An Atlas of Human Brain Cell Variation

项目总结/摘要 人类大脑在生物功能和对疾病的脆弱性方面表现出深刻的多样性。尽管 尽管我们对个体间变异的生物医学和文化重要性了解甚少，但我们对其潜在的 细胞和分子基质。在这项工作中，我们将利用新技术，在单细胞和空间 基因组学来构建人脑细胞变异图谱。我们将分析数千万个细胞， 200多人通过单核RNA-seq和单核ATAC-seq，其中一个子集通过空间 转录组学对这些数据的分析将试图理解：静态与动态的分子和空间 每种细胞类型的特征;人类遗传变异塑造每种细胞类型分子库的方式 细胞类型;以及共同变化的细胞和分子特征的星座，一起出现在同一个细胞中。 大脑我们特别希望通过这项工作来了解这些表型之间的功能联系 以及：（i）驱动和塑造它的基因调控过程;（ii）与大脑相关的遗传变异 疾病;（iii）在数百项神经影像学研究中测量的大脑结构变化。该项目将 为细胞、分子、遗传和转化神经科学提供必要的数据资源， 扩展了我们对人类大脑在不同人之间的差异的理解。

PROJECT SUMMARY/ABSTRACT The human brain exhibits profound diversity in biological function and vulnerability to disease. Despite the biomedical and cultural importance of inter-individual variation, we know relatively little about its underlying cellular and molecular substrates. In this work we will leverage new technologies in single-cell and spatial genomics to construct an Atlas of Human Brain Cell Variation. We will analyze tens of millions of cells from more than 200 people by single-nucleus RNA-seq and single-nucleus ATAC-seq, and a subset of these by spatial transcriptomics. Analysis of these data will seek to understand: the static versus dynamic molecular and spatial features of each cell type; the ways in which human genetic variation shapes the molecular repertoire of each cell type; and the constellations of cellular and molecular features that co-vary, appearing together in the same brains. We seek especially with this work to understand the functional connections between these phenotypes and: (i) the gene regulatory processes that drive and shape it; (ii) genetic variation associated with brain diseases; and (iii) structural brain variation measured in hundreds of neuroimaging studies. The project will deliver an essential data resource for cellular, molecular, genetic and translational neuroscience – while expanding our understanding of the ways the human brain varies across different people.