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Zhang, G.

Publications and source records attributed to Zhang, G..

At least 145 records · Page 8Linked to original sources

The first chromosomal-level genome assembly of an allotetraploid oyster

Tetraploid oysters are used to cross with diploids to produce triploid oysters that have become an important part of the oyster aquaculture industry worldwide. Although most tetraploid oysters are artificially induced autotetraploids, allotetraploids can be produced between closely related species, providing new opportunities for polyploid breeding and studying genome interactions. Using PacBio sequencing, Illumina sequencing, and high-throughput chromosome conformation capture scaffolding, we assembled the first high-quality genome assembly of an artificially induced allotetraploid between the Pacific oyster Crassostrea gigas and Portuguese oyster Crassostrea angulata. The assembled genome is 1.23 Gb, with a contig N50 of 2.56 Mb and a scaffold N50 of 57.22 Mb, and anchored to 20 chromosomes. The assembly contains 58,330 protein-coding genes, 98.34% of which are functionally annotated. The heterozygosity and the ratio of repetitive sequences is 5.50% and 46.43%, respectively. This chromosomal-level genome assembly of an allotetraploid oyster provides a valuable genetic resource for studying genome biology of molluscs and for advanced breeding of polyploids that are critical for the oyster aquaculture industry.

genomics↗

ProteoAutoNet: high-throughput co-eluted protein analysis with robotics and a multi-database search strategy

Co-fractionation mass spectrometry (CF-MS) enables large-scale profiling of endogenous protein-protein interactions. Protein complexes identified by CF-MS using different databases are typically integrated. However, this integration uses varying cutoffs, leading to inconsistencies in protein complex identification. Here, we present ProteoAutoNet, a robotic experimental platform integrating multi-database search strategy into machine learning models, for high-throughput CF-MS analysis. This workflow increases the throughput of sample processing from protein complex to peptide by about two times. We then applied this workflow to map protein interaction networks in thyroid cancer cell lines, identifying significantly upregulated proteasome and prefoldin complexes in lung metastatic follicular thyroid carcinoma cell line FTC238 compared to normal thyroid cell line Nthy-ori 3-1. Notably, we identified a novel protein interaction network comprising PFAS, TGM2, and HK1 that was significantly upregulated in the papillary thyroid carcinoma cell line TPC-1. ProteoAutoNet provides an improved approach for investigating protein-protein interactions and uncovering novel networks, driving advancements in high-throughput proteomics research.

biochemistry↗

Neutralizing antibodies elicited by Nipah virus G-head nanoparticle target diverse sites and inhibit receptor binding and fusion

Nipah virus (NiV) and Hendra virus (HeV), two highly pathogenic Henipaviruses (HNVs), pose a significant public health threat. The attachment glycoprotein (G) plays a crucial role in viral attachment and entry, making it an attractive target for vaccine and therapeutic antibody development. However, the antigenic landscape and neutralization sensitivity of the G protein remain poorly defined. Here, we systematically characterize 27 monoclonal antibodies (mAbs) elicited by NiV G head (GH) nanoparticle-immunized mice. Among these, 25 mAbs exhibit neutralizing activity against two major NiV strains, NiV-Malaysia and NiV-Bangladesh, with five mAbs also cross-inhibiting HeV infection. Although all mAbs target GH, they inhibit viral infection through distinct mechanisms, either by blocking receptor ephrin-B2 engagement with the G protein or by preventing viral membrane fusion. Notably, mAbs from two distinct groups conferred complete protection to hamsters against lethal NiV-Malaysia infection. Structural analysis of NiV GH in complex with four representative Fabs reveals four non-overlapping epitopes, including two novel antigenic sites and one shared protective epitope identified across species. Our study provides a comprehensive map of the antigenic determinants of NiV GH, elucidates the relationship between epitopes, neutralization mechanisms, and protection, and offers new insights and opportunities for antibody-based therapies and vaccine development. HighlightsMost mAbs induced in G head nanoparticle-immunized mice are potent neutralizers MAbs recognizing the G head block receptor binding or viral fusion Structural analysis shows mAbs target four distinct epitopes on G head protein Receptor competition site on G head is a shared protective antigenic site in human and multiple animals

