Biology subjects

Zhou, Z.

Publications and source records attributed to Zhou, Z..

At least 289 records · Page 16Linked to original sources

bioRxiv2023

Highly efficient induction of functionally mature excitatory neurons from feeder-free human ES/iPS cells

Cortical excitatory neurons (Cx neurons) are the most dominant neuronal cell type in the cerebral cortex, which play a central role in cognition, perception, intellectual behavior and emotional processing. Robust in vitro induction of Cx neurons may facilitate as a tool for the elucidation of brain development and pathomechanism of the intractable neurodevelopmental and neurodegenerative disorders including Alzheimers disease, and thus potentially contribute to drug development. Here, we report a defined method for efficient induction of Cx neurons from the feeder-free-conditioned human embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells). By using this method, human ES/iPS cells could be differentiated into ~99% MAP2-positive neurons by three weeks, and these induced neurons, within five weeks, presented various characteristics of mature excitatory neurons such as strong expression of glutamatergic neuron-specific markers (subunits of AMPA and NDMA receptors and CAMKII), highly synchronized spontaneous firing and excitatory postsynaptic current (EPSC). Moreover, the Cx neurons showed susceptibility to the toxicity of A{beta}42 oligomers and excitotoxicity of excessive glutamates, which is another advantage in terms of toxicity test and searching for the therapeutic agents. Taken together, this study provides a novel research platform for the study of neural development and degeneration based on the feeder-free human ES/iPS cell system.

neuroscience↗

bioRxiv2023

Spanve: an Effective Statistical Method to Detect Spatially Variable Genes in Large-scale Spatial Transcriptomics Data

Depicting gene expression in a spatial context through spatial transcriptomics would be beneficial for inferring cell function mechanisms. The identification of spatially variable genes is a crucial step in leveraging the spatial transcriptome to understand intricate spatial dynamics. In this study, we developed Spanve, a nonparametric statistical method for detecting spatially variable genes in large-scale ST data by quantifying expression differences between spots and their spatial neighbours. This method offers a nonparametric approach to identifying spatial dependencies in gene expression without assuming specific distributions. Compared to traditional methods, Spanve decreases the number of false-positive outcomes, leading to more accurate identification of spatially variable genes. Furthermore, Spanve could facilitate downstream spatial transcriptomics analyses, including spatial domain detection and cell type deconvolution. These results show the broad applications of Spanve in advancing our understanding of spatial gene expression patterns within complex tissue microenvironments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/527623v3_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1574cfcorg.highwire.dtl.DTLVardef@7f3f56org.highwire.dtl.DTLVardef@1732a3org.highwire.dtl.DTLVardef@fdaafa_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

Epoxyeicosatrienoic acids and sEH inhibition prevent cardiac dysfunction in CVB3-induced myocarditis by positively regulating type I interferon signaling

Myocarditis is a challenging inflammatory disease of the heart and better understanding of its etiology is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by cytochrome P450 enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus (CVB3)-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and, in the murine heart, and correlated with the increased expression and activity of the sEH after CVB3 infection. Administration of a sEH inhibitor prevented CVB3-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated vial infection/ improved viral resistance by activating type I interferon (IFN) signaling. At the molecular level, EETs enhanced the interaction between glycogen synthase kinase 3{beta} (GSK3{beta}) and TANK-binding kinase 1 (TBK1) to promote IFN-{beta} production. Our findings revealed that EETs and sEH inhibitors prevent the progress of CVB3-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.

