Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Noonan, James

Abstract

Over one hundred risk genes have been identified that, when disrupted, contribute to increased likelihood of an autism diagnosis. Studies have shown that expression of these risk genes converge in co-expression networks in human mid-fetal cortex. However, knowledge of these networks and the neurodevelopmental mechanisms they regulate remains limited. Several studies have focused on one risk gene in particular, the chromatin remodeler CHD8. Decreased CHD8 expression due to a gene disrupting variant is hypothesized to affect autism-associated transcriptional networks in the developing brain, thereby contributing to autism risk. In this work, we used single-cell RNA-sequencing to characterize gene expression during embryonic cortical development in wild type and Chd8+/− mice. I developed a novel analysis pipeline for 1) characterizing gene expression along a primary trajectory of differentiation and 2) identifying groups of genes with convergent transcriptional patterns, termed “metagenes.” I identified metagenes in Chd8+/− and wildtype mouse neocortex and determined that autism risk genes were enriched in metagenes correlated with the Chd8 expression trajectory and CHD8 target genes. I also applied my analysis pipeline to a published human neocortex dataset and found that metagene expression trajectories identified in human neocortex were highly correlated with those identified in the mouse, including conserved autism risk gene trajectories. These findings present an avenue for identifying transcriptional networks and biological pathways implicated in CHD8 haploinsufficiency. Furthermore, the metagene approach provides a biological basis for interpreting the role of additional risk genes in neurodevelopment and autism etiology.

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