Biology subjects

Shi, J.

Publications and source records attributed to Shi, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

NF1 deficiency induces metabolic reprogramming and epithelial-mesenchymal transition in glioblastoma

BackgroundMetabolic reprogramming is a common occurrence in tumor cells, where enhanced glycolysis promotes cell growth, invasion and migration. NF1 is tumor suppressor gene that downregulates the encoded neurofibromin protein. However, the effects of NF1 on energy metabolism and epithelial-mesenchymal transition (EMT) in glioblastoma multiforme (GBM), as well as the underlying molecular mechanisms, remain unclear. MethodsCRISPR/Cas9 gene editing technology was employed to construct GBM cell lines with NF1 gene mutations. Metabolomics was utilized to examine the impact of NF1 on metabolic remodeling in GBM. The Seahorse XF24 extracellular flux analyzer was used to detect the effect of NF1 knockdown on glycolysis and mitochondrial oxidative phosphorylation in GBM cells. Wound healing assay and Transwell chamber assay were utilized to detect the effect of NF1 on GBM cell invasion. Orthotopic tumor model in nude mice was established to explore the role of NF1 in vivo. In addition, Co-IP, western blotting, and immunofluorescence were used to explore the changes of key enzymes in glycolysis and mitochondrial oxidative phosphorylation and the relationship between NF1 and MFN1. ResultsThe expression of NF1 is decreased in glioma tissues and is significantly correlated with patient prognosis. NF1 knockdown may promote the invasion, migration, and EMT of GBM cells. At the same time, the activation of the AKT/mTOR signaling pathway promotes aerobic glycolysis in GBM cells, promotes mitochondrial division through targeted regulation of MFN1, and inhibits mitochondrial oxidative phosphorylation. NF1 deficiency promotes EMT in GBM cells by enhancing aerobic glycolysis and mitochondrial division. ConclusionNF1 deficiency promotes GBM glycolysis by activating the AKT/mTOR signaling pathway and inhibits the mitochondrial oxidative phosphorylation by regulating MFN1; NF1 deletion promotes GBM EMT by remodeling the pattern of energy metabolism.

Cancer Biology↗

bioRxiv2026

Confidence-supported label-free metabolic imaging with FPhaS phase autofluorescence microscopy

Label-free optical redox imaging utilizes endogenous NAD(P)H and FAD autofluorescence to evaluate metabolism in living specimens. The conventional optical redox ratio collapses these two channels into a single value; however, it does not indicate whether a pixel has sufficient photon support or the cellular context necessary for quantitative aggregation. To address this limitation, we introduce FPhaS, a fixed-calibration phase- autofluorescence framework that integrates quantitative phase imaging (QPI) with simultaneous label-free autofluorescence multi-harmonic microscopy (SLAM), using fluorescence lifetime imaging (FLIM) solely for validation. Because QPI and SLAM are acquired with the same objective, a unified non-biological calibration aligns phase-derived structural data with the autofluorescence frame, yielding a residual error of 0.39 pixels. This calibration is maintained across all biological specimens. This shared geometric reference enables local evaluation of structural and metabolic information, rather than comparing approximately aligned images. FPhaS decomposes the data into cell presence, ratio credibility, and confidence-supported pooling. We validated FPhaS on A549 cells under high and low-photon conditions; the framework is designed to generalize to other cell and tissue types. Confidence-weighted intensity redox estimates were compared with lifetime-derived measurements within mask-locked cellular regions. Concordance improved exclusively when both the denominator photon support and an independent structural criterion were satisfied. The same reference layer generated cell-level descriptors of metabolic content, metabolic-structural organization, and measurement reliability, while also constraining the CombinedWLS reconstruction under diminished fluorescence acquisition. FPhaS redefines label-free metabolic imaging from producing comprehensive ratio maps to identifying regions where optical evidence substantiates quantitative inference.

bioengineering↗

bioRxiv2026

EditorForge: An Active-Site-Aware Framework for Inverse-Folding-Based Protein Redesign

