A5006194205- Cancer Genomics and Diagnostics
- Acute Myeloid Leukemia Research
- Single-cell and spatial transcriptomics
- Evolution and Genetic Dynamics
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Hematopoietic Stem Cell Transplantation
- SARS-CoV-2 and COVID-19 Research
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Epigenetics and DNA Methylation
- SARS-CoV-2 detection and testing
- Geriatric Care and Nursing Homes
- Genomics and Rare Diseases
- Mitochondrial Function and Pathology
- CAR-T cell therapy research
- Multiple Myeloma Research and Treatments
- Zebrafish Biomedical Research Applications
- Iron Metabolism and Disorders
- T-cell and B-cell Immunology
- Bacteriophages and microbial interactions
- Hemoglobinopathies and Related Disorders
- Mesenchymal stem cell research
- Motor Control and Adaptation
- Polyomavirus and related diseases
- Chromatin Remodeling and Cancer
Wellcome Sanger Institute
2012-2025
Wellcome/MRC Cambridge Stem Cell Institute
2021-2024
University of Cambridge
2021-2024
British Society for Haematology
2022
Hammersmith Hospital
2018-2021
Imperial College Healthcare NHS Trust
2020-2021
Cambridge University Hospitals NHS Foundation Trust
2020
St Mary's Hospital
2018
St. Mary's Hospital
2018
Barts Health NHS Trust
2015
Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity 1 , cytopenias 2 immune dysfunction 3 and increased risk of blood cancer 4–6 but the reason for such abrupt functional decline after 70 years age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies haematopoietic cells across 10 subjects 0 to 81 age. Haematopoietic stem or multipotent progenitors (HSC/MPPs) accumulated a mean 17 mutations per year birth lost 30 base pairs...
Abstract Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where phenomenon is termed clonal haematopoiesis 1–4 . The understanding of how and when develops, factors that govern its behaviour, it interacts ageing these variables relate to malignant progression remains limited 5,6 Here we track 697 clones from 385 individuals 55 years age or older over a median 13 years. We find 92.4% expanded at stable...
Starting from the zygote, all cells in human body continuously acquire mutations. Mutations shared between different imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues three adult individuals using whole-genome sequencing 511 laser capture microdissections. Reconstructed embryonic progenitors same generation phylogeny often contribute to extents body. The degree this asymmetry varies...
Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around world. The modest mutation rate rapid prevents reconstruction from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe patterns in 1181 samples sequenced to high depth duplicate. 95.1% show mutations at detectable allele frequencies. Analyses mutational spectra revealed strong...
Abstract Human aging is marked by the emergence of a tapestry clonal expansions in dividing tissues, particularly evident blood as hematopoiesis (CH). CH, linked to cancer risk and aging-related phenotypes, often stems from somatic mutations set established genes. However, majority clones lack known drivers. Here we infer gene-level positive selection whole exomes 200,618 individuals UK Biobank. We identify 17 additional genes, ZBTB33 , ZNF318 ZNF234 SPRED2 SH2B3 SRCAP SIK3 SRSF1 CHEK2...
Abstract DNA is subject to continual damage, leaving each cell with thousands of individual lesions at any given moment 1–3 . The efficiency repair means that most known classes lesion have a half-life minutes hours 3,4 , but the extent which damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising 818 persisted across multiple cycles in normal human stem cells blood, liver and bronchial epithelium...
Abstract Gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD); however, the occurrence of myeloid malignancies in GT clinical trials has prompted concern, several postulated mechanisms. Here, we used whole-genome sequencing to track hematopoietic stem cells (HSCs) from six SCD at pre- and post-GT time points map somatic mutation clonal landscape gene-modified unmodified HSCs. Pre-GT, phylogenetic trees were highly polyclonal burdens...
<title>Abstract</title> Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those harvested from a donor, and is received by 40,000 patients worldwide each year. To quantify dynamics of long-term engraftment, we sequenced whole genomes 2,824 single-cell-derived colonies samples 10 donor-recipient pairs taken 9-31 years after HLA-matched sibling HCT. With younger donors, 10,000–50,000 had engrafted were still contributing to...
Abstract Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those from a donor 1,2 . Here, to quantify dynamics of long-term engraftment, we sequenced genomes 2,824 single-cell-derived colonies ten donor–recipient pairs taken 9–31 years after HLA-matched sibling HCT 3 With younger donors (18–47 at transplant), 5,000–30,000 had engrafted and were still contributing haematopoiesis time sampling; estimates tenfold lower older...
