Biology subjects

Lu, J.

Publications and source records attributed to Lu, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Sex-specific Genetic Regulatory Effects in Chickens

Sexual dimorphism is a defining vertebrate feature, yet its sex-specific molecular architecture remains poorly understood. Here we established a sex-balanced, uniformly reared chicken cohort to map this landscape, integrating individual whole-genome sequencing with 7,969 bulk and 779,380 single nucleus transcriptomes across 32 tissues from 280 birds. We identified 495,098 independent expression quantitative trait loci for 20,194 genes, including 10,937 loci modulated by cell-type composition. Notably, 340 genes were regulated by 449 loci in a sex-dependent manner, significantly enrichment in endocrine tissues like adipose and the adrenal gland. Furthermore, we fine-mapped 1,219 structural variants, demonstrating their unique roles to tissue- and sex-specific expression beyond SNPs. Ultimately, we showed the utility of these regulatory effects in elucidating the molecular basis of metabolism and complex traits in both chickens and humans. This comprehensive atlas of regulatory effects provides profound insights into the genomic and molecular basis of sexual dimorphism in vertebrates.

genomics↗

bioRxiv2026

Opposing regulatory logics converge on ABA receptors to govern the trade-off between growth and drought acclimation

Plants dynamically balance growth with stress responses through abscisic acid (ABA). How ABA signaling, but how ABA sensitivity is finely tuned is unclear. Here, we uncover a regulatory network of leucine-rich repeat receptor-like kinases (LRR-RLKs) that directly controls ABA receptors stability. We identify GASSHO1 (GSO1) as a core component that phosphorylates the PYL2 and PYL4 receptors, targeting them for degradation and thus serving as a brake on ABA signaling. Under drought stress, ABA accumulates and suppresses expression of GSO1-activating CIF peptides, releasing this brake to increase PYLs and sensitivity. This mechanism opposes our previously identified CEPR2 pathway, where drought-induced CEP peptides inhibit the kinase to stabilize PYLs. The integration of these two antagonistic modules within an LRR-RLK network enables precise, dynamic control of ABA perception. This work reveals a molecular framework explaining how plants calibrate the critical balance between growth and drought acclimation.

molecular biology↗

bioRxiv2026

Geoclimatic oscillations and ancient reciprocal adaptive introgression shape the evolutionary trajectories of threatened Coilia

Geoclimatic oscillations have repeatedly reshaped biodiversity, yet how ancient lineages persist and diversify through profound environmental upheavals remains a central question in evolutionary genomics. By integrating chromosome-level genome assemblies, population genomics, and transcriptomic data across the Coilia species complex, we reconstruct deep evolutionary histories of Coilia along the dynamic East Asian margins. Our analyses reveal divergences dating to the Miocene, coinciding with major tectonic and climatic transitions, including Tibetan Plateau uplift-linked reorganization of the Yangtze drainage toward the East China Sea, and the Middle Miocene Climatic Optimum. Despite long-term separation, we uncover evidence for ancient, reciprocal introgression among Coilia lineages, with gene flow confined to discrete genomic regions rather than distributed genome-wide. These introgressed regions are enriched for loci associated with immune function, vascular development, and osmoregulatory processes, and exhibit population genetic signatures consistent with positive selection. Temporal modelling indicates that this window of adaptive exchange preceded Pleistocene glacial intensification, after which gene flow became effectively restricted. Together, our results suggest that transiently permeable species boundaries historically acted as reservoirs of adaptive variation, shaping evolutionary trajectories and facilitating niche differentiation under repeated geoclimatic oscillations. This study highlights ancient adaptive introgression as an important evolutionary process contributing to the long-term persistence of threatened coastal fishes.

evolutionary biology↗

bioRxiv2026

Allosteric disulfide control of ligand binding and endocytosis of the natural killer cell receptor for HLA-G

