Biology subjects

Fang, W.

Publications and source records attributed to Fang, W..

At least 19 recordsLinked to original sources

bioRxiv2026

Urban planning leaves an audible legacy in a megacity's bird soundscape

Cities are planned for people, yet planning also determines where wildlife persists and where residents hear it. How can this acoustic footprint guide planning and monitoring? We combined AI-powered passive acoustic monitoring at 31 stations with detection-corrected models and spatial validation to map Asian Koel activity across Shenzhen. Koel acoustic opportunity declined with tree and built cover and increased with starling and myna opportunity; host information improved prediction at unmonitored sites. Weekly opportunity expanded in spring and varied across the city; sampled-minute exposure concentrated around dawn. Supported predictions intersected planning-sensitive places, while 51.5% of the city grid remained a monitoring gap. We translated these boundaries into monitoring priorities for underrepresented environments and uncertain spring predictions. This reproducible workflow reveals the acoustic imprint of the present-day urban landscape and connects ecological diagnosis, prediction boundaries and adaptive monitoring to inform urban coexistence.

ecology↗

bioRxiv2026

Multi-omics reveals accumulation mechanisms underlying differences in sesquiterpenoid content across different growth environments of Atractylodes macrocephala rhizome

This study aimed to explore mechanisms driving differential sesquiterpenoid accumulation in Atractylodes macrocephala rhizome (AMR) under different growth environments. Root and rhizosphere soil samples were collected from wild, imitated wild, one- and two-year cultivated AMR. Combined metabolomic, transcriptomic and microbiomic profiling was carried out to investigate alterations in sesquiterpenoid levels, root-associated microbiota, and terpenoid biosynthetic genes under different growth environments. Metabolomics revealed that wild AMR exhibited higher pyruvate consumption and accumulated more atractylone and atractylenolides. Transcriptomic analysis demonstrated that the genes encoding key MEP pathway enzymes (DXS, DXR, MCT, HDS) and the genes encoding the sesquiterpenoid biosynthetic enzyme GDS were significantly upregulated in wild AMR. In contrast, the genes encoding triterpenoid synthetic enzymes (SQS, SQE, {beta}-AS) were downregulated, redirecting metabolic precursors toward sesquiterpenoid synthesis. Microbial community structures differed substantially across groups. Further analysis suggested rhizosphere microorganisms were important contributors to AMR medicinal quality, and sesquiterpenoid metabolites accumulated in AMR roots, together with the rhizosphere microenvironment, jointly shape specific rhizosphere fungal assembly. This study systematically revealed the synergistic regulatory relationships among sesquiterpenoids metabolism, gene expression, growth environment, and root-associated microbes, providing multi-omics evidence for clarifying the mechanism by which these factors coordinately regulate the quality of AMR.

plant biology↗

bioRxiv2026

Dissecting the TMEM132A-EGFR Dependency to Unlock Translational Therapeutic Opportunities for Pan-Solid Tumor

Solid tumors remain refractory to conventional treatments, yet cell surface proteins, by virtue of their extracellular accessibility and critical roles in tumor signaling, represent an attractive class of targets for precision-targeted therapy. Here, we report that TMEM132A is an essential and previously unrecognized pan-cancer target. TMEM132A interacts directly with EGFR and stabilizes its expression, thereby tethering EGFR at the plasma membrane and sustaining constitutive activation of lipid synthesis. Mechanistically, the TMEM132A-EGFR axis promotes lipogenesis by facilitating SREBP nuclear translocation, which in turn upregulates ACLY and ACSS2 expression to drive acetyl-CoA production and downstream lipid biosynthesis, ultimately disrupting lipid droplet homeostasis. To therapeutically target this axis, we developed a nanobody, LFNanoT132A#3, which effectively blocks the TMEM132A-EGFR interaction, abrogates downstream signaling activation, and potently inhibits proliferation across multiple solid tumor types. Notably, LFNanoT132A also exerts robust antitumor activity against H1975 xenografts, a model resistant to first- and second- generation EGFR inhibitors, underscoring its potential to overcome conventional drug resistance. Our findings establish TMEM132A#3 as a critical node in membrane-tethered oncogenic signaling and metabolic rewiring, and position LFNanoT132A#3 as a promising therapeutic candidate for precision cancer therapy.

cancer biology↗

bioRxiv2026

Propagation electrodynamics and differential conduction of action potentials in geometrically branched squid giant axons