Abstract 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 cells, triggering cell death. However, there is limited understanding the extent long-term consequences collateral normal tissues. To investigate impact on mutation burdens population structure a tissue we sequenced blood genomes from 23 individuals, aged 3–80 years, treated with range regimens. Substantial...
Abstract Progressive dysfunction of mitochondria, organelles responsible for energy provision to cells, is a major hallmark ageing. How the steadily accrues over lifetime remains unclear, given transient nature free radical damage and high turnover mitochondria. Here, we leveraged whole-genome sequencing data from single-cell derived foetal adult haematopoietic stem/progenitor cell colonies study clonal dynamics selection in mitochondrial genomes throughout life. We found that genetic drift...
COVID-19 poses a major challenge to care homes, as SARS-CoV-2 is readily transmitted and causes disproportionately severe disease in older people. Here, 1167 residents from 337 homes were identified dataset of 6600 cases the East England. Older age being home resident associated with increased mortality. genomes available for 700 292 homes. By integrating genomic temporal data, 409 viral clusters within identified, indicating two different patterns – outbreaks among independent introductions...
Monitoring the spread of SARS-CoV-2 and reconstructing transmission chains has become a major public health focus for many governments around world. The modest mutation rate rapid prevents reconstruction from consensus genome sequences, but within-host genetic diversity could theoretically help identify close contacts. Here we describe patterns in 1,181 samples sequenced to high depth duplicate. 95% show mutations at detectable allele frequencies. Analyses mutational spectra revealed strong...
Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations lose clonal diversity with age, processes implicated in the development of myeloid malignancies
Abstract Sequencing mitochondrial DNA (mtDNA) variants from single cells has resolved clonality and lineage in native human samples clinical specimens. Prior work established that heteroplasmic mtDNA can be used to delineate hematopoiesis, but they have limited ability reconstruct cellular phylogenies. However, a recent report by Weng et al . challenges the current paradigm describing an unprecedented number of shared between reportedly resolve high-resolution phylogenetic trees. We...
Summary Human cells acquire somatic mutations throughout life, some of which can drive clonal expansion. Such expansions are frequent in the haematopoietic system healthy individuals and have been termed haematopoiesis (CH). While CH predisposes to myeloid neoplasia other diseases, we limited understanding how when develops, what factors govern its behaviour, it interacts with ageing these variables relate malignant progression. Here, track 697 clones from 385 aged 55 or older over a median...
Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity 1 , cytopenias 2 immune dysfunction 3 and increased risk of blood cancer. The cellular alterations that underpin the abruptness this functional decline after age 70 years remain elusive. We sequenced 3579 genomes from single-cell-derived colonies haematopoietic stem cell/multipotent progenitors (HSC/MPPs) across 10 haematologically normal subjects aged 0-81 years. HSC/MPPs accumulated 17 mutations/year...
Abstract DNA suffers continual damage leaving a cell with thousands of individual lesions at any given moment 1–3 . The efficiency repair means that most known classes lesion have half-life minutes to hours 3,4 , but whether some can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising 832 persisted across multiple cycles in normal human stem cells blood, liver and bronchial epithelium 5–12 Persistent...
Summary. This study aimed to assess the potential of human cord blood (CB) cells engraft in xenogenic non‐obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model after vitro expansion culture. We also studied quality haemopoiesis arising from transplantation fresh or expanded this model. Cord CD34 + were cultured for 3, 7 10 d with stem cell factor, Flt3, thrombopoietin, interleukin 3 (IL‐3), IL‐6 and granulocyte colony‐stimulating all at ng/ml serum‐replete conditions....
Abstract 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) 511 single-cell derived colonies from healthy foetuses 8 and 18 post-conception weeks (pcw) coupled with deep targeted tissues known embryonic origin to reconstruct a phylogenetic tree blood development. We found that in foetuses, individual progenitors acquire tens somatic mutations by pcw....
Abstract COVID-19 poses a major challenge to care homes, as SARS-CoV-2 is readily transmitted and causes disproportionately severe disease in older people. Here, 1,167 residents from 337 homes were identified dataset of 6,600 cases the East England. Older age being home resident associated with increased mortality. genomes available for 700 292 homes. By integrating genomic temporal data, 409 viral clusters within identified, indicating two different patterns - outbreaks among independent...