The mutational landscape of human somatic and germline cells

Luiza Moore; Alex Cagan; Tim H H Coorens; Matthew D C Neville; Rashesh Sanghvi; Mathijs A Sanders; Thomas R W Oliver; Daniel Leongamornlert; Peter Ellis; Ayesha Noorani; Thomas J Mitchell; Timothy M Butler; Yvette Hooks; Anne Y Warren; Mette Jorgensen; Kevin J Dawson; Andrew Menzies; Laura O'Neill; Calli Latimer; Mabel Teng; Ruben van Boxtel; Christine A Iacobuzio-Donahue; Inigo Martincorena; Rakesh Heer; Peter J Campbell; Rebecca C Fitzgerald; Michael R Stratton; Raheleh Rahbari

doi:10.1038/s41586-021-03822-7

The mutational landscape of human somatic and germline cells

Luiza Moore, Alex Cagan, Tim H H Coorens, Matthew D C Neville, Rashesh Sanghvi, Mathijs A Sanders, Thomas R W Oliver, Daniel Leongamornlert, Peter Ellis, Ayesha Noorani, Thomas J Mitchell, Timothy M Butler, Yvette Hooks, Anne Y Warren, Mette Jorgensen, Kevin J Dawson, Andrew Menzies, Laura O'Neill, Calli Latimer, Mabel TengRuben van Boxtel, Christine A Iacobuzio-Donahue, Inigo Martincorena, Rakesh Heer, Peter J Campbell, Rebecca C Fitzgerald, Michael R Stratton, Raheleh Rahbari

Group van Boxtel

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

174 Citations (Scopus)

Abstract

Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.

Original language	English
Pages (from-to)	381-386
Number of pages	6
Journal	Nature
Volume	597
Issue number	7876
DOIs	https://doi.org/10.1038/s41586-021-03822-7
Publication status	Published - Sept 2021

Keywords

Aged
Clone Cells/metabolism
Female
Germ Cells/metabolism
Germ-Line Mutation
Health
Humans
Male
Microdissection
Middle Aged
Mutation Rate
Organ Specificity/genetics
Oxidative Stress
Spermatogonia/metabolism

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10.1038/s41586-021-03822-7

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Moore, L., Cagan, A., Coorens, T. H. H., Neville, M. D. C., Sanghvi, R., Sanders, M. A., Oliver, T. R. W., Leongamornlert, D., Ellis, P., Noorani, A., Mitchell, T. J., Butler, T. M., Hooks, Y., Warren, A. Y., Jorgensen, M., Dawson, K. J., Menzies, A., O'Neill, L., Latimer, C., ... Rahbari, R. (2021). The mutational landscape of human somatic and germline cells. Nature, 597(7876), 381-386. https://doi.org/10.1038/s41586-021-03822-7

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title = "The mutational landscape of human somatic and germline cells",

abstract = "Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.",

keywords = "Aged, Clone Cells/metabolism, Female, Germ Cells/metabolism, Germ-Line Mutation, Health, Humans, Male, Microdissection, Middle Aged, Mutation Rate, Organ Specificity/genetics, Oxidative Stress, Spermatogonia/metabolism",

author = "Luiza Moore and Alex Cagan and Coorens, {Tim H H} and Neville, {Matthew D C} and Rashesh Sanghvi and Sanders, {Mathijs A} and Oliver, {Thomas R W} and Daniel Leongamornlert and Peter Ellis and Ayesha Noorani and Mitchell, {Thomas J} and Butler, {Timothy M} and Yvette Hooks and Warren, {Anne Y} and Mette Jorgensen and Dawson, {Kevin J} and Andrew Menzies and Laura O'Neill and Calli Latimer and Mabel Teng and {van Boxtel}, Ruben and Iacobuzio-Donahue, {Christine A} and Inigo Martincorena and Rakesh Heer and Campbell, {Peter J} and Fitzgerald, {Rebecca C} and Stratton, {Michael R} and Raheleh Rahbari",

note = "{\textcopyright} 2021. Crown.",

year = "2021",

month = sep,

doi = "10.1038/s41586-021-03822-7",

language = "English",

volume = "597",

pages = "381--386",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7876",

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Moore, L, Cagan, A, Coorens, THH, Neville, MDC, Sanghvi, R, Sanders, MA, Oliver, TRW, Leongamornlert, D, Ellis, P, Noorani, A, Mitchell, TJ, Butler, TM, Hooks, Y, Warren, AY, Jorgensen, M, Dawson, KJ, Menzies, A, O'Neill, L, Latimer, C, Teng, M, van Boxtel, R, Iacobuzio-Donahue, CA, Martincorena, I, Heer, R, Campbell, PJ, Fitzgerald, RC, Stratton, MR & Rahbari, R 2021, 'The mutational landscape of human somatic and germline cells', Nature, vol. 597, no. 7876, pp. 381-386. https://doi.org/10.1038/s41586-021-03822-7

TY - JOUR

T1 - The mutational landscape of human somatic and germline cells

AU - Moore, Luiza

AU - Cagan, Alex

AU - Coorens, Tim H H

AU - Neville, Matthew D C

AU - Sanghvi, Rashesh

AU - Sanders, Mathijs A

AU - Oliver, Thomas R W

AU - Leongamornlert, Daniel

AU - Ellis, Peter

AU - Noorani, Ayesha

AU - Mitchell, Thomas J

AU - Butler, Timothy M

AU - Hooks, Yvette

AU - Warren, Anne Y

AU - Jorgensen, Mette

AU - Dawson, Kevin J

AU - Menzies, Andrew

AU - O'Neill, Laura

AU - Latimer, Calli

AU - Teng, Mabel

AU - van Boxtel, Ruben

AU - Iacobuzio-Donahue, Christine A

AU - Martincorena, Inigo

AU - Heer, Rakesh

AU - Campbell, Peter J

AU - Fitzgerald, Rebecca C

AU - Stratton, Michael R

AU - Rahbari, Raheleh

PY - 2021/9

Y1 - 2021/9

N2 - Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.

AB - Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.

KW - Aged

KW - Clone Cells/metabolism

KW - Female

KW - Germ Cells/metabolism

KW - Germ-Line Mutation

KW - Health

KW - Humans

KW - Male

KW - Microdissection

KW - Middle Aged

KW - Mutation Rate

KW - Organ Specificity/genetics

KW - Oxidative Stress

KW - Spermatogonia/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85113490990&partnerID=8YFLogxK

U2 - 10.1038/s41586-021-03822-7

DO - 10.1038/s41586-021-03822-7

M3 - Article

C2 - 34433962

SN - 0028-0836

VL - 597

SP - 381

EP - 386

JO - Nature

JF - Nature

IS - 7876

ER -

The mutational landscape of human somatic and germline cells

Abstract

Keywords

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