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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2026

Half-match recombination drives bridge RNA-guided excision and off-target insertion

IS110-family bridge recombinases are a recently identified class of compact, RNA-guided editors in which a bridge RNA (bRNA) directs the recombination of a donor DNA into a target site. In the current model, the bRNA engages fully complementary donor and target sequences within a single synaptic complex to drive double-stranded recombination, implying that the transposon is cut from its donor site rather than copied, yet neither the strandedness of the excised intermediate nor the requirement for full complementarity has been tested directly. Here we reconstituted IS621 recombination in a cell-free transcription-translation system, building representative arrangements of the excision and insertion reactions and characterizing the outcomes. We find that IS621 predominantly excises a single strand, releasing a single-stranded circle and leaving the donor site intact, consistent with copy-and-paste transposition. By introducing mismatches into the bRNA target sequences, we further find that excision proceeds independently of target-site complementarity, relying strictly on donor-arm recognition; we term this "half-match" recombination, because a substrate matching only half of the bRNA is sufficient. We also find half-match activity during insertion, both in vitro and in a published genome-editing experiment, where it accounts for approximately half of non-target insertion reads. Half-match recombination provides both a mechanistic explanation for off-target insertion and a framework for the rational design of high-fidelity bridge recombinases.

molecular biology↗

bioRxiv2026

Inheritance of a Single Edited CD46 Allele Is Associated with Reduced Ex Vivo Susceptibility to Bovine Viral Diarrhea Virus

Bovine viral diarrhea virus (BVDV) remains an economically important pathogen of cattle despite widespread vaccination. A homozygous CD46-edited Gir heifer (Ginger) was previously shown to have significantly reduced susceptibility to BVDV. The edited allele contains an in-frame six amino acid substitution within the virus-binding domain of the BVDV entry receptor CD46, replacing residues G82QVLAL with A82LPTFS. Here, we investigated whether reduced BVDV susceptibility is maintained when the edited allele is inherited in the heterozygous state. Ginger was artificially inseminated with semen from an unedited Gir bull and produced a healthy heterozygous CD46-edited bull calf (Giraldo). Whole-genome sequencing confirmed the inheritance and structural integrity of Giraldo's edited allele. Compared with Ginger, Giraldo exhibited similarly reduced ex vivo BVDV susceptibility across primary fibroblasts, lymphocytes, and monocytes, despite inheriting a wild-type CD46 allele from the sire. Allele-specific CD46 RNA expression analysis demonstrated expression of both the edited and wild-type CD46 alleles. Thus, the reduced-susceptibility phenotype was not attributable to transcriptional silencing of the wild-type allele. Lentiviral complementation studies in CD46-knockout Madin-Darby bovine kidney (MDBK) cells further demonstrated that this wild-type CD46 allele was competent to support BVDV infection when expressed independently. Together, these findings indicate that the CD46 A82LPTFS allele can confer reduced BVDV susceptibility in the heterozygous state despite expression of a functional wild-type CD46 allele. This result suggests the potential to more rapidly disseminate reduced BVDV susceptibility through conventional breeding using homozygous CD46-edited sires.

molecular biology↗

bioRxiv2026

A replicated patient-specific component of tumour telomere length across two pan-cancer cohorts

