AbstractSomatic mutations have causative roles in many diseases and contribute to neuropsychiatric disorders. Here, we analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic single nucleotide and structural mutations after whole genome sequencing to a depth of over 200X. Typically, brains had 20 to 60 detectable single nucleotide mutations that likely arose in early development; however, about 5% of brains harbored hundreds and up to 2000 somatic mutations. Hypermutability was associated with age and putative damaging mutations in genes previously implicated in cancer and likely reflectsin vivoclonal expansions. Somatic duplications of likely early developmental origin were present in 1 out of 20 normal and diseased brains, reflecting background mutagenesis. Brains of individuals with autism were enriched in somatic deletions and in point mutations that create putative transcription factor binding motifs in enhancers that are active in the developing brain. The most affected motifs corresponded to MEIS transcription factors, suggesting a potential link between their involvement in gene regulation and autism.