Human Leukocyte Antigen (HLA)-G is selectively expressed by fetal trophoblast cells that invade maternal tissue and encounter maternal natural killer (NK) cells early in pregnancy. In NK cells, the endosomal receptor KIR2DL4 responds to soluble HLA-G by inducing a broad transcriptional program to support placental development. Structural features of KIR2DL4 that control ligand binding and endocytosis are unclear. Random mutagenesis revealed that three cysteines in the first immunoglobulin domain of KIR2DL4 regulate endocytosis and uptake of HLA-G. We found that the atypical Cys10-Cys28 disulfide bond observed in the KIR2DL4 crystal structure is an allosteric disulfide with potential to switch to a conventional Cys28-Cys74 bond. KIR2DL4 in human cells exists in both disulfide-bonded states, as shown by mass spectrometry analysis. The Cys10-Cys28 bond in a Cys74Ser KIR2DL4 mutant was reduced by protein disulfide isomerase (PDI) in vitro. Inhibition of PDI prevented HLA-G uptake by KIR2DL4 in both transfected 293T cells and primary NK cells. Mutants in the Cys10-Cys28 configuration endocytosed spontaneously but did not bind HLA-G. Conversely, KIR2DL4 with a Cys28-Cys74 bond was at the plasma membrane and responded to soluble HLA-G by endocytosis and transcription of the interferon stimulated gene IFI44L, like wild-type cells. A purified Cys10Leu KIR2DL4 mutant, which exhibited a reduced tendency to oligomerize, bound HLA-G in a peptide dependent manner with an affinity in the low micromolar range. Disulfide switching from the Cys10-Cys28 to the Cys28-Cys74 form correlated with a distant allosteric change, as predicted by AlphaFold, that could reorient a D0 domain loop to facilitate HLA-G binding. Thus, conversion from an inactive state to an HLA-G binding form regulates KIR2DL4 cellular localization and function to promote fetal development.

immunology↗

bioRxiv2026

MG53 Protects Against Intestinal Inflammation by Inhibiting NLRP3 Inflammasome Activation

Background and ObjectivesInflammatory bowel disease (IBD) involves dysregulated immune responses and chronic intestinal inflammation. The nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in IBD pathogenesis, but regulatory mechanisms remain not fully understood. Mitsugumin 53 (MG53, also known as TRIM72), originally identified as a critical membrane repair protein, has emerged as a novel regulator of inflammatory processes. To investigate the protective role of MG53 in colitis and elucidate its mechanisms in regulating NLRP3 inflammasome activation in IBD. MethodsWe used dextran sodium sulfate (DSS)-induced colitis models comparing MG53 knockout (MG53-/-) and wild-type (WT) mice, assessing disease severity, MG53 tissue uptake, and therapeutic effects of recombinant human MG53 (rhMG53). In vitro studies examined rhMG53s effects on NLRP3 inflammasome activation, caspase-1 cleavage, interleukin-1{beta} (IL-1{beta}) secretion, and MG53-NLRP3 interactions. ResultsMG53-/- mice showed more severe colitis with increased weight loss, higher disease activity scores, shortened colons, and greater inflammation. DSS treatment induced the accumulation of circulating MG53 in inflamed colonic tissue. rhMG53 administration ameliorated colitis severity in MG53-/- mice and dose-dependently suppressed NLRP3 inflammasome activation in vitro. MG53 interacted with NLRP3 and reduced apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and NLRP3 oligomerization without affecting upstream signaling or NLRP3 stability. ConclusionMG53 is a physiological regulator of NLRP3 inflammasome activation that protects against colitis, suggesting therapeutic potential for IBD.

immunology↗

bioRxiv2026

Base-resolution DNA methylome of human MDS hematopoietic stem cell reveals TET2-GFI1 epigenetic axis repressing MDS