immunology↗

Drivers of avian genomic change revealed by evolutionary rate decomposition

Modern bird diversity spans a striking array of forms, behaviours, and ecological roles. Analyses of molecular evolutionary rates can reveal the links between genomic and phenotypic change, but disentangling the drivers of rate variation has been difficult across large numbers of whole-genomes. Using comprehensive estimates of traits and evolutionary rates across a family-level phylogeny of birds, we show that clutch size, generation length, and beak shape are dominant predictors of genome-wide mutation rates. To identify the major axes of evolutionary rate variation, we employ covariance matrix eigendecomposition from rates estimated for branches of the avian phylogeny and across genomic loci. We find that the majority of rate variation occurs along the terminal branches of the phylogeny associated with extant families of birds. Additionally, we use principal components analyses to show that several axes of variation are linked with rapid evolution in microchromosomes immediately after the Cretaceous-Palaeogene transition. These apparent pulses of evolution are consistent with major changes in evolutionary rates in the machineries for meiosis, heart performance, and RNA splicing, surveillance, and translation. They also correlate with the diversification of ecological niches reflected in increased tarsus length. Collectively, our analyses paint a nuanced picture of avian evolutionary rates through time, revealing that the ancestors of the most diverse lineages of birds underwent major genomic changes related to mutation, gene usage, and niche expansion near the beginning of the Palaeogene period.

evolutionary biology↗

Pneumo-Typer: a high-throughput capsule genotype visualization tool with integrated serotype and sequence type prediction for Streptococcus pneumoniae

BackgroundStreptococcus pneumoniae persists as a leading global pathogen, with current capsule-based vaccines like PCV13 offering limited coverage against its extensive serotype diversity (>100 serotypes). This restricted coverage drives the emergence of non-vaccine serotypes. Moreover, vaccine efficacy is further compromised by immune evasion caused by capsule genotype (CapT) variations within vaccine-covered serotypes, while existing genome-based tools lack robust analytical capabilities for CapT. ResultsWe developed Pneumo-Typer, a CapT visualization tool enabling rapid identification of CapT variations in S. pneumoniae. Application to 17,407 publicly available genomes from the NCBI database revealed widespread CapT variations across vaccine-covered serotypes, providing critical insights for optimizing vaccine formulations. In addition, Pneumo-Typer integrates high-accuracy serotype prediction (98.44% accuracy across 93 serotypes) and multilocus sequence typing (ST), facilitating comprehensive genomic surveillance. Besides, CapT and ST information can assist in serotype determination. Pneumo-Typer enables integrated analysis of serotype-CapT-ST relationships, demonstrating that while most serotypes associate with multiple STs and CapTs, ST and CapT lineages evolve independently. Strikingly, multi-serotype serogroups exhibited pronounced CapT diversity, suggesting evolutionary processes driving serogroup expansion through CapT plasticity. ConclusionsIn summary, Pneumo-Typer is an integrated platform for genomic surveillance of pneumococcal populations. By resolving previously underexplored serotype-CapT-ST linkages, the tool provides a framework for next-generation vaccine design, emphasizing the need for vaccine formulations that address both serotype replacement and CapT-driven immune evasion.

