Frequency and signature of somatic variants in 1461 human brain exomes.
Authors
Wei, Wei
Keogh, Michael J
Aryaman, Juvid
Golder, Zoe
Kullar, Peter J
Wilson, Ian
Talbot, Kevin
Turner, Martin R
McKenzie, Chris-Anne
Troakes, Claire
Attems, Johannes
Smith, Colin
Sarraj, Safa Al
Morris, Chris M
Ansorge, Olaf
Jones, Nick S
Ironside, James W
Chinnery, Patrick F
Publication Date
2019-04Journal Title
Genet Med
ISSN
1098-3600
Publisher
Elsevier BV
Volume
21
Issue
4
Pages
904-912
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Wei, W., Keogh, M. J., Aryaman, J., Golder, Z., Kullar, P. J., Wilson, I., Talbot, K., et al. (2019). Frequency and signature of somatic variants in 1461 human brain exomes.. Genet Med, 21 (4), 904-912. https://doi.org/10.1038/s41436-018-0274-3
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.
Keywords
brain, embryogenesis, exome sequencing, neurodegenerative disorders, somatic variant, Brain, DNA Mismatch Repair, Exome, Genetic Diseases, Inborn, High-Throughput Nucleotide Sequencing, Humans, Mutation, Sequence Analysis, DNA, Exome Sequencing
Sponsorship
Wellcome Trust
Funder references
Wellcome Trust (101876/Z/13/Z)
Wellcome Trust (101876/B/13/A)
MRC (via University of Edinburgh) (162126)
Wellcome Trust (212219/Z/18/Z)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/s41436-018-0274-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280058
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