Dysfunctional hematopoietic stem cells (HSCs) drive the initiation of myelodysplastic syndromes (MDS), yet the genome-wide DNA methylation landscape in MDS primitive HSCs and its mechanistic contribution to disease pathogenesis remain poorly defined. Here, we establish single-base resolution DNA methylomes of bone marrow HSCs from MDS patients and healthy donors. We uncover widespread hypermethylation within CpG islands, alongside hypomethylation in repetitive elements such as Alu. Differentially methylated regions (DMRs) are enriched for genes involved in cancer-related pathways, as well as extrinsic signaling pathways and intrinsic transcriptional networks essential for HSC function. Among these, we identify GFI1 and BMI1 as key targets of DNA methylation dysregulation in MDS. Notably, using either MDS or Tet2-deficient mouse model, we demonstrate that loss of Tet2, a frequently mutated epigenetic regulator in MDS, induces promoter hypermethylation and transcriptional repression of Gfi1, contributing to expansion of the MDS or aged hematopoietic stem and progenitor cell pool. Our study not only charts the base-resolution DNA methylome of human MDS HSCs but also reveals a TET2-GFI1 axis that safeguards HSC homeostasis. These findings provide mechanistic insight into how aberrant DNA methylation drives HSC dysfunction in MDS and offer an epigenomic resource for discovering novel regulators and therapeutic targets at the stem cell level.

immunology↗

bioRxiv2026

GP130 Y814 SIGNALING IS REQUIRED FOR THE DYNAMIN-MEDIATED ENDOCYTOSIS, MAPK/P38 ACTIVATION AND PERSISTENCE OF CHRONIC SYSTEMIC INFLAMMATION INDUCED BY HIGH FAT DIET

In chronic inflammatory diseases such as obesity, tissue and cellular homeostasis are disrupted by persistent low-grade inflammation, where one of the most prominent pro-inflammatory cytokines that correlates with age and body mass index (BMI) is IL-6. All members of the IL-6 family of cytokines signal through their obligate co-receptor gp130, in whichsignaling tyrosines on the intracellular portion of gp130 activate multiple downstream pathways such as the canonical STAT and MAPK pathways. However, non-canonical gp130 pathways such as SRC family of kinases (SFKs) signaling have emerged as drivers of cellular stress response. Our recently published mutant mouse model carrying a constitutive inactivation of gp130-Y814 (F814 mice), which impairs SFK activation, exhibited an enhanced resolution of inflammatory responses and improved regenerative outcomes in both acute skin wound healing and post-traumatic osteoarthritis models. The current study was designed to explore whether the gp130-Y814 mutation reduces systemic chronic inflammation and multimorbidity in a high-fat diet (HFD)-induced model and to interrogate the possible downstream cellular mechanisms that are affected. In response to HFD, F814 mice showed significantly reduced systemic and tissue-specific inflammatory responses and protection from obesity-induced bone loss and osteoarthritis compared to wild type (WT) mice. After extensive characterization, the role of gp130-Y814 in monocytes/macrophages appeared to be dispensable, but we discovered that the F814 mutation blunts gp130 receptor internalization, p38/MAPK activation and the release of matrix metalloproteinases (MMPs) in chondrocytes. Finally, we showed that F814 chondrocytes had markedly reduced activation of the SFK-dependent GTPase dynamin 2 (Dyn2) in response to catabolic IL-6 cytokines. Introduction of a dominant-negative Dyn2 mutant into WT chondrocytes phenocopied the effects of the F814 mutation, resulting in attenuated p38/MAPK signaling and reduced MMP activation following stimulation with IL-6 cytokines. This study demonstrates, for the first time, that the Y814 residue is directly implicated in Dyn2-mediated internalization of the gp130 receptor, thereby modulating downstream signaling and contributing to pathological outcomes in chronic inflammatory and degenerative diseases in a cell type-specific manner.

cell biology↗

bioRxiv2026

Detection of Somatic Point Mutations Directly from Spatial Transcriptomics Enables in vivo Spatiotemporal Lineage Tracing

