High prevalence of focal and multi-focal somatic genetic variants in the human brain.
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ABSTRACT:
SUBMITTER: Keogh MJ
PROVIDER: S-EPMC6189186 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
Publications
High prevalence of focal and multi-focal somatic genetic variants in the human brain.
Keogh Michael J MJ Wei Wei W Aryaman Juvid J Walker Lauren L van den Ameele Jelle J Coxhead Jon J Wilson Ian I Bashton Matthew M Beck Jon J West John J Chen Richard R Haudenschild Christian C Bartha Gabor G Luo Shujun S Morris Chris M CM Jones Nick S NS Attems Johannes J Chinnery Patrick F PF
Nature communications 20181015 1
Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesia ...[more]
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Project description:PurposeTo systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders.MethodsIn 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.ResultsWe 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.ConclusionThese 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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