2/2 - 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。努力澄清非政府组织的贡献 编码变体也在进行中，预计在未来几年内将迅速加速。而这些 进步极大地提高了我们对遗传格局神经精神病学的理解。 在疾病方面，对分子病理生理学仍缺乏更深层次的了解。这一知识差距是由于 在一定程度上，由于所涉及的风险基因的异质性，它们在调节大分子的表达方面的潜在作用 基因的数量、风险基因的多效性以及神经精神障碍的高可能性 由涉及多种细胞类型和大脑区域的功能失调的电路所致，总共使 识别疾病的分子和细胞机制是有问题的，特别是在 大脑发育的长期性和复杂性的背景。因此，这一发现和 人脑中活跃的功能基因组成分的全谱表征，以及 它们在时空维度上的活动/表达模式，对于澄清何时， 在哪里，什么细胞类型与神经精神障碍的病因和治疗有关。这是 尤其是在非编码变体的上下文中，这些变体很难注释，但可能持有 承诺提供高度特定的空间、时间和细胞类型特定信息。要解决这个问题 知识鸿沟和继续我们对心理编码联盟的贡献，我们提出了四个 确定人类神经发育的基因调控和细胞类型特定机制的特定目标。在……里面 目的1，我们确定了跨单个细胞(核)、细胞类型、区域和 神经型人脑和猕猴死后脑的发育时间点。在目标2中，我们将 神经典型人类和猕猴死后脑的时空蛋白质组。在《目标3》中，我们表演 病脑和IPSC来源的功能基因组元件和蛋白质组学的综合鉴定 神经细胞。在目标4中，我们集成了来自目标1-3的结果，以及与独立的 神经精神病学群体，识别非编码元件、基因或分子途径，将导致 更好地了解神经精神障碍的潜在病理生理机制。 最后，这些机制将在模型系统中进行功能表征。此提案中的数据将 也是社区成员的重要新资源，他们可以用它来交叉他们的 结果，并得出更深层次和更有意义的结论，特别是在来自 神经精神障碍继续累积。

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.