immunology↗

bioRxiv2023

Bird wings are shaped by thermoregulatory demand for heat dissipation

The tendency for animals in warmer climates to be longer-limbed (Allens Rule) is widely attributed to the demands of thermoregulation. However, the underlying mechanism remains unclear, because variation in limb-length can typically be driven by selection for both efficient heat retention and increased heat dissipation capacity. Using comparative phylogenetic models, we find that occurrence in warmer climates is associated with longer wing bones for 1,520 species of passerine birds. The highly vascularized musculature along these bones is only uncovered during flight, when the wings function as the primary site of heat exchange, cooling the organism by dissipating excess heat generated by muscular activity. Conversely, the musculature along the wing bones is insulated by feathering when at rest, playing a negligible role in heat retention, even in colder climates. Given this asymmetry in thermoregulatory roles, we can identify the positive relationship between temperature and wing bone length as a phenotypic gradient shaped by increased demand for heat dissipation in warmer climates. Our findings provide a clear illustration of the mechanism by which global warming can drive spatial and temporal trends in appendage length, and also highlight the role of heat dissipation in reshaping even the most critical features of vertebrate anatomy. Significance StatementAnimals tend to be longer-limbed in warmer climates, but it remains unclear whether this pattern is driven by selection for cold tolerance at low temperatures or efficient heat dissipation at high temperatures. We show that for 1,520 species of passerines, bird wing bones are relatively longer in warmer climates. The vascularized musculature along these bones primarily functions in heat exchange during flight, when the overwhelming thermoregulatory challenge is dissipating heat, suggesting longer wing-bone length is driven by heat dissipation demands. Our findings reveal the pervasive impacts of thermoregulatory demands on even the most important functional traits.

ecology↗

bioRxiv2023

ViWrap: A modular pipeline to identify, bin, classify, and predict viral-host relationships for viruses from metagenomes

Viruses are increasingly being recognized as important components of human and environmental microbiomes. However, viruses in microbiomes remain difficult to study because of difficulty in culturing them and the lack of sufficient model systems. As a result, computational methods for identifying and analyzing uncultivated viral genomes from metagenomes have attracted significant attention. Such bioinformatics approaches facilitate screening of viruses from enormous sequencing datasets originating from various environments. Though many tools and databases have been developed for advancing the study of viruses from metagenomes, there is a lack of integrated tools enabling a comprehensive workflow and analyses platform encompassing all the diverse segments of virus studies. Here, we developed ViWrap, a modular pipeline written in Python. ViWrap combines the power of multiple tools into a single platform to enable various steps of virus analysis including identification, annotation, genome binning, species- and genus-level clustering, assignment of taxonomy, prediction of hosts, characterization of genome quality, comprehensive summaries, and intuitive visualization of results. Overall, ViWrap enables a standardized and reproducible pipeline for both extensive and stringent characterization of viruses from metagenomes, viromes, and microbial genomes. Our approach has flexibility in using various options for diverse applications and scenarios, and its modular structure can be easily amended with additional functions as necessary. ViWrap is designed to be easily and widely used to study viruses in human and environmental systems. ViWrap is publicly available via GitHub (https://github.com/AnantharamanLab/ViWrap). A detailed description of the software, its usage, and interpretation of results can be found on the website. HighlightsO_LIViWrap integrates state-of-the-art tools and databases for comprehensive characterization and study of viruses from metagenomes and genomes. C_LIO_LIViWrap offers a highly flexible, modular, customizable, and easy-to-use pipeline with options for various applications and scenarios. C_LIO_LIViWrap enables a standardized and reproducible pipeline for viral metagenomics, genomics, ecology, and evolution. C_LI

bioinformatics↗

bioRxiv2023

Real-Time Quantification of Cell Mechanics and Functions by Double Resonator Piezoelectric Cytometry -Theory and Study of Cellular Adhesion of HUVECs

Cell mechanics is closely associated with cellular structure and function. However, the inability to measure both cellular force and viscoelasticity of statistically significant number of cells noninvasively remains a challenge for quantitative characterizations of various cellular functions and practical applications. Here a double resonator piezoelectric cytometry (DRPC), using AT and BT cut quartz crystals of the same frequency and surface morphology is developed to simultaneously quantify the cells-generated forces ({Delta}S) and viscoelastic moduli (G', G'') of a population of isolated single cells or cells with different degrees of cell-cell interactions in a non-invasive and real time manner. DRPC captures the dynamic mechanical parameters {Delta}S and G', G'' during the adhesions of human umbilical vein endothelial cells (HUVECs) under different ligand densities of adhesion molecules fibronectin or Arg-Gly-Asp (RGD) modified on the gold surfaces of 9 MHz AT and BT cut quartz crystals, and different seeding densities of HUVECs. It is found that both the ligand density and cell seeding density affect the magnitudes of {Delta}S and G', G'' and their correlations are revealed for the first time by DRPC. The validity of DRPC is further verified by mechanical changes of the cells in response to treatments with cytoskeleton regulators.

