Clonal dynamics of haematopoiesis across the human lifespan

Emily Mitchell, Michael Spencer Chapman, Nicholas Williams, Kevin J. Dawson, Nicole Mende, Emily F. Calderbank, Hyunchul Jung, Thomas Mitchell, Tim H. H. Coorens, David H. Spencer, Heather Machado, Henry Lee-Six, Megan Davies, Daniel Hayler, Margarete A. Fabre, Krishnaa Mahbubani, Federico Abascal, Alex Cagan, George S. Vassiliou, Joanna Baxter, Inigo Martincorena, Michael R. Stratton, David G. Kent, Krishna Chatterjee, Kourosh Saeb Parsy, Anthony R. Green, Jyoti Nangalia (), Elisa Laurenti () and Peter J. Campbell ()
Additional contact information
Emily Mitchell: Wellcome Sanger Institute
Michael Spencer Chapman: Wellcome Sanger Institute
Nicholas Williams: Wellcome Sanger Institute
Kevin J. Dawson: Wellcome Sanger Institute
Nicole Mende: Cambridge Biomedical Campus
Emily F. Calderbank: Cambridge Biomedical Campus
Hyunchul Jung: Wellcome Sanger Institute
Thomas Mitchell: Wellcome Sanger Institute
Tim H. H. Coorens: Wellcome Sanger Institute
David H. Spencer: Washington University
Heather Machado: Wellcome Sanger Institute
Henry Lee-Six: Wellcome Sanger Institute
Megan Davies: Cambridge Molecular Diagnostics
Daniel Hayler: Cambridge Biomedical Campus
Margarete A. Fabre: Wellcome Sanger Institute
Krishnaa Mahbubani: University of Cambridge
Federico Abascal: Wellcome Sanger Institute
Alex Cagan: Wellcome Sanger Institute
George S. Vassiliou: Wellcome Sanger Institute
Joanna Baxter: University of Cambridge
Inigo Martincorena: Wellcome Sanger Institute
Michael R. Stratton: Wellcome Sanger Institute
David G. Kent: University of York
Krishna Chatterjee: University of Cambridge
Kourosh Saeb Parsy: University of Cambridge
Anthony R. Green: Cambridge Biomedical Campus
Jyoti Nangalia: Wellcome Sanger Institute
Elisa Laurenti: Cambridge Biomedical Campus
Peter J. Campbell: Wellcome Sanger Institute

Nature, 2022, vol. 606, issue 7913, 343-350

Abstract: Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4–6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000–200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30–60% of haematopoiesis was accounted for by 12–18 independent clones, each contributing 1–34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.

Date: 2022
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DOI: 10.1038/s41586-022-04786-y

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