The mutational landscape of human somatic and germline cells

doi:10.1038/s41586-021-03822-7

. 2021 Sep;597(7876):381-386.

doi: 10.1038/s41586-021-03822-7. Epub 2021 Aug 25.

The mutational landscape of human somatic and germline cells

Luiza Moore^#^{1

2}, Alex Cagan^#¹, Tim H H Coorens^#¹, Matthew D C Neville¹, Rashesh Sanghvi¹, Mathijs A Sanders^{1

3}, Thomas R W Oliver^{1

2}, Daniel Leongamornlert¹, Peter Ellis^{1

4}, Ayesha Noorani¹, Thomas J Mitchell^{1

5}, Timothy M Butler¹, Yvette Hooks¹, Anne Y Warren², Mette Jorgensen⁶, Kevin J Dawson¹, Andrew Menzies¹, Laura O'Neill¹, Calli Latimer¹, Mabel Teng¹, Ruben van Boxtel⁷, Christine A Iacobuzio-Donahue^{8

9}, Inigo Martincorena¹, Rakesh Heer^{10

11}, Peter J Campbell¹, Rebecca C Fitzgerald¹², Michael R Stratton¹³, Raheleh Rahbari¹⁴

Affiliations

¹ Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
² Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
³ Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.
⁴ Inivata, Cambridge, UK.
⁵ Department of Surgery, University of Cambridge, Cambridge, UK.
⁶ Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁷ Princess Máxima Center for Pediatric Oncology and Oncode Institute, Utrecht, Netherlands.
⁸ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
¹¹ Newcastle Urology, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
¹² MRC Cancer Unit, University of Cambridge, Cambridge, UK.
¹³ Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. mrs@sanger.ac.uk.
¹⁴ Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. rr11@sanger.ac.uk.

^# Contributed equally.

PMID: 34433962
DOI: 10.1038/s41586-021-03822-7

The mutational landscape of human somatic and germline cells

Luiza Moore et al. Nature. 2021 Sep.

. 2021 Sep;597(7876):381-386.

doi: 10.1038/s41586-021-03822-7. Epub 2021 Aug 25.

Authors

Affiliations

¹ Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK.
² Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
³ Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.
⁴ Inivata, Cambridge, UK.
⁵ Department of Surgery, University of Cambridge, Cambridge, UK.
⁶ Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁷ Princess Máxima Center for Pediatric Oncology and Oncode Institute, Utrecht, Netherlands.
⁸ Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
¹¹ Newcastle Urology, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
¹² MRC Cancer Unit, University of Cambridge, Cambridge, UK.
¹³ Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. mrs@sanger.ac.uk.
¹⁴ Cancer, Ageing and Somatic Mutation (CASM), Wellcome Sanger Institute, Hinxton, UK. rr11@sanger.ac.uk.

^# Contributed equally.

PMID: 34433962
DOI: 10.1038/s41586-021-03822-7

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.

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Comment in

Mutation fingerprints encode cellular histories.
Naxerova K. Naxerova K. Nature. 2021 Sep;597(7876):334-336. doi: 10.1038/d41586-021-02269-0. Nature. 2021. PMID: 34433973 No abstract available.
A body-wide view of somatic mutations.
Burgess DJ. Burgess DJ. Nat Rev Genet. 2021 Nov;22(11):689. doi: 10.1038/s41576-021-00420-1. Nat Rev Genet. 2021. PMID: 34522034 No abstract available.

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References

1. Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015). - PubMed - DOI
1. Rouhani, F. J. et al. Mutational history of a human cell lineage from somatic to induced pluripotent stem cells. PLoS Genet. 12, e1005932 (2016). - PubMed - PMC - DOI
1. Coorens, T. H. H. et al. Extensive phylogenies of human development reveal variable embryonic patterns. Preprint at bioRxiv https://doi.org/10.1101/2020.11.25.397828 (2020).
1. Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016). - PubMed - PMC - DOI
1. Bae, T. et al. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 359, 550–555 (2018). - PubMed - DOI

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[1] Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015). - PubMed - DOI

[2] Martincorena, I. & Campbell, P. J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015). - PubMed - DOI

[3] Rouhani, F. J. et al. Mutational history of a human cell lineage from somatic to induced pluripotent stem cells. PLoS Genet. 12, e1005932 (2016). - PubMed - PMC - DOI

[4] Rouhani, F. J. et al. Mutational history of a human cell lineage from somatic to induced pluripotent stem cells. PLoS Genet. 12, e1005932 (2016). - PubMed - PMC - DOI

[5] Coorens, T. H. H. et al. Extensive phylogenies of human development reveal variable embryonic patterns. Preprint at bioRxiv https://doi.org/10.1101/2020.11.25.397828 (2020).

[6] Coorens, T. H. H. et al. Extensive phylogenies of human development reveal variable embryonic patterns. Preprint at bioRxiv https://doi.org/10.1101/2020.11.25.397828 (2020).

[7] Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016). - PubMed - PMC - DOI

[8] Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016). - PubMed - PMC - DOI

[9] Bae, T. et al. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 359, 550–555 (2018). - PubMed - DOI

[10] Bae, T. et al. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 359, 550–555 (2018). - PubMed - DOI

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The mutational landscape of human somatic and germline cells

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The mutational landscape of human somatic and germline cells

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