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，它所有的祖先也将携带突变。因此，如果一个细胞在早期获得突变， 在胚胎发育过程中，突变将由体内的许多细胞携带。然而，如果突变 在发育后期发生，那么只有少数细胞可能携带它。因此，有可能发生突变， 发生在大脑或大脑的一个小区域。一段时间以来，人们已经知道体细胞突变可以 导致癌症，最近的研究表明，体细胞突变与神经发育有关， 与自闭症谱系障碍（ASD）相似的疾病，既有高的从头突变率， 就其相关症状而言，如智力残疾和癫痫。 我们假设体细胞突变是ASD的一个重要原因， 与ASD相关的新生突变率，一些已知基因中的体细胞突变的重要性， 导致ASD，以及体细胞突变在其他发育性脑疾病中的重要性， 与自闭症重叠由于技术和资源方面的限制，无法系统地研究 由于下一代测序（NGS），ASD中的体细胞突变现在已经被克服， 允许对基因及其转录物进行深度测序，并具有分析每个序列的能力，以及2] 组织库收集了自闭症患者的大脑标本。 在这一合作性的UO 1中，我们将采用互补的方法，系统地确定和 在功能上表征与ASD相关的体细胞脑突变。对于致病性体细胞突变 在ASD大脑中识别，我们将使用我们实验室开发的技术来检查单个脑细胞， 体细胞突变的存在。这将为我们提供一个大脑区域的地图， 大脑中的类型携带这些体细胞突变。我们还将对ASD进行建模和功能表征- 在诱导多能细胞和小鼠中发现相关的脑突变。 这项研究可以1]通过评估体细胞遗传缺陷的患病率， 突变作为ASD的原因，2]提供了一个范例，可能适用于其他复杂的神经精神疾病 疾病（如精神分裂症），和3]提高我们对ASD潜在机制的理解， 绘制了ASD相关的大脑区域和细胞类型的地图。

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.