Spatial transcriptomics reveals tissue organization but lacks in vivo lineage-tracing methods applicable to humans. We introduce SpaceTracer, a computational framework that accurately detects somatic single-nucleotide variants (SNVs) directly from spatial transcriptomics data. By leveraging naturally occurring somatic SNVs, SpaceTracer reconstructs cellular phylogenies within native tissue architecture, enabling the mapping of lineage spread, migration, lineage-coupled expression changes and lineage-aware local interactions. Applied to human cutaneous squamous cell carcinoma, it traced tumor initiation and progressions, uncovered widespread pre-invasive migration of dedifferentiated epithelial cells and characterized mutant B cells migrating from tertiary lymphoid structures (TLS) into the tumor boundary. The framework also reconstructed developmental lineages across multiple tissues and identified tissue-resident mutant immune cells. SpaceTracer thus provides a perturbation-free platform for high-resolution spatiotemporal lineage tracing, offering a transformative tool for elucidating complex biological systems--especially tumor-immune ecosystems--with direct implications for advancing cancer immunotherapy.

bioinformatics↗

bioRxiv2026

PhyloSOLID: Robust phylogeny reconstruction from single-cell data despite inherent error and sparsity

While lineage tracing based on somatic mutations in single-cell sequencing data offers a powerful approach to reconstructing cellular histories in vivo, its reliability is fundamentally limited by pervasive technical artifacts--specifically, high error rates and data sparsity. These issues introduce false phylogenetic signals that corrupt tree topology and lead to spurious evolutionary conclusions. To overcome these limitations, we present PhyloSOLID, a phylogenetic algorithm designed to be inherently robust to these data imperfections. PhyloSOLID employs a progressive scaffolding strategy that begins with graph-based construction of a low-resolution, high-confidence backbone tree from reliable and uniformly covered mutations. This scaffold is then refined through the iterative integration of remaining data, guided by a Bayesian statistical model that penalizes phylogenetic inconsistencies to effectively separate the true evolutionary signal from technical artifacts. Benchmarking on both simulated datasets and multiple ground-truth datasets demonstrates that PhyloSOLID achieves superior lineage reconstruction accuracy over existing methods, for both single-cell RNA-seq and DNA-seq data. Additionally, a user-friendly web interface enables customized quality assessment, artifact removal, and interpretation of lineage structures. PhyloSOLID provides a powerful solution for decoding cellular evolution in developmental and disease contexts.

bioinformatics↗

bioRxiv2026

Unravelling genome-wide mosaic microsatellite mutations at single-cell resolution

Short tandem repeats (STRs), or microsatellites, are highly mutable genomic elements that modulate gene regulations and are implicated in a range of human diseases. However, detecting mosaic STR mutations at single-cell resolution remains challenging due to both technical and biological complexities. To address this, we developed BayesMonSTR, a robust algorithm that enables accurate detection of mosaic STR mutations. Using this tool in single-cell analysis of human tissues, we reveal an accumulation of longer mosaic STR insertions and deletions (indels) in aging mitotic and post-mitotic cells. Strikingly, prefrontal cortex (PFC) neurons accumulate a higher burden of STR mutations than B cells or lung epithelium, with aged neurons exhibiting a particularly pronounced increase in longer STR deletions. These mutations are enriched at transcription start sites (TSSs) and active enhancers of highly expressed genes. Our work establishes a foundation for genome-wide, hypothesis-free discovery of disease-associated mosaic STR mutations and reveals a previously unexplored landscape of mosaic STR variation in development and aging.

