Unraveling correlations between Mendelian and common disease using functional genomics

项目摘要/摘要 临床、基因组、表观遗传学等相结合的个体化诊疗 生物标记物代表着精准医学的前景。虽然大多数精准医疗计划都是 对于癌症治疗和常见病，影响到超过5%的人口，这项提议 旨在将精准医学的目标带给那些受到孟德尔罕见遗传病影响的人。目标是 我的研究小组的主要任务是通过镜头解开孟德尔病和常见病之间的关系 罕见的孟德尔综合症。我们的总体方法将整合多种功能基因组研究 (RNA-SEQ和CHIP-SEQ)从罕见孟德尔综合征患者到全基因组公开可用 联合研究(GWAS)数据。使用这些数据，我们将实现1)揭示 罕见疾病的潜在生物学机制2)它们与与以下相关的遗传位点的交集 常见病。我们将把我们的研究重点放在全球发育迟缓的新型遗传综合征上 我们首次确认是由KAT6A(赖氨酸(K)乙酰转移酶6A)的从头突变引起的。KAT6A属于 乙酰基转移酶基因家族，其主要功能之一是修饰组蛋白和控制组蛋白 表达一系列广泛的下游基因。在目标1中，我们将使用患者-来识别KAT6A靶基因 获得真皮成纤维细胞系，并产生功能基因组数据，如RNA-SEQ和CHIP-SEQ。 这些数据将被整合，以识别高优先级的目标基因，并在人类细胞系中进行功能验证。 目标2将解决孟德尔病突变影响潜在基因表达的假设 常见病(即自身免疫性疾病、自闭症)，从而改变常见病的风险。 将进行神经认知、行为和发育表型分析，以量化共存的共同 疾病表型，并将与个体功能基因组数据和疾病特定的GWAs相结合。 这些研究的发现将提高我们解释孟德尔基因突变对 单个个体内的常见疾病基因座，因此在孟德尔和普通之间提供了关键的联系 疾病。在这样做的过程中，我们将推进关于孟德尔病的精准医学方法， 确定合理的基因靶点的最终目标是用来确定这些罕见疾病的未来治疗方法 条件。

PROJECT SUMMARY/ABSTRACT Individualized diagnosis and treatment based on the integration of clinical, genomic, epigenetic and other biomarkers represent the promise of precision medicine. While most precision medicine initiatives are geared towards cancer treatment and common disease, which affect more than 5% of the population, this proposal seeks to bring the goals of precision medicine to those affected by rare Mendelian genetic diseases. The goal of my research group is to unravel the relationships between Mendelian and common disease through the lens of rare Mendelian syndromes. Our overarching approach will integrate multiple functional genomic studies (RNA-seq and ChIP-seq) from patients with rare Mendelian syndromes to publically available genome wide association study (GWAS) data. Using these data, we will achieve the parallel objectives of 1) revealing the underlying biological mechanisms of rare disease and 2) their intersection with genetic loci associated with common diseases. We will focus our study on the novel genetic syndrome of global developmental delay that we first identified as caused by de novo mutations in KAT6A (Lysine (K) acetyltransferase 6A). KAT6A belongs to a family of acetyltransferase genes and one of its main functions is to modify histones and control the expression of a wide set of downstream genes. In Aim 1, we will identify KAT6A target genes using patient- derived dermal fibroblast cell lines and generate functional genomic data such as RNA-seq and ChIP-seq. These data will be integrated to identify high priority target genes and functionally validated in human cell lines. Aim 2 will address the hypothesis that Mendelian disease mutations affect expression of genes underlying common disease (i.e. autoimmune disease, autism) thereby altering the risk of common disease. Neurocognitive, behavioral and developmental phenotyping will be performed to quantify co-existing common disease phenotypes and will be integrated with individual functional genomic data and disease-specific GWAS. Findings from these studies will advance our ability to interpret the influence of Mendelian gene mutations on common disease loci within a single individual, thus providing a critical link between Mendelian and common disease. In doing so, we will advance precision medicine approaches with respect to Mendelian disease, with the ultimate goal of identifying rational gene targets to use in identification of future therapies for these rare conditions.