Biology subjects

Jones, P. H.

Publications and source records attributed to Jones, P. H..

10 recordsLinked to original sources

bioRxiv2026

A comprehensive atlas of somatic mutation rates and mutational signatures in normal human cells

Over the course of a lifetime, somatic mutations accrue in normal human cells, causing variation in cell phenotype and engendering somatic evolution with outcomes ranging from the adaptive immune system to cancer. To inform understanding of somatic evolution in the human body we report the mutation rates and mutational signatures of 53 normal cell types. Most show evidence of linear mutation accumulation over time with single base substitution mutation rates ranging from ~3.5/year/diploid genome in spermatogonia and sperm, to ~20/year in postmitotic neurons, ~50/year in mitotically active colorectal epithelial cells, ~60/year in kidney proximal tubule cells and hepatocytes, 100s/year in sun-exposed skin epidermal cells and 10-50/year in the remainder. Certain cell types, including skin epidermis, cardiac myocytes, bladder urothelium, kidney proximal tubule cells, and hepatocytes, show substantial variability in mutation burdens around the linear age trend, indicating the influence of additional factors which differ between individuals and modulate mutation accumulation, including exogenous mutagen exposures. At least 18 single-base substitution and nine small insertion and deletion mutational signatures are present, some in all cell types, some in a subset and others in a single cell type. Known exogenous mutagen exposures and endogenous mutational processes account for some mutational signatures, but the origins and mechanisms underlying many are uncertain. This comprehensive survey of mutagenesis provides a foundation for understanding somatic evolution of human cell populations in health and disease.

genomics↗

bioRxiv2024

Somatic mutant selection is altered by prior NOTCH1 mutation in aging esophageal epithelium

The ageing mid esophagus is progressively colonized by somatic mutations, including oncogenic TP53 and antioncogenic NOTCH1 mutants. Most esophageal squamous carcinomas are TP53 mutant, NOTCH1 wild type. By middle age, much of the esophagus is NOTCH1 mutant. We hypothesised that prior NOTCH1 mutation may alter subsequent mutant selection. Here we show that selection of mutant NOTCH2 was increased and mutant TP53 decreased within NOTCH1 mutant epithelium. Potential mechanisms include spatial competition between adjacent clones and/or epistasis altering the fitness NOTCH1 double mutants. We investigated these possibilities in transgenic mice. Spontaneous Notch2 mutant clones emerged in aged Notch1 null, but not wild type, esophagus, consistent with epistasis increasing Notch1/Notch2 double mutant fitness. However, there was no evidence of epistasis between Notch1 and Trp53, as Notch1 mutation alone increased fitness. In consequence, over time, Trp53 mutant Notch1 wild type clones were outcompeted by expanding Notch1 and Trp53/Notch1 mutants. NOTCH1 mutant takeover of the aging esophagus alters the trajectory of somatic evolution, decreasing selection of TP53 mutants and potentially reducing cancer risk.

genomics↗

bioRxiv2023

Modelling red blood cell optical trapping by machine learning improved geometrical optics calculations

Optically trapping red blood cells allows to explore their biophysical properties, which are affected in many diseases. However, because of their nonspherical shape, the numerical calculation of the optical forces is slow, limiting the range of situations that can be explored. Here we train a neural network that improves both the accuracy and the speed of the calculation and we employ it to simulate the motion of a red blood cell under different beam configurations. We found that by fixing two beams and controlling the position of a third, it is possible to control the tilting of the cell. We anticipate this work to be a promising approach to study the trapping of complex shaped and inhomogeneous biological materials, where the possible photodamage imposes restrictions in the beam power.

biophysics↗

bioRxiv2023

Epithelioids: Self-sustaining 3D epithelial cultures to study long-term processes

