The Landscape of Somatic Mutation in Human Cerebral Cortex

Although roles of somatic mutations-- acquired post-fertilization and present in only a subset of an individual’s cells1-- in cancer and certain focal epilepsies are well established2, the extent to which such mutations shape the normally developing human brain or affect risk of neuropsychiatric disease is poorly understood3,4. Here we characterize the landscape of developmental somatic mutations in the human brain by identifying those somatic mutations present in ≥2-3% of cells using ultra-deep (~250X) whole-genome sequencing (WGS) of DNA isolated from the dorsolateral prefrontal cortex (PFC) of 60 postmortem brains of individuals with a diagnosis of autism spectrum disorder (ASD)—the largest such collection ever assembled—as well as 15 neurotypical brains. We identify on average 15 ± 7 somatic single nucleotide variants (sSNVs) per brain (range 3–34), detectable at mosaic fractions (percentage of mutant cells) of 4–83% (mean 18%). Our data reveal that ~5 sSNVs occur in the 1st cell generation after fertilization and ~3 sSNVs occur in each of the 2nd-4th generations, with enrichment of C>T substitutions indicating evolving mutational mechanisms during early development. This mutation rate suggests that a typical individual possesses ~100 mosaic mutations present in ≥2% of cells, and the majority of individuals possess a function-altering sSNV present in ≥2% of cells somewhere in the cortex, levels associated with focal disease. Exons and open chromatin are relatively enriched for mutations, while sSNVs in active, brain-specific enhancers are more common in ASD cases than controls. This suggests that mosaic enhancer mutations contribute to ASD risk and reveals a mechanism of how transcriptional effects in the brain may occur without necessarily impairing non-CNS gene function. The high rate of damaging sSNV in humans suggests they are a routine feature of normal development, and deserve further exploration in other complex neuropsychiatric diseases.