Bulk telomere length measured from tumour sequencing is routinely interpreted as a property of the cancer cells. However, a tumour specimen is a mixture, and the patient who supplies it has a telomere length of their own. Here I re-analyse published pan-cancer telomere estimates and ask how much of a tumour's telomere length is patient-specific. A calibration step comes first. Whole-genome and low-pass estimates recover the known cross-sectional attrition of leukocyte telomeres with age, at 26.6 bp per year in blood normals, whereas whole-exome estimates do not. After adjustment for cancer type, sequencing centre and sex, the exome slope is minus 0.6 bp per year. In 684 blood-normal aliquots sequenced by both assays, the whole-genome estimate declines at 38.9 bp per year, whereas the exome estimate from the same DNA shows no detectable decline. The difference between assays is 41.5 bp per year, with P = 3 x 10^-10. Because exome data constitute 78.6% of the original resource, downstream analyses use only whole-genome and low-pass libraries. Within those data, tumour telomere length tracks the patient's matched-normal telomere length. The Spearman correlation is 0.395 in TCGA, with positive associations in 22 of 23 cancer types. This finding replicates in PCAWG using a different telomere estimator, with a correlation of 0.472 and positive associations in all 24 histologies examined. Adjustment for cancer type, sequencing centre and library type leaves a regression coefficient of 0.385. The association is also stable after adjustment for age, sex, tumour purity, leukocyte fraction, ploidy, sequencing coverage and continental ancestry, with coefficients ranging from 0.406 to 0.429. Pure normal-cell admixture is rejected as the sole explanation. Under a two-compartment mixture model, the coefficient for host telomere length is expected to equal 1 and the host-by-purity interaction to equal minus 1. These restrictions are jointly rejected with P = 0.001. Tumour purity, leukocyte fraction and age each explain only about 1 to 3% of within-cohort variance and do not alter the cross-cancer ranking. By contrast, the between-cohort coefficient is not directly interpretable. Its apparent near one-to-one relationship with tissue-associated telomere length depends strongly on which tissue supplies the matched-normal reference and on the statistical spread of that predictor, falling to 0.44 when organ-matched solid tissue is used. Bulk tumour telomere length is therefore a composite phenotype containing a replicated patient-specific component. Telomere biomarker studies should include matched-normal telomere length as a covariate rather than treating tumour telomere length as exclusively tumour-intrinsic.

cancer biology↗

bioRxiv2026

From Prompt to Provenance: BloClaw, a Capability-Gated AI4S Workstation for Auditable Computational Biology

Scientific agents can produce plausible answers while remaining unable to establish whether the computation behind an answer is executable, recoverable, or reproducible. We present BloClaw, an AI4S workstation built around a simple principle: a scientific agent should know what it can do, show how it did it, and state what remains unvalidated. Each capability declares an execution state, input constraints, dependencies, expected outputs, and scientific limitations. Natural-language requests are translated into structured tasks, validated against this registry, executed through scientific tools, and recorded in a provenance-aware Living Lab Notebook. The system is designed to detect invalid inputs, failed tool calls, missing dependencies, and remote timeouts, and to route them to repair, retry, or escalation. The implemented and tested scope comprises RDKit-based molecular property and rule screening, protein structure analysis, docking-pose inspection, 3D visualization, and structured reporting. We demonstrate the workflow on a PubChem-retrieved osimertinib structure and a supplied 6LU7 docking artifact: the former yields deterministic descriptors (molecular weight 499.619 Da, cLogP 4.5098, TPSA 87.55 A^2), while the latter contains 2,387 protein ATOM records, 309 residues, and nine pose records. These examples are workflow demonstrations, not efficacy or affinity studies. Beyond retrospective prediction, the manuscript specifies a prior-minimized constructive mode in which a desired function is compiled into explicit physical, chemical, and systems constraints, candidate mechanisms are simulated, and observations are reintroduced for calibration and falsification; this is a proposed extension rather than a result of the present case studies. We describe an evaluation protocol that compares BloClaw with a standard single-agent workflow and fixed-script execution using task completion, scientific correctness, recovery success, provenance completeness, reproducibility, human review time, latency, and cost. This manuscript reports the system design, verified capability boundary, deterministic software artifacts, and a reproducible evaluation protocol; it does not claim benchmark improvements before those experiments are run. BloClaw is an execution and accountability layer for AI-assisted research, complementing expert review and experimental validation rather than replacing them.

