Single-cell analysis of prenatal and postnatal human cortical development

Human cortical development involves birth, differentiation and maturation of a multitude of cellular lineages over the course of prenatal and postnatal life. Single-cell genomics provided insight into the molecular changes that underlie the development of early cortical lineages but has mostly been applied to the second trimester of prenatal human cortical development. Here, we utilize single-nucleus RNA sequencing to capture the development of the main human cortical lineages across prenatal and postnatal stages until adulthood and generate a comprehensive single-cell transcriptomic atlas of human cortical development. We collected more than 350,000 single-nucleus RNA-seq profiles from 108 tissue samples from 60 donors representing the second and third trimester of gestation, as well as neonatal, early and late postnatal stages of development. We identify lineage-specific developmental programs that underlie the development of specific subtypes of excitatory cortical neurons, interneurons, glial cell types and brain vasculature. Moreover, we discover sex- and region-specific developmental changes in each of these lineages. By intersecting our results with genetic risk factors for autism, we identify the cortical cell types and lineages most vulnerable to genetic insults that cause autism. We show that lineage-specific gene expression programs upregulated in female cells are especially enriched for the genetic risk factors of autism. Since these genes are expressed at lower levels in males during development, they may be more susceptible to heterozygous loss of function in ASD, providing a basis for the increased male to female ratio of autism incidence. ### Competing Interest Statement The authors have declared no competing interest.