White matter tracts are understudied brain regions with respect to the pathophysiology of autism spectrum disorder (ASD). Most molecular and genomics research into the etiology of ASD has focused on neurons and the gray matter in which most neurons reside. This neuron-centric approach has potentially missed the important contributions of white matter abnormalities to ASD etiology and progression.

In this project, Genevieve Konopka and colleagues propose to provide data on white matter tracts with a focus on changes in ASD. Her lab aims to generate single-cell specific multi-omic datasets from white matter tracts in brain tissue from neurotypical individuals and those with ASD. They will analyze single-cell expression and chromatin profiles from the corpus callosum (genu, body and splenium), internal capsule, superior longitudinal fasciculus and white matter of the cerebellum.

Konopka and her team hypothesize that gene expression and epigenetic changes in white matter cell-types will predict differences between ASD and controls. They will assess the following cell-type specific measures in three aims: (1) profile single-cell level transcriptional maps and chromatin states of white matter in a cohort of ASD and control postmortem brain samples from the Autism BrainNet collection, (2) integrate cell-type multi-omic data with whole-genome sequencing (WGS) data and clinical information and (3) assess white matter integrity of ASD brain tissue using immunohistochemical methods.

The multi-omic datasets collected from this study are expected to provide unique insights into mechanisms driving ASD-specific gene expression and chromatin accessibility in non-neurons on a large scale and how selective cell mechanisms underlie white matter tracts at risk in ASD.