TY - JOUR T1 - Accelerating gene discovery by phenotyping whole-genome sequenced multi-mutation strains and using the sequence kernel association test (SKAT) JF - bioRxiv DO - 10.1101/027540 SP - 027540 AU - Tiffany A. Timbers AU - Stephanie J. Garland AU - Swetha Mohan AU - Stephane Flibotte AU - Mark Edgley AU - Quintin Muncaster AU - Donald G. Moerman AU - Michel R. Leroux Y1 - 2015/01/01 UR - http://biorxiv.org/content/early/2015/09/24/027540.abstract N2 - Forward genetic screens represent powerful, unbiased approaches to uncover novel components in any biological process. Such screens suffer from a major bottleneck, however, namely the cloning of corresponding genes causing the phenotypic variation. Reverse genetic screens have been employed as a way to circumvent this issue, but can often be limited in scope. Here we demonstrate an innovative approach to gene discovery. Using C. elegans as a model system, we used a whole-genome sequenced multi-mutation library together with the Sequence Kernel Association Test (SKAT) to rapidly screen for and identify genes associated with a phenotype of interest, namely defects in dye-filling of ciliated sensory neurons. Such anomalies in dye-filling are often associated with the disruption of cilia, organelles which in humans are implicated in sensory physiology (including vision, smell and hearing), development and disease. Beyond identifying several well characterised dye-filling genes, our approach uncovered 17 genes not previously linked to ciliated sensory neuron development or function. From these putative novel dye-filling genes, we confirmed and characterised the involvement of BGNT-1 in ciliated sensory neuron development. Notably, BGNT-1 is the orthologue of human B3GNT1/B4GAT1, a glycosyltransferase associated with Walker-Warburg syndrome, a multigenic disorder characterised by muscular dystrophy as well as brain and eye anomalies. Together, our work unveils an effective and innovative approach to gene discovery, and provides the first evidence that B3GNT1-associated Walker-Warburg syndrome is a ciliopathy. ER -