1/2-Somatic mosaicism and autism spectrum disorder

项目摘要 体细胞突变是受精后发生的从头突变。一旦细胞获得了 体细胞突变，其所有祖先也将携带该突变。因此，如果细胞在早期获得突变 在胚胎发育过程中，突变会被体内的许多细胞携带。然而，如果突变 发生在发育后期，那么只有几个细胞可能携带它。因此，突变只有可能是 发生在大脑中，或大脑的一小部分。人们早就知道，体细胞突变可以 致癌，最近的研究表明，体细胞突变与神经发育有关 类似于自闭症谱系障碍(ASDS)的疾病，就其高从头突变率和 关于他们的相关症状，如智力残疾和癫痫。 我们假设体细胞突变是导致(ASDS)的一个重要原因，因为 与ASD相关的从头突变的比率，某些已知的基因的体细胞突变的重要性 引起自闭症，以及体细胞突变在其他具有特征的发育性大脑疾病中的重要性 与自闭症重叠。技术和资源的限制阻碍了对联合国系统的作用的研究 多亏了下一代测序(NGS)，ASD的体细胞突变现在已经被克服了 允许对基因及其转录本进行深度测序，并能够分析每个序列，以及2] 组织库收集了患有自闭症的人的大脑样本。 在这个协作的UO1中，我们将使用互补的方法来系统地识别和 与ASD相关的体细胞脑突变的功能特征。致病的体细胞突变 在ASD大脑中被确认，我们将使用我们实验室开发的技术来检查单个脑细胞 存在体细胞突变。这将为我们提供大脑的哪些区域和细胞的地图 大脑中的不同类型携带着这些体细胞突变。我们还将对ASD进行建模和功能描述- 诱导多能细胞和小鼠的相关脑部突变。 这项研究可以通过评估躯体疾病的患病率来提高ASD的基因诊断水平 突变是ASD的原因，2]提供了一种可能适用于其他复杂神经精神疾病的范例 疾病(如精神分裂症)，以及3]通过以下方式提高我们对ASD潜在机制的理解 创建一张涉及自闭症的脑区和细胞类型的地图。

Project Summary Somatic mutations are de novo mutations that occur after fertilization. Once a cell has acquired a somatic mutation, all of its progenitors will also carry that mutation. Thus, if a cell acquires a mutation early in embryonic development, the mutation will be carried by many of the cells in the body. However, if the mutation occurs late in development, then only a few cells might carry it. Thus, it is possible to have mutations that only occur in the brain, or a small region of the brain. It has been known for a while that somatic mutations can cause cancer, and recent studies are showing that somatic mutations are associated with neurodevelopmental disorders resembling autism spectrum disorders (ASDs) both in terms of their high de novo mutation rate and in terms of their associated symptoms such as intellectual disability and epilepsy. We hypothesize that somatic mutations represent a significant cause of (ASDs) because of the high rate of de novo mutations associated with ASDs, the importance of somatic mutations in some genes known to cause ASDs, and the importance of somatic mutations in other developmental brain disorders with features that overlap ASDs. The technical and resource limitations that had prevented a systematic study of the role of somatic mutations in ASDs have now been overcome thanks to 1] Next-Generation Sequencing (NGS), which allows for the deep sequencing of genes and their transcripts with the ability to analyze each sequence, and 2] tissue banks that have collected brain specimens from individuals who had ASD. In this collaborative UO1 we will employ complementary approaches to systematically identify and functionally characterize somatic brain mutations associated with ASD. For causative somatic mutations identified in ASD brain, we will use techniques developed in our labs to examine individual brain cells for the presence of somatic mutation. This will provide us with a map of what regions of the brain, and what cells types in the brain carry these somatic mutations. We will also model and functionally characterize ASD- associated brain mutations in induced pluripotent cells and mice. This study could 1] improve the genetic diagnosis of ASD; by assessing the prevalence of somatic mutations as a cause of ASD, 2] provide a paradigm that may apply to other complex neuropsychiatric diseases (such as schizophrenia), and 3] improve our understanding of the mechanisms underlying ASD by creating a map of brain regions and cell types involved in ASD.