Biology subjects

Singh, A.

Publications and source records attributed to Singh, A..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

One-Pot NADH-Mediated Physiological Redox-Controlled Synthesis of Papain-Stabilized Copper Nanoclusters with Preserved Bioactivity for Efficient Drug Delivery

Protein-protected copper nanoclusters are promising candidates for bioimaging and therapeutic applications. However, harsh reducing conditions required for their synthesis, compromising the proteins structural integrity and bioactivity. Here, we report a one-pot, physiologically compatible aqueous synthesis for papain-protected copper nanoclusters (Pap-CuNCs) with blue photoluminescence and excellent photostability using nicotinamide adenine dinucleotide (NADH) as a biological reducing agent. The mild conditions (ambient temperature, neutral pH) enable the simultaneous formation of a metallic Cu0 core while stabilizing the helical content of the protein. This approach introduces a physiologically redox-controlled strategy for nanocluster formation, establishing physiological redox chemistry as a governing principle for controlling nanoscale structure and protein conformational stability. Spectroscopic and microscopic studies have demonstrated the presence of crystalline nanoclusters with a protein corona that undergoes -helical stabilization as revealed by circular dichroism. Notably, atomistic simulation studies reveal preferential binding of the copper core in the proteins active site, enhancing the -helical content of papain, consistent with experimental observations. Functionally, the Pap-CuNCs possess biocompatibility and serve as an effective delivery platform for 5-fluorouracil, leading to a 50-fold decrease in IC50 for HeLa cells without causing cytotoxicity to normal cells. This establishes a generalizable framework for bio-integrated nanocluster design under biologically compatible conditions. TOC Text O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=44 SRC="FIGDIR/small/719779v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1ca9292org.highwire.dtl.DTLVardef@5cd82aorg.highwire.dtl.DTLVardef@173ed2forg.highwire.dtl.DTLVardef@1d8c30c_HPS_FORMAT_FIGEXP M_FIG C_FIG NADH-mediated physiological redox synthesis of papain-stabilized copper nanoclusters with enhanced -helical stability. This bio-integrated nanoplatform facilitates drug loading and delivery, resulting in a [~]50-fold increase in cytotoxicity in cancer cells while maintaining excellent biocompatibility toward normal cells.

bioengineering↗

bioRxiv2026

Gene Expression Variability with Feedback Regulation Implemented via Protein-Dependent Cell Growth

Variability in gene expression among single cells and growing cell populations can arise from the stochastic nature of protein synthesis, which often occurs in random bursts. This study investigates the variability in the expression of a growth-sustaining protein, whose concentration is regulated by a negative feedback loop due to cell growth-induced dilution. We model the distribution of protein concentration using a Chapman-Kolmogorov equation for single cells and a population balance equation for growing cell populations. For single cells, we derive an explicit solution for the protein concentration distribution in state space and represent it as a Bessel function in Laplace space. For growing populations, we find that the distribution satisfies a Heun differential equation with singular boundary conditions. By addressing the central connection problem for the Heun equation, we quantify the population-level protein distribution and determine the Mathusian parameter, which characterizes population growth. This work provides a comprehensive analytical framework for understanding how stochastic protein synthesis impacts gene expression variability and population dynamics.

systems biology↗

bioRxiv2026

Dietary Oxysterols Reprogram Hepatic Lipid Metabolism and Reshape the Gut Metabolome-Microbiome Interface

