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PURPOSE: To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders. METHODS: In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24. RESULTS: We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10-10 per base pair per individual. CONCLUSION: These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.

Original publication

DOI

10.1038/s41436-018-0274-3

Type

Journal article

Journal

Genet Med

Publication Date

04/2019

Volume

21

Pages

904 - 912

Keywords

brain, embryogenesis, exome sequencing, neurodegenerative disorders, somatic variant, Brain, DNA Mismatch Repair, Exome, Genetic Diseases, Inborn, High-Throughput Nucleotide Sequencing, Humans, Mutation, Sequence Analysis, DNA, Whole Exome Sequencing