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^*

^*Corresponding author for this work

Hematology

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

103 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
Early online date	25 Aug 2021
DOIs	https://doi.org/10.1038/s41586-021-03822-7
Publication status	Published - 16 Sept 2021

Bibliographical note

Funding Information:
Acknowledgements We thank the staff of WTSI Sample Logistics, Genotyping, Pulldown, Sequencing and Informatics facilities for their contribution; K. Roberts and the cgp-lab for their assistance; P. Robinson, M. Goddard, P. S. Tarpey and P. Scott for their assistance with sample collection and the LCM pipeline; and M. Hurles, A. Scally and Y. S. Ju for providing useful feedback. This research is supported by core funding from the Wellcome Trust. R.R. is funded by Cancer Research UK (CRUK; C66259/A27114). L.M. is a recipient of a CRUK Clinical PhD fellowship (C20/A20917) and the Jean Shank/Pathological Society of Great Britain and Ireland Intermediate Research Fellowship (grant reference no. 1175). T.J.M. is supported by CRUK and the Royal College of Surgeons (C63474/A27176). The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). Funding for sample collection was through the ICGC and was funded by a programme grant from CRUK (RG81771/84119). R.H. is a recipient of a PCF Challenge Research Award (ID #18CHAL11). I.M. is funded by CRUK (C57387/A21777) and the Wellcome Trust. P.J.C. is a Wellcome Trust Senior Clinical Fellow.

Publisher Copyright:
© 2021, Crown.

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10.1038/s41586-021-03822-7

https://www.biorxiv.org/content/10.1101/2020.11.25.398172v1.article-infoLicence: CC BY-NC-ND

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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{\textquoteright}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.",

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{\textquoteright}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 = "Funding Information: Acknowledgements We thank the staff of WTSI Sample Logistics, Genotyping, Pulldown, Sequencing and Informatics facilities for their contribution; K. Roberts and the cgp-lab for their assistance; P. Robinson, M. Goddard, P. S. Tarpey and P. Scott for their assistance with sample collection and the LCM pipeline; and M. Hurles, A. Scally and Y. S. Ju for providing useful feedback. This research is supported by core funding from the Wellcome Trust. R.R. is funded by Cancer Research UK (CRUK; C66259/A27114). L.M. is a recipient of a CRUK Clinical PhD fellowship (C20/A20917) and the Jean Shank/Pathological Society of Great Britain and Ireland Intermediate Research Fellowship (grant reference no. 1175). T.J.M. is supported by CRUK and the Royal College of Surgeons (C63474/A27176). The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). Funding for sample collection was through the ICGC and was funded by a programme grant from CRUK (RG81771/84119). R.H. is a recipient of a PCF Challenge Research Award (ID #18CHAL11). I.M. is funded by CRUK (C57387/A21777) and the Wellcome Trust. P.J.C. is a Wellcome Trust Senior Clinical Fellow. Publisher Copyright: {\textcopyright} 2021, Crown.",

year = "2021",

month = sep,

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

language = "English",

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pages = "381--386",

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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

N1 - Funding Information: Acknowledgements We thank the staff of WTSI Sample Logistics, Genotyping, Pulldown, Sequencing and Informatics facilities for their contribution; K. Roberts and the cgp-lab for their assistance; P. Robinson, M. Goddard, P. S. Tarpey and P. Scott for their assistance with sample collection and the LCM pipeline; and M. Hurles, A. Scally and Y. S. Ju for providing useful feedback. This research is supported by core funding from the Wellcome Trust. R.R. is funded by Cancer Research UK (CRUK; C66259/A27114). L.M. is a recipient of a CRUK Clinical PhD fellowship (C20/A20917) and the Jean Shank/Pathological Society of Great Britain and Ireland Intermediate Research Fellowship (grant reference no. 1175). T.J.M. is supported by CRUK and the Royal College of Surgeons (C63474/A27176). The laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council (RG84369). Funding for sample collection was through the ICGC and was funded by a programme grant from CRUK (RG81771/84119). R.H. is a recipient of a PCF Challenge Research Award (ID #18CHAL11). I.M. is funded by CRUK (C57387/A21777) and the Wellcome Trust. P.J.C. is a Wellcome Trust Senior Clinical Fellow. Publisher Copyright: © 2021, Crown.

PY - 2021/9/16

Y1 - 2021/9/16

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.

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VL - 597

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EP - 386

JO - Nature

JF - Nature

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ER -

The mutational landscape of human somatic and germline cells

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