Males are four times as likely as females to be diagnosed with autism, and females require significantly more autosomal genetic risk to manifest autism. This project investigates the hypothesis that these sex biases are a consequence of differences between the second sex chromosome in humans – ChrY in XY males and the “inactive X” (Xi) in XX females. Many Xi and Y-expressed genes are broadly expressed regulators of core biological processes that have been linked to autism, implying that they play key roles in regulating autism-relevant genes and pathways. Sex differential expression of Xi and Y genes could reduce female susceptibility (and heighten male susceptibility) to autosomal, autism-associated variation.

To understand Xi vs Y effects, this project utilizes the sex chromosome aneuploidy (SCA) platform, consisting of cells from individuals with one to four X chromosomes and zero to four Y chromosomes. First, Xi and Y effects will be studied at the epigenomic level by cataloging changes in chromatin conformation and histone modifications influenced by Xi and Y dosage. Second, the SCA platform will be applied to brain-relevant models, by generating iPSCs and then deriving microglia, neurons, and astrocytes with varying ChrY copy number. The consequences for genome-wide gene regulation and cell function will be investigated in vitro for all three cell types. Third, a specific X-Y gene pair – ZFX/ZFY – encoding transcription factors that have a significant impact on autosomal gene expression will be studied by knocking out their function and investigating their DNA binding sites in iPSC-derived microglia and neurons. Fourth, all of these learnings will be combined and synthesized with two decades of research into the genetic architecture of autism, yielding deep insights into the origins of the male bias in autism.