bioinformatics↗

Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model

Genetic defects in NOX2 can cause chronic granulomatous disease (CGD), characterized by increased susceptibility to infections and pronounced inflammatory responses that lead to granuloma formation. We developed a CGD model using Ncf2-/- mice through controlled environmental exposure. Unlike in specific pathogen-free environment, these mice spontaneously developed pulmonary granulomas under clean-grade conditions. Employing single-cell RNA sequencing, we observed an expansion of neutrophils and monocyte-derived macrophages (MDMs) within the lung tissue, identifying pro-inflammatory NOS2high-neutrophils and a distinct MDMs subset marked by NOS2 and ARG1. Spatial transcriptomics demonstrated that NOS2high-neutrophils were located at the core area, while the MDMs subset was positioned at the periphery, facilitating extracellular matrix remodeling. Pharmacological targeting of MIF, deletion of the pro-survival gene Morrbid, and elimination of Il1r1 all suppressed granuloma formation by mitigating inflammation. This study underscores how environmental control can establish a natural CGD model, elucidates the mechanisms of granuloma formation, and develops potent therapeutic interventions. HighlightsO_LIThrough installing a mutation in a NOX2 subunit gene Ncf2 and changing the husbandry environment, we generated a natural CGD mouse model with progressive pulmonary granuloma formation. C_LIO_LINOS2high neutrophils located in the core region of CGD lung granulomas, exhibit a pro-inflammatory transcriptional profile. C_LIO_LIMonocyte-derived macrophages marked by Nos2 and Arg1 are located at the periphery of granulomas and exhibit a profibrotic transcriptional profile. C_LIO_LIThe transcriptomic studies assist the development of three effective perturbations for treating the rare disease CGD via targeting Il1r1, Morrbid, and Mif respectively. C_LI

immunology↗

Glo1 reduction in mice results in age- and sex-dependent metabolic dysfunction

ObjectivesAdvanced glycation end products (AGEs) have been implicated as an important mediator of metabolic disorders including obesity, insulin resistance, and coronary artery disease. Glyoxalase 1 (Glo1) is a critical enzyme in the clearance of toxic dicarbonyl such as methylglyoxal, precursors of AGEs. The role of AGE-independent mechanisms that underly Glo1-induced metabolic disorders have yet to be elucidated. MethodsWe performed a longitudinal study of female and male Glo1 heterozygous knockdown (Glo1+/-) mice with [~]50% gene expression and screened metabolic phenotypes such as body weight, adiposity, glycemic control and plasma lipids. We also evaluated atherosclerotic burden, AGE levels, and gene expression profiles across cardiometabolic tissues (liver, adipose, muscle, kidney and aorta) to identify pathway perturbations and potential regulatory genes of Glo1 actions. ResultsPartial loss of Glo1 resulted in obesity, hyperglycemia, dyslipidemia, and alterations in lipid metabolism in metabolic tissues in an age- and sex-dependent manner. Glo1+/- females displayed altered glycemic control and increased plasma triglycerides, which aligned with significant perturbations in genes involved in adipogenesis, PPARg, insulin signaling, and fatty acid metabolism pathways in liver and adipose tissues. Conversely, Glo1+/- males developed increased skeletal muscle mass and visceral adipose depots along with changes in lipid metabolism pathways. For both cohorts, most phenotypes manifested after 14 weeks of age. Evaluation of methylglyoxal-derived AGEs demonstrated changes in only male skeletal muscle but not in female tissues, which cannot explain the broad metabolic changes observed in Glo1+/-mice. Transcriptional profiles suggest that altered glucose and lipid metabolism may be partially explained by alternative detoxification of methylglyoxal to metabolites such as pyruvate. Moreover, transcription factor (TF) analysis of the tissue-specific gene expression data identified TFs involved in cardiometabolic diseases such as Hnf4a (all tissues) and Arntl (aorta, liver, and kidney) which are female-biased regulators and whose targets are altered in response to Glo1+/-. ConclusionsOur results indicate that Glo1 reduction perturbs metabolic health and metabolic pathways in a sex- and age-dependent manner without significant changes in AGEs across metabolic tissues. Rather, tissue-specific gene expression analysis suggests that key transcription factors such as Hfn4a and Arntl as well as metabolite changes from alternative methylglyoxal detoxification such as pyruvate, likely contribute to metabolic dysregulation in Glo1+/- mice.

