Dissection of epistasis in oligogenic Bardet–Biedl syndrome

Epistasis, a phenomenon in which one gene influences the expression of a second gene at a different locus, is a major source of genetic variation, but the mechanisms involved have not been analysed in detail. Now Badano et al. have succeeded in demonstrating and closely examining epistasis in Bardet–Biedl syndrome, an illness often characterized by obesity and learning deficits. The severity of symptoms varies dramatically among patients with this disorder, in line with different combinations of mutations at different genes. A modifier gene called MGC1203 interacts with other genes known to be mutated in Bardet–Biedl syndrome, leading to a more severe form of the disease. Epistatic interactions have an important role in phenotypic variability, yet the genetic dissection of such phenomena remains challenging1. Here we report the identification of a novel locus, MGC1203, that contributes epistatic alleles to Bardet–Biedl syndrome (BBS), a pleiotropic, oligogenic disorder2,3,4,5,6,7,8,9. MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of two independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. Further analyses showed that the 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants. Our data demonstrate how the combined use of biochemical, genetic and in vivo tools can facilitate the dissection of epistatic phenomena, and enhance our appreciation of the genetic basis of phenotypic variability.