bioinformatics↗

bioRxiv2026

Uncertainty Quantification in Stochastic Dynamical Gene Regulatory Networks

The dynamics of gene regulatory networks are governed by intrinsic noise, stemming from the random nature of biochemical reactions, and by extrinsic noise, arising from fluctuations in cellular components and environmental conditions. Together, these sources can compromise the reliability of predictive computational models if not properly accounted for, and capturing both effects within a single framework remains a non-trivial task in computational biology. In this work, we propose an uncertainty quantification framework that addresses these two contributions jointly: intrinsic stochasticity is described through a partial integro-differential equation (PIDE) for the protein probability density function, whereas extrinsic noise is represented as parametric uncertainty in the kinetic parameters. The propagation of the uncertainty is carried out via an intrusive polynomial chaos expansion (PCE), in which the PCE coefficients are obtained from a stochastic Galerkin projection of the PIDE, yielding a coupled deterministic system that is solved with standard numerical methods. We illustrate the approach on a positive autoregulatory gene network with one and two uncertain kinetic parameters. The proposed approach accurately reproduces the mean, variance, and full protein probability density function, including the bimodal distributions, at a substantially lower computational cost.

synthetic biology↗

bioRxiv2026

Three new species of Thelymitra (Diurideae, Orchidaceae) endemic to Aotearoa New Zealand.

Three new species of sun orchid (Thelymitra) endemic to Aotearoa New Zealand are here described. These are T. palustris, T. scabrifolia and T. semaphora. The morphological distinctiveness of these three species has been acknowledged for decades; however, their taxonomic status has remained unresolved. Evidence from existing karyological data, recently generated DNA sequence data (LFY and ycf1) and morphological studies from historical and fresh collections are used here to support their formal description. Both, T. palustris and T. semaphora are restricted to wet habitats north of Auckland (North Island). Thelymitra scabrifolia inhabits mostly scrub, and it has a similar northern North Island distribution, but is has been found also in Manawat[a]whi / Three Kings Islands and historically in Otago (South Island). All three species are polyploids and are of conservation concern.

plant biology↗

bioRxiv2026

Nitrate regulates anchor root development

Nitrogen is a critical nutrient necessary for plant growth and survival. Plasticity in root architecture helps adapt to soil nitrogen levels for optimal nitrogen uptake; the nitrate form of soil nitrogen is a major modulator of root architecture. Although details of nitrate-regulated primary and lateral root growth are known, nitrate-regulated formation of anchor roots, which arise from the collet, is not understood. In this work, we uncover a role for nitrate in the regulation of anchor root formation. We find that cytokinin inhibits anchor root formation with rising nitrate. These cytokinin effects on anchor root formation rely on regulated indole-3-butyric acid (IBA) to indole-3-acetic acid (IAA) conversion. These data point toward a mechanism by which nitrate controls a previously underappreciated aspect of nitrate-dependent root architecture driven by anchor roots.

plant biology↗

bioRxiv2026

Invasive mosquito species Aedes aegypti and Aedes albopictus are competent vectors for Barmah Forest Virus

Barmah Forest Virus (BFV), an arthropod-born virus transmitted by mosquitoes, is of significant public health concern in Australia and regions in the Pacific. Recent climate change and globalization raise the potential for BFV to extend its geographic distribution. Despite the rising importance of BFV, its vector dynamics remain poorly understood, particularly concerning the vector competence of different mosquito species. This study aims to investigate the vector competence of BFV across various mosquito species, beyond those endemic to the Australasian region, especially focusing on global relevant vector species. No transmission was observed for Culex quinquefasciatus and Cx. torrentium as well as Anopheles stephensi. In contrast, both investigated Aedes species, Ae. aegypti as well as Ae. albopictus, exhibited BFV-positive saliva across all four temperature profiles (18{degrees}C, 21{degrees}C, 24{degrees}C or 27{degrees}C) examined. These two invasive mosquito species must therefore be classified as potential vectors for BFV, indicating the potential risk of BFV transmission outside of Australia.

molecular biology↗

bioRxiv2026

Learning and forecasting shared evolutionary pathways to multi-drug resistance across global pathogens