Inverse-folding models can rapidly generate protein sequences compatible with a supplied backbone, but unconstrained redesign is poorly suited to enzyme and genome-editor-associated domains, where catalytic, substrate-proximal, and conserved structural regions must remain protected. In this paper, we present EditorForge, a modular constraint-and-audit suite for editor-domain protein redesign that wraps fixed-backbone inverse folding with explicit design masks, fixed-position enforcement, active-site-proximity auditing, active-site-shielded regeneration, and downstream structural quality control. Using full-length Moloney murine leukemia virus reverse transcriptase structure 4MH8 (MMLV RT 4MH8) as a demonstration target, EditorForge first restricted redesign to a bounded 25-position envelope while fixing 428 residues. An initial audit detected active-site-proximal failure modes despite fixed-position integrity. Later, the Active Site Shield module then removed five unsafe design positions, replaced them with lower-contact alternatives, and regenerated candidates under stricter constraints. Post Shield Audit evaluated 24 regenerated candidates, all of which satisfied the hard sequence/mask and active-site-shield constraints. For the eight candidates that were selected or returned for structure-prediction/refolding quality control, Enhanced RefoldQC found that all 8 evaluated predicted structures passed the computational structure-QC screen. That said, the selected 8 candidates passed the computational structure-QC screen, with global C RMSD values of 1.2061-1.5555 {degrees}A, active-site C RMSD values of 0.4098-1.8397 {degrees}A, mutation-neighborhood C RMSD values of 1.3155-1.6848 {degrees}A, and average pLDDT-like confidence values of 94.87-95.11. In short, EditorForge provides a reproducible triage layer that converts general inverse-folding output into constrained and editor-specific candidate sets for downstream structural and biological review on top of existing structural prediction tools.

bioinformatics↗

bioRxiv2026

X-Gutor: a high-fidelity in vitro platform for long-term gut microbiome recovery

In vitro gut microbiome-culturing models are essential for studying host-microbe interactions, yet achieving high microbial recovery and long-term stability remains a long-standing challenge. Here we devise X-Gutor, an ecologically designed in vitro platform that recapitulates the monogastric digestive system with precise control of pH, redox potential, and a mucin-based biofilm matrix. Using an integrated assessment framework, microbial source tracking, a curated gut metabolism database (GutDB), and short-chain fatty acid profiling, we benchmarked gut community recovery. Building on this platform, HanGutor and PigGutor were developed to recover 96.27{+/-}4.92% and 90.48{+/-}5.95% of human and swine gut microbiota, respectively. Ecological fine-tuning revealed that redox potential drives the Prevotella-Bacteroides trade-off and that spatial biofilm structure suppresses cheater (Succinivibrio) growth. The X-Gutor provides a scalable, modular platform for gut microbiome engineering, dietary intervention, and microbiota-targeted therapy development.

microbiology↗

bioRxiv2026

Alveolar Epithelial Cell Loss of the Mitochondrial Regulator TFAM Drives Progressive Lung Fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by failed alveolar epithelial repair and progressive fibrotic remodeling. Although aberrant reprogramming of alveolar type 2 (AT2) cells and accumulation of transitional AT2 states are increasing recognized as central features of IPF, the epithelial-intrinsic mechanisms that initiate these pathogenic states remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM), a regulator of mitochondrial DNA maintenance, as a critical regulator of AT2 cell homeostasis. TFAM expression was reduced in AT2 cells from human IPF lungs. Inducible AT2 cell-specific Tfam deletion in mice caused spontaneous fibrotic remodeling and increased susceptibility to bleomycin-induced lung injury. TFAM-deficient AT2 cells acquired KRT8+ transitional and p21+ senescence-associated features before the onset of fibrotic transformation, accompanied by impaired oxidative phosphorylation, redox imbalance, mitochondrial superoxide accumulation, repression of mtDNA-encoded respiratory genes, and disrupted mitochondrial ultrastructure. TFAM-deficient AT2 cells developed a profibrotic secretory program that promoted extracellular matrix deposition and fibroblast activation. We further identified insulin-like growth factor-binding protein 2 (IGFBP2) as a secreted mediator induced in TFAM-deficient AT2 cells. IGFBP2 was elevated in AT2 cells in human IPF lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF. IGFBP2 was detected in supernatants from fibrotic human precision-cut lung slices (hPCLS). IGFBP2 neutralization attenuated profibrotic remodeling in fibrotic hPCLS. Collectively, our findings identify TFAM-dependent mitochondrial homeostasis as an epithelial checkpoint linking AT2 cell-state stability to impaired epithelial-mesenchymal crosstalk driving pulmonary fibrosis.

