that such interactions occur in other genetic conditions.

Professor Nicholas Katsanis and his colleagues at Duke University used zebrafish to study the effect of variations in the 14 genes associated with Bardet-Biedl syndrome (BBS), a rare cellular disorder. BBS can cause symptoms including blindness, heart problems and physical and mental retardation.

The researchers disrupted the fish versions of each of the 14 BBS genes to create mutant phenotypes, and then determined the ability of the 125 known human variants to restore the normal phenotype.

Many of these variants were thought to be benign and able to restore the phenotype, just like a wild type version. But they discovered that - for the majority of these variants - a spectrum of severity was observed, with some partially restoring the phenotype and others showing no improvement at all. Some (28 per cent) of the variants made the phenotype significantly worse.

Genetic studies traditionally focus on the search for rare variants, as the contribution of common variation is generally thought to be minor, but this study showed that common variations can also be detrimental to protein function.

The study is published in PNAS (Proceedings of the National Academy of Sciences).