Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, the Netherlands.
Theoretical Biology and Bioinformatics, Science faculty, Utrecht University, Utrecht, the Netherlands.
PLoS One. 2019 May 16;14(5):e0216705. doi: 10.1371/journal.pone.0216705. eCollection 2019.
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/.
纤毛是哺乳动物细胞表面的一种必需细胞器，其功能障碍会导致广泛的遗传疾病，统称为纤毛病。目前新的纤毛病基因的识别率表明，许多纤毛成分仍未被发现。我们生成并严格分析了基因组、蛋白质组、转录组和进化数据，并使用贝叶斯统计系统地将这些数据整合到一个预测纤毛功能的评分中。这导致了 285 个候选纤毛基因。我们使用多种细胞和动物模型系统（小鼠、斑马鱼和线虫）和技术，对 36 个分析候选蛋白中的 24 个进行了独立的实验证据验证。例如，我们表明，先前涉及两个不同非纤毛过程的 OSCP1 在斑马鱼中被耗尽时会引起纤毛发生和纤毛病相关的组织表型。候选基因列表构成了 CiliaCarta 的基础，这是一个全面的纤毛纲要，涵盖了 956 个基因。该资源可用于客观地优先考虑纤毛病患者外显子组或全基因组测序中的候选基因，可在 http://bioinformatics.bio.uu.nl/john/syscilia/ciliacarta/ 访问。
