16p11.2 microdeletion enhances gene expression variability between human IPSC-derived forebrain interneuron...

The 574-kilobase pair 16p11.2 microdeletion raises a person's odds for neurodevelopmental and energy balance conditions, particularly autism and obesity, with considerable clinical heterogeneity, and how much this reflects genetic versus environmental or stochastic factors is unclear. GABAergic forebrain interneurons originate from progenitors residing in the ventricular zones of the fetal ventral telencephalon, and their perturbation is implicated in 16p11.2 phenotypes, prompting investigation of how the 16p11.2 microdeletion impacts their development. Here we studied human-induced pluripotent stem cell (IPSC) derived ventral telencephalic interneuron progenitors in two-dimensional culture, comparing IPSCs isogenic except for a heterozygous 16p11.2 microdeletion to minimize confounding effects of genetic background. Single-cell RNA sequencing generated single-cell transcriptome populations for comparative bioinformatics, revealing hundreds of differentially expressed transcripts, many associated with cell signaling, chromatin biology, and neurodevelopmental conditions. Pertinently, we find that transcript level variation is significantly greater between 16p11.2 heterozygous progenitors than their isogenic wild type counterparts both for sets of genes comprising regulons, gene-sets functionally connected by transcription factor regulation, and for randomly selected gene sets. This indicates that the 16p11.2 locus itself has a genome-wide property in stabilizing transcription between cells. Regulons with the greatest increased variability in 16p11.2 heterozygous progenitors exhibit strong enrichment for cell cycle-related genes, and many are regulated by transcription factors themselves associated with autism and/or obesity, suggesting the hypothesis that enhanced transcriptional variation contributes to 16p11.2 microdeletion phenotypes.