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

doi:10.1038/s41436-018-0274-3

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^*

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

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 language	English
Pages (from-to)	904-912
Number of pages	9
Journal	GENETICS IN MEDICINE
Volume	21
Issue number	4
DOIs	https://doi.org/10.1038/s41436-018-0274-3
Publication status	Published - 1 Apr 2019

Keywords

brain
embryogenesis
exome sequencing
neurodegenerative disorders
somatic variant

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Wei, W., Keogh, M. J., Aryaman, J., Golder, Z., Kullar, P. J., Wilson, I., Talbot, K., Turner, M. R., McKenzie, C. A., Troakes, C., Attems, J., Smith, C., Sarraj, S. A., Morris, C. M., Ansorge, O., Jones, N. S., Ironside, J. W., & Chinnery, P. F. (2019). Frequency and signature of somatic variants in 1461 human brain exomes. GENETICS IN MEDICINE, 21(4), 904-912. https://doi.org/10.1038/s41436-018-0274-3

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title = "Frequency and signature of somatic variants in 1461 human brain exomes",

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{\textregistered} 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",

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

year = "2019",

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doi = "10.1038/s41436-018-0274-3",

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Wei, W, Keogh, MJ, Aryaman, J, Golder, Z, Kullar, PJ, Wilson, I, Talbot, K, Turner, MR, McKenzie, CA, Troakes, C, Attems, J, Smith, C, Sarraj, SA, Morris, CM, Ansorge, O, Jones, NS, Ironside, JW & Chinnery, PF 2019, 'Frequency and signature of somatic variants in 1461 human brain exomes', GENETICS IN MEDICINE, vol. 21, no. 4, pp. 904-912. https://doi.org/10.1038/s41436-018-0274-3

TY - JOUR

T1 - Frequency and signature of somatic variants in 1461 human brain exomes

AU - Wei, Wei

AU - Keogh, Michael J.

AU - Aryaman, Juvid

AU - Golder, Zoe

AU - Kullar, Peter J.

AU - Wilson, Ian

AU - Talbot, Kevin

AU - Turner, Martin R.

AU - McKenzie, Chris Anne

AU - Troakes, Claire

AU - Attems, Johannes

AU - Smith, Colin

AU - Sarraj, Safa Al

AU - Morris, Chris M.

AU - Ansorge, Olaf

AU - Jones, Nick S.

AU - Ironside, James W.

AU - Chinnery, Patrick F.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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.

AB - 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.

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KW - embryogenesis

KW - exome sequencing

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JO - GENETICS IN MEDICINE

JF - GENETICS IN MEDICINE

IS - 4

ER -

Frequency and signature of somatic variants in 1461 human brain exomes

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Keywords

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