Identification and impact of somatic mutations in regulatory regions in autism brain

  • Awarded: 2022
  • Award Type: Targeted: Autism BrainNet Analysis
  • Award #: 953759

Autism spectrum disorder (ASD) has a large genetic component, but the underlying cause of ASD has not been identified in most affected individuals. A previous study has shown that postmortem brain tissue from both ASD and neurotypical individuals have higher rates of somatic mutations in accessible chromatin and enhancer regions in general but that ASD brain samples exhibit higher somatic mutation rates in enhancers that are likely specifically active in brain1. The mechanisms behind this preferential mutation of neural enhancers are unknown.

Dividing cells accumulate somatic mutations during the course of development, and in non-brain cells this process can potentially be shaped by exogeneous or environmental factors. A recent study found that postmortem cortical tissue from individuals previously diagnosed with schizophrenia contained higher rates of congenital somatic mutations than neurotypical samples2, with this difference apparently reflecting an undefined maternal or prenatal mutagenic process that preferentially affects transcription factor binding sites. The same study also looked at ASD samples, with the findings appearing to suggest that ASD brains may share this mutagenic process.

Christopher A. Walsh and Peter Park aim to study high-coverage whole-genome sequencing on purified cortical neurons from postmortem brains of individuals with ASD to characterize somatic mutations with greater sensitivity and specificity than previously possible. They also plan to develop high-coverage ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) as an alternative method to study somatic mutations in accessible chromatin at far lower cost. The functional impact of ASD-associated neural enhancer mutations on gene activity will also be explored using in vitro cell models and mouse models.

The identification, characterization and functional analysis of these ASD-associated noncoding variants will help elucidate the contribution of somatic mutations in the pathogenesis of ASD as well as implicate potential mechanistic processes.


1.Rodin R.E. et al. Nat. Neurosci. 24, 176-185 (2021) PubMed
2.Maury E.A. et al. bioRxiv (2022) Preprint
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