Frequency and signature of somatic variants in 1461 human brain exomes.
Authors
Keogh, Michael J
Aryaman, Juvid
Golder, Zoe
Kullar, Peter
Wilson, Ian
McKenzie, Chris-Anne
Sarraj, Safa Al
Ansorge, Olaf
Jones, Nick S
Publication Date
2019-04Journal Title
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN
1098-3600
Publisher
Wolters Kluwer Health
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., Wilson, I., Talbot, K., et al. (2019). Frequency and signature of somatic variants in 1461 human brain exomes.. Genetics in medicine : official journal of the American College of Medical Genetics, 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. 88% 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 mis-match repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25x10-10 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, Humans, Genetic Diseases, Inborn, Sequence Analysis, DNA, Mutation, DNA Mismatch Repair, High-Throughput Nucleotide Sequencing, Exome, Whole 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