Classical neuronal cable theory relies on quasi-static electric field approximations and neglects magnetic induction, Lorentz force coupling, and transient electromagnetic currents, limiting its ability to fully characterize action potential propagation within geometrically branched axons and dendrites. This work develops a coupled Maxwell-electromagnetic cable framework by integrating finite-difference time-domain (FDTD) solutions of Maxwells equations with extended Hodgkin-Huxley and Fitzhugh-Nagumo membrane dynamics, incorporating magnetic gating perturbations, electromagnetic trans-membrane currents IEM, and nanoscale quantum corrections for thin neural segments. Controlled propagation experiments are designed to quantify deviations from standard cable predictions across asymmetric and symmetric axonal bifurcation geometries. Numerical results demonstrate that inductive magnetic effects lower the critical branch radius for junction conduction failure and break symmetric action potential invasion in geometrically identical child branches under external transverse magnetic fields. An electromagnetic corrected geometric ratio GREM is proposed to revise impedance-matching conditions at branch points, accounting for size-dependent axial current imbalance induced by magnetic and displacement currents. Parent axon conduction velocity deviates substantially from the canonical [Formula] scaling law when electromagnetic feedback and quantum charge distributions are included, triggering early signal blockage at large cable diameters. Collectively, this study establishes that quasi-static cable models underestimate electromagnetic corrections to propagation speed, waveform shape, and bifurcation transmission fidelity; the coupled Maxwell-cable framework provides a comprehensive multi-physics tool for modeling electrodynamic signal behavior in complex neuronal architectures.

biophysics↗

bioRxiv2026

Inhibitory network predicts microstimulation-induced circuit changes in the awake mammalian cortex

Intracortical microstimulation is a powerful tool to perturb neural circuits, yet how circuit changes post-stimulation remains poorly understood. Using two-photon imaging in the awake mouse visual cortex, we tracked genetically identified neurons before, during, and after microstimulation. Even after a short 15-min microstimulation, there is pronounced suppression in excitatory neurons, accompanied by increased activity in inhibitory neurons, particularly those not recruited during microstimulation. Our findings highlight inhibition as a key player in shaping stimulation-induced circuit changes: the magnitude of plasticity in excitatory neurons is not only dependent on the level of recruitment during stimulation, but also shaped by the recruitment level of neighboring inhibitory cells, whereas the inhibitory plasticity is best explained by pre-stimulation population coupling.

neuroscience↗

bioRxiv2026

FishMamba-1: A Linear-Complexity Foundation Model for Deciphering Polyploid Cyprinid Genomes

The Cypriniformes order, comprising essential aquaculture species like carps and minnows, presents unique genomic challenges due to complex whole-genome duplication (WGD) events and extensive repetitive elements. Conventional annotation tools and Transformer-based foundation models often struggle to capture long-range dependencies in these expanded genomes due to quadratic computational complexity. Here, we introduce FishMamba-1, the first genomic foundation model tailored for the aquatic clade, built upon the selective state-space model (SSM) architecture. By leveraging Mamba-2s linear scaling efficiency, FishMamba-1 processes context windows of 32,768 base pairs (32k)--significantly surpassing the 4-6k limit of standard DNA Transformers--enabling the modeling of distal regulatory patterns on a single GPU. We curated Cypri-24, a comprehensive dataset comprising 28.8 Gb of high-quality genome assemblies from 24 representative species, to pre-train FishMamba-1 on 15 billion tokens. Subsequent fine-tuning for genome segmentation (FishSegmenter) demonstrates the models capability to annotate gene structures at single-nucleotide resolution with remarkable precision. Evaluation on a held-out test set reveals that FishMamba-1 achieves a precision of 64.6% in exon identification, effectively distinguishing coding regions from the vast non-coding background without relying on RNA-seq evidence. Furthermore, interpretability analysis confirms that the model captures biological syntax such as splice acceptor motifs. FishMamba-1 provides a scalable, open-source framework for decoding the complex genomes of non-model organisms, providing a scalable computational resource to support downstream applications in molecular breeding and ecological monitoring. The complete source code, pre-trained model weights, and datasets are freely available at https://github.com/lu1000001/FishMamba. Additionally, the FishMamba Hub, a web-based inference platform, is accessible at https://huggingface.co/spaces/lu1000001/FishMamba-Hub to facilitate real-time genomic segmentation for the aquatic research community. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/710409v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@f5ee02org.highwire.dtl.DTLVardef@1dcfd31org.highwire.dtl.DTLVardef@1729ef8org.highwire.dtl.DTLVardef@22e4f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

