HSC_population_dynamics_KSP_samples

My research project aims to use the clonal dynamics of spontaneously occurring somatic mutations to answer fundamental questions about human haematopoietic stem cell (HSC) biology. The four major questions I will address are: 1. How do age and aging affect normal human HSC dynamics in vivo? 2. How do in vivo perturbations, particularly chemotherapy and increased levels of reactive oxygen species, affect HSC population dynamics? 3. Is response to in vitro perturbation heritable and/or correlated with other features such as age of individual and contribution of the lineage to peripheral blood? 4. How are HSC dynamics altered in people with early driver mutations (clonal haematopoiesis)?

Type: Cancer Genomics
Archiver: European Genome-Phenome Archive (EGA)

3 Datasets 3 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001007851	Age-related loss of function in the human haematopoietic system is well documented, manifesting as reduced regenerative capacity, age-related cytopenias and immune dysfunction. However, the cellular and population level changes that underpin both this functional decline and the increased risk of clonal haematopoiesis and blood cancer in the elderly remain elusive. Here we performed whole genome sequencing on >3350 single haematopoietic stem cell / multipotent progenitors (HSC/MPP) derived colonies across 10 haematologically normal subjects aged 0 to 81. We found that HSC/MPPs accumulated 17 single nucleotide variants per year post birth and had a reduction in telomere length of 50bp per year throughout young adult life. We reconstructed phylogenies of the sampled HSC/MPPs to interrogate changes in clonal dynamics through life. Haematopoiesis in adults aged less than 65 was predominantly polyclonal, with few known driver mutations. In contrast, individuals aged over 75 displayed a profound change in clonal structure, with frequent clonal expansions, many unexplained by known driver mutations. The ratio of non-synonymous to synonymous mutations revealed widespread positive selection, estimating around 1000 driver mutations in the dataset (10-fold more than the number of known drivers). We identified novel genes ZNF318 and HIST2H3D as being under positive selection, despite not being enriched in myeloid malignancies. Our data show that HSC clonal dynamics is more complex than previously thought. One implication is that by old age, the majority of HSCs carry at least one of a number of largely undescribed driver mutations, which may underlie aspects of their functional decline.	HiSeq X Ten Illumina NovaSeq 6000	-
EGAD00001008107	A lymphocyte suffers many threats to its genome, including programmed mutation during differentiation, antigen-driven proliferation and residency in diverse microenvironments. After developing protocols for single-cell lymphocyte expansions, we sequenced whole genomes from 717 normal naive and memory B and T lymphocytes and hematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells – the extra mutations were mostly acquired during differentiation, with burdens higher in memory than naive lymphocytes, although T cells also had a higher rate of mutation accumulation throughout life. Off-target effects of immunological diversification accounted for most of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every one on-target IGV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than stem cells, with ~15% of deletions being attributable to off-target RAG activity. Mutational processes associated with ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory lymphocytes. The mutation burden and signatures of normal B lymphocytes were broadly comparable to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.	HiSeq X Ten	1
EGAD00001015339	In developed countries, ~10% of individuals are exposed to systemic chemotherapy for cancer and other diseases. Many chemotherapeutic agents act by increasing DNA damage in cancer cells, hence triggering cell death. However, there is limited understanding of the extent and consequences of collateral DNA damage to normal tissues. To investigate the impact of chemotherapy on mutation burdens and cell population structure of a normal tissue we sequenced blood cell genomes from 23 individuals, aged 3-80 years, treated with a range of chemotherapy regimens. Substantial additional mutation loads with characteristic mutational signatures were imposed by some chemotherapeutic agents, but there were differences in burden between different classes of agent, different agents of the same class and different blood cell types. Chemotherapy also induced premature changes in the cell population structure of normal blood, similar to those of normal ageing. The results constitute an initial survey of the long-term biological consequences of cytotoxic agents to which a substantial fraction of the population is exposed during the course of their disease management, raising mechanistic questions and highlighting opportunities for mitigation of adverse effects.	HiSeq X Ten Illumina NovaSeq 6000	1

Publications	Citations
Clonal dynamics of haematopoiesis across the human lifespan. 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. Nature 606: 2022 343-350	166
Mitochondrial DNA mosaicism in normal human somatic cells. An J, Nam CH, Kim R, Lee Y, Won H, Park S, Lee WH, Park H, Yoon CJ, An Y, Kim JH, Jun JK, Bae JM, Shin EC, Kim B, Cha YJ, Kwon HW, Oh JW, Park JY, Kim MJ, Ju YS. Nat Genet 56: 2024 1665-1677	2
Prolonged persistence of mutagenic DNA lesions in somatic cells. Spencer Chapman M, Mitchell E, Yoshida K, Williams N, Fabre MA, Ranzoni AM, Robinson PS, Kregar LD, Wilk M, Boettcher S, Mahbubani K, Saeb Parsy K, Gowers KHC, Janes SM, Ng SWK, Hoare M, Green AR, Vassiliou GS, Cvejic A, Manz MG, Laurenti E, Martincorena I, Stratton MR, Nangalia J, Coorens THH, Campbell PJ. Nature 638: 2025 729-738	0