bioinformatics↗

bioRxiv2026

Monitoring Gene Expression in Retina with Synthetic Serum Markers

Gene expression underlies retinal development, function, and pathogenesis. However, monitoring retinal gene expression in vivo is challenging. In this study, we apply synthetic serum markers, called Released Markers of Activity, or RMAs, to quantify gene expression in an intact retina through a simple blood test. We show that RMAs can quantify transduction of multiple retinal cell-types and monitor cell implantation or cell loss. We found RMAs are sensitive enough to measure transduction of rare cell populations, such as retinal ganglion cells and could detect transplantation of as few as 100 stem cells. Expression of RMAs showed no evidence of cell loss or immune activation in the retina. Overall, these findings demonstrate that RMAs are highly sensitive, tissue non-destructive gene expression reporters that can continuously track gene delivery and cell survival in intact retina through a simple blood test.

bioengineering↗

bioRxiv2026

Dual Engram Architecture within a Single Striatal Cell Type Distinctly Controls Alcohol Relapse and Extinction

Relapse is a major obstacle in the treatment of alcohol and drug addiction and is thought to be driven by persistent drug-associated memories formed during their use. Behavioral therapies such as extinction training can reduce relapse and are proposed to work by creating a competing memory trace. However, where and how these opposing memories are stored in the brain is unknown. Here, we show that two anatomically and functionally distinct engram ensembles within the same genetically defined striatal cell type, direct-pathway medium spiny neurons (dMSNs), encode these opposing memories. Using engram-tagging tools in mice, we found that the acquisition of operant alcohol learning recruits a dMSN ensemble enriched in the striatal matrix compartment that stores alcohol-associated memories and whose activation selectively promotes relapse. Conversely, extinction of alcohol seeking recruits a dMSN ensemble enriched in the striosome compartment that stores extinction-related memories and whose activation suppresses relapse. Furthermore, we reveal that the physical memory trace storing the relapse-promoting memory is embedded within persistently strengthened corticostriatal synapses engaged during learning, and that artificially reproducing this plasticity is sufficient to trigger relapse-like behavior. These findings uncover a dual-engram architecture within dMSNs that governs relapse and extinction, providing a mechanistic framework for understanding how competing memories regulate drug-seeking behavior. HighlightsO_LIAcquisition and extinction of alcohol learning recruits distinct dMSN ensembles. C_LIO_LIAcquisition recruits matrix-enriched dMSN ensembles to promote relapse. C_LIO_LIExtinction recruits striosome-enriched dMSN ensembles to suppress relapse. C_LIO_LIEngram dMSNs show lasting synaptic potentiation and mimicking this potentiation triggers relapse. C_LI

neuroscience↗

bioRxiv2026

Optimizing Post-Transplantation Detection of Subcutaneously Transplanted Islets Using Dithizone Staining

IntroductionPancreatic islet transplantation is a promising therapeutic strategy to restore insulin independence in patients with type 1 diabetes mellitus. In addition to primary human islets, human pluripotent stem cell-derived islets have shown clinical promise. However, optimizing transplantation sites and improving methods for standardized islet dosing and post-transplant graft localization are key limitations. The subcutaneous space offers an alternative site for transplantation due to its accessibility and minimally invasive nature; nevertheless, poor vascularization and difficulty locating engrafted islets limit its experimental utility. The use of dithizone, a zinc-chelating dye that selectively binds the high intracellular zinc concentrations of insulin-producing {beta}-cells, may enable rapid graft localization through selective staining. Here, we investigate whether dithizone staining can reliably localize transplanted islet grafts within the subcutaneous space of murine models. MethodsSC-islets were generated from HUES8 stem cells and functionally validated using glucose-stimulated insulin secretion. Islet volume was standardized prior to transplantation using automated islet equivalent quantification with the BioRep Islet Cell Counter. Approximately 4,000 islet equivalents of either SC-islets or primary human islets were transplanted into the subcutaneous space of immunodeficient mice. Graft function was assessed longitudinally via blood glucose monitoring, glucose tolerance testing, and human C-peptide measurements. Four weeks post-transplantation, dithizone staining was applied to harvested skin tissue to localize islet grafts, and immunohistochemical validation was performed. ResultsAutomated quantification of islet equivalents enabled consistent dosing across transplantation groups. Transplanted islets maintained function in vivo, as demonstrated by reduced blood glucose levels, preserved glucose tolerance, and detectable human C-peptide. Dithizone staining produced clear and selective red labeling of insulin-producing {beta}-cell grafts within the subcutaneous tissue, enabling reliable localization and recovery of engrafted islets. Immunohistochemical analyses confirmed the presence of insulin-expressing cells at isolated islet grafts. DiscussionDithizone staining is a rapid, cost-effective approach to identify subcutaneous islet grafts and enables downstream analyses, addressing a significant limitation in islet transplantation research. When combined with standardized pre-transplant islet quantification, this approach provides a cohesive and reproducible framework for evaluating subcutaneous islet transplantation. Future studies could complement these results by assessing the potential effects of dithizone exposure and exploring its applicability across other transplantation sites and imaging modalities.

