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dc.contributor.authorMitchell, Emily
dc.contributor.authorSpencer Chapman, Michael
dc.contributor.authorWilliams, Nicholas
dc.contributor.authorDawson, Kevin J
dc.contributor.authorMende, Nicole
dc.contributor.authorCalderbank, Emily
dc.contributor.authorJung, Hyunchul
dc.contributor.authorMitchell, Thomas
dc.contributor.authorCoorens, Tim HH
dc.contributor.authorSpencer, David H
dc.contributor.authorMachado, Heather
dc.contributor.authorLee-Six, Henry
dc.contributor.authorDavies, Megan
dc.contributor.authorHayler, Daniel
dc.contributor.authorFabre, Margarete A
dc.contributor.authorMahbubani, Krishnaa
dc.contributor.authorAbascal, Federico
dc.contributor.authorCagan, Alex
dc.contributor.authorVassiliou, George
dc.contributor.authorBaxter, Joanna
dc.contributor.authorMartincorena, Inigo
dc.contributor.authorStratton, Michael R
dc.contributor.authorKent, David G
dc.contributor.authorChatterjee, Krishna
dc.contributor.authorParsy, Kourosh Saeb
dc.contributor.authorGreen, Tony
dc.contributor.authorNangalia, Jyoti
dc.contributor.authorLaurenti, Elisa
dc.contributor.authorCampbell, Peter J
dc.description.abstractAge-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.
dc.publisherNature Research
dc.rightsAttribution 4.0 International
dc.titleClonal dynamics of haematopoiesis across the human lifespan.
dc.publisher.departmentDepartment of Haematology
dc.contributor.orcidSpencer Chapman, Michael [0000-0002-5320-8193]
dc.contributor.orcidWilliams, Nicholas [0000-0003-3989-9167]
dc.contributor.orcidMende, Nicole [0000-0002-5078-2333]
dc.contributor.orcidCalderbank, Emily [0000-0002-9559-6593]
dc.contributor.orcidCoorens, Tim HH [0000-0002-5826-3554]
dc.contributor.orcidLee-Six, Henry [0000-0003-4831-8088]
dc.contributor.orcidMahbubani, Krishnaa [0000-0002-1327-2334]
dc.contributor.orcidAbascal, Federico [0000-0002-6201-1587]
dc.contributor.orcidCagan, Alex [0000-0002-7857-4771]
dc.contributor.orcidVassiliou, George [0000-0003-4337-8022]
dc.contributor.orcidMartincorena, Inigo [0000-0003-1122-4416]
dc.contributor.orcidStratton, Michael R [0000-0001-6035-153X]
dc.contributor.orcidKent, David G [0000-0001-7871-8811]
dc.contributor.orcidChatterjee, Krishna [0000-0002-2654-8854]
dc.contributor.orcidParsy, Kourosh Saeb [0000-0002-0633-3696]
dc.contributor.orcidGreen, Tony [0000-0002-9795-0218]
dc.contributor.orcidNangalia, Jyoti [0000-0001-7122-4608]
dc.contributor.orcidLaurenti, Elisa [0000-0002-9917-9092]
dc.contributor.orcidCampbell, Peter J [0000-0002-3921-0510]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (203151/Z/16/Z)
pubs.funder-project-idBloodwise (15008)
pubs.funder-project-idEuropean Research Council (715371)
pubs.funder-project-idWellcome Trust (210755/Z/18/Z)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International