Frequency and signature of somatic variants in 1461 human brain exomes
Genetics in Medicine(2018)
Abstract
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.
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Key words
somatic variant,brain,neurodegenerative disorders,exome sequencing,embryogenesis
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