The role of noncoding regulatory variants in orofacial clefts

非编码调控变异在口面部裂中的作用

• 批准号: 10302874
• 负责人: ELIZABETH JANE LESLIE
• 金额: $ 15.65万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302874
• 关键词: 3' Untranslated Regions; Accounting; Address; Affect; Architecture; Atlases; Biological Assay; Biological Models; Chromatin; Code; Collaborations; Complex; Congenital Abnormality; Data; Developmental Biology; Disease; Economics; Elements; Embryo; Enhancers; Environmental Exposure; Environmental Risk Factor; Etiology; Face; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genetic study; Genome; Genomics; Goals; Heritability; Heterogeneity; Human; Individual; Inherited; Knowledge; Maps; Medical Genetics; Mendelian disorder; MicroRNAs; Mus; Mutation; Newborn Infant; Nucleotides; Parents; Pathogenicity; Pediatric Research; Phenotype; Prevention; Prognosis; Regulatory Element; Research; Research Design; Resources; Risk; Risk Factors; Role; Source; Structure; Syndrome; Testing; Tissues; Translating; Untranslated RNA; Variant; Work; clinical application; cohort; craniofacial; craniofacial development; craniofacial tissue; empowered; exome sequencing; genetic architecture; genetic risk factor; genetic testing; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic locus; human disease; improved; insight; miRNA expression profiling; orofacial cleft; programs; promoter; rare variant; social; targeted sequencing; trait; transcriptome sequencing; usability; whole genome

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.

项目摘要 口面裂口（OFC）是人类最常见的颅面出生缺陷，是由多个引起的 遗传和环境风险因素。阐明OFC的病因不仅至关重要 发育生物学以及裂口的出现方式，但最终用于改善预防，治疗和 受OFC影响的个体的预后。基因组测序的临床应用正在增长，但是 OFC的可用性受到了遗传风险的很大一部分的阻碍，并且对 非编码调节元件中的变体如何促进OFC风险。这些要素包括（但不是 限于）增强子，启动子，非编码RNA（例如microRNA）和拓扑相关的域 边界。尽管有越来越多的证据表明非编码调节变体是重要的原因 人类疾病，对OFC中此类变异的广泛分析受到了缺乏大量资源的限制 OFC的个体的整个基因组序列和注释颅面调节的困难 变体。在此提案中，我们将利用一些最新的举措，这些举措直接解决这些问题 通过分析从1300多个案例父母的三重点分析稀有的从头，遗传和结构变体的障碍 OFC通过Gabriella Miller儿童第一研究计划进行了排序。我们将将这些数据与 由人和小鼠产生的染色质分析，microRNA和RNA序列数据的基因组图谱 颅面组织。这些分析将为OFC的遗传结构提供关键的见解，并将 揭示WGS数据对OFC的全部潜力。