Modeling neuronal consequences of autism-associated gene regulatory variants with human induced pluripotent stem cells

Abstract

Genetic factors contribute to the development of autism spectrum disorder (ASD), and although non-protein-coding regions of the genome are being increasingly implicated in ASD, the functional consequences of these variants remain largely uncharacterized. Induced pluripotent stem cells (iPSCs) enable the production of personalized neurons that are genetically matched to people with ASD and can therefore be used to directly test the effects of genomic variation on neuronal gene expression, synapse function, and connectivity. The combined use of human pluripotent stem cells with genome editing to introduce or correct specific variants has proved to be a powerful approach for exploring the functional consequences of ASD-associated variants in protein-coding genes and, more recently, long non-coding RNAs (lncRNAs). Here, we review recent studies that implicate lncRNAs, other non-coding mutations, and regulatory variants in ASD susceptibility. We also discuss experimental design considerations for using iPSCs and genome editing to study the role of the non-protein-coding genome in ASD.

Fig. 1

Graphical summary of how hPSC-derived neurons can be used to model the functional consequences of ASD-associated non-coding variants. WGS will identify de novo variants in people with ASD (*), which will then be mapped to specific locations in the genome. Genomic loci are annotated as functional elements based on transcriptomics, chromatin state analyses, and computation predictions. ASD-associated variants can be modeled using personalized iPSCs from people with ASD or by genome editing to introduce or repair ASD-associated variants. hPSC-derived neurons are then made by directed differentiation (via a NPC stage) or direct conversion, and functional consequences of non-coding variants are determined by analyzing gene expression and connectivity