C O' Ryan - Bridging the gap: an integrative approach to molecular autism research
Channel: Icgeb
Date: 2023-05-25

Autism spectrum disorder (ASD) is a complex, lifelong condition defined by difficulties in social interaction and communication, and the presence of repetitive behaviours and interests. ASD has a complex genetic architecture. Although there is a wealth of ASD genetic data from American and European populations, African populations are underrepresented. My research focuses on the epigenetics and molecular biology of ASD and uses a multi-disciplinary approach. My group published the first epigenome methylation screen from an autistic population from SA. This epigenome screen identified differentially methylated genes associated with ASD and we found a significant enrichment of mitochondrial metabolic canonical pathways directly linked to ATP production. This mitochondrial dysfunction was supported in our cohort using urinary mitochondrial metabolites and, mitochondrial copy number. We then examined the relationship between methylation and specific mitochondrial compensatory processes in our ASD cohort. We found a link between mitochondrial dysfunction and differential methylation of the promoter of the gene central to mitochondrial biogenesis, as well as other genes involved in mitochondrial biogenesis 
and dynamics. This highlighted an unexplored role for methylation in regulating mitochondrial biogenesis, contributing to mitochondrial dysfunction in ASD. To identify the pathways that crosstalk 
with mitochondrial pathways, we completed an analysis of 19 molecular datasets to identify common pathways that were implicated with ASD. We found that ASD data converged on four biological pathways, namely mitochondrial metabolism, neurogenesis and neuroinflammation. We 
identified key players in specific pathways that are now being experimentally tested in a neuronal cell model system. My current research examines the intersection of mitochondrial metabolism with neuronal cell fate in a cell model system. ASD research spans disparate psychosocial and biomedical disciplines that traditionally work in isolation; however, autism research requires an integrative approach. Molecular research is moving towards a biopsychosocial framework that can be informed by autistic experiences. I will also discuss my group’s approach to trying to integrate autistic experiences within a molecular framework.