| Title: |
Clonal dynamics of haematopoiesis across the human lifespan. |
| Authors: |
Mitchell, E; Spencer Chapman, M; Williams, N; Dawson, KJ; Mende, N; Calderbank, EF; Jung, H; Mitchell, T; Coorens, THH; Spencer, DH; Machado, H; Lee-Six, H; Davies, M; Hayler, D; Fabre, MA; Mahbubani, K; Abascal, F; Cagan, A; Vassiliou, GS; Baxter, J; Martincorena, I; Stratton, MR; Kent, DG; Chatterjee, K; Parsy, KS; Green, AR; Nangalia, J; Laurenti, E; Campbell, PJ |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2022 |
| Collection: |
Queen Mary University of London: Queen Mary Research Online (QMRO) |
| Subject Terms: |
Adolescent; Adult; Aged; 80 and over; Aging; Child; Preschool; Clonal Hematopoiesis; Clone Cells; Female; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans; Infant; Newborn; Longevity; Male; Middle Aged; Multipotent Stem Cells; Young Adult |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
343 - 350 |
| Language: |
English |
| Relation: |
Nature; https://qmro.qmul.ac.uk/xmlui/handle/123456789/104102 |
| DOI: |
10.1038/s41586-022-04786-y |
| Availability: |
https://qmro.qmul.ac.uk/xmlui/handle/123456789/104102; https://doi.org/10.1038/s41586-022-04786-y |
| Rights: |
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. ; © The Author(s) 2022 |
| Accession Number: |
edsbas.19F5F538 |
| Database: |
BASE |