CsFDL1-CsFTL3 complex represses CsFTL3 via negative feedback to fine-tune flowering in Chrysanthemum seticuspe

In many flowering plants, the transition from vegetative growth to reproductive development is regulated by seasonal changes in photoperiod. Under inductive photoperiods, leaves produce the florigen FT (FLOWERING LOCUS T), which is transported to the shoot apex to promote flowering. The photoperiod is known to have a major effect on the flowering of chrysanthemum. In the perennial short-day (SD) plant Chrysanthemum seticuspe, the expression of CsFTL3 (FT-like gene) does not increase immediately after shifting from long-day (LD) to SD conditions but gradually accumulates under continuous SD conditions, peaking during inflorescence development. However, the underlying mechanism remains elusive. We show that CsFDL1 (an ortholog of FD) and CsFTL3 exhibit a significant inverse expression pattern in leaves during the initial stage of short-day inductions. Furthermore, the expression of CsFTL3 is upregulated in the leaves of CsFDL1-knockdown transgenic lines. CsFDL1 is expressed in leaves and forms a complex with CsFTL3 to recognize several TCGA- and ACGT-containing motifs in the CsFTL3 promoter. The CsFTL3-CsFDL1 complex downregulates CsFTL3 expression, thereby preventing its excessive induction by SD signals and inhibiting precocious floral transition. This study reveals that CsFDL1 acts as a key early repressor in the photoperiodic flowering pathway of chrysanthemum leaf, mediating negative feedback regulation by forming a complex with CsFTL3 to achieve precise temporal control of short-day-dependent flowering responses.

plant biology↗

bioRxiv2026

Evolutionary genomics of local adaptation, climate vulnerability, and linarin metabolism in Opisthopappus longilobus

Global climate change and human activities are posing substantial threats to biodiversity. The genus Opisthopappus (O. taihangensis and O. longilobus), endemic to Chinas Taihang Mountains, possesses great ecological, ornamental and medicinal value. However, it is confronted with the pressures of habitat fragmentation and climate change. Here, we present the first haplotype-resolved, chromosome-scale genome assembly of O. longilobus ([~]2.95 Gb) and re-sequence 115 individuals across its range. Comparative analyses show Opisthopappus is sister to Artemisia-Chrysanthemum, with Opisthopappus and Chrysanthemum diverging at 5.15-5.18 million years ago. A profound genetic divergence is evident between O. taihangensis and O. longilobus, resulting in two distinct lineages within each species, driven by geography and climate. Our analyses indicate restricted gene flow, low diversity, and recurrent demographic bottlenecks collectively contribute to their endangerment. By integrating population genomics and environmental variables, we identified 4,437 core adaptive genes linked to water deprivation, and metabolism. Genomic offset predicts higher maladaptation risk in populations under drastic climate change. Furthermore, diverged promoters of two O-methyltransferase genes, OMT250 and OMT310, likely underlie the differential acacetin/linarin accumulation between C. morifolium and O. longilobus. These findings advance understanding of Opisthopappus evolution and climate vulnerability, offering a model for genomics-guided biodiversity conservation.

plant biology↗

bioRxiv2026

Spatiotemporal Mapping of Tertiary Lymphoid Structure Heterogeneity Shapes Immune Niches and Clinical Outcomes in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy with limited therapeutic options. The spatial architecture and functional diversity of tertiary lymphoid structures (TLSs) in iCCA remain unclear. Here, we present a multimodal spatial atlas of TLSs and identified Intra-tumoral TLSs (iTLSs) as independent prognostic markers. Bulk proteomic profiling of 214 discovery and 155 validation cases identified a four-tier TLS-based TME classification system and supported development of a TLS-predictive random forest classifier. Imaging mass cytometry revealed that iTLS tumors harbor structured immune architectures, where M1-like tissue-resident macrophages (RTMs), dendritic cells, and CXCL13 CD4 T cells co-localize to form antigen-presenting neighborhoods (apc-CNs) spatially coupled to TLS core regions (TLScore-CNs). Single-cell spatial transcriptomics further resolved 61 TLSs into 14 spatial niches and defined a pseudo-temporal maturation continuum: aggregated, activated, and post-activated. Intra-niche communication, primarily mediated by ifnCAFs, iCAFs, and CXCL12 macrophages, evolved dynamically with maturation. Single-nucleus RNA-sequencing combined with Tangram-based spatial mapping revealed CXCL12 macrophages and iCAFs forming a peripheral band in aggregated TLSs, while ifnCAFs infiltrated TLS interiors during activation. These findings define TLS heterogeneity and provide insights for stroma-directed immunotherapy. TeaserAn atlas of tertiary lymphoid structures reveals immune-stroma interactions in Intrahepatic cholangiocarcinoma.