pathology↗

bioRxiv2026

Decoding Immune Reconstitution Failure in People Living with HIV through Single-cell Genomics

Immune non-responders (INRs), a subset of people living with HIV (PLWH), fail to achieve full immune reconstitution and remain at increased risk of morbidity, mortality, and non-AIDS-related illnesses. As the mechanisms underlying this impaired immune recovery remain poorly understood, we performed single-cell multi-omics profiling on peripheral blood mononuclear cells from 43 INRs, 47 immune responders and 53 healthy donors. Our dataset comprises 2,744,009 transcriptomes and 1,226,658 chromatin-accessibility profiles across 58 identified immune cell types. INRs exhibited markedly elevated inflammatory signaling, increased apoptotic activity, and dysregulation of immune-activating ligand-receptor interactions. Additionally, we identified 2,996 interaction cis-eGenes and 5,938 cis-caPeaks, and validated key cell type-specific cis-xQTL effects associated with immune reconstitution failure. Furthermore, we identified 3,551 sc-eQTLs and 872 cell-state interaction eQTLs (ieQTLs) in CD4+ T cells. A genotype-specific upregulation of OAS3 in INRs, likely regulated by STAT1, was identified based on these results. We developed scPRISM (single cell Predictive Reconstitution Immune Status Model), a multi-modal framework that integrates scRNA-seq and scATAC-seq data to perform the dual tasks of differentiating disease states and predicting gene expression from chromatin accessibility, thereby deciphering the cell type-specific cis-regulatory basis of the disease. Our study delineates the transcriptional and epigenomic landscape of immune dysregulation in INRs and provides new genetic insights into HIV-associated immune reconstitution failure. These findings offer a foundation for developing biomarkers and precision therapies to restore immune function in PLWH.

genetics↗

bioRxiv2026

An Essential Role of the AMPK-Related Kinase SNRK in Regulating Drosophila Sleep

Protein kinases are important regulators of sleep in animals, but their loss-of-function mutations usually show moderate phenotypes. We report here that sucrose non-fermenting related kinase (SNRK), a member of the AMP-activated protein kinase-related kinase (ARK) family, plays an essential role in sleep regulation: Snrk gene knockout resulted in a profound loss of night-time sleep phenotype, much stronger than that of the well-known ARK member Sik3. This phenotype was completely rescued by neuronal SNRK expression. SNRK in adulthood was required for sleep. Catalytic and regulatory sites in SNRK were important for sleep. A chemoconnectomic (CCT) screen revealed SNRK functioning in cholinergic neurons whose activation is known to inhibit sleep. Sleep loss in SNRK mutants was rescued by pharmacological blockade of nicotinic acetylcholine receptors. Our findings have uncovered a fundamental role for SNRK in cholinergic neurons to regulate sleep.

