The complete genome sequences, unique mutational spectra and developmental potency of adult neurons revealed by cloning

Somatic mutation in neurons is linked to neurologic disease and implicated in cell type diversification. However, the origin, extent and patterns of genomic mutation in neurons remain unknown. We established a nuclear transfer method to clonally amplify the genomes of neurons from adult mice for whole genome sequencing. Comprehensive mutation detection and independent validation revealed that individual neurons harbor ~100 unique mutations from all classes, but lack recurrent rearrangements. Most neurons contain at least one gene disrupting mutation and rare (0-2) mobile element insertions. The frequency and gene bias of neuronal mutations differs from other lineages, potentially due to novel mechanisms governing post- mitotic mutation. Fertile mice were cloned from several neurons, establishing the compatibility of mutated adult neuronal genomes with reprogramming to pluripotency and development.