1/2-Somatic mosaicism and autism spectrum disorder

 描述(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，它的所有祖先也将携带该突变。因此，如果细胞在胚胎发育早期获得突变，体内的许多细胞都会携带突变。然而，如果突变发生在发育后期，那么可能只有几个细胞携带它。因此，突变只有可能是 发生在大脑中，或大脑的一小部分。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(ASDS)的神经发育障碍有关，这既是因为它们的高从头突变率，也是因为它们的相关症状，如智力残疾和癫痫。我们假设体细胞突变是ASDS的一个重要原因，因为与ASD相关的从头突变的比率很高，一些已知导致ASD的基因中体细胞突变的重要性，以及体细胞突变在其他发育性大脑疾病中的重要性，这些疾病的特征与ASD重叠。由于1)下一代测序技术(NGS)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)组织银行收集了自闭症患者的脑组织样本，因此阻碍了对自闭症患者体细胞突变作用的系统研究的技术和资源限制现已被克服。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功能表征与ASD相关的体细胞脑突变。对于在ASD大脑中发现的致病体细胞突变，我们将使用我们实验室开发的技术来检查单个脑细胞是否存在体细胞突变。这将为我们提供大脑的哪些区域，以及大脑中哪些细胞类型携带这些体细胞突变的地图。我们还将在诱导的多能细胞和小鼠中建立模型并对ASD相关的脑突变进行功能表征。这项研究可以1)改进ASD的基因诊断；通过评估作为ASD原因的体细胞突变的流行率，2)提供一个可能适用于其他复杂的神经精神疾病(如精神分裂症)的范例，以及3)通过创建ASD所涉及的大脑区域和细胞类型的地图，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.