Frequency and signature of somatic variants in 1461 human brain exomes

Wei Wei, Michael J Keogh, Juvid Aryaman, Zoe Golder, Peter J Kullar, Ian Wilson, Kevin Talbot, Martin R Turner, Chris-Anne McKenzie, Claire Troakes, Johannes Attems, Colin Smith, Safa Al Sarraj, Chris M Morris, Olaf Ansorge, Nick S Jones, James W Ironside, Patrick F Chinnery

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalGenetics in Medicine
Early online date14 Sep 2018
DOIs
Publication statusE-pub ahead of print - 14 Sep 2018

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