The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing

Rodin and Dou et al. characterized genome-wide somatic mutation in autistic and control brains, revealing that even unaffected individuals may possess dozens of brain somatic mutations and providing insight into the role of somatic mutation in autism. We characterize the landscape of somatic mutations-mutations occurring after fertilization-in the human brain using ultra-deep (similar to 250x) whole-genome sequencing of prefrontal cortex from 59 donors with autism spectrum disorder (ASD) and 15 control donors. We observe a mean of 26 somatic single-nucleotide variants per brain present in >= 4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces similar to 3.4 mutations, followed by 2-3 mutations in subsequent generations. This suggests that a typical individual possesses similar to 80 somatic single-nucleotide variants present in >= 2% of cells-comparable to the number of de novo germline mutations per generation-with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. ASD brains show an excess of somatic mutations in neural enhancer sequences compared with controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.

Automated summary

Through characterizing genome-wide somatic mutations in autistic and control brains, this study reveals that unaffected individuals may also possess brain somatic mutations, shedding light on the role of somatic mutations in autism. The analysis shows that there are a certain number of somatic single-nucleotide variants present in each brain cell, which may affect coding and regulatory regions.