molecular biology↗

Intrinsic Opening of BK Channels Derives from Inherent Leakage in Hydrophobic Gating

The big potassium (BK) channels remain open with a small limiting probability of Po [~] 10-7 at minimal Ca2+ and negative voltages < -100 mV. The molecular origin and functional significance of such "intrinsic opening" are not understood. Here we combine atomistic simulations and electrophysiological experiments to show that the intrinsic opening of BK channels is an inherent property of the vapor barrier, generated by hydrophobic dewetting of the BK inner pore in the deactivated state. The vapor barrier only gives rise to a finite free energy barrier, of [~] 8 kcal/mol, and cannot completely shut down K+ flow even when the voltage sensor domains are fully deactivated. This results in the leaking currents that can be measured at negative voltages as the indication of intrinsic opening. The shallow limiting slope of Po at negative voltages results primarily from the electric field effects on the permeating ion through the vapor barrier. We further demonstrate that the vapor barrier can be perturbed by inner pore mutations and truncation of the cytosolic domains, leading to predicable changes in limiting slope measurements. Therefore, the intrinsic opening in BK channels, and possibly in other ion channels, opens up an opportunity to experimentally study hydrophobic gating. Our results further suggest that intrinsic opening in BK channels is the fundamental basis for the allosteric mechanism of activation by both voltage and Ca2+.

biophysics↗

Engineered spermidine-secreting Saccharomyces boulardii ameliorate colitis and colon cancer in mice

Experimental studies suggest that the probiotic yeast Saccharomyces boulardii can mitigate the symptoms of inflammatory bowel disease. However, these results are equivocal and S boulardii probiotic therapy has not gained widespread acceptance in clinical practice. To assess whether the therapeutic properties of S boulardii might be improved upon, we engineered S boulardii to overproduce and secrete spermidine, a pro-regenerative natural metabolite. We employed CRISPR gene deletion and transposon-mediated gene integration to manipulate expression of key enzymes in the polyamine synthetic and transport pathways. We tested the engineered yeast by oral gavage of mice treated with azoxymethane and dextran sulfate sodium to induce chronic colitis and colon cancer. We demonstrate that oral delivery of spermidine-secreting S boulardii in mice populates the gastrointestinal tract with viable spermidine-secreting S boulardii cells and raises free spermidine levels in the gastrointestinal tract. Strikingly, spermidine-secreting S boulardii strains were significantly more effective than wild-type S boulardii in reducing dextran sulfate sodium-induced colitis as well as colitis-associated colon cancer in mice. These results suggest that in situ spermidine secretion by engineered synthetic biotic yeast strains may be an effective and low-cost therapy to mitigate inflammatory bowel disease and colon cancer.

cancer biology↗

NimA promotes cell adhesion at the blood brain barrier of Drosophila nervous system

Glial cells are crucial for nervous system development and function, by clearing debris, protecting neurons, and ensuring neuronal survival. In Drosophila, glia also form the blood-brain barrier (BBB), which regulates neural stem cell proliferation and shields the nervous system while maintaining organism-wide communication. To uncover glial-specific roles, we compared their transcriptome with that of neurons and macrophages. Our study identifies NimA, an uncharacterized member of the Nimrod scavenger receptor family, as a glial-specific protein consistently expressed during development. Unlike other family members, i.e. NimC1 (macrophage-specific), Draper (shared by glia and macrophages), and NimC4/Simu (restricted to embryonic stages), NimA is not involved in phagocytosis. Instead, it regulates cell-cell interactions and adhesion, crucial for maintaining the tight septate junctions of the larval BBB. Loss of NimA compromises BBB integrity, delays development, reduces brain size and impairs neural stem cell proliferation. Altogether, the identification of a novel molecular player and more in general, of the glial-specific molecular landscape, are key to understand the contribution of glia to the construction and the function of the nervous system.

developmental biology↗

An explainable artificial intelligence framework reveals mutations associated with drug resistance in Mycobacterium tuberculosis

