Alex Cagan's research while affiliated with Wellcome Sanger Institute and other places

Publications (36)

Article
Full-text available
The lymphocyte genome is prone to many threats, including programmed mutation during differentiation¹, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoieti...
Article
Full-text available
Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here,...
Article
Full-text available
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 of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10...
Article
Full-text available
The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1–7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208...
Preprint
Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here,...
Article
The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authori...
Article
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Over the course of an individual’s lifetime, normal human cells accumulate mutations¹. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but...
Article
Full-text available
Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser...
Preprint
Full-text available
The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species and on long-standing hypotheses regarding the evolution of somatic mutation rates and their role in cancer and ageing. Here, we used whole-genome sequencing of 208 int...
Preprint
Age-related change in human haematopoiesis causes reduced regenerative capacity, cytopenias, immune dysfunction 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 s...
Article
Full-text available
Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanor...
Preprint
Full-text available
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...
Article
Somatic mutations accumulate in healthy tissues as we age, giving rise to cancer and potentially contributing to ageing. To study somatic mutations in non-neoplastic tissues, we developed a series of protocols to sequence the genomes of small populations of cells isolated from histological sections. Here, we describe a complete workflow that combin...
Preprint
Full-text available
During the course of a lifetime normal human cells accumulate mutations. Here, using multiple samples from the same individuals we compared the mutational landscape in 29 anatomical structures from soma and the germline. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types but t...
Preprint
Full-text available
Starting from the zygote, all cells in the developing and adult human body continuously acquire mutations. A mutation shared between two different cells implies a shared progenitor cell and can thus be used as a naturally occurring marker for lineage tracing. Here, we reconstruct extensive phylogenies of normal tissues from three adult individuals...
Article
The acquisition of mutations within the genome of hematopoietic stem cells (HSCs) is of particular importance as this is a likely driver of malignant transformation for many leukemias, as well as a hallmark of aging. Importantly, the study of normal physiologic mediators of HSC mutation acquisition is an underdeveloped area. We have developed a met...
Article
Full-text available
Background: Pancreatic organoid systems have recently been described for the in vitro culture of pancreatic ductal cells from mouse and human. Mouse pancreatic organoids exhibit unlimited expansion potential, while previously reported human pancreas organoid (hPO) cultures do not expand efficiently long-term in a chemically defined, serum-free med...
Article
Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 c...
Article
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Tissue-resident immune cells are important for organ homeostasis and defense. The epithelium may contribute to these functions directly or by cross-talk with immune cells. We used single-cell RNA sequencing to resolve the spatiotemporal immune topology of the human kidney. We reveal anatomically defined expression patterns of immune genes within th...
Article
Full-text available
Background: Full Bayesian inference for detecting copy number variants (CNV) from whole-genome sequencing (WGS) data is still largely infeasible due to computational demands. A recently introduced approach to perform Forward-Backward Gibbs sampling using dynamic Haar wavelet compression has alleviated issues of convergence and, to some extent, spe...
Data
Table S6. Mutations Detected by Deep-Exome Sequencing Analyzed by Shearwater, Related to Figures 7 and S7 See STAR Methods for details.
Data
A visualization of the non-spatial simulation shown in Figure 7F. A transgenic mutant (green) is induced at 1% frequency in a background of wild-type cells (yellow). Subsequently, new mutations (shades of green if in transgenic cells, other colors if in wild-type cells) are induced at random and assigned a fitness value as described in the Suppleme...
Data
Table S1. Differentially Expressed Genes from RNA-Seq Analysis, Related to Figures 2, S4, and S5
Data
Table S7. Source Data and Statistical Tests for Figures, Related to Figures 3, 4, 5, 6, 7, S2, S4, S5, and S7
Article
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by...
Preprint
Full-text available
Inflammation in autoimmune disease is mediated by a complex network of interacting cells. Their identity and cross-talk are encoded in messenger RNA (mRNA). Juvenile idiopathic arthritis (JIA), a chronic autoimmune arthritis of childhood, is characterised by synovial inflammation with infiltration of both innate and adaptive immune cells. Activated...
Article
Full-text available
Aging human tissues, such as sun-exposed epidermis, accumulate a high burden of progenitor cells that carry oncogenic mutations. However, most progenitors carrying such mutations colonize and persist in normal tissue without forming tumors. Here, we investigated tissue-level constraints on clonal progenitor behavior by inducing a single-allele p53...
Article
Full-text available
Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cel...