cell biology↗

bioRxiv2026

Integrative transcriptomic identification of cellular senescence beyond marker limitations

Cellular senescence lacks a universal marker and varies across cell types, tissues, and stressors, complicating identification. Using SPiDER SA-{beta}-gal labeled single-cell RNA-seq from regenerating mouse muscle, we found that curated gene sets show opposing enrichment patterns in experimentally defined senescent cells, suggesting apparent concordance in prior studies may reflect circular validation. Machine learning classifiers outperformed marker-centric approaches by capturing coordinated transcriptional features largely absent from differentially expressed genes. These features traced senescence progression, positioning senescent cells at late pseudotime with reduced transcriptional entropy. Ligand-receptor analysis identified IGF signaling as a directional axis of secondary senescence from senescent to non-senescent cells. When applied to bulk RNA-seq and an independent aging dataset, the classifier detected age-associated senescence patterns while the entropy-senescence relationship held across most cell types. These findings demonstrate that transcriptome-based classification provides a robust alternative to marker-centric readouts while enabling mechanistic hypothesis generation.

bioinformatics↗

bioRxiv2025

TMPO promotes cellular dissemination and metastasis in circulating tumor cells

Metastasis--the process by which cancer cells spread beyond the primary tumor to distant organs--accounts for the vast majority of cancer-related deaths. To elucidate mechanisms underlying dissemination and metastasis in prostate cancer, we have investigated circulating tumor cells (CTCs) obtained from genetically engineered mouse models (GEMMs). The phenotypic and molecular properties of the CTCs, and organoids derived from these CTCs, closely model the tumor and metastatic phenotypes of their parental GEMMs. Moreover, organoids derived from individual CTCs exhibit molecular and morphological heterogeneity that is associated with distinct metabolic states as well as differences in human prostate cancer outcome. Using computational systems analyses, we have identified TMPO, encoding the nuclear membrane protein lamina-associated polypeptide 2 (Lap2), as a key driver of this heterogeneity. TMPO activity is upregulated in advanced human prostate tumors, metastases, and CTCs, and is associated with adverse clinical outcome. Our findings indicate that TMPO promotes dissemination and metastasis in vivo by enhancing survival in conditions of metabolic stress, and reveal a novel mechanistic link between CTC heterogeneity, stress adaptation, and metastatic potential.

cell biology↗

bioRxiv2025

MetAlyzer to Perform Streamlined, Interactive, and Pathway-Mapping Analysis of Targeted Metabolomics Data from the biocrates Platform

