The role of noncoding regulatory variants in orofacial clefts

项目摘要 口面裂（OFC）是人类最常见的颅面出生缺陷， 遗传和环境风险因素。阐明OFC的病因不仅对我们了解OFC的发病机制至关重要， 发育生物学和裂缝是如何产生的，但最终是为了改善预防，治疗， OFC患者的预后。基因组测序的临床应用正在增长，但 OFC的可用性受到遗传风险的大量缺失和对 非编码调控元件的变异如何导致OFC风险。这些要素包括（但不包括 限于）增强子，启动子，非编码RNA（例如，microRNA）和拓扑相关结构域 边界尽管越来越多的证据表明，非编码调节变异是重要的贡献者， 人类疾病，在OFC中对这些变体的广泛分析受到缺乏大量资源的限制 OFC患者的全基因组序列，并难以注释颅面调节 变体。在本提案中，我们将利用最近直接解决这些问题的几项举措， 通过分析来自1,300多个病例父母三人组的罕见从头，遗传和结构变异， 通过加布里埃拉米勒儿童优先研究计划对OFC进行测序。我们将这些数据与 从人类和小鼠中生成的染色质图谱、microRNA和RNA-seq数据的基因组图谱 颅面组织这些分析将为OFC的遗传结构提供关键的见解， 揭示了WGS数据对OFC的全部潜力。

PROJECT SUMMARY Orofacial clefts (OFCs) are the most common craniofacial birth defect in humans and are caused by multiple genetic and environmental risk factors. Elucidating the etiology of OFCs is critical not only for our knowledge of developmental biology and for how clefts arise, but ultimately for improved prevention, treatment, and prognosis for individuals affected by OFCs. Clinical applications of genome sequencing are growing, but the usability for OFCs is hindered by a substantial missing fraction of heritable risk and a poor understanding of how variants in non-coding regulatory elements contribute to OFC risk. These elements include (but are not limited to) enhancers, promoters, noncoding RNAs (e.g., microRNA), and topologically associated domain boundaries. Despite the mounting evidence that non-coding regulatory variants are important contributors to human disease, widespread analysis of such variants in OFCs has been limited by the lack of a large resource of whole genome sequences in individuals with OFCs and difficulties annotating craniofacial regulatory variants. In this proposal, we will take advantage of several recent initiatives that directly address these barriers by analyzing rare de novo, inherited, and structural variants from over 1,300 case-parent trios with OFCs sequenced through the Gabriella Miller Kids First Research Program. We will integrate these data with genomic atlases of chromatin profiling, microRNAs, and RNA-seq data generated from human and mouse craniofacial tissues. These analyses will provide key insights into the genetic architecture of OFCs and will reveal the full potential of WGS data for OFCs.