Extensive phylogenies of human development inferred from somatic mutations

Tim H. H. Coorens, Luiza Moore, Philip S. Robinson, Rashesh Sanghvi, Joseph Christopher, James Hewinson, Moritz J. Przybilla, Andrew R. J. Lawson, Michael Spencer Chapman, Alex Cagan, Thomas R. W. Oliver, Matthew D. C. Neville, Yvette Hooks, Ayesha Noorani, Thomas J. Mitchell, Rebecca C. Fitzgerald, Peter J. Campbell, Iñigo Martincorena, Raheleh Rahbari and Michael R. Stratton ()
Additional contact information
Tim H. H. Coorens: Wellcome Sanger Institute
Luiza Moore: Wellcome Sanger Institute
Philip S. Robinson: Wellcome Sanger Institute
Rashesh Sanghvi: Wellcome Sanger Institute
Joseph Christopher: Wellcome Sanger Institute
James Hewinson: Wellcome Sanger Institute
Moritz J. Przybilla: Wellcome Sanger Institute
Andrew R. J. Lawson: Wellcome Sanger Institute
Michael Spencer Chapman: Wellcome Sanger Institute
Alex Cagan: Wellcome Sanger Institute
Thomas R. W. Oliver: Wellcome Sanger Institute
Matthew D. C. Neville: Wellcome Sanger Institute
Yvette Hooks: Wellcome Sanger Institute
Ayesha Noorani: Wellcome Sanger Institute
Thomas J. Mitchell: Wellcome Sanger Institute
Rebecca C. Fitzgerald: University of Cambridge, Biomedical Campus
Peter J. Campbell: Wellcome Sanger Institute
Iñigo Martincorena: Wellcome Sanger Institute
Raheleh Rahbari: Wellcome Sanger Institute
Michael R. Stratton: Wellcome Sanger Institute

Nature, 2021, vol. 597, issue 7876, 387-392

Abstract: 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 tracing1,2. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03790-y

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