Single cell transcriptomic analysis of autism associated gene expression in human cerebral cortex development

Abstract

Autism spectrum disorder (ASD) is a range of developmental brain disorders characterized by poor nonverbal communication skills, impaired behaviour and social interaction, and a limited diversity of social activities and interests. As the most common pervasive developmental disorder, it affects people of all economic backgrounds and races. Although the cause of ASD is still controversial, many studies indicated that genetic factors play an important role in the ASD pathology. It has been shown that there is a remarkable genetic heterogeneity among ASD cases and thousands of genes may be associated with this disorder. The human brain can be separated into different regions in terms of their functions, and these regions are composed of distinct cell types. It has been shown that ASD risk genes are differentially expressed across different brain regions and at different embryonic stages. Some studies also revealed that the mutation of ASD risk genes may affect specific cell types more strongly than others. However, the extent to which ASD risk genes can converge on distinct cell types during human brain development remains unclear. Recently developed single-cell RNA sequencing (scRNA-seq) dramatically advanced our knowledge of the cellular taxonomy of the brain and allowed us to map ASD risk genes or genomic loci onto specific brain cell types. In the present study, I aimed to uncover essential cell types underlying the development of ASD during human prefrontal cortex development by re-analysing a set of published scRNA-seq datasets. I mainly focused upon two sets of candidate ASD risk genes from the SFARI database, including 86 high confidence ASD risk genes (monogenic mutations in ASD) and 30 genes at the 16p11.2 locus (CNV in ASD). We found that distinct sets of ASD risk genes are enriched in neural progenitor cells, excitatory neurons, interneurons and glia cells. Such enrichments were due to cell subtypes within these major cell types having significant differences in ASD risk gene expression. Cell-type based gene network analysis further demonstrated that common signalling pathways and biological processes converged on cell types with enriched expression patterns of ASD risk genes. Through comparative analysis, I further identified conserved and distinct expression patterns of ASD risk genes between human and mouse during brain development. Taken together, this study provides important new insights into the cell typespecific molecular pathology of the ASD. The findings from this study also highlight the conserved and distinct functions of ASD risk genes implicated in the normal brain development between human and mouse.