Studying long-term biological processes such as the colonization of aging epithelia by somatic mutant clones has been slowed by the lack of suitable culture systems. Here we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia. Esophageal epithelioids self-maintain without passaging for at least a year, recapitulating the 3D structure, cell dynamics, transcriptome, and genomic stability of the esophagus. Live imaging over 5 months showed epithelioids replicate in vivo cell dynamics. Epithelioids enable the study of cell competition and mutant selection in 3D epithelia, and how anti-cancer treatments modulate the competition between transformed and wild type cells. Epithelioids are a novel method with a wide range of applications in epithelial tissues, particularly the study of long term processes, that cannot be accessed using other culture models.

cell biology↗

bioRxiv2022

p53 mutation in normal esophagus promotes multiple stages of carcinogenesis but is constrained by clonal competition

Aging normal human epithelia, such as the esophagus, accumulate a substantial burden of TP53 mutant clones. These are the origin of most esophageal squamous carcinomas, in which biallelic TP53 disruption is almost frequent. However, the cellular mechanisms by which p53 mutants colonize the esophagus and participate in the subsequent stages of transformation are unclear. Here we show that inducing the p53R245W mutant in single esophageal progenitor cells in transgenic mice confers a proliferative advantage that drives clonal expansion but does not disrupt normal epithelial structure or function. Loss of the remaining p53 allele in mutant cells does not increase their competitive fitness, creating a bottleneck to the development of chromosomally unstable p53R245W/null epithelium. In carcinogenesis, p53 mutation does not initiate tumor formation, but tumors developing from areas with p53 mutation and LOH are larger and show extensive chromosomal instability compared to lesions arising in wild type epithelium. We conclude that p53 has distinct functions at different stages of carcinogenesis and that LOH within p53 mutant clones in normal epithelium is a critical step in malignant transformation.

cancer biology↗

bioRxiv2021

Levelling out differences in aerobic glycolysis neutralizes the competitive advantage of oncogenic PIK3CA mutant progenitors in the esophagus

Normal human tissues progressively accumulate cells carrying mutations. Activating mutations in PIK3CA generate large clones in the aging human esophagus, but the underlying cellular mechanisms are unclear. Here, we tracked mutant PIK3CA esophageal progenitor cells in transgenic mice by lineage tracing. Expression of an activating heterozygous Pik3caH1047R mutation in single progenitor cells tilts cell fate towards proliferation, generating mutant clones that outcompete their wild type neighbors. The mutation leads to increased aerobic glycolysis through the activation of Hif1 transcriptional targets compared with wild type cells. We found that interventions that level out the difference in activation of the PI3K/HIF1/aerobic glycolysis axis between wild type and mutant cells attenuate the competitive advantage of Pik3caH1047R mutant cells in vitro and in vivo. Our results suggest that clinically feasible interventions that even out signaling imbalances between wild type and mutant cells may limit the expansion of oncogenic mutants in normal epithelia.

cancer biology↗

bioRxiv2020

Methods for analysing lineage tracing datasets

A single population of stem cells maintains many epithelial tissues. Transgenic mouse cell tracking has frequently been used to study the growth dynamics of competing clones in these tissues. A mathematical model (the single progenitor model) has been argued to reproduce the observed stem cell dynamics accurately. This requires three parameters to describe the growth dynamics observed in transgenic mouse cell tracking- a division rate, a stratification rate, and the probability of dividing symmetrically. Deriving these parameters is time intensive and complex process. We compare the alternative strategies for analysing this source of experimental data, identifying an approximate Bayesian computation-based approach as the best in terms of efficiency and appropriate error estimation. We support our findings by explicitly modelling biological variation and consider the impact of different sampling regimes. All tested solutions are made available to allow new datasets to be analysed following our workflows. Based on our findings we make recommendations for future experimental design.

systems biology↗

bioRxiv2019

Membrane tension mediated mechanotransduction drives fate choice in embryonic stem cells

