1/2 Cell Type and Region-Specific Regulatory Networks in Human Brain Development and Disorders

摘要 遗传学和基因组学的最新进展已经确定了数百种编码变体，它们增加了罹患癌症的风险 主要的神经精神障碍，如自闭症谱系障碍。努力澄清非编码的贡献 变种也在进行中，预计在未来几年内将迅速加速。虽然这些进步 大大提高了我们对遗传景观神经精神障碍的理解，更深层次地 对分子病理生理学的了解仍然很少。这种知识差距在一定程度上是由于 涉及的风险基因的异质性，它们在调节大量基因表达方面的潜在作用， 风险基因的多效性，以及神经精神障碍由功能障碍引起的可能性很高 涉及多种细胞类型和大脑区域的电路，共同使分子和 一种疾病的细胞机制有问题，特别是在旷日持久和复杂的 大脑发育的本质。因此，全光谱功能的发现和表征 人类大脑中活跃的基因组元件，以及它们在整个大脑中的活动/表达模式 时空维度，对于澄清何时、何地以及哪些单元类型与 神经精神障碍的病因和治疗。这在非编码的上下文中尤其如此 很难注解的变体，但有可能提供高度特定的空间， 特定于时间和细胞类型的信息。为了解决这一知识鸿沟并继续我们的贡献 对于心理编码联盟，我们提出了四个特定的目标来识别基因调控和细胞类型- 人类神经发育的特定机制。在目标1中，我们确定了以下功能基因组元件 神经典型人类和猕猴的单个细胞(核)、细胞类型、区域和发育时间点 死后大脑。在目标2中，我们绘制了神经典型人类和猕猴的时空蛋白质组图。 死后大脑。在目标3中，我们进行了功能基因组元件的综合鉴定和 病脑和ipsc来源的神经细胞的蛋白质组学。在目标4中，我们将目标1-3的结果整合为 以及神经精神病学人群的独立遗传数据集，以识别非编码元件， 基因，或分子途径，将导致更好地了解潜在的病理生理 神经精神障碍的机制。最后，这些机制的功能特征将在 模型系统。这项提案的数据还将作为关键的新资源，供 社区，他们可以在那里交流他们的结果，并得出更深层次和更有意义的结论， 尤其是在神经精神障碍的基因组数据不断积累的情况下。

ABSTRACT Recent advances in genetics and genomics have identified hundreds of coding variants that increase risk for major neuropsychiatric disorders, such autism spectrum disorder. Work to clarify the contribution of non-coding variants is also underway and is expected to accelerate rapidly in the next few years. While these advances have considerably improved our understanding of the genetic landscape neuropsychiatric disorders, a deeper understanding of molecular pathophysiology is still missing. This knowledge gap is due to, in part, the heterogeneity of risk loci involved, their potential roles in regulating expression of a large number of genes, the pleiotropic nature of risk genes, and the high likelihood that neuropsychiatric disorders result from dysfunctional circuitry involving multiple cell types and brain regions, altogether making the identification of molecular and cellular mechanisms underlying a disease problematic, especially in the context of the protractive and complex nature of brain development. Therefore, the discovery and characterization of the full spectrum of functional genomic elements active in the human brain, as well as their activity/expression patterns across the spatiotemporal dimensions, is essential for clarifying when, where, and what cell types are relevant to the etiology and treatment of neuropsychiatric disorders. This is particularly so in the context of non-coding variants, which are difficult to annotate, yet potentially hold the promise of providing highly specific spatial, temporal, and cell type specific information. To address this knowledge gap and to continue our contributions to the PsychENCODE Consortium, we propose four specific aims that identify gene regulatory and cell type- specific mechanisms of human neurodevelopment. In Aim 1, we identify functional genomic elements across single cells (nuclei), cell types, regions and developmental time points of neurotypical human and macaque postmortem brains. In Aim 2, we map the spatio-temporal proteome of neurotypical human and macaque postmortem brains. In Aim 3, we perform integrative identification of functional genomic elements and proteomics in diseased brains and iPSC-derived neural cells. In Aim 4, we integrate results from Aims 1-3, as well as with independent genetic datasets of neuropsychiatric populations, to identify non-coding elements, genes, or molecular pathways that will lead to a better understanding of the underlying pathophysiological mechanisms of neuropsychiatric disorders. Finally, these mechanisms will be functionally characterized in model systems. Data from this proposal will also serve as a critical new resource for members of the community, with which they can intersect their results and draw deeper and more meaningful conclusions, especially as the wealth of genomic data from neuropsychiatric disorders continues to accumulate.