Dietary oxysterols are biologically active cholesterol oxidation products ubiquitous in Western diets, yet their systemic effects on host metabolism and the gut microbiome remain largely unexplored. Here, we employed an integrated multi-omics approach - shotgun metagenomics, quantitative proteomics, untargeted metabolomics, and bulk RNA-seq - to characterize the impact of DOxS exposure on the gut-liver axis in rats fed a Western diet (WD vs. WD-DOxS). Hepatic proteomics revealed near-complete suppression of the mevalonate/cholesterol biosynthesis pathway, particularly in males, while de novo lipogenesis enzymes (Scd1, Fasn, Plin2) were paradoxically upregulated, consistent with dual oxysterol signaling through SREBP inhibition and LXR activation. Bile acid synthesis was concurrently suppressed, confirmed by metabolomics. Strikingly, RNA-seq across liver, heart, and brain detected virtually no differentially expressed genes, establishing that DOxS act predominantly through post-transcriptional mechanisms. In the gut, DOxS increased microbial -diversity while depleting Limosilactobacillus reuteri, with concomitant loss of the barrier-protective metabolite 3-indoleacrylic acid. Tissue-specific responses were widespread, with liver and colon frequently mounting opposing metabolic and immune responses to the same dietary challenge. Cross-omics integration revealed convergent microbiome-metabolite axes connecting microbial remodeling to both hepatic lipid reprogramming and colonic barrier disruption. These findings reposition dietary oxysterols from food-quality markers to active modulators of the gut-liver axis, with implications for metabolic disease and intestinal barrier integrity.

biochemistry↗

bioRxiv2026

Thermoaminiphila catenidiffluenda gen. nov., sp. nov.: A novel thermophilic, strictly anaerobic bacterium representing Thermoaminiphilia class nov., a newly described class thriving in hydrocarbon-rich habitats and biogas fermenters

Axenic cultivation of novel bacterial lineages, referred to as "gold standard in microbiology", remains challenging for fastidious or uncultured taxa due the challenges of replicating adequate growth conditions. We isolated strain PM69, a representative of the previously undescribed Bacillota class SHA-98, from a phenyl acid degrading, oligotrophic batch culture. By employing a broad spectrum of (anaerobic) culture techniques, biochemical, physiological, and genomic analyses, we characterised the strain as Thermoaminiphila catenidiffluenda, gen. nov., sp. nov., a thermophilic, strictly anaerobic, bacterium fermenting monosaccharides to acetate. Its motility, biofilm forming capacity, and ecological niche in biogas fermenters and hydrocarbon-associated habitats suggest adaptive strategies for harsh environments exhibiting e.g., high concentrations of aromatic compounds. This description of a new bacterial class not only expands the taxonomic diversity of phylum Bacillota but also provides insights into the metabolic versatility of yet uncultured microorganisms, with implications for carbon cycling and biotechnological applications. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/718153v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1501615org.highwire.dtl.DTLVardef@d9cfd6org.highwire.dtl.DTLVardef@1dc019borg.highwire.dtl.DTLVardef@ed6f3f_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2026

REST-AKT-SOX2 axis controls neuronal lineage state and Midkine-mediated communication in SHH-medulloblastoma.

Stem/progenitor-like cells are known drivers of tumor progression, chemoresistance, and relapse in Sonic-Hedgehog medulloblastoma (SHH-MB), yet the regulatory mechanisms that sustain these resilient cellular states remain incompletely defined. Here, we identify the RE1-silencing transcription factor (REST) as a key transcriptional regulator that preserves the progenitor compartment in SHH-MB through stabilization of the stemness factor SOX2. Mechanistically, REST activates AKT signaling, which in turn enhances SOX2 protein stability, revealing a REST-AKT-SOX2 axis that supports stem/progenitor identity and ongoing tumor maintenance. Beyond maintaining intrinsic stem-like programs, REST also orchestrates the extrinsic communication network of SHH-MB tumors. Single cell transcriptomic profiling and ligand-receptor interaction mapping highlight Midkine (MDK)-mediated signaling as one of the most upregulated intercellular communication routes in MB. We demonstrate that REST drives this signaling cascade through its control of SOX2. Perturbation of REST or SOX2 results in reduced MDK and its receptor, SDC2 expression, and chromatin immunoprecipitation assays show that SOX2 directly binds and regulates MDK/SDC2 expression, establishing and reinforcing a REST/SOX2 centered transcriptional mechanism that coordinates both progenitor maintenance and cell-cell communication in the malignant compartment. Together, these findings position REST as an integrator of intrinsic progenitor cell programs and extrinsic MDK-mediated signaling in SHH-MB. By linking stemness, communication and potential for therapeutic resistance, the REST-AKT-SOX2-MDK signaling axis emerges as a targetable vulnerability to suppress stem/progenitor driven tumor program in REST-driven SHH-MBs.

