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.

PROJECT NARRATIVE The focus of our project is to understand how the cells of the human brain vary from person to person, in the genes they use, and in how they are spatially organized within brain tissue. Through a detailed study of this variation, we seek to deepen our understanding of how the human brain works, and uncover the cellular and molecular basis for vulnerability to neurodevelopmental, neuropsychiatric, and neurological disorders.