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异，这些变异增加了 严重的神经精神障碍，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。虽然这些 这些进展极大地提高了我们对神经精神疾病遗传景观的理解， 尽管对疾病的分子病理生理学的更深入的理解仍然缺失。这种知识差距是由于 在某种程度上，涉及的风险基因座的异质性，他们在调节大的表达的潜在作用， 基因的数量，风险基因的多效性，以及神经精神疾病 这是由于涉及多种细胞类型和大脑区域的功能失调的电路， 确定潜在的分子和细胞机制的疾病问题，特别是在 大脑发育的持久性和复杂性的背景。因此，发现和 表征人类大脑中活跃的功能基因组元件的全谱，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，什么样的细胞类型与神经精神疾病的病因和治疗有关。这是 特别是在非编码变体的上下文中，这些变体难以注释，但潜在地保持了 提供高度特异性的空间、时间和细胞类型特异性信息的前景。为了解决这个 知识差距，并继续我们的贡献PsychENCODE联盟，我们提出四个 确定人类神经发育的基因调控和细胞类型特异性机制的特定目标。在 目的1，我们确定跨单细胞（细胞核），细胞类型，区域和 神经典型的人类和猕猴死后大脑的发育时间点。在目标2中，我们绘制了 人类和猕猴死后脑神经元时空蛋白质组。在目标3中， 在患病的脑和iPSC衍生的脑中整合鉴定功能基因组元件和蛋白质组学 神经细胞在目标4中，我们整合了目标1-3的结果，以及独立的遗传数据集， 神经精神病人群，以确定非编码元件，基因，或分子通路，将导致 更好地理解神经精神疾病的潜在病理生理机制。 最后，这些机制将在模型系统的功能特点。本提案中的数据将 也是社区成员的重要新资源，他们可以与他们的 结果，并得出更深入，更有意义的结论，特别是作为丰富的基因组数据， 神经精神疾病继续积累。

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.