cancer biology↗

bioRxiv2026

SETD5 dysfunction in human astrocytes drives IL-6-mediated neuronal impairments via the JAK/STAT signaling pathway

Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental conditions marked by lifelong impairments in cognitive, motor, and social functions. Hundreds of genetic variants have been linked to these disorders, including mutations in chromatin regulators such as the SET-domain-containing protein 5 (SETD5) gene. Most studies linking SETD5 loss-of-function to ASD/ID have focused primarily on neurons. However, while SETD5 is highly expressed in astrocytes, its role in glia cells remains poorly understood. Here, we examine how dysfunction of SETD5 in human-induced pluripotent stem cell (hiPSC)-derived astrocytes affects neuronal physiology. We show that SETD5-deficient astrocytes have increased levels of extracellular reactive oxygen species (ROS), glutamate, and interleukins-6 and 8 (IL-6 and IL-8). Elevated astrocytic IL-6 exerts a non-cell autonomous harmful effect on healthy neurons. Using SETD5-deficient astrocytes as a screening platform, we identify the JAK/STAT pathway as an upstream regulator of abnormal IL-6 accumulation associated with SETD5 dysfunction. Accordingly, pharmacological inhibition of JAK-STAT signaling restores extracellular IL-6 to basal levels and partially rescues astrocyte morphology and neuronal deficits. Collectively, these findings highlight the JAK/STAT pathway as a key regulator of SETD5-mediated astrocytic function and suggest its potential as a therapeutic target for astrocytic-driven neuronal impairments in ASD and ID.

neuroscience↗

bioRxiv2026

KNOB K180 CONSTITUTIVE HETEROCHROMATIN OF MAIZE EXHIBIT TISSUE-SPECIFIC CHROMATIN SENSTITIVE PROFILES DISTINCT FROM OTHER TYPES OF HETEROCHROMATINS

BackgroundMaize knobs are regions of constitutive heterochromatin that are readily identified in both meiotic and somatic chromosomes. These structures have been characterized as stable throughout the cell cycle, exhibiting late replication during the S-phase, and are composed of two specific families of highly repetitive DNA sequences: K180 and TR-1. Although widely used as cytogenetic markers due to their variability in number and chromosomal position across inbred lines, hybrids, and landraces, little is known about their chromatin structure and dynamics. In this study, we analyzed chromatin accessibility of knobs using DNS-seq data across four maize tissues representing distinct developmental stages. ResultsOur results reveal that K180 knobs exhibit tissue-specific variation in chromatin accessibility, transitioning between open and closed states during development. In contrast, the TR-1 knob of chromosome 4 remained consistently inaccessible across all tissues analyzed. A knob composed of both K180, and TR-1 further supported this observation, with only the K180 region showing dynamic accessibility. To validate these findings, we also analyzed other repetitive regions such as centromeres, which showed a uniformly closed chromatin structure similar to TR-1. These results suggest a unique developmental modulation of chromatin accessibility associated with K180 repeats. While the chromatin accessibility of knobs does not reach the levels observed at Transcription Start Sites (TSS), the comparison among different classes of repetitive DNA within maize constitutive heterochromatin provides compelling evidence for sequence-specific and tissue-specific chromatin dynamics. ConclusionsOur findings uncover a previously unrecognized property of maize knobs and establish a reference for future studies on chromatin organization and epigenetic regulation of repetitive DNA in plant genomes.

genetics↗

bioRxiv2026

Domestication drives changes in floral functional traits that impact generalist pollinator visitation

