The Human Brain as a Mosaic: Somatic Mutation in Autism Spectrum Disorder, Aging, and Neurodegeneration

Abstract

Post-zygotic mutations to DNA can occur throughout every stage of the human lifespan, such that the human body is truly a mosaic of cells with different genomes. This phenomenon of somatic mosaicism has important implications for health and disease in every organ system, and the role of somatic mutation in the brain is of particular interest given the long lifespans of neurons and the possibility that their genomic integrity could affect brain function, behavior, and diseases of both development and old age. In this thesis I describe my research on the dynamics of somatic mutation in the human brain in autism spectrum disorder (ASD), normal aging, and diseases of premature neurodegeneration. Somatic mutation is hypothesized to play a role in the etiology of ASD, but to date there have been no genome-wide investigations into somatic mutations in ASD brain. In this thesis I present our work studying genome-wide mosaicism in postmortem brain DNA from 61 ASD cases and 15 controls, and show that ASD brains are enriched for clonal somatic mutations in critical regulatory regions of the genome. I also highlight the potential contribution of large mosaic structural variants to ASD risk, reporting on a pathogenic mosaic rearrangement on chromosome 2 of an ASD patient. Additionally, it has long been hypothesized that DNA damage and subsequent somatic mutation are associated with neurological aging and neurodegeneration; however, methodological hurdles have prevented testing this hypothesis. Here, I describe our work on genome-wide single-nucleotide variant identification in 143 single neurons from the prefrontal cortex and hippocampal dentate gyrus of eleven normal individuals aged 4 months to 82 years and nine individuals with early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome, CS or Xeroderma pigmentosum, XP). We show for the first time that single neurons in the prefrontal cortex and dentate gyrus accumulate somatic mutations during life, with a greater rate of accumulation in the dentate gyrus. Further, mutation counts in CS and XP neurons greatly exceed those in age-matched controls. The existence of distinct mutational profiles implies diverse mechanisms of neuronal mutation accumulation in development, normal aging, and degenerative disease.