Biology subjects

Fowler, J. C.

Publications and source records attributed to Fowler, J. C..

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↗

bioRxiv2026

Atmospheric nitrogen deposition and anthropogenic land use linked to changing fungal endophyte prevalence in cool-season grasses

Background and AimsAnthropogenic global change is altering the environmental stressors facing plants and their microbial symbionts. Changes in drought and temperature have received wide attention, but how other pervasive human impacts - land conversion for agricultural development and urbanization, and changes in nutrient conditions and pollutants - impact plant- microbe symbioses is relatively unknown. Here, we investigated how these anthropogenic global change drivers influence historic changes in the prevalence of widespread symbionts of grasses, Epichloe fungal endophytes. MethodsWe examined 8,739 seeds from 1,951 herbarium specimens collected between 1895 and 2019 for the presence of seed-transmitted Epichloe fungal endophytes in three grass host species (Agrostis hyemalis, Agrostis perennans, and Elymus virginicus). We hypothesized that the symbiosis provides fitness benefits under anthropogenic stresses (i.e. increased nitrogen deposition and land use change) that should translate to increased prevalence of the interaction among specimens exposed to those stresses. Key ResultsAnthropogenic stresses had contrasting effects on endophyte prevalence. Notably, among Agrostis host species, high nitrogen deposition was associated with high endophyte prevalence and with increasing trends in prevalence through time. We also found that highly urbanized landscapes were associated with reduced prevalence and negative temporal trends in endophyte prevalence across species. We also identified a weak positive relationship between agricultural land cover and average endophyte prevalence for Elymus virginicus, though temporal trends in prevalence did not differ between high and low levels of agricultural land cover. ConclusionsAnthropogenic stressors influenced endophyte prevalence in diverse ways. While we found increasing prevalence in the face of nitrogen deposition, a sign of the potential resilience of the symbiosis, urban land cover was associated with declining endophyte prevalence, a sign that anthropogenic activity may contribute to a breakdown of the symbiosis.

ecology↗

bioRxiv2026

Do microbial effects on hosts vary across life stage and vitalrate?

Interactions with microbial symbionts are widespread and can influence host fitness through effects on survival, growth, and reproduction. Demographic and evolutionary theory suggests that symbiont effects on components of host fitness should often vary in strength and even in direction as host and symbiont allocate limited resources. Through a meta-analysis of 1,736 host-symbiont effect size measurements, we evaluated how commonly the direction of symbiont effects varies across host life history stages and vital rates, and whether these effects across stages and vital rates differ across taxa. Contrary to our prediction, we found that, compared to a null expectation, published effects on host vital rates more often occurred consistently in the same direction, rather than in opposition. This finding suggests that symbiosis often provides benefits to host performance that manifest across vital rates. While the direction of symbiotic effect was often consistent, the magnitude of effects differed across fitness components and across host taxonomic groups, highlighting diverse demographic mechanisms by which symbiosis can influence host fitness. For hosts in the Poaceae family, we also found that effects of symbiosis varied across symbiont type: vertically-transmitted Epichloe fungi most strongly benefited seed germination, while the benefits of mycorrhizal fungi and bacterial endophytes were stronger for adult growth and reproduction. Importantly, this literature survey also highlights gaps in the current literature on host-microbe symbiosis. Most studies measure growth during juvenile stages for taxa from iconic, well-studied symbioses. Meta-analytic estimates of symbiotic effects on host life history provide a path towards quantitatively modeling host-symbiont demography across the tree of life.

ecology↗

bioRxiv2025

Climate variability disrupts mutualism-driven increases in population persistence

Understanding how species interactions impact population dynamics and long-term persistence over broad temporal and spatial scales is crucial for predicting species distributions and responses to global change. Here, we integrate range-wide field surveys of [~]90 grass host populations spanning 13 years with demographic modeling based on six-year common garden experiments conducted across the host range to demonstrate that mutualistic fungal endophytes promote population-level persistence and growth of their native host grass across its distribution, with non-mutualistic populations four times more likely to go locally extinct. Despite providing population-level benefits, endophyte prevalence declined eight-fold more in historically mutualistic populations that experienced high climate variability. Thus, mutualisms can underpin population persistence and buffer hosts against environmental stress, but may themselves be vulnerable to global change, with concerning implications for long-term population viability and, ultimately, species distributions under an increasingly uncertain climate.

ecology↗

bioRxiv2025

Estrogen Receptors/E2F1/CDKN3 Axis Protects from UV-induced Skin Cancers in Females

