Haploinsufficiency describes a case in which one of two copies of a gene is mutated and the remaining copy is insufficient to maintain normal function; this mechanism is likely acting in many cases of de novo mutations occurring in autism spectrum disorder (ASD). In the current project, Daniel Geschwind’s team aims to utilize enhancer-targeting gene activation methods to correct the effect of these mutations; stem cell–derived cortical spheroids will be used to comprehensively visualize the development of neuronal subtypes at the cellular and molecular level. This study will enhance our understanding of how haploinsufficiency in ASD genes impacts neuronal development and provide a proof-of-principle for gene activation as a therapeutic intervention.

In the current project, Omer Bayraktar, in collaboration with Tomasz Nowakowski, plans to generate a spatio-temporal autism gene expression (STAGE) resource where intact human brain tissue will be surveyed using a new spatial transcriptomic methodology. The primary focus will be on validating the expression of autism risk genes in cortical subplate neurons across brain development.

The discovery of rare genetic variants in individuals with autism spectrum disorders (ASD) has led to the identification of nearly 100 high-confidence ASD risk genes. What is currently missing is clear convergent pathways linking the proteins encoded by these genes at the molecular level. In this project, Paul Jenkins’ team plans to study the interaction of two proteins encoded by the ASD risk genes ANK2 and SCN2A to understand how they work together to control neuronal signaling during development.

The abundance of mutations in chromatin regulatory proteins in ASDs highlights the significance of chromatin structure in brain development. Kavitha Sarma and colleagues plan to study whether RNA-containing chromatin structures called R-loops are molecular drivers of deregulated gene expression in ASDs. They will also test the possibility of targeting R-loops for future therapy in ASDs.

How autism-associated genes are differentially spliced during brain development remains largely unknown. Xiaochang Zhang aims to combine single cell RNA-seq with long-read sequencing to investigate cell-type-specific mRNA isoforms that are expressed during neocortical development. He plans to apply this knowledge to the interpretation of mutations associated with autism risk, leading to a better understanding of how gene expression and development may be affected in autism.