Infections with bacteria which have evolved multi-drug resistance (MDR) cause millions of deaths worldwide. Large-scale efforts are gathering genotypic and phenotypic data on MDR bacteria, but methods for learning the structure, diversity, and predictors of evolutionary pathways to MDR have yet to take full advantage of these data. Here, we use evolutionary accumulation modelling (EvAM), an emerging class of machine learning methods with roots in cancer progression, to infer these evolutionary pathways across ESKAPEE pathogens (seven bacterial species that dominate health burdens), using a database of over 635k genotyped phenotypic observations from around the world. We identify global patterns in MDR evolutionary pathways, remarkably shared across multiple ESKAPEE species. Species-specific deviations from these stereotypical pathways are connected with geographical and demographic covariates, facilitating predictions of future MDR evolution. We verify these predictions with several hundred new phenotypes from ESKAPEE samples spanning decades of clinical infections in sub-Saharan Africa, demonstrating the capacity to forecast future MDR evolution from these inferred shared pathways.

evolutionary biology↗

bioRxiv2026

Euchromatin Peripheral Organization Follows Anterograde Signalling Under Anaesthetic Stress

Anterograde and retrograde signalling establish bidirectional communication between the nucleus and chloroplasts. Retrograde signals from chloroplasts regulate nuclear gene expression while anterograde signals from the nucleus coordinate chloroplast development and maintain cellular homeostasis. How this bidirectional signalling framework extends beyond locus-specific regulation to shape the global spatial organization of nuclear chromatin across tissues remains unclear. Although anaesthesia can alter chromatin organisation, the role of chloroplast dysfunction in these changes remains unclear. Here, we investigate how chloroplast dysfunction and anaesthesia influence euchromatin and heterochromatin organisation in Solanum lycopersicum seedlings across tissues with contrasting photosynthetic competence. Using confocal and super-resolution radial fluctuation (SRRF) imaging with quantitative multiparameter analysis, we identify distinct, tissue-specific chromatin responses to chloroplast disruption and anaesthesia. Notably, anaesthesia induces distinct spatial chromatin changes across tissues that are independent of chloroplast dysfunction, suggesting a direct nuclear response to anaesthesia rather than a chloroplast-mediated retrograde effect. These findings highlight chromatin topology as a potential quantitative biomarker of cellular disruption and provide a framework for investigating anterograde chloroplast-nucleus coordination and stress-responsive nuclear organisation in plants.

plant biology↗

bioRxiv2026

Male Age and Sexual Maturity: Lipopolysaccharide-induced tumor necrosis factor influences sperm quality and reproduction in Anopheles culicifacies

Elucidating the biological and molecular mechanisms that govern male fertility and mating behavior in mosquitoes is critical for optimizing genetic and sterile insect technique-based vector control strategies. Here, we examined age-related changes in male reproductive capacity in Anopheles culicifacies, using female egg output as an indirect indicator of male fertility. Our results demonstrated that male reproductive age follows a non-linear pattern of fertility. Morphometric analysis from emergence to day 13 post-eclosion revealed a strong correlation between seminal vesicle capacity and female fecundity, suggesting that age-dependent gonadal development directly influences reproductive potential. At the molecular level, we identified AcLITAF6 as a key regulator of male reproductive homeostasis. RNAi-mediated knockdown of AcLITAF6 impaired apoptosis-associated and phagocytic clearance, reduced sperm viability, and decreased female productive outcomes. Conclusively, we reveal a previously unrecognized role of LITAF in sperm quality control and male reproductive fitness, highlighting AcLITAF6 as a potential target for mosquito population suppression strategies.

developmental biology↗

bioRxiv2026

Seed Microbiome Transfer Mitigates Intergenerational Dysbiosis, Modulates Plant Defenses and Suppresses Foliar Disease