biophysics↗

bioRxiv2023

Homeostatic control of an iron repressor in a GI tract resident

The transition metal iron plays a crucial role in living cells. However, high level of iron is potentially toxic through the production of reactive oxygen species (ROS), serving as a deterrent to the commensal fungus Candida albicans for colonization in the iron-rich gastrointestinal (GI) tract. We observe that the mutant lacking an iron-responsive transcription factor Hap43 is hyper-fit for colonization in murine gut. We demonstrate that high iron specifically triggers multiple post-translational modifications (PTMs) and proteasomal degradation of Hap43, a vital process guaranteeing the precision of intestinal ROS detoxification. Reduced levels of Hap43 lead to de-repression of antioxidant genes and therefore alleviate the deleterious ROS derived from iron metabolism. Our data reveal that Hap43 functions as a negative regulator for oxidative stress-adaptation of C. albicans to gut colonization and thereby provide a new insight into understanding the interplay between iron homeostasis and fungal commensalism. ImportanceIron homeostasis is critical for creatures. Candida albicans is one of the major commensals in the GI tract where is iron-replete environment. Transcriptional factor Hap43 was believed to repress iron utilizations genes in iron-depleted conditions for decades. However, the mystery in iron-replete conditions of Hap43 has never been uncovered. We discovered that reduced levels of Hap43 via phosphorylation-dependent nuclear export, followed by proteosome-mediated protein degradation, leads to de-repression of downstream antioxidant genes and promote its colonization in GI tract. We propose that C. albicans has a strict detoxification process to ensure its survival, which has important implications for understanding how the fungi survives in the mammalian host.

microbiology↗

bioRxiv2023

Contrasting patterns of somatic mutations in neurons and glia reveal differential predisposition to disease in the aging human brain

Characterizing the mechanisms of somatic mutations in the brain is important for understanding aging and disease, but little is known about the mutational patterns of different cell types. We performed whole-genome sequencing of 71 oligodendrocytes and 51 neurons from neurotypical individuals (0.4 to 104 years old) and identified >67,000 somatic single nucleotide variants (sSNVs) and small insertions and deletions (indels). While both cell types accumulate mutations with age, oligodendrocytes accumulate sSNVs 69% faster than neurons (27/year versus 16/year) whereas indels accumulate 42% slower (1.8/year versus 3.1/year). Correlation with single-cell RNA and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These patterns highlight differences in the mutagenic processes in glia and neurons and suggest cell type-specific, age-related contributions to neurodegeneration and oncogenesis.

neuroscience↗

bioRxiv2023

The arginine dihydrolase pathway shapes human gut microbial community assembly, functions, and mammalian host colonization

The arginine dihydrolase pathway (arc operon) present in a subset of diverse human gut species enables arginine catabolism. This specialized metabolic pathway can alter environmental pH and nitrogen availability, which in turn could shape gut microbiota inter-species interactions. By exploiting synthetic control of gene expression, we investigated the role of the arc operon in probiotic Escherichia coli Nissle 1917 on human gut community assembly and health-relevant metabolite profiles in vitro and in the murine gut. By stabilizing environmental pH, the arc operon reduced variability in community composition across different initial pH perturbations. The abundance of butyrate producing bacteria were altered in response to arc operon activity and butyrate production was enhanced in a physiologically relevant pH range. While the presence of the arc operon altered community dynamics, it did not impact production of short chain fatty acids. Dynamic computational modeling of pH-mediated interactions reveals the quantitative contribution of this mechanism to community assembly. In sum, our framework to quantify the contribution of molecular pathways and mechanism modalities on microbial community dynamics and functions could be applied more broadly.

systems biology↗

bioRxiv2023

CircPLXNA2 affects the proliferation and apoptosis of myoblast through circPLXNA2/gga-miR-12207-5P/MDM4 axis

