Extensive phylogenies of human development inferred from somatic mutations

doi:10.1038/s41586-021-03790-y

. 2021 Sep;597(7876):387-392.

doi: 10.1038/s41586-021-03790-y. Epub 2021 Aug 25.

Extensive phylogenies of human development inferred from somatic mutations

Tim H H Coorens^#¹, Luiza Moore^#^{1

2}, Philip S Robinson^{1

3}, Rashesh Sanghvi¹, Joseph Christopher^{1

3

4}, James Hewinson¹, Moritz J Przybilla¹, Andrew R J Lawson¹, Michael Spencer Chapman^{1

5

6}, Alex Cagan¹, Thomas R W Oliver^{1

4}, Matthew D C Neville¹, Yvette Hooks¹, Ayesha Noorani¹, Thomas J Mitchell^{1

4

7}, Rebecca C Fitzgerald⁸, Peter J Campbell¹, Iñigo Martincorena¹, Raheleh Rahbari¹, Michael R Stratton⁹

Affiliations

¹ Wellcome Sanger Institute, Hinxton, UK.
² Department of Pathology, University of Cambridge, Cambridge, UK.
³ Department of Paediatrics, University of Cambridge, Cambridge, UK.
⁴ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
⁶ Department of Haematology, University of Cambridge, Cambridge, UK.
⁷ Department of Surgery, University of Cambridge, Cambridge, UK.
⁸ MRC Cancer Unit, University of Cambridge, Biomedical Campus, Cambridge, UK.
⁹ Wellcome Sanger Institute, Hinxton, UK. mrs@sanger.ac.uk.

^# Contributed equally.

PMID: 34433963
DOI: 10.1038/s41586-021-03790-y

Extensive phylogenies of human development inferred from somatic mutations

Tim H H Coorens et al. Nature. 2021 Sep.

. 2021 Sep;597(7876):387-392.

doi: 10.1038/s41586-021-03790-y. Epub 2021 Aug 25.

Authors

Affiliations

¹ Wellcome Sanger Institute, Hinxton, UK.
² Department of Pathology, University of Cambridge, Cambridge, UK.
³ Department of Paediatrics, University of Cambridge, Cambridge, UK.
⁴ Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
⁶ Department of Haematology, University of Cambridge, Cambridge, UK.
⁷ Department of Surgery, University of Cambridge, Cambridge, UK.
⁸ MRC Cancer Unit, University of Cambridge, Biomedical Campus, Cambridge, UK.
⁹ Wellcome Sanger Institute, Hinxton, UK. mrs@sanger.ac.uk.

^# Contributed equally.

PMID: 34433963
DOI: 10.1038/s41586-021-03790-y

Abstract

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing^1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.

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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. Behjati, S. et al. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513, 422–425 (2014). - DOI - PubMed - PMC
1. Ju, Y. S. et al. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 543, 714–718 (2017). - DOI - PubMed - PMC
1. Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev. Biol. 56, 110–156 (1977). - DOI - PubMed
1. Keller, P. J., Schmidt, A. D., Wittbrodt, J. & Stelzer, E. H. Reconstruction of zebrafish early embryonic development by scanned light sheet microscopy. Science 322, 1065–1069 (2008). - DOI - PubMed
1. Strnad, P. et al. Inverted light-sheet microscope for imaging mouse pre-implantation development. Nat. Methods 13, 139–142 (2016). - DOI - PubMed

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[1] Behjati, S. et al. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513, 422–425 (2014). - DOI - PubMed - PMC

[2] Behjati, S. et al. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513, 422–425 (2014). - DOI - PubMed - PMC

[3] Ju, Y. S. et al. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 543, 714–718 (2017). - DOI - PubMed - PMC

[4] Ju, Y. S. et al. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 543, 714–718 (2017). - DOI - PubMed - PMC

[5] Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev. Biol. 56, 110–156 (1977). - DOI - PubMed

[6] Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev. Biol. 56, 110–156 (1977). - DOI - PubMed

[7] Keller, P. J., Schmidt, A. D., Wittbrodt, J. & Stelzer, E. H. Reconstruction of zebrafish early embryonic development by scanned light sheet microscopy. Science 322, 1065–1069 (2008). - DOI - PubMed

[8] Keller, P. J., Schmidt, A. D., Wittbrodt, J. & Stelzer, E. H. Reconstruction of zebrafish early embryonic development by scanned light sheet microscopy. Science 322, 1065–1069 (2008). - DOI - PubMed

[9] Strnad, P. et al. Inverted light-sheet microscope for imaging mouse pre-implantation development. Nat. Methods 13, 139–142 (2016). - DOI - PubMed

[10] Strnad, P. et al. Inverted light-sheet microscope for imaging mouse pre-implantation development. Nat. Methods 13, 139–142 (2016). - DOI - PubMed

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Extensive phylogenies of human development inferred from somatic mutations

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