RRC ID 53537
Author Timbers TA, Garland SJ, Mohan S, Flibotte S, Edgley M, Muncaster Q, Au V, Li-Leger E, Rosell FI, Cai J, Rademakers S, Jansen G, Moerman DG, Leroux MR.
Title Accelerating Gene Discovery by Phenotyping Whole-Genome Sequenced Multi-mutation Strains and Using the Sequence Kernel Association Test (SKAT).
Journal PLoS Genet
Abstract 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, from the Million Mutation Project, 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 three genes not previously linked to ciliated sensory neuron development or function. From these putative novel dye-filling genes, we confirmed the involvement of BGNT-1.1 in ciliated sensory neuron function and morphogenesis. BGNT-1.1 functions at the trans-Golgi network of sheath cells (glia) to influence dye-filling and cilium length, in a cell non-autonomous manner. Notably, BGNT-1.1 is the orthologue of human B3GNT1/B4GAT1, a glycosyltransferase associated with Walker-Warburg syndrome (WWS). WWS is 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 may be considered a ciliopathy.
Volume 12(8)
Pages e1006235
Published 2016-8-1
DOI 10.1371/journal.pgen.1006235
PMID 27508411
PMC PMC4980031
MeSH Animals Brain / metabolism Brain / pathology Caenorhabditis elegans / genetics Cilia / genetics Cilia / metabolism Eye Abnormalities / genetics* Eye Abnormalities / pathology Genome Humans Morphogenesis / genetics* Muscular Dystrophies / genetics Muscular Dystrophies / pathology Mutation N-Acetylglucosaminyltransferases / genetics* Phenotype Sensory Receptor Cells / metabolism* Sensory Receptor Cells / pathology Walker-Warburg Syndrome / genetics trans-Golgi Network / genetics
IF 5.175
Times Cited 10
C.elegans tm4314