Biology subjects

Spencer Chapman, M.

Publications and source records attributed to Spencer Chapman, M..

4 recordsLinked to original sources

bioRxiv2026

Persistence of tobacco-mutated alveolar progenitor cells after smoking cessation mirrors long term risk of lung adenocarcinoma

Tobacco smoke shapes mutations, selection and clonal expansion in lung epithelial cells. Smoking cessation leads to divergent epidemiology in the two most common lung cancers: squamous cell carcinoma risk declines sharply, while adenocarcinoma risk is preserved. To investigate this discrepancy, we analysed 806 genomes of alveolar type II (AT2) cells and found persistently elevated mutation burdens after cessation. In contrast, in the proximal airway, rare basal stem cells with near-normal mutation burden expand after cessation, protecting against squamous cell carcinoma. Targeted single-molecule DNA sequencing of AT2 cells revealed positive selection for TP53 and cell cycle and MAPK genes, supporting continued cancer risk. A multistage carcinogenesis model emphasised the importance of a small population of hypermutated cells in the alveoli and reproduced the divergent epidemiological trajectories following cessation due to distinct regenerative dynamics. Our findings suggest that differences in mutational burden and clonal regeneration explain post-cessation trends in lung cancer subtypes. One sentence summaryCancer risk reflects not only cumulative exposure to toxins, but the capacity of tissues to erase genomic damage through regeneration from protected cells with clonal advantage.

genomics↗

bioRxiv2024

The long-term effects of chemotherapy on normal blood cells

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, triggering cell death. However, there is limited understanding of the extent and long-term 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.

cell biology↗

bioRxiv2021

Clonal dynamics of haematopoiesis across the human lifespan

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer. The cellular alterations that underpin the abruptness of this functional decline after the age of 70 years remain elusive. We sequenced 3579 genomes from single-cell-derived colonies of haematopoietic stem cell/multipotent progenitors (HSC/MPPs) across 10 haematologically normal subjects aged 0-81 years. HSC/MPPs accumulated 17 mutations/year after birth and lost 30bp/year of telomere length. Haematopoiesis in adults aged <65 was massively polyclonal, with high indices of clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. In contrast, haematopoiesis in individuals aged >75 showed profoundly decreased clonal diversity. In each elderly subject, 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 age 40, but only 22% had known driver mutations. Genome-wide selection analysis estimated that 1/34 to 1/12 non-synonymous mutations were drivers, occurring at a constant rate throughout life, affecting a wider pool of genes than identified in blood cancers. Loss of Y chromosome conferred selective benefits on HSC/MPPs in males. Simulations from a simple model of haematopoiesis, with constant HSC 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.

genomics↗

bioRxiv2020

Lineage tracing of human embryonic development and foetal haematopoiesis through somatic mutations

To date, ontogeny of the human haematopoietic system during foetal development has been characterized mainly through careful microscopic observations. Here we used whole-genome sequencing (WGS) of 511 single-cell derived haematopoietic colonies from healthy human foetuses of 8 and 18 post-conception weeks (pcw) coupled with deep targeted sequencing of tissues of known embryonic origin to reconstruct a phylogenetic tree of blood development. We found that in healthy foetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 pcw. Using these mutations as barcodes, we timed the divergence of embryonic and extra-embryonic tissues during development and estimated the number of blood antecedents at different stages of embryonic development. Our analysis has shown that ectoderm originates from a smaller set of blood antecedents compared to endoderm and mesoderm. Finally, our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.

genomics↗