neuroscience↗

bioRxiv2026

Neuronal calcium sensors emerge as novel adenylyl cyclase 8 regulators

Adenylyl cyclase 8 (AC8) is a Ca2+-sensitive membrane adenylyl cyclase highly expressed in the central nervous system. AC8-mediated intracellular cyclic adenosine monophosphate (cAMP) accumulation shapes synaptic function, plasticity, and memory formation and is tightly controlled by intracellular Ca2+ and G protein-coupled receptor signaling. Although it is well known that the effects of Ca2+ on AC8 activity are directly mediated by calmodulin, it has remained unclear until now whether other Ca2+-binding proteins also regulate AC8 function. Here, we identify the neuronal calcium sensor hippocalcin-like protein 1 (HPCAL1) as a direct interaction partner of AC8. Using biochemistry, structural proteomics, integrative modeling, cryo-EM and cell-based FRET approaches, we show that HPCAL1 associates with AC8 in a Ca2+-dependent manner. HPCAL1 shows weak positive modulation of AC8 activity in vitro, with sub micromolar affinity. HPCAL1 interacts with flexible regulatory regions of AC8, including the C1b domain and the N- and C-terminal regions. Interestingly, other members of the neuronal calcium sensor family can bind AC8 via the same sites. Together, our study reveals a previously unrecognized mode of Ca2+-dependent AC8 recognition by a group of neuronal calcium sensor proteins, which may be relevant to context-dependent regulation of cAMP signaling.

biochemistry↗

bioRxiv2026

Dissecting polycomb complexes for enhanced fetal hemoglobin production

Polycomb repressive complexes PRC1 and PRC2 regulate diverse developmental processes, including the fetal-to-adult switch in hemoglobin production, a process whose reversal is a goal for the treatment of sickle cell disease and {beta}-thalassemia. PRC inhibitors show promise for various disorders, but use is limited because of pleiotropic PRC activities. We explored whether fetal hemoglobin (HbF) can be reactivated in adult erythroid cells by selective perturbations of PRC1 or PRC2 components without complete loss of PRC function. A high-density CRISPR-Cas9 mutagenesis screen identified a region in the EZH2 subunit where Cas9 induced exon 14 skipping (EZH2{Delta}14). EZH2{Delta}14, which lacks a portion of the CXC domain, relieves HbF repression while largely maintaining cellular fitness. EZH2{Delta}14 retains H3K27 methylation and repression of a PRC target gene subset. Experiments in cells derived from mice bearing human {beta}-globin genes confirm that pathways mediating EZH2 control of HbF expression can function in a mouse model of HBG switching. These findings demonstrate that partial disruption of PRC can yield selective phenotypes, highlighting the therapeutic potential of targeting non-enzymatic domains within chromatin-modifying complexes. Key PointsO_LICRISPR-Cas9 screen across PRC1 and a saturating mutagenesis screen of PRC2 found the EZH2 CXC domain a desirable target for HbF induction C_LIO_LIthe EZH2-CXC domain leads to exon 14 exclusion, resulting in de-repression of HbF but maintenance of cell fitness. C_LI

molecular biology↗

bioRxiv2026

Whole-genome 3D architectural screen reveals modulators of brain DNA structure

Three-dimensional (3D) genome architecture is the foundation of gene regulation, and plays a critical role in normal physiology and disease. However, our understanding of its biochemical determinants has long been limited by technology: imaging-based screens only profile a small number of loci, while sequencing-based studies rarely exceed 100 samples or conditions. Here we present "in-plate chromosome conformation capture" (Plate-C), a high-throughput, cost-effective platform that profiles thousands of whole-genome architectures in a day. Plate-C enabled the first chemical screen for whole-genome structural changes--profiling 2,956 samples from 834 conditions across 5 neuronal and glial types, accompanied by 6,081 single cells using "easy diploid chromosome conformation capture" (Easy Dip-C) and 200,893 single-cell transcriptomes. We discovered that diverse, dose/time-dependent, and cell type/species-specific modes of DNA structural changes can be rapidly induced by manipulating epigenetic (HDAC, BET), metabolic (mTOR), proteostatic (UPR), developmental (GSK3/Wnt, Hedgehog), immune (cGAS/STING), and neurotransmission pathways. To validate our finding in vivo, we demonstrated in newborn mice that HDAC inhibition drives brain-wide genome rewiring within hours, highly correlated with changes in vitro and inducing a latent structural and transcriptional state orthogonal to normal differentiation. By enabling massively parallel profiling of whole-genome structures, Plate-C paves the way for systematic discovery of DNA folding principles to better understand and engineer the human genome in 3D.

