1/2-Somatic mosaicism and autism spectrum disorder

 描述（由申请人提供）：体细胞突变是受精后发生的从头突变。一旦一个细胞获得了体细胞突变，它的所有祖细胞也将携带该突变。因此，如果一个细胞在胚胎发育的早期获得突变，该突变将由体内的许多细胞携带。然而，如果突变发生在发育后期，那么只有少数细胞可能携带它。 发生在大脑或大脑的一个小区域。众所周知，体细胞突变会导致癌症，最近的研究表明，体细胞突变与类似自闭症谱系障碍（ASD）的神经发育障碍有关，无论是在其高从头突变率方面，还是在其相关症状方面，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，因为与ASD相关的新生突变率很高，体细胞突变在一些已知导致ASD的基因中的重要性，以及体细胞突变在其他具有与ASD重叠特征的发育性脑疾病中的重要性。由于1]下一代测序（NGS），其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]从患有ASD的个体收集脑标本的组织库，已经克服了阻止系统研究体细胞突变在ASD中的作用的技术和资源限制。 在这个合作的UO 1中，我们将采用互补的方法来系统地识别和功能表征与ASD相关的体细胞脑突变。对于ASD大脑中鉴定的致病性体细胞突变，我们将使用我们实验室开发的技术来检查个体脑细胞是否存在体细胞突变。这将为我们提供一个大脑区域的地图，以及大脑中哪些细胞类型携带这些体细胞突变。我们还将在诱导多能细胞和小鼠中模拟和功能表征ASD相关的脑突变。 这项研究可以1]改善ASD的遗传诊断;通过评估体细胞突变作为ASD原因的患病率，2]提供可能适用于其他复杂神经精神疾病（如精神分裂症）的范例，3]通过创建ASD涉及的脑区和细胞类型的地图，提高我们对ASD潜在机制的理解。

 DESCRIPTION (provided by applicant): 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.