Noncoding mutations in neurodevelopmental disorders

项目摘要 神经发育障碍（NDD）影响>1%的人口，并且由多种神经发育障碍组成。 表型包括自闭症、智力残疾和其他发育迟缓。在过去 十年来，在了解稀有蛋白质的贡献方面取得了相当大的进展， NDD中的编码变体。然而，罕见的非编码变异的作用一直不太清楚， 到有限数量的个人与全基因组测序（WGS）数据之前， available.我们是第一批鉴定启动子和增强子聚集富集的人之一 在WGS评估的前516个家庭中;现在已经被多个其他家庭看到的信号 组目前，我们已经分析了约2,700个自闭症家庭，并确定了一个 顶级增强剂在拟议研究的目标1中，我们将扩展这项工作，分析10，719个家庭 用NDD鉴定特定的非编码区，使用统计学检验鉴定富集 基于序列上下文（fitDNM）、变体的富集聚类（GRUMP），以及 传递不平衡检验。我们将执行大规模并行报告 分析（MPRA）以追踪富集元件中的特定非编码变体，并将联合收割机 这与使用现有和新的参考基因组（ACES）进行的深入系统发育评估有关。我们 最近的研究表明，剂量敏感性是一个重要的特点，考虑时， 测试用于富集NDD的特异性启动子和增强子。在目标2中，我们将构建一个副本 来自普通疾病中心的92，081名没有NDD的个体的数字地图 基因组数据集。我们将专门评估1，327，879个非编码调控区， 人类基因组的剂量敏感性。如目标1所述，我们将采用以下方法跟进已确定的要素： MPRA和我们的ACES系统发育检查。拟议研究的主要目标是改善 我们对非编码变异的理解我们将通过1）识别非编码 具有NDD变异富集的调控区和2）发展剂量敏感性 非编码调控区的图谱，为NDD研究提供信息。这一独特的建议，其 镜像目标，侧重于非编码变异，而不是大多数NDD侧重于蛋白质- 编码区域，并在大型高质量WGS数据集中测试剂量。这项工作将是不可或缺的 NDD的遗传理解和非编码变异的后果。它还将 提供了关键的见解，他们的作用，在整体遗传结构的NDD。

PROJECT SUMMARY Neurodevelopmental disorders (NDDs) affect >1% of the population and are comprised of multiple phenotypes including autism, intellectual disability, and other developmental delays. Over the last ten years, there has been considerable progress in understand the contribution of rare protein- coding variants in NDDs. However, the role of rare noncoding variation has been less clear due to the limited number of individuals with whole-genome sequencing (WGS) data previously available. We were one of the first to identify aggregate enrichment for promoters and enhancers in the first 516 families assessed by WGS; signals that have now been seen by multiple additional groups. Currently, we have analyzed ~2,700 families with autism and identified enrichment in a top enhancer. In Aim 1 of proposed studies we will expand this work to analyze 10,719 families with NDDs to identify specific noncoding regions using statistical tests to identify enrichment based on sequence context (fitDNM), enriched clustering of variants (GRUMP), and a transmission-disequilibrium based test, respectively. We will perform massively parallel reporter assays (MPRA) to follow up specific noncoding variants in the enriched elements and combine this with deep phylogenetic assessment using existing and new reference genomes (ACES). Our recent work suggests that dosage sensitivity is an important characteristic to consider when testing specific promoters and enhancers for enrichment in NDDs. In Aim 2, we will build a copy number map from 92,081 individuals, without NDDs, from the Centers for Common Disease Genomics dataset. We will specifically assess 1,327,879 noncoding regulatory regions for dosage-sensitivity in the human genome. As in Aim 1, we will follow up identified elements using MPRA and our ACES phylogenetic workup. The primary goal of proposed studies is to improve our understanding of noncoding variants in NDDs. We will do this by 1) identifying noncoding regulatory regions with enrichment of variation in NDDs and 2) developing a dosage sensitivity map of noncoding regulatory regions to inform studies of NDDs. This unique proposal, with its mirrored aims, focuses on noncoding variation as opposed to the majority NDD focus on protein- coding regions and it tests dosage in a large high-quality WGS dataset. This work will be integral to the genetic understanding of NDDs and the consequences of noncoding variation. It will also provide key insights into their role in the overall genetic architecture of NDDs.