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

School of Regeneration and Repair

Research output: Contribution to journal › Article › peer-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 language	English
Journal	Genetics in Medicine
Early online date	14 Sept 2018
DOIs	https://doi.org/10.1038/s41436-018-0274-3
Publication status	E-pub ahead of print - 14 Sept 2018

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s41436-018-0274-3Final published version, 866 KBLicence: Creative Commons: Attribution (CC-BY)

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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. (2018). Frequency and signature of somatic variants in 1461 human brain exomes. Genetics in Medicine. Advance online publication. 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.",

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 Chris-Anne McKenzie 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 = "2018",

month = sep,

day = "14",

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

language = "English",

journal = "Genetics in Medicine",

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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 - 2018/9/14

Y1 - 2018/9/14

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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DO - 10.1038/s41436-018-0274-3

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SN - 1098-3600

JO - Genetics in Medicine

JF - Genetics in Medicine

ER -

Frequency and signature of somatic variants in 1461 human brain exomes

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