bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/360446

Modelling genotypes in their physical microenvironment to predict single- and multi-cellular behaviour

Buffa, F.·Voukantsis, D.·Kahn, K.·Hadley, M.·Wilson, R.
View original source ↗Export metadata ↓

Abstract

A cells phenotype is the set of observable characteristics resulting from the interaction of the genotype with the surrounding environment, determining cell behaviour. Deciphering genotype-phenotype relationships has been crucial to understand normal and disease biology. Analysis of molecular pathways has provided an invaluable tool to such understanding; however, it does typically not consider the physical microenvironment, which is a key determinant of phenotype.\n\nIn this study, we present a novel modelling framework that enables to study the link between genotype, signalling networks and cell behaviour in a 3D microenvironment. To achieve this we bring together Agent Based Modelling, a powerful computational modelling technique, and gene networks. This combination allows biological hypotheses to be tested in a controlled stepwise fashion, and it lends itself naturally to model a heterogeneous population of cells acting and evolving in a dynamic microenvironment, which is needed to predict the evolution of complex multi-cellular dynamics. Importantly, this enables modelling co-occurring intrinsic perturbations, such as mutations, and extrinsic perturbations, such as nutrients availability, and their interactions.\n\nUsing cancer as a model system, we illustrate the how this framework delivers a unique opportunity to identify determinants of single-cell behaviour, while uncovering emerging properties of multi-cellular growth.\n\nAvailability and ImplementationFreely available on the web at http://www.microc.org. Research Resource Identification Initiative ID (https://scicrunch.org/): SCR 016672

Explore related subjects

bioinformaticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Buffa, F., Voukantsis, D., Kahn, K., Hadley, M., Wilson, R.. 2018-07-03. Modelling genotypes in their physical microenvironment to predict single- and multi-cellular behaviour. https://doi.org/10.1101/360446

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

scRM: A single-cell foundation model trained on scRNA-seq reads

To our knowledge, scRM is the first single-cell foundation model trained on sequencing reads, demonstrating that raw data pretraining is not only feasible but competitive at a fraction of the computational cost. We anticipate that scaling this framework and exploring alternative architectures will unlock biological information inaccessible to count models and extend the dataset-specific pretraining it already makes possible. The source code is available at https://github.com/altos-labs/scRM.

bioinformatics↗
bioRxiv2026

Local fractal dimension as an indicator of functional reorganization in molecular interaction networks

Changes in protein abundance incompletely describe how molecular perturbations reshape cellular organization. Here we introduce DIFFRACT, a framework that integrates quantitative proteomics with protein-protein interaction networks to identify reorganization through changes in local fractal dimension. Molecular associations define effective distances between connected proteins, allowing the geometry of their surrounding network neighborhoods to be compared across conditions. Analyses across four organisms (E. coli, A. thaliana, C. elegans, and H. sapiens) and three interaction resources (STRING, BioGRID, and IntAct) establish heterogeneous local scaling, while controlled perturbations demonstrate sensitivity to regional changes and invariance to uniform distance rescaling. Applied to RAVER1-deficient A549 cells, DIFFRACT identifies components associated with established RNA-regulatory functions and candidate roles in tRNA biology, mitochondrial organization and ciliogenesis. Selected RNA-regulatory and ciliary themes are not significantly enriched by abundance-ranked gene set analysis, supporting complementary information from network geometry. Selected functional annotations also recur in HEK293T cells. Guided by the ciliary predictions, we show that RAVER1 depletion increases the proportion of ciliated A549 cells 2.57-fold and increases cilium length. DIFFRACT thus connects changes in molecular network geometry to experimentally testable biological responses, extending the interpretation of proteomic perturbations beyond differential abundance.

bioinformatics↗
bioRxiv2026

Peripheral Exercise Transcriptomes Do Not Converge on Glutamatergic or Neuroinflammatory Signatures: A Cross-Platform Meta-Analysis

Executive dysfunction following physical overtraining has been linked to glutamatergic dysregulation in the lateral prefrontal cortex (LPFC), but whether this central mechanism is reflected in peripheral gene expression is unknown. This study tested whether peripheral transcriptomic responses to exercise converge on the glutamatergic or neuroinflammatory pathways implicated in LPFC dysfunction. Three publicly available GEO datasets spanning skeletal muscle, whole blood, and circulating neutrophils were analyzed across four exercise groups using limma, with a discovery threshold of nominal p < 0.05 and absolute log2 fold change above 0.5. Differential expression analysis identified 7,311 unique differentially expressed genes (DEGs) across the four contrasts, but overlap between datasets was limited: 7 genes were shared between skeletal muscle and blood, 38 between skeletal muscle and the GSE43856 contrasts, and 90 between blood and the GSE43856 contrasts, with none significant across all three studies. Gene Ontology and KEGG enrichment of the DEG union identified ribonucleoprotein complex biogenesis, ribosome biogenesis, protein folding, and T cell activation as the dominant biological processes; no glutamatergic or neuroinflammatory terms reached significance. Cross-tissue concordance between skeletal muscle and blood was absent (r = 0). Effect sizes among the genes driving the top enriched pathways were dominated by ribosomal proteins, heat shock proteins, and translation initiation factors rather than glutamate receptors or transporters. These findings indicate that peripheral transcriptomic responses to exercise are tissue-specific and dominated by proteostasis, translational, and immune programs rather than glutamatergic signaling. Direct assessment of central nervous system tissue or fluid-based glutamatergic biomarkers may be required to link overtraining-induced fatigue to LPFC dysfunction.

bioinformatics↗