Changes in cell shape and mechanics frequently accompany cell fate transitions. Yet how mechanics affects the regulatory path-ways controlling cell fate is poorly understood. To probe the interplay between shape, mechanics and fate, we used embryonic stem (ES) cells, which spread as they undergo early differentiation. We found that this spreading is regulated by a beta-catenin mediated decrease in plasma membrane tension. Strikingly, preventing the membrane tension decrease obstructs early differentiation of ES cells. We further find that blocking the decrease in membrane tension inhibits endocytosis of FGF signalling components, which direct the exit from the ES cell state. The early differentiation defects we observed can be rescued by increasing Rab5a-facilitated endocytosis. Thus, we show that a mechanically-triggered increase in endocytosis regulates fate transitions. Our findings are of fundamental importance for understanding how cell mechanics regulates biochemical signaling, and therefore cell fate.

cell biology↗

bioRxiv2019

The single-progenitor model as the unifying paradigm of squamous epithelial maintenance

Adult tissues such as the epidermis of the skin and the epithelium lining the esophagus are continuously turned over throughout life. Cells are shed from the tissue surface and replaced by cell division. Yet, the cellular mechanisms that underpin these tissues homeostasis remain poorly established, having important implications for wound healing and carcinogenesis. Lineage tracing, in which of a cohort of proliferating cells and their descendants are genetically labelled in transgenic mice, has been used to study the fate behavior of the proliferating cells that maintain these tissues. However, based on this technique, distinct mutually irreconcilable models, differing in the implored number and hierarchy of proliferating cell types, have been proposed to explain homeostasis. To elucidate which of these conflicting scenarios should prevail, here we performed cell proliferation assays across multiple body sites in transgenic H2BGFP mouse epidermis and esophagus. Cell-cycle properties were then extracted from the H2BGFP dilution kinetics and adopted in a common analytic approach for a refined analysis of a new lineage-tracing experiment and eight published clonal data sets from esophagus and different skin territories. Our results show H2BGFP dilution profiles remained unimodal over time, indicating the absence of slow-cycling stem cells across all tissues analyzed. We find that despite using diverse genetic labelling approaches, all lineage-tracing data sets are consistent with tissues maintenance by a single population of proliferating cells. The outcome of a given division is unpredictable but, on average the likelihood of producing proliferating and differentiating cells is balanced, ensuring tissue homeostasis. The fate outcomes of sister cells are anticorrelated. We conclude a single cell population maintains squamous epithelial homeostasis.

cell biology↗

bioRxiv2018

Relating evolutionary selection and mutant clonal dynamics in normal epithelia

Cancer develops from mutated cells in normal tissues. Whether somatic mutations alter normal cell dynamics is key to understanding cancer risk and guiding interventions to reduce it. An analysis of the first incomplete moment of size distributions of clones carrying cancer-associated mutations in normal human eyelid skin gives a good fit with neutral drift, arguing mutations do not affect cell fate. However, this suggestion conflicts with genetic evidence in the same dataset that argues for strong positive selection of a subset of mutations. This implies cells carrying these mutations have a competitive advantage over normal cells, leading to large clonal expansions within the tissue. In normal epithelium, clone growth is constrained by the limited size of the proliferating compartment and competition with surrounding cells. We show that if these factors are taken into account, the first incomplete moment of the clone size distribution is unable to exclude non-neutral behavior. Furthermore, experimental factors can make a non-neutral clone size distribution appear neutral. We validate these principles with a new experimental data set showing that when experiments are appropriately designed, the first incomplete moment can be a useful indicator of non-neutral competition. Finally, we discuss the complex relationship between mutant clone sizes and genetic selection.\n\nSignificance StatementAging normal epithelial tissues are extensively colonised by clones carrying cancer associated mutations. Insight into the emergence of mutant clones is key to guide cancer prevention. However, the statistical evidence as to whether mutant clones emerge by neutral competition or due to a competitive advantage conferred by mutation is conflicted. We reconcile this apparent contradiction by demonstrating that the previously presented metrics for measuring neutrality from clone sizes are dependent on the spatial constraints imposed by the tissue structure and experimental design. Furthermore, we show that clonal competition within a recently reported dataset of healthy human oesophageal tissue is non-neutral. Finally, we discuss how discrepancies between measures of clone size and genetic selection can provide insight into early carcinogenesis.

cancer biology↗