Antibiotic-induced disruption of plant-associated microbiomes has the potential to alter host health beyond the directly exposed generation, yet whether the effects of dysbiosis are transmitted through the seed microbiome remains unknown. Here, we investigated the intergenerational impacts of streptomycin-induced dysbiosis in tomato (Solanum lycopersicum), demonstrated that seed microbiome transfer (SMT) restores progeny microbiome function and disease resistance, and characterized the underlying physiological and genetic mechanisms. Parental streptomycin exposure altered the composition of progeny rhizosphere bacterial communities, reduced expression of defense-associated genes, and increased susceptibility to Xanthomonas perforans. Suppression of immune gene expression was strongly associated with increased disease severity, indicating that parental dysbiosis impaired progeny plants ability to mount effective immune responses. Transfer of the seed microbiome from healthy plant donors partially restored rhizosphere community composition, reduced disease severity and recovered defense gene expression of three genes. Together, our findings demonstrated that antibiotic exposure microbiome disturbance generates intergenerational legacy effects that influence plant immunity and disease susceptibility and seed microbiome transfer can counteract this dysbiosis across generations.

plant biology↗

bioRxiv2026

Comparison of evolutionary rescue via biological and cultural evolution

Rapid evolution allows populations to persist in environments where they would otherwise go extinct. This phenomenon, known as evolutionary rescue, is typically studied in the framework of biological evolution, yet adaptive traits can also arise and spread through cultural evolution. The present study developed a stochastic eco-evolutionary model to compare rescue probabilities through biological and cultural evolution. Transmission bias governed the rescue probability under cultural evolution by setting how readily a rare adaptive trait was copied. Conformity bias suppressed population persistence because a rare trait was the least likely to be copied. Content bias toward the adaptive trait enabled evolutionary rescue when social learning was rapid, but it typically yielded a lower rescue probability than biological evolution. Only anticonformity bias, together with a high social learning rate, exceeded the rescue probability of biological evolution by enabling the adaptive trait to be established more rapidly. These results demonstrate that transmission bias alters the demographic consequences of cultural evolution and highlight the importance of transmission processes in evolutionary rescue theory. Understanding how adaptive behaviours are socially transmitted may also improve predictions of animal population persistence and inform conservation efforts in rapidly changing environments.

evolutionary biology↗

bioRxiv2026

Injury size regulates glucose allocation locally and systemically during vertebrate tissue regeneration

Tissue regeneration requires careful allocation of metabolic resources, yet how organisms adjust this allocation in response to varying amounts of tissue loss remains poorly understood. Here, we show that the regenerative metabolic response is not fixed: the size of an injury regulates how glucose is allocated at both local and organism-wide levels. We first demonstrate that tail regeneration requires glucose metabolism in the axolotl (Ambystoma mexicanum), a salamander capable of regenerating centimetre-scale tissues. We then mapped glucose uptake in axolotls regenerating from small or large tail injuries using positron emission tomography/magnetic resonance imaging (PET/MRI) and the radiolabelled glucose analogue [18F]FDG. Glucose uptake was elevated in regenerating tails compared to uninjured tails. During early regeneration, larger injuries induced higher glucose uptake than smaller injuries, correlating with faster regenerative outgrowth. Larger injuries also increased glucose uptake in distant organs, indicating a systemic metabolic response. Together, our findings suggest that metabolic responses tuned to injury size underlie faithful tissue regeneration and establish PET/MRI as a powerful approach for studying whole-body metabolic dynamics in large regenerating vertebrates.

developmental biology↗

bioRxiv2026

Predictability failure in glucose-insulin system for ICU patients

Modern medicine implicitly assumes that physiological responses to intervention are predictably determined by administered treatments. However, physiological systems containing intrinsic delays between the detection of a stimulus and the biological response may violate this assumption. We investigate the human glucose-insulin system as described by the Ultradian model and mathematically demonstrate that clinically relevant forcing protocols-such as pulsatile insulin delivery and step-wise glucose infusion, both commonly used in intensive care units (ICUs)-can induce sustained temporal chaos that may hamper accurate prediction of the physiological response. If not accounted for, these chaotic dynamics could create difficulties in achieving optimal dosing and timing when administering glucose and insulin in clinical or home care settings. This phenomenon, termed delay-induced uncertainty (DIU), arises from the interaction between physiological delay, intrinsic shear near a limit cycle, and external forcing. Using the Ultradian glucose-insulin model, we compute top Lyapunov exponents to quantify predictability. Across a range of pulsatile and step-wise forcing regimes, including stochastic amplitudes drawn from Markov processes, we observe positive Lyapunov exponents, indicating sustained chaos. Our results suggest that delayed endocrine regulation may fundamentally limit the predictive value of the models used to develop glycemic management strategies, with implications for clinical protocols in the ICU.