Citations

... Analyses of the mutation spectrum in humans indicate that 75% of DNMs and 80% of mutations in adult seminiferous tubules are due to mutation 'signatures' SBS5/40 (Rahbari et al., 2016;Moore et al., 2021), which are clock-like, uncorrelated with cell division rates in the soma (Alexandrov et al., 2015;Alexandrov et al., 2020), and also predominant in post-mitotic cell types such as neurons (Lodato et al., 2018;Abascal et al., 2021). In addition, most substitutions in post-pubertal germ cell tumors are attributed to SBS5/40, in both females and males (Oliver et al., 2022). More generally, cell division rates do not appear to be a major determinant of mutation rates across somatic tissues (Blokzijl et al., 2016): notably, post-mitotic neurons accumulate mutations at a similar rate as mitotic somatic cell types that are the product of ongoing cell divisions (Abascal et al., 2021). ...
... They detected around 450 SNVs per cells in a 26-year-old donor and around 1,000 SNVs per cell in people in their sixties (Osorio et al., 2018). Machado et al. (2022) found SNVs to increase in memory T lymphocytes at a rate of 25 per cell per year, a little faster than in naïve T lymphocytes where the rate was 22 per cell per year. Somatic mutation rates in memory (17 SNVs/cell/year) and naïve B lymphocytes (15 SNVs/ Linear fitted from published SNVs counts per cell with the age of donors. ...
... Specifically, in mixed chimeric animals exposed to SF, Tet2mutant cells expand at a faster rate relative to animals whose sleep was unaltered, resulting in mutants encompassing a greater proportion of blood myeloid cells and BM HSPCs (Heyde et al., 2021). However, the majority of CH cases arise in the absence of detectable driver mutations (Zink et al., 2017;Poon et al., 2021;Mitchell et al., 2022). We predicted that heightened proliferation of HSPCs would not only accelerate the expansion of mutant clones but would also expedite neutral evolutionrandom fluctuations in mutant frequencies due to stochastic loss and self-renewal of HSPCs (Heyde et al., 2021). ...
... The significance of the cost of reproduction as a cause of mortality appears to be variable among fish populations and is fundamentally contested (Hutchings, 1994;Kuparinen et al., 2012;Trippel et al., 2014). Senescence is a decline in individual biological function with age and is thought to result from multiple underlying mechanisms including oxidative damage, accumulation of alleles whose deleterious expression during old age falls beyond the effective reach of natural selection, or accumulation of somatic mutations (Carnes et al., 1996;Cagan et al., 2022;Purchase et al., 2022). Senescence may affect reproductive performance (reproductive senescence) or mortality (actuarial senescence). ...
... Another genomic analysis of the B.1.177 lineage in England showed it had a small advantage relative to the other lineages in September 2020 [51], although the advantage was not seen in all of the sublineages of B.1.177. However, almost 80% of all the B.1.177 ...
... From all GI cancers, SBS1, SBS5 and SBS40 signatures have been most frequently found in colorectal adenocarcinomas and SBS5 is ubiquitous also in benign GI tissues (3,12). Both SBS5 and SBS40 are flat signatures, and their misattribution has not been excluded (3,13). The activity of both SBS5 and SBS40 correlate with age, but the etiology especially behind SBS40 is still unknown (3). ...
... For example, mTOR-pathway-activating somatic mutations cause two types of intractable epilepsy (hemimegalencephaly and focal cortical dysplasia) depending on the time of occurrence of the mutation and VAFs (10%-30% VAFs in hemimegalencephaly, and 1%-10% of VAFs in focal cortical dysplasia) [8][9][10]. Advances in genetic technologies and increased sequencing efficiencies have helped identify characteristics of somatic mutations at the single-cell or mono-clonal levels [11][12][13][14][15]. However, the detectable variants identified using these methods may not be fully representative of the tissue types and mutational processes involved because of the technical challenges associated with single-cell sequencing (e.g., whole gene amplification), restricted cell types (e.g., stem/progenitor cell or reprogrammed cells), or culturing procedure used. ...
... The patterns of aging-related somatic mutagenesis are conserved even across mammalian species with the mutation rate inversely correlated with species lifespan. This suggests that beyond risk of cancer, somatic mutation rate may be a determinant of lifespan (14). Mathematical reconstruction of HSPC lineage histories suggests that CH mutations may arise as early as childhood (even in utero) with some mutations undergoing a gradual expansion throughout life (11,15). ...
... Article using them to reconstruct lineage relationships among both malignant and normal blood cells in patients with MPN 20 . As somatic mutation burden does not differ significantly between HSCs and myeloid progenitors [20][21][22][23] , we undertook WGS of in vitro expanded single-cell-derived haematopoietic colonies as faithful surrogates for the genomes of their parental HSCs. We 'recaptured' somatic mutations in bulk peripheral blood cells using targeted sequencing to longitudinally track clones (Fig. 1a). ...
... Prostatic epithelium (Grossmann et al., 2021;Moore et al., 2021). HSPCs (Osorio et al., 2018;Abascal et al., 2021;Machado et al., 2021;Mitchell et al., 2021). Satellite cells (Franco et al., 2018). ...