Abstract
The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse, zebrafish and nematode) and techniques. For example, we show that OSCP1, which has previously been implicated in two distinct non-ciliary processes, causes ciliogenic and ciliopathy-associated tissue phenotypes when depleted in zebrafish. The candidate list forms the basis of CiliaCarta, a comprehensive ciliary compendium covering 956 genes. The resource can be used to objectively prioritize candidate genes in whole exome or genome sequencing of ciliopathy patients and can be accessed at http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/.
Highlights
Cilia are microtubule-based organelles extending from the surface of most eukaryotic cells, serving critical functions in cell and fluid motility, as well as the transduction of a plethora of sensory and biochemical signals associated with developmental processes [1]
Because the tandem-affinity purification and mass spectrometry (TAP-middle segment (MS)) and SILAC data sets are based on a similar methodology and have a large bait overlap (14 out of 16 SILAC baits were used in the TAP-MS data set), we merged them into a single data set (Mass-spec based protein-protein interaction (PPI)) to avoid bias
With the current interest in cilia biology, it is certain that many new genes will be implicated in ciliary function for several years to come
Summary
Cilia are microtubule-based organelles extending from the surface of most eukaryotic cells, serving critical functions in cell and fluid motility, as well as the transduction of a plethora of sensory and biochemical signals associated with developmental processes [1]. The cilium is a complex and highly organized structure, typically comprised of a ring of nine microtubule doublets extending from a centriole-derived basal body and enveloped by an extension of the plasma membrane. Cilia are compartmentalized structures, with a protein composition of the membrane and lumen differing significantly from that of the plasma membrane and cytoplasm [4,5]. Several hundred proteins are thought to be involved in the formation and function of ciliary structures and associated signaling and transport pathways. It is likely that many more ciliary proteins remain to be identified, as new genes for this organelle are still frequently uncovered—often in relation to genetic disorders. [2]
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