Mass spectrometry (MS)-based metabolomics has emerged as a powerful tool to address multifaceted biological questions. Commercial solutions like the ones developed at biocrates allow reliable and quantitative targeted metabolic profiling, including the conversion of the raw MS spectra into absolute concentrations of metabolites. These results can be exported for further analysis under several formats with varying levels of human-vs. machine-readability. The default output format is an Excel spreadsheet that favours human readability and therefore requires extra preparation steps for downstream bioinformatic analysis and data exploration. To streamline this next step for users of this platform, we developed MetAlyzer, an R package (https://github.com/Lu-Group-UKHD/MetAlyzer) specifically designed to handle the spreadsheets generated by WebIDQ, the biocrates workflow manager software. MetAlyzer converts WebIDQ-generated spreadsheets into flexible SummarizedExperiment objects and provides functions for data preprocessing, statistical testing, and visualization of differential metabolites. To further support data exploration and hypothesis generation by users without coding experience, we also developed an interactive and intuitive Shiny app (https://metalyzer.shinyapps.io/MetAlyzer_ShinyApp/) that interfaces with MetAlyzers core functionality, enabling users to execute the complete analysis workflow without writing code. This combination can help scientists deepen their understanding of metabolomics results, supporting the broader adoption of metabolomics in the life sciences community.

bioinformatics↗

bioRxiv2025

Simulation-templated photorealistic prediction of bacterial patterns

Pattern formation underlies biological organization across scales, but predicting experimentally observed patterns remains difficult because mechanistic models and data-driven generative models fail in complementary ways. Coarse-grained mechanistic models can encode causal constraints and global morphology, yet they omit fine-scale features such as texture, color gradients, and stochastic replicate-to-replicate variation. In contrast, generative image models can produce realistic images but are not inherently grounded in the biophysical rules that shape real patterns. Here, we introduce a simulation-conditioned generative framework that uses mechanistic simulations as spatial priors for generating biologically realistic pattern data. As a concrete test, we use a synthetic-to-real inverse task to show that these generated patterns preserve information needed for inference on real experimental images, beyond merely reproducing plausible visual appearance. Using branching colony expansion of Pseudomonas aeruginosa as a model system, we combine a coarse-grained PDE model with latent representations from a foundation image model and a conditional diffusion model. The resulting framework preserves the global structures imposed by simulation while restoring experimentally observed fine-scale morphology and stochastic variability. A model trained exclusively on simulation-conditioned synthetic patterns transfers without fine-tuning to real experimental patterns, enabling inference of initial seeding configurations from experimental colony morphology. Together, these results establish simulation-conditioned generative modeling as a strategy for converting coarse mechanistic models into scientifically structured synthetic data, enabling inference tasks on real biological patterns where experimental data are scarce.

systems biology↗

bioRxiv2025

A near-complete lamprey genome illuminates ancestral vertebrate innovations

The origin of vertebrates is characterized by a suite of phenotypic innovations, yet the underlying genetic mechanisms remain poorly understood. As a living representative of jawless vertebrates, the lamprey serves as a pivotal model for investigating the genomic basis of early vertebrate evolutioin. Here, we report a near telomere-to-telomere (T2T) genome assembly of the reissner lamprey (Lethenteron reissneri), generated from sperm DNA that is not subject to programmed genome rearrangement. The 1.25 Gb assembly resolves over 97% of chromosome sequences into single contigs, enabling reconstruction of previously inaccessible genomic regions. Centromeres display highly diversified, lamprey-specific repeat units and structural architectures, whereas telomeres contain both conserved and lineage-specific satellite repeats. Deep transcriptomic profiling across representative organs and developmental stages substantially improved genome annotation. Comparative genomic analyses revealed a major expansion of 1,562 gene families at the base of the vertebrate lineage, and they are significantly enriched for functions related to neural development, skeletal formation, and cardiac function, echoing the known phenotypic innovations in vertebrates. Notably, the CDH2 gene family underwent vertebrate-specific copy number expansion and acquired conserved cis-regulatory elements (CREs), highlighting its potential role in shaping the early vertebrate circulatory system. Histological analyses and functional knockout experiments demonstrated that one CDH2 paralog (CDH2_H) is essential for lamprey heart development and chamber formation, playing a critical role in the emergence of the closed circulatory system in early vertebrates. This high-quality lamprey genome provides a foundational resource for dissecting the genetic basis of key innovations that shaped vertebrate evolution.

genomics↗