|Title||Frequency and signature of somatic variants in 1461 human brain exomes.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Wei, W, Keogh, MJ, Aryaman, J, Golder, Z, Kullar, PJ, Wilson, I, Talbot, K, Turner, MR, McKenzie, C-A, Troakes, C, Attems, J, Smith, C, Sarraj, SAl, Morris, CM, Ansorge, O, Jones, NS, Ironside, JW, Chinnery, PF|
|Date Published||2018 Sep 14|
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 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.
|Alternate Journal||Genet. Med.|
|Grant List||G1100540 / / Medical Research Council / United Kingdom |
MC_UP_1501/2 / / Medical Research Council / United Kingdom
G0900652 / / Medical Research Council / United Kingdom
G0502157 / / Medical Research Council / United Kingdom
G0400074 / / Medical Research Council / United Kingdom
MR/L016397/1 / / Medical Research Council / United Kingdom