BackgroundcircRNAs are new-identified special endogenous RNA molecules that covalently close a loop by backsplicing with pre-mRNA. In the cytoplasm, circRNAs would act as molecular sponges to bind with specific miRNA to promote the expression of target genes. However, there is still in its fancy of knowing circRNA functional alternation in skeletal myogenesis. In this study, we favor a model to identify the circRNA-miRNA-mRNA interaction network in which the axis may be implicated in the progression of chicken primary myoblasts (CPMs) myogenesis by a combination of multi-omics (i.e., circRNA-seq and ribo-seq). ResultsIn total, 314 circRNA-miRNA-mRNA regulatory axis containing 66 circRNAs, 70 miRNAs, and 24 mRNAs that may be relevant to myogenesis were collected. With these, the circPLXNA2-gga-miR-12207-5P-MDM4 axis aroused our research interest. The circPLXNA2 is highly differentially expressed during differentiation versus proliferation. It was demonstrated that circPLXNA2 inhibited the process of apoptosis while at the same time stimulating cell proliferation. Furthermore, we demonstrated that circPLXNA2 could inhibit the repression of gga-miR-12207-5p to MDM4 by directing binding to gga-miR-12207-5p, thereby restoring MDM4 expression. ConclusionsCircPLXNA2 could function as a competing endogenous RNA (ceRNA) to inhibit the repression of gga-miR-12207-5p to MDM4 by directing binding to gga-miR-12207-5p, thereby recovering the expression of MDM4.

molecular biology↗

bioRxiv2022

Spatial transcriptomics deconvolution at single-cell resolution by Redeconve

Computational deconvolution with single-cell RNA sequencing data as reference is pivotal to interpreting spatial transcriptomics data, but the current methods are limited to cell type resolution. Here we present Redeconve, an algorithm to deconvolute spatial transcriptomics data at single-cell resolution, enabling interpretation of spatial transcriptomics data with thousands of nuanced cell states. We benchmarked Redeconve with the state-of-the-art algorithms on diverse spatial transcriptomics datasets and platforms and demonstrated the superiority of Redeconve in terms of accuracy, resolution, robustness, and speed. Applications to a human pancreatic cancer dataset revealed cancer clone-specific T cell infiltration, and application to lymph node samples identified subtle cellular surroundings between IgA+ and IgG+ spots, providing novel insights into tumor immunology and the regulatory mechanisms underlying antibody class switch.

bioinformatics↗

bioRxiv2022

Clonally-Expanded, Thyrotoxic Autoimmune Mediator CD8+ T cells Driven by IL21 Contribute to Checkpoint Inhibitor Thyroiditis

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) cancer therapy and is an increasing clinical challenge with the expanding use of these treatments. To date, human immunopathogenic studies of immune related adverse events (IRAEs) have relied upon sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from subjects with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates to those from subjects with spontaneous autoimmune Hashimotos thyroiditis (HT) or no thyroid disease. Single cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells ("CD8+ autoimmune mediators) present in ICI-thyroiditis, but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin 21, a cytokine secreted by intrathyroidal T follicular (Tfh) and T peripheral helper (Tph) cells, as a driver of these thyrotoxic CD8+ autoimmune mediators. In the presence of IL21, human CD8+ T cells acquired the autoimmune mediator phenotype with upregulation of cytotoxic molecules (IFN{gamma}, granzyme); the chemokine receptor CXCR6; and thyrotoxic capacity. We validated these findings in vivo using a novel mouse model of IRAEs, and further demonstrated that genetic blockade of IL21 signaling protected ICI-treated mice from thyroid immune infiltration. Taken together these studies reveal novel mechanisms and therapeutic targets by which IL21+ Tfh/Tph cells drive thyrotoxic CD8+ autoimmune mediators for the development of IRAEs in humans. One Sentence SummaryScRNAseq reveals a novel role for CD8+ autoimmune mediators and IL21+ T helper cells in the pathogenesis of human checkpoint inhibitor thyroiditis.

immunology↗

bioRxiv2022

Alteration of pro-carcinogenic gut microbiota is associated with clear cell renal cell carcinoma tumorigenesis

