Somatic mutation in human cerebellum illustrates neuron type-specific patterns of age-related mutation

Human neurodegenerative disorders are characterized by exquisite specificity for neuronal types, but the basis of this is unknown. Here, we show that cerebellar granule neurons (GN)—the most abundant neuronal type in the human brain—accumulate somatic mutations in patterns highly distinct from cerebral cortical neurons, and more closely resembling oligodendroglia and other dividing cells. We find shared mutational signatures between normal aging GNs and medulloblastoma subtypes, suggesting the GN lineage as a tumor cell of origin. Whole-genome sequence of multiple single GNs from the same donor allowed analysis of specific times of neurogenesis, revealing a rich lineage tree that includes GNs that become postmitotic 2 years or more after birth, yet migrating postnatally to populate both the cerebellar vermis and the distant cerebellar hemisphere. Our results show that neuronal type-specific somatic mutation patterns enlighten normal development, cancer origins and potentially the cell type-specificity of neurodegeneration.