systems biology↗

bioRxiv2026

The trade-off between parsimony and model complexity for understanding biomedical mechanisms from mathematical models

Mechanistic mathematical models have been used extensively to provide a deeper understanding of biological mechanisms, including unveiling the regulation of tumour growth and its response to various treatments. However, given the breadth of biological regulatory mechanisms, these models are frequently large and thus prone to potential issues with parameter identifiability. Statistical metrics like the Akaike and Bayesian information criteria can help identify a parsimonious model by balancing goodness of fit against model complexity. Yet simple models may fail to provide sufficient biological insight if they do not adequately capture known physiological processes or mechanisms. A modeller must therefore balance hypothesis generation and biological learning with model tractability. Here, we illustrate this balance using models of ovarian cancer growth and treatment response to cisplatin and immune checkpoint blockade in homologous recombination (HR)-deficient and HR-proficient immunocompetent mouse models. We develop a hierarchy of mathematical models of increasing complexity to describe tumour growth, treatment response, and immune dynamics. Our results highlight the limits of relying purely on statistical metrics for model selection, particularly when the goal is to obtain biological insight and underscore the importance of balancing model complexity to avoid overfitting and parameter unidentifiability.

systems biology↗

bioRxiv2026

Critical Fragility Emerges from Chromosomal Instability in Cancer

Genomic instability is a major driver of tumor evolution, promoting diversification and adaptation while simultaneously increasing the accumulation of deleterious alterations. How tumor populations balance these opposing effects remains poorly understood. Here, we introduce a computational framework that explicitly represents diploid genomes, functional gene classes, point mutations, and chromosome-segregation errors in spatially constrained and well-mixed tumor populations. We identify a viability boundary separating sustained tumor expansion from instability-induced population collapse. Within the viable regime, mutation and selection generate a stable distribution of genomic-instability classes that is accurately captured by an analytical replicator--mutator description. Near the viability boundary, tumor dynamics exhibit prolonged extinction transients and strong sensitivity to stochastic fluctuations, with important differences between solid and liquid architectures. Chromosomal alterations further modify growth by creating transient benefits through increased gene dosage and genetic redundancy, while ultimately increasing genomic fragility. Finally, simulated interventions show that eliminating low-instability subpopulations or increasing the global mutational burden can displace tumors beyond their viability boundary and trigger irreversible collapse. These results identify genome instability as both an evolutionary advantage and an intrinsic vulnerability, providing a quantitative framework for developing therapies that exploit the limits of tumor evolution.

cancer biology↗

bioRxiv2026

Rate of meristem initiation driven by the MADS-WUS axis contributes to floral survival and inflorescence evolution in grasses

Crop domestication has repeatedly shaped inflorescence architecture to improve floral production, but mechanisms coordinating the rate of floral initiation, maturation and survival remain unclear. Combining morphometry, modelling and molecular genetic analyses, we show that floral production in the indeterminate barley (Hordeum vulgare L.) inflorescence follows an "initiate fast-die young" strategy orchestrated by a main MADS-box gene, SPIKELET INITIATION AND FERTILITY (SIF). SIF accomplishes this duality by coordinately terminating the inflorescence meristem via WUSCHEL and activating the floral meristem via APETALA1 (Vrn-H1). Hereby, the ancestral SIF "slow" allele promotes a timely commitment to floral maturation, whereas the derived "fast" allele permits more floral initiations. Postdomestication selection of SIF alleles thus enables diversified reproductive strategies in barley populations to maintain yield traits in the field. Finally, we show that a lineage-specific SIF duplication contributed to meristem fate transition and inflorescence evolution during Triticeae cold adaptation. Our results establish developmental rate as a key driver of architectural innovation and reproductive success.

plant biology↗