Crop domestication is an evolutionary process that has led to extraordinary plant phenotypic changes in response to artificial selection. The extent to which domestication has altered floral phenotypes and the implications of these changes for plant-pollinator interactions remain unclear. Here, we characterized the floral phenotypes of wild and domesticated species in the genus Cucurbita (squash and pumpkins) and quantified their relative attractiveness to generalist and specialist pollinators. Our results show that functional floral traits change with domestication and that some of these changes impact the visitation of generalist pollinators but not specialists. Crops displayed larger flowers with shorter anthers and wider corollas, lower volatile richness, higher sugar content in pollen, and lower sucrose:glucose ratios in nectar. These trait shifts were associated with pollinator behavior in generalist pollinators, which preferentially visited domesticated flowers. We demonstrate that domestication alters functional plant traits and that these changes affect generalist pollinator preference in agricultural settings.

ecology↗

bioRxiv2026

Stochastic Gene Expression Model with State-Dependent Protein Activation Delay

Cells must maintain stable protein levels despite the inherently stochastic nature of gene expression, as excessive fluctuations can disrupt cellular function and impair the reliability of decision-making. Regulatory mechanisms, such as negative feedback, buffer protein fluctuations. Yet, it remains unclear how fluctuations are affected by delays that depend on a molecules specific state. Here, we develop a stochastic model in which proteins are produced in bursts as inactive molecules and pass through a series of intermediate steps before becoming active. The duration of such activation delays depends on the current level of active protein, creating a state-dependent feedback loop. Our model provides explicit analytical expressions relating the delay structure and feedback strength to the variability of active protein levels, quantified using the Fano factor, and shows that state-dependent delays can reduce fluctuations below the baseline expected from simple bursty production. Stochastic simulations confirm these predictions, and incorporating negative feedback in burst production further decreases variability while keeping system behavior predictable. These results reveal how temporal and state-dependent regulation stabilizes protein expression, offering guidance for understanding natural cellular control and designing robust synthetic gene circuits.

systems biology↗

bioRxiv2026

All-trans retinoic acid recalibrates macrophage transcriptional responses to drug-resistant Mycobacterium tuberculosis through strain-specific immunometabolic reprogramming

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) remains the leading infectious cause of death worldwide, with multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains presenting an escalating therapeutic crisis. All-trans retinoic acid (ATRA), an active vitamin A metabolite with established immunomodulatory properties, has emerged as a candidate host-directed therapy, yet its genome-wide transcriptional effects on macrophage across strains of differing drug-resistance profiles remain uncharacterized. We performed RNA sequencing of murine peritoneal macrophages infected with drug-susceptible H37Rv, MDR-2261, or XDR-MCY M.tb strains, with and without ATRA treatment, validated by RT-PCR and flow cytometry. All three strains activated a conserved pro-inflammatory program dominated by Nos2, Il1b, and Acod1 induction with progressive suppression of host translational and mitochondrial machinery. XDR-MCY uniquely induced Ifnb1/IFN-{beta}, suppressed Prdx1 and Gpx4, the latter shared with MDR-2261 and showed selective downregulation of MHC-II processing genes, suggesting a multilayered immune evasion strategy. ATRA activated canonical retinoid signaling across all infection states and consistently induced Arg1-mediated resolution signaling, with Nos2 suppression observed in H37Rv- and MDR-infected macrophages. ATRA selectively restored Epas1/HIF-2 in H37Rv- and MDR-infected macrophages without disrupting the HIF-1-driven antimicrobial program or itaconate biosynthesis. ATRA responsiveness progressively attenuated with drug resistance, with XDR-MCY-infected macrophages largely refractory to transcriptional reprogramming. These findings provide a transcriptional rationale for evaluating ATRA as a host-directed adjunct in drug-resistant TB and identify Gpx4 suppression in drug-resistant strains and XDR-specific Ifnb1 induction as vulnerabilities necessitating further investigation.

