Frequency and signature of somatic variants in 1461 human brain exomes.

TitleFrequency and signature of somatic variants in 1461 human brain exomes.
Publication TypeJournal Article
Year of Publication2018
AuthorsWei, 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
JournalGenet Med
Date Published2018 Sep 14
ISSN1530-0366
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 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.

DOI10.1038/s41436-018-0274-3
Alternate JournalGenet. Med.
Citation Key10.1038/s41436-018-0274-3
PubMed ID30214067
Grant ListG1100540 / / 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