Men have a significantly higher risk of developing cutaneous squamous cell carcinoma (SCC) compared to women, but models and comprehensive analysis of signaling pathways highlighting this sexual dimorphism are missing. In this study, we display a UV-induced SCC model in hairless mice recapitulating this sex difference, with enhanced SCC development in males. While UV-induced DNA damage is similar between sexes, we uncovered sex-specific responses in epidermal cell proliferation and differentiation. Using global transcriptional profile analyses, we identified E2F transcription factors as key sex-specific markers involved in the proliferative response to UV. Notably, E2F1/2, along with their target gene CDKN3, were selectively downregulated in female mice and human epidermis following UV exposure. Mechanistically, UV-induced and sex-specific modulation of E2F1 and CDKN3 expression is mediated by Estrogen Receptors. Lastly, low levels of CDKN3 in head and neck SCC are observed exclusively in female patients correlating with better prognosis. These findings shed new light on fundamental mechanisms protecting women from cancer after carcinogen exposure and could lead to better sex-targeted preventive and therapeutic strategies in SCC and other malignancies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/637819v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@7edcc5org.highwire.dtl.DTLVardef@d0215corg.highwire.dtl.DTLVardef@3e248forg.highwire.dtl.DTLVardef@1d25cb9_HPS_FORMAT_FIGEXP M_FIG C_FIG Sex differences in UV-Induced cutaneous Squamous Cell Carcinoma: key insights into female cancer protection

cancer biology↗

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↗

bioRxiv2024

Increasing prevalence of plant-fungal symbiosis across two centuries of environmental change

Species distributions and abundances are shifting in response to ongoing global climate change. Mutualistic microbial symbionts can provide hosts with protection from environmental stress that may promote resilience under environmental change, however this change may also disrupt species interactions and lead to declines in hosts and/or symbionts. Symbionts preserved within natural history specimens offer a unique opportunity to quantify changes in microbial symbiosis across broad temporal and spatial scales. We asked how the prevalence of seed-transmitted fungal symbionts of grasses (Epichloe endophytes) has changed over time in response to climate change, and how these changes vary across host species distributions. Specifically, we examined 2,346 herbarium specimens of three grass host species (Agrostis hyemalis, Agrostis perennans, Elymus virginicus ) collected over the past two centuries (1824 - 2019) for the presence or absence of Epichloe symbiosis. Analysis of an approximate Bayesian spatially-varying coefficients model revealed that endophytes increased in prevalence over the last two centuries from ca. 25% to ca. 75% prevalence, on average, across three host species. Changes in seasonal climate drivers were associated with increasing endophyte prevalence. Notably, increasing precipitation during the peak growing season for Agrostis species and decreasing precipitation for E. virginicus were associated with increasing endophyte prevalence. Changes in the variability of precipitation and temperature during off-peak seasons were also important predictors of increasing endophyte prevalence. Our model performed favorably in an out-of-sample predictive test with contemporary survey data from across 63 populations, a rare extra step in collections-based research. However, there was greater local-scale variability in endophyte prevalence in contemporary data compared to model predictions, suggesting new directions that could improve predictive accuracy. Our results provide novel evidence for a cryptic biological response to climate change that may contribute to the resilience of host-microbe symbiosis through fitness benefits to symbiotic hosts.

ecology↗

bioRxiv2024

Pre-cancerous Niche Remodelling Dictates Nascent Tumour Survival

Interactions between mutant cells and their environment play a key role in determining cancer susceptibility. However, our understanding of how the pre-cancer microenvironment contributes to early tumorigenesis remains limited. Here, we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive "pre-cancer niche", which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound healing response that triggers a dramatic remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour-derived stroma, demonstrate that the pre-cancerous niche alone is sufficient to confer tumour properties to healthy epithelial cells. We propose a model where both mutations and the stromal response to genetic stress defines the likelihood of early tumours to survive and progress towards more advanced disease stages.

cancer biology↗

bioRxiv2021

Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors

Human epithelial tissues accumulate cancer-driver mutations with age1-7, yet tumor formation remains rare. The positive selection of these mutations argues they alter the behavior and fitness of proliferating cells8-10. Hence, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less-competitive neighbors9-12. However, little is known about how such dynamic competition in normal epithelia impacts early tumorigenesis. Here we show that the majority of newly formed esophageal tumors are eliminated through competition with mutant clones in the surrounding normal epithelium. We followed the fate of microscopic tumors in a mouse model of esophageal carcinogenesis. Most neoplasms are rapidly lost despite no indication of tumor cell death, decreased proliferation, or an anti-tumor immune response. Deep-sequencing of 10-day and 1-year-old tumors shows evidence of genetic selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased tumor removal, while pharmacologically inhibiting clonal competition reduced tumor loss. The results are consistent with a model where survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the adjacent normal tissue. We have identified an unexpected anti-tumorigenic role for mutant clones in normal epithelium by purging early neoplasms through cell competition, thereby preserving tissue integrity.

cancer biology↗

bioRxiv2021

Notch1 mutation drives clonal expansion in normal esophageal epithelium but impairs tumor growth

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age, but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations may promote clonal expansion but impede carcinogenesis1-3. Here we test this hypothesis. Visualizing and sequencing NOTCH1 mutant clones in aging normal human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild type cells, an effect enhanced by loss of the second allele. Notch1 loss alters transcription but has minimal effects on epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. We conclude that Notch1 mutations in normal epithelium are beneficial as wild type Notch1 promotes tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.

cancer biology↗