genomics↗

bioRxiv2026

Rete Ridge Topography as a Determinant of Epidermal Stem Cell Identity: Implications for Skin Aging

Stem cell niches are dynamic microenvironments that regulate tissue homeostasis. Epidermal stem cells (EpiSC) preferentially localize to concave regions of epidermal rete ridges, which serve as primary niches for stem cell maintenance. EpiSC number and functional integrity decline during chronological aging. A defining feature of aged skin is epidermal atrophy, in which the prominent rete ridges present in young skin become flattened. Whether such topographical alterations influence EpiSC homeostasis and differentiation remains unclear. To address this, we generated anatomically accurate rete ridge structures using 3D bioprinting of collagen matrices as an ex vivo model and compared EpiSC cultured within concave topography to those maintained on a flat matrix resembling aged skin. Transcriptomic analysis revealed that concave niches promoted keratinocyte differentiation, marked by increased type I and II keratin gene expression and downregulation of cell cycle-associated genes. ATAC-seq identified topography-dependent chromatin accessibility changes enriched for transcription factors regulating epidermal differentiation, including upregulation of KLF4 and GRHL3 and downregulation of SOX9, HOXA1, and ETS1. Consistently, aged human skin showed reduced KLF4 and GRHL3 and increased SOX9 compared with young skin. Our findings demonstrate that concave niche topography imposes a spatially defined EpiSC microenvironment that promotes differentiation, alters cell cycle, and when perturbed, potentially contributes to the aging process. We conclude that spatial localization within rete ridge regions significantly affects epidermal progenitor stemness properties as fundamental differences in the physical microenvironment appear to influence cell fate decisions, thus, form shapes function of EpiSC.

cell biology↗

bioRxiv2026

A transcriptomic axis aligns with in vivo functional dynamics in hippocampal inhibitory circuits

Linking molecular identity to function in vivo at single-cell resolution remains an outstanding challenge in neuroscience. Here, we bridge this gap in the mouse hippocampus with an end-to-end pipeline of cell-resolved two-photon imaging and spatial transcriptomics. CA1 interneurons exhibiting heterogeneous physiological responses during a virtual-reality navigation task were post hoc clustered by gene expression into 5 GABAergic subclasses and 14 types. Physiological responses of individual cells aligned with a transcriptomic axis, and a classifier trained on physiological features alone recovered the same ordered organization. Our approach establishes a direct, scalable framework for linking in vivo circuit dynamics to constituent cell identity, revealing a transcriptomic axis that encompasses the structural and functional diversity of hippocampal inhibitory neurons. One-Sentence SummaryTracking neurons from behavior to spatial transcriptomics links in vivo function to molecular identity in the hippocampus.

neuroscience↗

bioRxiv2026

Single-cell full-length transcriptome of human lung reveals genetic effects on isoform regulation beyond gene-level expression

Genetic regulation of splicing uniquely contributes to trait-associated genome-wide association studies (GWAS) signals. However, quantitative trait loci (QTL) analysis using short-read sequencing of bulk tissues fails to capture full-length and cell-type-specific isoforms. Here, we present an isoform-level lung cell atlas from 129 never-smoking Korean women using single-cell long-read RNA-sequencing, identifying abundant unannotated and cell-type-specific isoforms. Isoform-level signatures of 37 lung cell types display a larger difference and therefore improve cell-type classification compared to gene-level expression. Notably, isoform-QTLs (isoQTLs) detect unannotated and/or cell-type-specific isoforms with independent genetic regulation from expression-QTL (eQTL), supported by enriched splicing functional elements. IsoQTLs nominate susceptibility isoforms from previously unexplained lung function and cancer GWAS loci, via eQTL-independent signals. We highlight a potentially functional novel variant of PPIL6 in multiciliated cells underlying lung cancer risk through alternative splicing. This isoform-level resource advances our understanding of cell-type-specific isoform regulation and its contribution to lung traits and diseases.

