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Clonal dynamics of haematopoiesis across the human lifespan.

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Peer-reviewed

Repository DOI


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Authors

Mitchell, Emily 
Spencer Chapman, Michael  ORCID logo  https://orcid.org/0000-0002-5320-8193
Dawson, Kevin J 

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.

Description

Acknowledgements: This work was supported by the WBH Foundation. Investigators at the Sanger Institute are supported by a core grant from the Wellcome Trust. P.J.C. was a Wellcome Trust Senior Clinical Fellow (WT088340MA) until 2020. N.M. was supported by a DFG Research Fellowship (ME 5209/1-1). Work in the D.G.K. laboratory is supported by a Bloodwise Bennett Fellowship (15008), a Cancer Research UK Programme Foundation Award (DCRPGF\100008), and a European Research Council Starting Grant (ERC-2016-STG–715371). Work in the A.R.G. laboratory is supported by the Wellcome Trust, Bloodwise, Cancer Research UK, the Kay Kendall Leukaemia Fund, and the Leukemia and Lymphoma Society of America. Work in the E.L. laboratory is supported by a Wellcome Trust Sir Henry Dale Fellowship, BBSRC and a European Haematology Association Non-Clinical Advanced Research Fellowship. The E.L. and A.R.G. laboratories are supported by a core support grant from the Wellcome Trust and Medical Research Council to the Cambridge Stem Cell Institute. K.M. is supported by the Chan-Zuckerberg Initiative. K.C. is supported by a Wellcome Investigator award (210755/Z/18/Z). We thank the Cambridge Blood and Stem Cell Biobank; the Cambridge Biorepository for Translational Medicine for access to human bone marrow and matched peripheral blood; and the Cambridge NIHR BRC Cell Phenotyping Hub for their flow cytometry services and advice. We acknowledge further assistance from the National Institute for Health Research Cambridge Biomedical Research Centre and the Cambridge Experimental Cancer Medicine Centre. We are grateful to the donors, families of donors and the Cambridge Biorepository for Translational Medicine for the gift of tissues. We thank T. Ley for his help with analysis of AML genomes. For the purpose of Open Access, the author has applied a CC-BY public copyright license to any Author Accepted Manuscript version arising from this submission. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, Aging, Child, Child, Preschool, Clonal Hematopoiesis, Clone Cells, Female, Hematologic Neoplasms, Hematopoietic Stem Cells, Humans, Infant, Infant, Newborn, Longevity, Male, Middle Aged, Multipotent Stem Cells, Young Adult

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

606

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (203151/Z/16/Z)
Bloodwise (15008)
European Research Council (715371)
Wellcome Trust (210755/Z/18/Z)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_PC_17230)
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