Understanding the mechanisms of drug resistance in Mycobacterium tuberculosis (MTB) is essential for the rapid detection of resistance and for guiding effective treatment, ultimately contributing to reducing the global burden of tuberculosis (TB). Under anti-TB drugs pressure, MTB continues to accumulate resistance loci. The current repertoire of known resistance-associated mutations requires further refinement, necessitating efficient methods for the timely identification of potential resistance sites. Here, we introduce xAI-MTBDR, an explainable artificial intelligence framework designed to identify new resistance-associated mutations and predict drug resistance in MTB. It outperforms state-of-the-art methods in predicting drug resistance for all first-line drugs, and scoring each mutations contribution to resistance. By leveraging public whole-genome sequencing data from nearly 40,000 MTB isolates, the framework identified 788 candidate resistance-related mutations and revealed 30 potential resistance markers, several of which are structurally located closer to their respective drugs compared to known resistance mutations. Furthermore, these scores enabled the framework to efficiently subgroup isolates with different resistance mechanisms and reflect varying levels of resistance. The framework serves as a valuable tool for accurate detection of drug-resistant MTB and offers new insights into its underlying mechanisms.

microbiology↗

Deciphering the thiolactonization mechanism in thiolactomycin biosynthesis

Thiolactomycin (1), which features a unique{gamma} -thiolactone ring, is a promising antibiotic candidate that specifically targets bacterial type II fatty acid synthase. Despite extensive studies on its pharmacological activities, modes of action, and chemical synthesis, the enzymatic processes responsible for forming the activity-determining{gamma} -thiolactone ring have remained largely unknown. Here, we resolve this problem by revealing that the condensation and heterocyclization (Cy) domain of the nonribosomal peptide synthetase (NRPS) TlnC (TlnCCy), along with the cytochrome P450 enzyme TlnA, cooperatively enable the{gamma} -thiolactone assembly. TlnCCy mediates an unusual sulfurtransfer reaction to sulfurate the polyketide intermediate, generating a thiocarboxylate intermediate. Subsequently, TlnA acts as a{gamma} -thiolactone synthase, converting the linear thiocarboxylate intermediate into 1 via a distal radical-based cyclization mechanism. These findings not only expand the functional and catalytic repertoires of NRPS Cy domains and P450 enzymes, but also highlight a special enzymatic strategy for{gamma} -thiolactone biosynthesis in nature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/629141v2_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@7e0ad2org.highwire.dtl.DTLVardef@f86b80org.highwire.dtl.DTLVardef@159d136org.highwire.dtl.DTLVardef@1b633ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

Incomplete lineage sorting of segmental duplications defines the human chromosome 2 fusion site early during African great ape speciation

All great apes differ karyotypically from humans due to the fusion of chromosomes 2a and 2b, resulting in human chromosome 2. Yet, the structure, function, and evolutionary history of the genomic regions associated with this fusion remain poorly understood. Here, we analyze finished telomere-to-telomere chromosomes in great apes and macaques to show that the fusion was associated with multiple pericentric inversions, segmental duplications (SDs), and the rapid turnover of subterminal repetitive DNA. We characterized the fusion site at single-base-pair resolution and identified three distinct SDs that originated more than 5 million years ago. These three distinct SDs were differentially distributed among African great apes as a result of incomplete lineage sorting (ILS) and lineage-specific duplication. Most conspicuously, one of these SDs shares homology to a hypomethylated SD spacer sequence present in hundreds of copies in the subterminal heterochromatin of chimpanzees and bonobos. The fusion in human was accompanied by a systematic degradation of the three divergent -satellite arrays representing the ancestral centromere creating five distinct structural haplotypes in humans. CRISPR/Cas9-mediated depletion of the fusion site in human cell lines significantly alters the expression of 108 genes, indicating a potential regulatory consequence to this human-specific karyotypic change.

evolutionary biology↗

Mouse Forebrain Region-specific Molecular Characteristics and Cholinergic Neurons Subtyping: An Integrated Analysis Based on Spatial Multi-omics