immunology↗

bioRxiv2026

Coronavirus Nucleocapsid Proteins Hijack Host Protein Kinase A Catalytic Subunit α into Nucleus to Evade from STAT1 Signaling

The role of the cAMP/PKA pathway in antiviral innate immunity, including during coronavirus infections, remains unclear. We discovered coronavirus N proteins initiate cAMP-ADCY10-PKA cascade. Cytoplasmic PKA activates STAT1 independently of canonical JAK/TYR2 signaling. Coronavirus N proteins, via a conserved arginine (e.g., PEDV R58, SARS-CoV-2 R92), directly bind and sequester PKA C into the nucleus to evade STAT1 activation. Using PEDV as a model, mutant viruses with NmutNLS and NR58A were generated. Wildtype PEDV infection suppressed STAT1 activation in cells expressing PKA C/PKA CS339A deficient in STAT1 phosphorylation. However, in rXS0101mutNLS- or rXS0101R58A-infected cells, only PKA CS339A expression inhibited STAT1 activation. Downregulation of STAT1 activation is accompanied with increased viral replication. This study first elaborates that PKA C activates STAT1 in the cytoplasm of infected cells distinctly from canonical JAK/STAT1 signaling, while coronaviruses evade this antiviral response by sequestering PKA C into the nucleus via direct N protein interaction.

microbiology↗

bioRxiv2025

Structural basis for hydrolytic splicing of a circularly permuted group II intron

Group II introns are self-splicing ribozymes that are considered the ancestors of the eukaryotic spliceosome. Unlike canonical group II introns that self-splice to generate linear exons and lariats, circularly permuted (CP) group II introns identified in various bacterial phyla perform back-splicing, resulting in the production of circular RNAs and branched products via branching pathway. Furthermore, CP introns may switch to a hydrolysis pathway resulting in distinct products to differentially regulate retrotransposition. In this study, we present biochemical data and high-resolution cryogenic electron microscopy (cryo-EM) structures of a CP group II intron from Comamonas testosteroni KF-1 (Cte 1), allowing mechanistic dissection of the switch from the branching pathway to the hydrolysis pathway, and enabling reconstruction of both steps of the hydrolysis pathway. The structures reveal that CP group II intron undergoes the hydrolysis pathway upon mutations of the branch point or splice sites (SS) due to rearrangements in the active site. Here, the branching nucleotide in domain D6 is retracted from its catalytically competent conformation, giving way to the nucleophilic water molecule to attack the 5' splice site. Furthermore, we visualized the intermediates of the second splicing step, which reveal the movement of domain D6 out of the way for the 3'-splicing to occur, closely resembling the second-step structures of the branching pathway. Finally, our structures provide direct evidence for domains D1-D3 acting as a scaffold in group II introns. Together, these findings visualize the complete hydrolysis pathway and offer a new strategy to engineer CP group II introns for circular RNA production, with potential applications in both basic research and therapeutic development.

biophysics↗

bioRxiv2025

Robust brain complexity measurement using T2* informed multivariate sample entropy from multi-echo BOLD fMRI

Sample entropy is a useful tool to analyze resting-state fMRI data and evaluate the complexity of neural activity. However, sample entropy computed from conventional BOLD signals is not highly resistant to artifacts. In contrast, T2* may be more sensitive to certain neural-related changes, and directly incorporating T2* information enables the detection of features that are often lost in BOLD-only sample entropy due to noise influences. To further improve the robustness and reliability of complexity estimation, we introduce a multivariate sample entropy approach that incorporates T2* signals derived from multi-echo BOLD signal. We applied this method to compare a cohort of 23 elder adults and 12 younger adults, and observed significant group differences in several brain regions. Notably, the proposed method yielded more pronounced group differences than conventional sample entropy computed without T2* information. Moreover, in regions with reduced neural activity due to ischemia, as well as in ventricular areas, our approach demonstrated superior performance. These results indicate that the proposed method enhances the ability to characterize the complexity of neural activity.

