The role of noncoding regulatory variants in orofacial clefts

项目总结 口面部裂(OFC)是人类最常见的头面部出生缺陷，由多种原因引起 遗传和环境风险因素。阐明OFCS的病因学不仅对我们了解 发育生物学和裂隙是如何产生的，但最终是为了改进预防、治疗和 受离岸金融中心影响的个人的预后。基因组测序的临床应用正在增长，但 OFC的可用性受到可遗传风险的大量缺失以及对 非编码监管要素的变体如何导致OFC风险。这些元素包括(但不是 仅限于)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，非编码调控变体是导致 由于缺乏大量资源，对离岸金融中心中此类变种的广泛分析受到了限制。 OFC患者的全基因组序列和难以注释颅面调节的个体 变种。在这项提案中，我们将利用最近几项直接解决这些问题的举措 通过分析来自1300多个病例-父母三人组的罕见的从头开始、遗传和结构变异来排除障碍 OFCs通过加布里埃拉·米勒儿童第一研究计划进行了测序。我们将把这些数据与 人类和小鼠产生的染色质图谱、microRNAs和RNA-SEQ数据的基因组图谱 头面部组织。这些分析将提供对离岸金融中心基因结构的关键见解，并将 充分展示离岸金融中心WGS数据的潜力。

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.