An Atlas of Human Brain Cell Variation

项目摘要/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 个体间变异的生物医学和文化重要性，但我们对其潜在原因知之甚少 细胞和分子底物。在这项工作中，我们将利用单细胞和空间领域的新技术 基因组学构建人脑细胞变异图谱。我们将分析来自更多的数千万个细胞 单核rna-seq和单核atac-seq的200多人，以及其中的一个子集的空间分布 转录学。对这些数据的分析将试图理解：静态与动态分子和空间 每种细胞类型的特征；人类遗传变异如何塑造每种细胞的分子谱系 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 大脑。我们特别试图通过这项工作来理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；以及(Iii)在数百项神经成像研究中测量到的大脑结构变异。该项目将 提供细胞、分子、遗传和翻译神经科学的基本数据资源-同时 扩大了我们对人脑在不同人之间变化方式的理解。

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.