Date of Award

Spring 2019

Degree Type



Biological Sciences

Director of Thesis

Dr. Sofia Lizarraga

Second Reader

Dr. Katherine Kathrein


Autism spectrum disorders (ASD) are associated with defects in neuronal connectivity and are highly heritable. A significant proportion of ASD cases are of complex genetic etiology; complexity which might reflect the impact of gene-environment interactions. However, there is a gap in our understanding of the mechanisms that underlie the gene-environment interaction in autism complex etiology. Genome wide association studies in large ASD cohorts identified high risk variants associated with autism in genes that regulate histone modifications and remodel chromatin. These findings highlight the relevance of chromatin regulatory mechanisms in the pathology of ASD. Changes in Histone H3 methylation have been identified in a subset of neuronal genes in postmortem cerebral cortex of autism patients. ASH1L is a histone H3-methyltransferase that was previously identified in whole exome sequencing studies, as a gene strongly enriched for variants likely to increase ASD risk. However, the role of ASH1L during human neurodevelopment is not well understood on a cellular or molecular basis. To investigate ASH1L during human brain development, I analyzed developmental transcriptome data collected from donated post-mortem human brain tissue; tissues that was processed in the Allen Brain Atlas. My analysis suggests that ASH1L is active during early prenatal development, along with other genes important to chromatin modification. Furthermore, I find that co-expression network analysis implicates ASH1L in a cluster of genes important to the development of neuronal projections, protein ubiquitination, and neurotrophin signaling pathways. This analysis supports cellular and molecular phenotypes seen in ASH1L knockdown studies performed in human-induced neurons. Through these analyses, ASH1L is shown to be important both in early neurodevelopment, and to be strongly associated with ASD pathology.

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