High prevalence of focal and multi-focal somatic genetic variants in the human brain

Michael J Keogh; Wei Wei; Juvid Aryaman; Lauren Walker; Jelle van den Ameele; Jon Coxhead; Ian Wilson; Matthew Bashton; Jon Beck; John West; Richard Chen; Christian Haudenschild; Gabor Bartha; Shujun Luo; Chris M Morris; Nick S Jones; Johannes Attems; Patrick F Chinnery

doi:10.1038/s41467-018-06331-w

High prevalence of focal and multi-focal somatic genetic variants in the human brain

Michael J Keogh, Wei Wei, Juvid Aryaman, Lauren Walker, Jelle van den Ameele, Jon Coxhead, Ian Wilson, Matthew Bashton, Jon Beck, John West, Richard Chen, Christian Haudenschild, Gabor Bartha, Shujun Luo, Chris M Morris, Nick S Jones, Johannes Attems, Patrick F Chinnery

Applied Sciences Department

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Abstract

Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.

Original language	English
Article number	4257
Journal	Nature Communications
Volume	9
Issue number	1
Early online date	15 Oct 2018
DOIs	https://doi.org/10.1038/s41467-018-06331-w
Publication status	Published - Dec 2018

Keywords

Brain/metabolism
Clone Cells
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation
Genotyping Techniques
Humans
Mutation/genetics
Reproducibility of Results

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Keogh, M. J., Wei, W., Aryaman, J., Walker, L., van den Ameele, J., Coxhead, J., Wilson, I., Bashton, M., Beck, J., West, J., Chen, R., Haudenschild, C., Bartha, G., Luo, S., Morris, C. M., Jones, N. S., Attems, J., & Chinnery, P. F. (2018). High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nature Communications, 9(1), Article 4257. https://doi.org/10.1038/s41467-018-06331-w

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title = "High prevalence of focal and multi-focal somatic genetic variants in the human brain",

abstract = "Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.",

keywords = "Brain/metabolism, Clone Cells, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotyping Techniques, Humans, Mutation/genetics, Reproducibility of Results",

author = "Keogh, {Michael J} and Wei Wei and Juvid Aryaman and Lauren Walker and {van den Ameele}, Jelle and Jon Coxhead and Ian Wilson and Matthew Bashton and Jon Beck and John West and Richard Chen and Christian Haudenschild and Gabor Bartha and Shujun Luo and Morris, {Chris M} and Jones, {Nick S} and Johannes Attems and Chinnery, {Patrick F}",

year = "2018",

month = dec,

doi = "10.1038/s41467-018-06331-w",

language = "English",

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Keogh, MJ, Wei, W, Aryaman, J, Walker, L, van den Ameele, J, Coxhead, J, Wilson, I, Bashton, M, Beck, J, West, J, Chen, R, Haudenschild, C, Bartha, G, Luo, S, Morris, CM, Jones, NS, Attems, J & Chinnery, PF 2018, 'High prevalence of focal and multi-focal somatic genetic variants in the human brain', Nature Communications, vol. 9, no. 1, 4257. https://doi.org/10.1038/s41467-018-06331-w

TY - JOUR

T1 - High prevalence of focal and multi-focal somatic genetic variants in the human brain

AU - Keogh, Michael J

AU - Wei, Wei

AU - Aryaman, Juvid

AU - Walker, Lauren

AU - van den Ameele, Jelle

AU - Coxhead, Jon

AU - Wilson, Ian

AU - Bashton, Matthew

AU - Beck, Jon

AU - West, John

AU - Chen, Richard

AU - Haudenschild, Christian

AU - Bartha, Gabor

AU - Luo, Shujun

AU - Morris, Chris M

AU - Jones, Nick S

AU - Attems, Johannes

AU - Chinnery, Patrick F

PY - 2018/12

Y1 - 2018/12

N2 - Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.

AB - Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.

KW - Brain/metabolism

KW - Clone Cells

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genotyping Techniques

KW - Humans

KW - Mutation/genetics

KW - Reproducibility of Results

U2 - 10.1038/s41467-018-06331-w

DO - 10.1038/s41467-018-06331-w

M3 - Article

C2 - 30323172

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4257

ER -

High prevalence of focal and multi-focal somatic genetic variants in the human brain

Abstract

Keywords

UN SDGs

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