genetics↗

bioRxiv2026

Single-cell lung eQTL dataset of Asian never-smokers highlights the roles of alveolar cells in lung cancer etiology

Single-cell expression quantitative trait loci (sc-eQTL) analyses are powerful in identifying context-specific susceptibility genes from genome-wide association studies (GWAS) loci. However, few studies have comprehensively investigated cells of lung cancer origin in non-European populations. Here, we built a lung sc-eQTL dataset from 129 Korean women never-smokers with epithelial cell enrichment. eQTL mapping identified 2,229 genes with an eQTL in 33 cell types, including East Asian-specific findings when compared to predominantly European datasets. Integration with single-cell chromatin accessibility data demonstrated an enrichment of cell-type specific eQTLs in cell-type matched candidate enhancers, while shared eQTLs were more frequently found near promoters. Colocalization and transcriptome-wide association study unveiled 36 susceptibility genes from 22 cell types in 22 lung cancer loci, including 10 loci not achieving genome-wide significance in prior GWAS. Around 47% of these genes were from cells of the alveoli, underscoring their importance, especially in lung adenocarcinoma (LUAD) susceptibility. Focusing on the trajectory of alveolar epithelial cell regeneration, we detected 785 cell-state-interacting QTLs, which overlapped with 28% (10) of the identified susceptibility genes. Finally, we experimentally validated East Asian-and alveolar type 2 cell-specific eQTL of TCF7L2 underlying East Asian LUAD locus, 10q25.2. Consistent with its role as a Wnt/{beta}-catenin effector, TCF7L2 displayed significant effect on lung adenocarcinoma cell growth. Our data highlighted context-specific susceptibility genes, especially from alveolar cells of lung, contributing to lung cancer etiology.

genetics↗

bioRxiv2026

Cryo-EM image processing of amyloid filaments in RELION-5.1

We present new tools for the structure determination of amyloid filaments from electron cryo-microscopy (cryo-EM) images. We introduce a new algorithm for automated filament picking, based on their characteristic 4.75 [A] repeat signal; we implement the new auto-picker in a fully automated procedure for on-the-fly pre-processing of cryo-EM data sets of amyloid filaments; we present a graphical tool to select filament types based on bi-hierarchical clustering of filaments and 2D class assignments; and we introduce a denoising neural network for Blush regularisation that is re-trained on amyloid reconstructions. The implementation of these tools in release 5.1 of our open-software package RELION ensures broad applicability. We demonstrate their usefulness on two experimental data sets, including a previously described data set on recombinant human islet amyloid protein (hIAPP) with the S20G mutation for which we identify two new filament types.

biophysics↗

bioRxiv2026

The Pick fold in tau filaments from human MAPT mutants

Mutations in MAPT, the tau gene, give rise to forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), with abundant filamentous tau inclusions in brain cells. Some mutations that encode missense and deletion variants can give rise to a clinical picture of Picks disease and filaments made of three-repeat tau. Here we report the electron cryo-microscopy (cryo-EM) structures of tau filaments from individuals with MAPT mutations D252V, G272V, S320F and {Delta}G389-I392. The two-layered Pick fold was present in the individuals with mutations D252V and {Delta}G389-I392. By contrast, mutations G272V and S320F gave rise to a more open variant of the Pick fold, with residues 272-341 rotated by 20-25{degrees} with respect to the rest of the structure. These findings show that missense mutations within the filament core can modify the Pick fold, generating closely related structural variants. In addition, we were able to reconstitute the Pick fold and some of its variants using seeded assembly with recombinant 0N3R tau carrying 12 serine or threonine to aspartate substitutions (PAD12) and missense mutations D252V, G272V or S320F. This work provides a foundation for the development of structure-based diagnostic and therapeutic approaches.

biophysics↗

bioRxiv2026

gSV: a general structural variant detector using the third-generation sequencing data