microbiology↗

bioRxiv2026

Postsynaptic integration of excitatory and inhibitory signals based on an adaptive firing threshold

A key component of intraneuronal communication is the modulation of postsynaptic firing frequencies by stochastic transmitter release from presynaptic neurons. The time interval between successive postsynaptic firings is called the inter-spike interval (ISI), and understanding its statistics is integral to neural information processing. We start with a model of an excitatory chemical synapse with postsynaptic neuron firing governed as per a classical integrate-and-fire model. Using a first-passage time framework, we derive exact analytical results for the ISI statistical moments, revealing parameter regimes driving precision in postsynaptic action potential timing. Next, we extended this analysis to include both an excitatory and an inhibitory presynaptic connection onto the same postsynaptic neuron. We consider both a fixed postsynaptic-firing threshold and a threshold that adapts based on the postsynaptic membrane potential history. Our analysis shows that the latter adaptive threshold can result in scenarios where increasing the inhibitory input frequency increases the postsynaptic firing frequency. Moreover, we characterize parameter regimes where ISI noise is hypo-exponential or hyperexponential based on its coefficient of variation being less than or higher than one, respectively.

neuroscience↗

bioRxiv2026

DNA ligase Lig E increases transformation with damaged extracellular DNA

Lig E is a periplasm-targeted ATP-dependent DNA ligase found in many Gram-negative bacteria including Neisseria gonorrhoeae. Although Lig E has been shown to have a role in biofilm formation, many Lig E-possessing bacteria are also naturally competent, suggesting a possible function in transformation with extracellular DNA. Here, we demonstrate that Lig E participates in bacterial competence by increasing transformation with nuclease-damaged extracellular DNA that contains single-stranded or cohesive breaks. We show that increased transformation with this restricted DNA is ATP-dependent, and that the ATP concentration increases in the extracellular milieu during maintenance of N. gonorrhoeae in liquid culture. Impact StatementNatural transformation is an important route of horizontal gene transfer that enables competent bacteria to acquire novel phenotypic traits such as antibiotic resistance or virulence factors. By demonstrating that Lig E increases transformation of N. gonorrhoeae with damaged resistance-encoding DNA, we provide a mechanism which competent bacteria can use to overcome nucleolytic damage sustained by environmental DNA, making this more readily available as a source of novel and potentially pathogen-enhancing genes.

microbiology↗

bioRxiv2026

Morphotype-Resolved 3D Morphometry Reveals a Structure-Density-Location Coupling in Mitochondrial Networks

Mitochondrial architecture plays a critical role in cellular function, yet how organelle structure, metabolic density, and subcellular position are jointly remodeled across whole cells remains poorly understood. We applied quantitative 3D soft X-ray tomography to analyze intact INS-1E cells in a native, cryo-hydrated state. By integrating morphometric profiling with voxel-level linear absorption coefficients (LAC) and contour-based radial mapping, we tracked the structural, biochemical, and spatial remodeling of fragmented, intermediate, and interconnected mitochondrial morphotypes under high glucose and Exendin-4 stimulation. High glucose induces morphotype-specific hypertrophy, fission, and perinuclear redistribution of low-density fragments. Co-stimulation with Exendin-4 stabilizes interconnected networks and increases metabolic density at the cell periphery. Morphotype-resolved analysis uncovers a structure-density-location coupling in which mitochondrial shape, macromolecular packing, and radial position shift in concert. These results offer a quantitative framework and high-resolution spatial constraints for whole-cell modeling of organelle dynamics. HighlightsO_LIMitochondrial morphotypes occupy distinct regions during metabolic stimulation C_LIO_LIHigh glucose drives early mitochondrial swelling, fission, and spatial dispersion C_LIO_LIExendin-4 prevents structural collapse and preserves dense interconnected networks C_LIO_LIMorphotype-resolved analysis uncovers a structure-density-location coupling in mitochondrial networks. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/712811v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1d495ecorg.highwire.dtl.DTLVardef@1bee80dorg.highwire.dtl.DTLVardef@74df9dorg.highwire.dtl.DTLVardef@104db6d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

