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

Rodin, Rachel E.; Brain Somatic Mosaicism Network; Walsh, Christopher A.

doi:http://dx.doi.org/10.1038/s41593-020-00765-6

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

Citation

Rodin RE, Dou Y, Kwon M, Sherman MA, D'Gama AM, Doan RN, Rento LM, Girskis KM, Bohrson CL, Kim SN, Nadig A, Luquette LJ, Gulhan DC; Brain Somatic Mosaicism Network, Park PJ, Walsh CA. The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing. Nat Neurosci. 2021;24(2):176-85. DOI: 10.1038/s41593-020-00765-6

Abstract

We characterize the landscape of somatic mutations-mutations occurring after fertilization-in the human brain using ultra-deep (~250×) 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 ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This suggests that a typical individual possesses ~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.