Structural variants (SVs) are major contributors to genome diversity and disease susceptibility, particularly in cancer. Although third-generation sequencing technologies have substantially improved SV detection sensitivity, accurate detection of complex SVs remains challenging due to fragmented and heterogeneous alignment signals, as well as the dependence of many existing methods on predefined variant models. In this paper, we propose gSV, a general SV detector that integrates alignment-based and assembly-based approaches with the maximum exact match (MEM) strategy, with particular emphasis on resolving SVs with complex or atypical alignment signatures. Without predefined assumptions about SV types, gSV captures diverse variant signals, enabling the detection of SVs that are usually missed by conventional tools. Benchmarking using both simulated datasets and real long-read sequencing data demonstrates that gSV achieves improved sensitivity and overall detection performance compared with current state-of-the-art SV callers, particularly for simple and complex SV events with complex alignment patterns. Unique SV discoveries in four breast cancer cell lines, particularly in cancer-associated genes, demonstrate the potential biological relevance of gSV-enabled discoveries. Furthermore, analysis of a breast cancer cohort from the Chinese population highlights the utility of gSV for population-scale genomic studies. Collectively, gSV provides a unified framework for comprehensive SV discovery in both research and clinical genomics settings. O_TEXTBOXKey PointsO_LIExisting structural variant (SV) detection tools are limited in resolving SVs with complex alignment patterns due to their reliance on predefined variant models. C_LIO_LIgSV integrates alignment-based and assembly-based evidence using a maximum exact match (MEM) strategy, enabling capture of diverse and complex SV signals. C_LIO_LIBenchmarking on simulated and real long-read sequencing datasets demonstrates that gSV achieves competitive performance on canonical SV classes and improved sensitivity for complex SV patterns. C_LIO_LIApplication of gSV to breast cancer cell lines and a population-scale breast cancer cohort reveals previously unresolved SVs in cancer-associated genes, highlighting its utility in genomic and clinical studies. C_LI C_TEXTBOX

bioinformatics↗

bioRxiv2026

Epigenome-informed prioritization of bivalent chromatin SNPs enhances genomic prediction robustness: a proof-of-concept study in Pacific white shrimp (Litopenaeus vannamei)

BackgroundGenomic selection (GS) has revolutionized animal breeding, spanning livestock sectors such as pigs and cattle to aquatic species like fish and shrimp. However, its broader application across these industries is often constrained by high genotyping costs and reduced predictive reliability across divergent populations or generations. Developing cost-effective, biologically informed genotyping strategies to overcome these limitations remains a critical goal in animal agriculture. Epigenetic annotations, particularly histone modifications, provide direct functional insights into regulatory elements underlying complex trait variation and represent a promising but underexplored resource for marker prioritization. ResultsHere, using the Pacific white shrimp (Litopenaeus vannamei) as a model organism, we conducted a proof-of-concept study integrating resequencing and phenotypic data from 972 individuals. We generated high-resolution epigenomic maps by profiling four histone marks (H3K4me1, H3K4me3, H3K27me3, and H3K27ac) across multiple embryonic stages and adult muscle tissue using CUT&Tag. These functional annotations were then leveraged to prioritize single nucleotide polymorphism (SNP) subsets for genomic prediction. Among the tested strategies, SNPs located in the muscle-specific bivalent promoter/enhancer (E6) state--characterized by the co-occurrence of active and repressive marks--consistently maximized prediction accuracy under the BayesA model. Notably, even at a moderate density (15k), E6-derived SNPs achieved prediction accuracies exceeding those obtained using substantially larger genome-wide SNP sets. Most importantly, in a challenging cross-population validation using an independent strain, the E6-derived SNP subset significantly improved prediction accuracy by 47.6% (increasing from 0.21 {+/-} 0.05 to 0.31 {+/-} 0.04, p < 0.05) compared to random subsets at equivalent density. ConclusionsThese results demonstrate that epigenetic annotation-guided SNP prioritization provides a biologically informed and cost-effective strategy to enhance genomic prediction accuracy and stability. This framework is broadly transferable across species and offers a practical strategy for designing low-density genotyping panels that reduce costs while maintaining reliable selection outcomes in large-scale breeding programs.

genetics↗