FMR1 reduction alters cellular and circuit properties in human cortex

Transcriptional silencing of FMR1 results in Fragile X syndrome (FXS), the leading inherited cause of intellectual disability (ID) and autism. The Fmr1-/y mouse model has been used to identify FXS disease mechanisms, whereas mechanistic insights from human brain are lacking. By leveraging organotypic human cortical slices and viral tools to reduce FMR1 expression, we create a new model that captures cell type-specific transcriptomic changes similar to FXS patient cortex that are not seen in the Fmr1-/y mouse. Among these are ion channel subunit changes in deep layer pyramidal neurons, which are consistent with a robust hyperexcitability seen by whole-cell patch-clamp recordings, and increased synchronized activity revealed by 2-photon calcium imaging. Together, this work defines the impact of FMR1 reduction in human cortex and provides a new model for testing therapeutic interventions in FXS.

neuroscience↗

bioRxiv2026

Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation

Methotrexate (MTX) therapy in inflammatory bowel disease (IBD) is often limited by inter-individual variability in clinical response and adverse effects. Gut microbiota contribute to MTX therapeutic response and toxicity by metabolizing MTX and altering its bioavailability. However, how inflammation alters microbial MTX metabolism and how its metabolites influence the host remain poorly understood. Here, we identify Clostridium asparagiforme as a potent and efficient metabolizer of methotrexate, producing deoxyaminopteroic acid (DAMPA) in the distal gastrointestinal tract. We demonstrate that DAMPA preserves mitochondrial integrity by promoting mitophagy in intestinal epithelial cells through mitochondrial STAT3 signaling. DAMPA administration attenuates intestinal inflammation in vivo, and improves metabolic dysfunction associated with IBD. Together, these findings reveal an unappreciated role for a gut microbial MTX metabolite in mediating epithelial homeostasis during intestinal inflammation, thus reframing microbial MTX metabolism from passive drug detoxification to active regulation of host mitochondrial and inflammatory homeostasis.

microbiology↗

bioRxiv2026

MESSI: Multimodal Experiments with SyStematic Interrogation using nextflow

BackgroundMultimodal biomedical studies increasingly profile multiple molecular and clinical modalities from the same samples, creating new opportunities for disease prediction and biological discovery. However, benchmarking multimodal integration methods remains difficult because studies often use inconsistent preprocessing, unequal tuning strategies, and non-comparable evaluation schemes, limiting fair assessment across methods. ResultsWe developed MESSI (Multimodal Experiments with SyStematic Interrogation), a reproducible Nextflow-based benchmarking framework for multimodal outcome prediction that standardizes data preparation, supports interoperable R and Python workflows, and enforces leakage-free nested cross-validation for model selection and model assessment. MESSI currently implements representative intermediate- and late-integration methods and supports bulk multiomics, bulk multimodal, and single-cell multiomics datasets. In simulation studies with known ground truth, most methods were well calibrated in the absence of signal and achieved high performance under strong signal, whereas differences emerged under weaker signal and in feature recovery. We then applied MESSI to 19 real datasets spanning cancer, neurodevelopmental, neurodegenerative, infectious, renal, transplant, and metastatic disease settings, with diverse modality combinations including transcriptomic, epigenomic, proteomic, imaging, electrical, clinical, and single-cell-derived features. Across bulk multimodal datasets, classification differences were generally modest, although DIABLO and multiview cooperative learning tended to rank highest, while MOFA+glmnet and MOGONET were weaker overall. Biological enrichment analyses revealed clearer differences: DIABLO, RGCCA, MOFA, and IntegrAO more consistently recovered significant Reactome, oncogenic, and tissue-relevant gene signatures. In single-cell multiomics benchmarks, method rankings were more dataset dependent, but DIABLO performed consistently well across all case studies, while RGCCA also showed strong performance in specific settings. Computational analyses further showed that DIABLO and MOFA had the most favorable runtime and memory profiles, whereas multiview was the most time-intensive and IntegrAO the most memory-demanding. ConclusionsMESSI provides a reproducible, extensible, and equitable framework for benchmarking multimodal integration methods under a common model assessment strategy. Our results indicate that no single method is uniformly optimal across datasets and objectives; instead, method choice should balance predictive performance, biological interpretability, and computational efficiency. MESSI establishes a foundation for transparent benchmarking and future extensions to broader multimodal learning tasks.

