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Frequency and signature of somatic variants in 1461 human brain exomes

Lookup NU author(s): Dr Peter Kullar, Dr Ian Wilson, Professor Johannes Attems, Dr Christopher Morris



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018, American College of Medical Genetics and Genomics. 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.

Publication metadata

Author(s): 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 SA, Morris CM, Ansorge O, Jones NS, Ironside JW, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2019

Volume: 21

Pages: 904-912

Online publication date: 14/09/2018

Acceptance date: 06/08/2018

Date deposited: 10/10/2018

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Nature Publishing Group


DOI: 10.1038/s41436-018-0274-3


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Funder referenceFunder name
101876/Z/13/ZWellcome Trust
13044Bloodwise (Formerly Leukaemia and Lymphoma Research)
13044Medical Research Council (MRC)