Dissection of epistasis in oligogenic Bardet–Biedl syndrome

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Abstract
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.