bioinformatics↗

bioRxiv2026

Pleiotropy and repeated mutation drove convergent domestication of grain amaranth

Humans reshaped environments for domesticated plants, yet the extent of human agency in the domestication process remains unresolved. Color variation has been used as evidence for an intended process by humans, as the trait has been mainly linked to visual properties. In the ancient pseudocereal grain amaranth major domestication traits have not changed, but the seed color changed repeatedly from dark to white during multiple domestication processes. Here, we show that the transition to white seed color was of major ecological significance beyond human preference through mechanistic links to seed germination. We identify major metabolomic and transcriptomic changes in the proanthocyanidin pathway leading to loss of seed color and dormancy in domesticated amaranth. Despite the potentially large mutational target size of the proanthocyanidin pathway, the repeated mutation in a single gene led to the domestication phenotype. Multiple independent knock-out mutations in this gene reveal the repeated selection for the loss of seed dormancy in different parts of the Americas. Competition experiments show that the pleiotropic link between seed color and seed dormancy provides a competitive advantage to white seeds in agricultural environments. The reduction of proanthocyanidin content in the seed is observed in numerous crops, including rice and beans, suggesting a common ecological adaptation after early humans altered their environment through changing lifestyles. Our findings establish a direct mechanistic link between individual mutations, pathway-level biochemical reconfiguration, and ecological fitness, illustrating how plants adapted to human-modified environments largely without intentional human agency.

evolutionary biology↗

bioRxiv2026

Interclonal cooperation and suppression shape early Ras-driven tumour growth

Cancer is generally thought to be caused by expansion of a single mutant cell. However, analyses of human early lesions show that tumours can originate from several genetically distinct cell populations1-5. How neighbouring mutant clones interact to shape tumourigenesis, and which driver genes mediate these effects is largely unexplored. Here, we use an in vivo mosaic Drosophila epithelial model to systematically test interclonal interactions during early Ras-driven tumourigenesis. We screened 88 recurrent RAS co-mutated driver genes in human carcinomas for their ability to modify Ras-clone growth when disrupted in neighbouring epithelial clones. This uncovered two opposing classes of interactions: Interclonal cooperativity, where neighbouring mutant clones promote the overgrowth of Ras mutant tumours, and interclonal suppression, in which neighbours restrain Ras tumours, unexpectedly improving host survival. The strongest suppressive modifiers included canonical cell competition regulators, including Myc, archipelago (ago/FBXW7), and taiman (tai/NCOA1-3). In contrast, the strongest cooperative modifiers were disruptions of XNP/ATRX and SWI/SNF chromatin remodelling subunits (including Osa/ARID1A, Bap170/ARID2, Polybromo/PBRM1, among others), which in neighbouring cells induce a wound-like inflammatory program and drive an anabolic, pro-growth state in Ras tumours. Notably, the disruption of SWI/SNF components cell autonomously within Ras tumours confers no cooperativity. We show that interclonal cooperative Ras tumour growth requires reactive oxidative species and prostaglandin synthesis in SWI/SNF-disrupted clones. Together, this study provides a catalogue and emerging principles of cooperative and suppressive interclonal interactions among recurrent RAS co-mutated drivers, extending the rules of oncogenic cooperation beyond cell intrinsic co-mutation.

cancer biology↗