biophysics↗

bioRxiv2025

Antibacterial Activity of the Natural Product Elaiophylin against Streptococcus suis and its Biofilm Eradication Effect

The multidrug resistance (MDR) problem in Streptococcus suis(S. suis) is becoming increasingly severe, necessitating the development of novel antibacterial agents and strategies. In this study, seven Elaiophylin derivatives were isolated from Streptomyces sp. WS-30248, and the antibacterial activity and mechanism of action of the principal compound, Elaiophylin, against S. suis were systematically evaluated for the first time. Through comprehensive approaches including in vitro efficacy assays, biofilm inhibition and eradication tests, bacterial membrane integrity analysis, reactive oxygen species (ROS) level detection, and a mouse infection model, Elaiophylin was found to exhibit significant antibacterial activity against multiple clinically MDR S. suis strains. Its minimum inhibitory concentration (MIC) was as low as 0.5 g/mL, and complete bactericidal activity was achieved within 24 hours at 4xMIC. The compound effectively inhibited and eradicated bacterial biofilms, directly killing embedded cells within the biofilm matrix. Mechanistic studies revealed that Elaiophylin functions through multiple synergistic pathways, including disruption of bacterial membrane integrity and induction of massive ROS accumulation, thereby interfering with the proton motive force (PMF), depleting intracellular ATP, and blocking energy metabolism. In the mouse infection model, the Elaiophylin-treated group showed a significantly increased survival rate of 60% and effectively reduced bacterial loads in tissues. This study demonstrates that Elaiophylin is a highly promising natural candidate drug with multi-target synergistic effects, offering a new strategy to combat MDR S. suis and biofilm-associated infections.

microbiology↗

bioRxiv2025

Genomic and genetic insights into speciation and pigment pattern diversification in Danio fishes

The Danioninae subfamily of teleost fishes boasts up to four hundred distinct species that have evolved to display a stunning diversity of morphological forms. Here we use newly assembled genome sequences of four laboratory and wild zebrafish strains as well as eleven species of the Danio and Danionella genera to explore their phylogenetic history and the genetic basis of pigment pattern diversification. Phylogenomic analyses uncover extensive introgression and incomplete lineage sorting that have obscured phylogenetic relationships within Danio and corroborate an ancient hybrid origin of zebrafish. Whereas D. rerio inherited ancestral horizontal stripes, relatives repeatedly evolved spots and vertical bars. Interspecific complementation tests reveal functional divergence of the adhesion molecule gene igsf11 and the gap junction gene gja5b between the striped zebrafish and Danio species with divergent patterns. Comparative genomic and transcriptomic analyses suggest that protein and regulatory evolution have accompanied pigment pattern diversification. Our analyses elucidate complex genetic changes underlying the phylogenetic history and morphological diversification in the Danio genus. Resolved phylogenetic relationships, available genome assemblies, transcriptomes, and genetic tractability establish Danio fish species as excellent models for biomedical research in vertebrates.

genomics↗

bioRxiv2025

Multiscale modeling of cell-substrate adhesion dynamics: effects of integrin activation, clustering and internalization

Cell adhesion is a fundamental biological process that governs cell proliferation, differentiation, migration, and tissue development. Cells adhere to the extracellular matrix through specialized transmembrane proteins, whose structures and functions are well studied. However, how mechanical, chemical, and biological factors interact to regulate these proteins and hence to shape cross-scale adhesion dynamics from molecular clustering to cellular migration remains unclear. Here, we propose a multiscale mechano-biochemical coupling framework to investigate the dynamics of cell-substrate adhesions, incorporating comprehensive molecular steps in the integrin life cycle, including activation, clustering, signal transduction and internalization. Our model elucidates the roles of caveolin transport and actin flow in modulating integrin dynamics and FA morphology. We identify the antagonistic interplay between integrin internalization and clustering that governs cross-scale adhesion dynamics. Furthermore, our model quantitatively demonstrates how the substrate stiffness regulates the integrin clustering size and internalization rate. These findings provide mechanistic insights into the regulation of cell migration, particularly the transition between durotaxis and negative durotaxis, driven by intracellular and extracellular microenvironmental factors. Our model offers an effective framework for understanding the cross-scale regulation process of cell adhesion involved in physiological and pathological activities, such as stem cell differentiation and cancer metastasis.

