Transcriptional Regulators in Normal Human Brain Development and Autism
- Author(s): Parikshak, Neelroop
- Advisor(s): Geschwind, Daniel H
- et al.
Autism spectrum disorder (ASD) is a group of etiologically and phenotypically heterogeneous neurodevelopmental disorders defined by deficits in social communications and mental flexibility. It is established that variation in hundreds of genetic loci contributes substantially to ASD risk. This has raised the question of whether these mutations, which are found across disparate genes, affect similar biological pathways, perturb brain development at a particular time point, or disrupt a specific brain system. Addressing this is critical to develop a molecular and neurobiological understanding of ASD. However, searching for such convergence is made challenging by the genetic complexity of ASD and the molecular, cellular, and circuit-level complexity of the brain. Here, I apply comprehensive profiling of RNA levels (the transcriptome) by RNA sequencing (RNA-seq) to characterize the role of genes in normal human brain development and ASD. My overarching hypothesis is that there exist molecular regulators of transcription which are particularly susceptible to mutations in ASD, and that their regulatory targets are affected in ASD brain. My general approach is to organize the hundreds to thousands of disparate changes in transcript levels into more tractable and biologically meaningful gene sets or modules that are differentially expressed, co-expressed, or co-regulated. I then integrate these gene sets or modules with molecular and phenotypic information from whole genome studies and targeted experimental studies in order to systematically reveal new insights about ASD neurobiology and highlight specific genes and pathways worth investigating further. I first assess the role of ASD risk genes in normal brain development and then apply RNA-seq to measure transcriptomic changes in postmortem ASD brain to evaluate whether convergent neurobiological pathways are affected. I find robust evidence that developmentally co-expressed, co-regulated, and physically interacting genes are affected in ASD during normal brain development. Rare, highly deleterious variants predominantly exert their effect by disrupting major transcriptional and chromatin regulators in early fetal development, while less deleterious inherited variants affect late prenatal and early postnatal cellular and circuit maturation through alterations in synaptic function. Additionally, across most individuals with ASD, I find strongly shared changes in synaptic and neuronal genes at both a gene expression and transcript splicing level in cortex. Moreover, shared cortical changes are also seen in a genetically defined subtype of autism, duplication 15q syndrome (dup15q). In contrast, ASD-associated changes in cerebellum are weaker. Co-expression network analysis identifies specific cell types and circuits that are affected, and highlights specific transcriptional regulators likely to play a role in ASD pathology. Taken together, these results identify roles for transcriptional regulators in ASD and define the potential consequences of their dysregulation.