Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions

Interindividual variation in phenotypic penetrance and severity is found in many neurodevelopmental conditions, including the autosomal aneuploidy Trisomy 21 (T21). However, mechanisms underlying such variation remain incompletely resolved. Here, we investigate the hypothesis that T21 can drive differential gene variance, not just differential gene expression. Leveraging multiple, independent single-cell and single-nucleus RNA sequencing datasets from human brain-relevant cell and tissue types, we identify a significant increase in transcriptional variance driven by T21 as well as CHD8 haploinsufficiency. Our analyses are consistent with a global and in part stochastic increase in transcriptional variance which is uncoupled from changes in transcript abundance. Highly variable genes tend to be lineage-restricted with modest enrichment for H3K27me3, while least variable genes are more likely to be constrained and associate with active histone marks. Our results show that neurodevelopmental conditions can drive increased transcriptional variance in brain cell types, and provide a scaffold for understanding variance in disease. Single cell RNA sequencing of neural progenitor cells derived from human iPSCs