biophysics↗

bioRxiv2025

Cross-ancestry information transfer framework improves protein abundance prediction and protein-trait association identification

Genetics-informed proteome-wide association studies (PWAS) provide an effective way to map the complex molecular landscape of biological mechanisms for complex diseases. PWAS relies on an ancestry-matched reference panel to model protein expression using genetic variants as features and determine the proteins impact on phenotype. However, reference panels from underrepresented populations remain relatively limited. In this study, we developed an analytic framework that borrows information from potentially multiple ancestries to boost the protein abundance prediction accuracy in an underrepresented population. We illustrate the frameworks utility and reproducibility through application to PWAS in East Asians: BioBank Japan (BBJ), Korean Genome and Epidemiology Study (KoGES), and Taiwan Biobank (TWB). An ensemble of information-sharing approaches was integrated to build the Multi-Ancestry-based Best-performing Model (MABM). MABM substantially improved the prediction performance with higher performance observed in both cross-validation and an external validation dataset (Tongji-Huaxi-Shuangliu Birth Cohort). Leveraging the BBJ, we identified three times as many significant PWAS associations with MABM as with the baseline Lasso model. Notably, 47.5% of the MABM specific associations were reproduced in independent East Asian datasets with concordant effect sizes. Furthermore, MABM enhanced gene/protein prioritization for downstream functional validation by (1) confirming a greater number of well-established gene/protein-trait associations and (2) identifying previously uncharacterized trait-associated genes. The benefits of MABM were further validated in additional ancestries and demonstrated in brain tissue-based PWAS, underscoring its broad applicability. Our findings close critical gaps in multi-omics research, develop a new reference resource of genetic models of protein abundance, and facilitate trait-relevant protein discovery in underrepresented populations.

genomics↗

bioRxiv2024

A consensus variant-to-function score to functionally prioritize variants for disease

Identifying and functionally characterizing causal disease variants in genome-wide association studies remains a pressing challenge. Here, we construct a consensus variant-to-function (cV2F) score that assigns a single value to each common single-nucleotide variant in the genome, and helps to predict and characterize causal disease variants. The cV2F score leverages features reflecting variant-level experimentally and computationally predicted function (e.g. allelic imbalance and sequence-based deep learning models) and element-level function (e.g. predicted enhancers), and learns optimal combinations of features by training a gradient boosting model on GWAS fine-mapping results. The cV2F-annotated variants attained an AUPRC of 0.822 at identifying held-out fine-mapped variants. Variants with high cV2F scores are highly enriched for heritability (14.2x, s.e. 0.5) across 66 diseases/traits, are uniquely informative for disease heritability, and are highly predictive of variants implicated by reporter assays; cV2F substantially outperforms previous variant-to-function scores using all of these metrics. GWAS fine-mapping of 110 diseases/traits informed by cV2F identified 14.3% more confidently fine-mapped (PIP > 0.95) variants than non-functionally informed fine-mapping. We further constructed tissue/cell line-specific cV2F scores that prioritize variants based on regulatory potential in specific tissues/cell lines, attaining high heritability enrichment for tissue-related diseases/traits (15.6x, s.e. 2.3) while providing independent information (average correlation of 0.27 with the primary cV2F score). We highlight examples of GWAS loci for which cV2F pinpoints causal variants with high confidence and elucidates their functional role.

genetics↗

bioRxiv2024

Quantifying Functional Conservation of Human and Mouse Regulatory Elements via FUNCODE

Evolutionary conservation is crucial for understanding genome functions and lays the foundation for using animal models in studying human diseases. However, conventional conservation scores based on DNA sequence evolution do not capture the dynamic biochemical activities of DNA elements, termed functional conservation. Quantifying functional conservation has been limited by the availability of functional genomic data matched across species. To address this, we developed FUNCODE, a framework for characterizing functional conservation through in silico sample matching. Applying FUNCODE to 2,595 uniformly processed datasets from the Encyclopedia of DNA Elements (ENCODE), we generated genome-wide FUNCODE scores for human and mouse regulatory elements, identifying 3.3 million functionally conserved human-mouse element pairs. We demonstrate FUNCODEs diverse applications, including annotating 78,501 novel regulatory elements, transferring 37,968 high-resolution human ENCODE Hi-C loops in immune lineages to mice, identifying conserved functional signals for disease modeling, and enhancing cross-species integration of single-cell omics data.

genomics↗