Increasing evidence suggests that gut microbiota is involved in the occurrence and progression of urinary system diseases such as clear cell renal cell carcinoma (ccRCC). However, the mechanism of how alteration of gut metagenome promotes ccRCC remains unclear. Here we aim to elucidate the association of specific gut bacteria and their metabolites with ccRCC. In a pilot case-control study among 30 ccRCC patients and 30 healthy controls, 16S ribosomal RNA (rRNA) gene sequencing were analyzed from fecal samples collected prior to surgery or hospitalization. Alpha diversity and beta diversity analysis of the gut microbiota were performed, and differential taxa were identified by multivariate statistics. Meanwhile, serum metabolism was measured by UHPLC-MS, and differential genes were identified based on the TCGA database. Random Forests revealed the relative abundances of 20 species differed significantly between the RCC group and the Control group, among which 9 species, such as Desulfovibrionaceae, were enriched in the RCC group, and 11 species, such as four kinds of Lactobacillus, were less abundant. Concomitantly, serum level of taurine, which was considered to be consumed by Desulfovibrionaceae and released by Lactobacillus, has decreased in the RCC group. In addition, macrophage-related genes such as Gabbr1 was upregulated in ccRCC patients from our results. IMPORTANCETo our knowledge, few studies investigate the correlation of gut microbiota and ccRCC tumorigenesis. Overall, our sequencing data suggest that changes in the composition of specific gut microbiota, especially Lactobacillus and Desulfovibrionaceae, may be involved in ccRCC. Numerous serum metabolites, for example, taurine, which were modified in concert with dysregulation of gut microbiota, were associated with metabolic status during ccRCC development. Furthermore, through comparative analysis of clinical indicators, we found that gut dysbiosis could potentially reshape systemic inflammation, which participated in ccRCC tumorigenesis and we performed bioinformatics analysis to draw this conclusion. In Summary, it could be concluded from our study that the reduction of protective bacteria Lactobacillus, proliferation of sulfide-degrading bacteria Desulfovibrionaceae, reduction of taurine, and enrichment of macrophage related genes might be the risk predictors of ccRCC.

microbiology↗

bioRxiv2022

Predicting Drug Repurposing Candidates and Their Mechanisms from A Biomedical Knowledge Graph

BackgroundComputational drug repurposing is a cost- and time-efficient approach that aims to identify new therapeutic targets or diseases (indications) of existing drugs/compounds. It is especially critical for emerging and/or orphan diseases due to its cheaper investment and shorter research cycle compared with traditional wet-lab drug discovery approaches. However, the underlying mechanisms of action (MOAs) between repurposed drugs and their target diseases remain largely unknown, which is still a main obstacle for computational drug repurposing methods to be widely adopted in clinical settings. ResultsIn this work, we propose KGML-xDTD : a Knowledge Graph-based Machine Learning framework for explainably predicting Drugs Treating Diseases. It is a two-module framework that not only predicts the treatment probabilities between drugs/compounds and diseases but also biologically explains them via knowledge graph (KG) path-based, testable mechanisms of action (MOAs). We leverage knowledge-and-publication based information to extract biologically meaningful "demonstration paths" as the intermediate guidance in the Graph-based Reinforcement Learning (GRL) path-finding process. Comprehensive experiments and case study analyses show that the proposed framework can achieve state-of-the-art performance in both predictions of drug repurposing and recapitulation of human-curated drug MOA paths. ConclusionsKGML-xDTD is the first model framework that can offer KG-path explanations for drug repurposing predictions by leveraging the combination of prediction outcomes and existing biological knowledge and publications. We believe it can effectively reduce "black-box" concerns and increase prediction confidence for drug repurposing based on predicted path-based explanations, and further accelerate the process of drug discovery for emerging diseases.

bioinformatics↗

bioRxiv2022

Epigenomic tomography for probing spatially-defined molecular state in the brain

Spatially-resolved genomic profiling is critical for understanding biology in a spatially ordered organ such as mammalian brain. Single-cell spatial genomic assays were developed recently for this purpose but they remain costly and labor-intensive for examining brain tissues across substantial dimensions and surveying a collection of brain samples. Here we demonstrate a new approach, brain epigenomic tomography, that maps spatial epigenomic variations at the scale of centimeters. We profiled neuronal and glial fractions of mouse neocortex slices with 0.5 mm thickness using a low-input technology. H3K27me3 or H3K27ac features across these slices were grouped into clusters based on their spatial variation patterns. Our approach reveals striking dynamics in frontal and caudal cortex due to kainic acid-induced seizure, linked with transmembrane ion transporter, exocytosis of synaptic vesicles, and secretion of neurotransmitter. Epigenomic tomography provides a powerful and cost-effective tool for profiling and discerning brain samples based on their spatial epigenomes.

genomics↗

bioRxiv2022

Massively parallel single-cell sequencing of genetic loci in diverse microbial populations

