Divergent somatic mutation patterns among human cerebellar neuron types

Neurons accumulate somatic mutations with age, but how mutation processes vary among neuronal types remains unclear. Characterizing this variability may elucidate the role of genome integrity in brain function and disease and reveal determinants of mutation rates and patterns. Using high-fidelity duplex DNA sequencing, we profiled somatic mutations across the lifespan in human cerebellar Purkinje and granule neurons, which differ markedly in size and physiology. Surprisingly, they exhibited similar substitution rates, including rates of SBS5, the body's predominant mutational signature, whose mechanism is unknown. However, their substitution patterns and insertion/deletion rates and patterns differed, with transcription associated with these differences. In surviving granule neurons from five cerebellar ataxias, we detected only a small disease effect on mutation profiles. Our work indicates that neuronal types can differ in aging-related mutagenesis and that key features distinguishing Purkinje and granule neurons are unlikely, in these neurons, to be major determinants of SBS5 activity.