Single cell genetic heterogeneity is ubiquitous in microbial populations and an important aspect of microbial biology. However, we lack a broadly applicable and accessible method to study this heterogeneity at the single cell level. Here, we introduce a simple, robust, and generalizable platform for quantitative and massively parallel single cell sequencing of target genetic loci in microbes using ultrahigh-throughput droplet microfluidics (Droplet Targeted Amplicon Sequencing or DoTA-seq). Using DoTA-seq, we elucidate the highly diverse single cell ON/OFF states of the phase-variable capsule synthesis operons in the prevalent human gut species Bacteroides fragilis. In addition, we quantify the shifts in antibiotic resistance gene abundances in different species in a 25 member human gut microbial community in response to antibiotics. By sequencing tens of thousands of single-cells derived from a human fecal sample, we identify links between plasmid replicons and the taxonomic lineages of their associated hosts. In sum, DoTA-seq is an accessible and broadly applicable tool for profiling single-cell genetic variation in microbiomes.

microbiology↗

bioRxiv2022

Metagenome-based metabolic modelling predicts unique microbial interactions in deep-sea hydrothermal plume microbiomes

Deep-sea hydrothermal vents are abundant on the ocean floor and play important roles in ocean biogeochemistry. In vent ecosystems such as hydrothermal plumes, microorganisms rely on reduced chemicals and gases in hydrothermal fluids to fuel primary production and form diverse and complex microbial communities. However, microbial interactions that drive these complex microbiomes remain poorly understood. Here, we use microbiomes from the Guaymas Basin hydrothermal system in the Pacific Ocean to shed more light on the key species in these communities and their interactions. We built metabolic models from metagenomically assembled genomes (MAGs) and infer possible metabolic exchanges and horizontal gene transfer (HGT) events within the community. We highlight possible archaea-archaea and archaea-bacteria interactions and their contributions to robustness of the community. Cellobiose, D-Mannose 1-phosphate, O2, CO2, and H2S were among the most exchanged metabolites. Ten microbes, including eight bacteria and two archaea, were identified as key contributors. These microorganisms uniquely enhanced the metabolic capabilities of the community by donating metabolites that cannot be produced by any other community member. Archaea from the DPANN group stood out as key microbes, benefiting significantly from accepting metabolites from other members of the microbiome. Amino acids were the key auxotrophy driving metabolic interactions in the community. Finally, over 200 horizontal gene transfer events were predicted in the community, the majority of which were between Gammaproteobacteria and Alphaproteobacteria. Overall, our study provides key insights into the microbial interactions that drive community structure and organisation in complex hydrothermal plumes and deep-sea microbiomes.

microbiology↗

bioRxiv2022

Chinese fir genome and the evolution of gymnosperms

Seed plants comprise angiosperms and gymnosperms. The latter includes gnetophytes, cycads, Ginkgo, and conifers. Conifers are distributed worldwide, with 630 species distributed across eight families and 70 genera. Their distinctiveness has triggered much debate on their origin, evolution, and phylogenetic placement among seed plants. To better understand the evolution of gymnosperms and their relation to other seed plants, we report here a high-quality genome sequence for a tree species, Chinese fir (Cunninghamia lanceolata), which has excellent timber quality and high aluminum adaptability and is a member of Cupressaceae with high levels of heterozygosity. We assembled an 11.24 Gb genome with a contig N50 value of 2.15 Mb and anchored the 10.89 Gb sequence to 11 chromosomes. Phylogenomic analyses showed that cycads sister to Ginkgo, which place to sister in all gymnosperm lineages, and Gnetales within conifers sister to Pinaceae. Whole-genome duplication (WGD) analysis showed that the ancestor of seed plants has differentiated into angiosperms and gymnosperms after having experienced a WGD event. The ancestor of extant gymnosperm has experienced a gymnosperm-specific WGD event and the extant angiosperms do not share a common WGD before their most recent common ancestor diverged into existing angiosperms lineages. Analysis of the MADS-box gene family of C. lanceolata revealed the developmental mechanism of the reproductive organs in C. lanceolata, which supported the (A)B(C) model of the development of gymnosperms reproductive organs. In addition, astringent seeds and shedding of whole branches (with withered leaves) might be a strategy of C. lanceolata that evolved during long-term adaptation to an aluminum-rich environment. The findings also reveal the molecular regulation mechanism of shade tolerance in C. lanceolata seedlings. Our results improve the resolution of ancestral genomic features within seed plants and the knowledge of genome evolution and diversification of gymnosperms.

genomics↗