The forebrain regions displays distinct yet under-characterized gene expression patterns. This study analyzed region-specific feature genes in forebrain regions and Isocortex sub-regions at both transcriptomic and proteomic levels. The key finding is the observation of low correlation but high functional similarity between mRNA and protein expression, which offers insights into the connection between gene expression forms in neuronal pathways and the neuronal activity state. Cholinergic neurons (CNs), play a vital role for the forebrains sensory and motor regulation. With Spatial-transcriptome and immunofluorescence joint analysis (STIF), which overcomes the limited resolution of the 10X Visium system, CNs- and CN-subtypes specific feature genes in the striatum and basal forebrain were identified, which providing crucial insights into the heterogeneity and functional diversity of these neuronal populations. The spatial distribution and expression pattern of the feature genes in this study were validated with either external datasets or rolling circle amplification-FISH, coincident results were revealed.

bioinformatics↗

Lifespan Normative Models of White Matter Fractional Anisotropy: Applications to Early Psychosis

This study presents large-scale normative models of white matter (WM) organization across the lifespan, using diffusion MRI data from over 25,000 healthy individuals aged 0-100 years. These models capture lifespan trajectories and inter-individual variation in fractional anisotropy (FA), a marker of white matter integrity. By addressing non-Gaussian data distributions, race, and site effects, the models offer reference baselines across diverse ages, ethnicities, and scanning conditions. We applied these FA models to the HCP Early Psychosis cohort and performed a multivariate analysis to map symptoms onto deviations from multimodal normative models using multi-view sparse canonical correlation analysis (msCCA). Our results reveal extensive white matter heterogeneity in psychosis, which is not captured by group-level analyses, with key regions identified, including the right uncinate fasciculus and thalami. These normative models offer valuable tools for individualized WM deviation identification, improving precision in psychiatric assessments. All models are publicly available for community use. TeaserLifespan models of white matter offer insights into brain health, providing tools for tracking individual deviations across ages.

neuroscience↗

Successful establishment of an exogenous gene expression system in Chlamydomnas chloroplast based on viral replication elements

Currently, transformation in unicellular green alga (Chlamydomonas reinhardtii) chloroplast is hindered by a low yield of target products, possibly due to the heterogeneity of the chloroplast genome. In this study, an expression platform was established in C. reinhardtii by leveraging replicative elements from beet curly top geminivirus, which led to a high level of heterologous gene expression, as previously reported in Nicotiana tabacum. Platform performance was verified by the successful expression of a linearized mvenus cassette, achieving a higher expression level than that obtained using the homologous-recombination-based approach. This study provides a new strategy in microalgae synthetic biology and opens new avenue for accumulating valuable bioproducts at high concentrations.

synthetic biology↗

DeepAssembly2: A Web Server for Protein Complex Structure Assembly Based on Domain-Domain Interactions

Proteins often perform biological functions by forming complexes, thereby accurately predicting the structure of protein complexes is crucial to understanding and mastering their functions, as well as facilitating drug discovery. Protein monomeric structure prediction has made a breakthrough in recent years, but the accurate prediction of complex structure remains a challenge. In this work, we present DeepAssembly2, a web server for automatically assembling protein complex structure based on domain-domain interactions. First, the features are constructed according to the input complex sequence and monomeric structures, then these features are used to predict the inter-chain residue distance through a deep learning model, and finally, the complex structure is assembled under the guidance of inter-chain residue distances. Compared with the previously developed version, DeepAssembly2 is trained on a newly constructed inter-chain domain-domain interaction dataset. Meanwhile, several important features have been added, such as Interface Residue Propensity and Ultrafast Shape Recognition. In addition, we introduced the inter-chain residue distance from the AlphaFold-Multimer model to further improve the accuracy. Finally, we also integrate our recently developed model quality assessment method to select the output models. The performance of DeepAssembly2 is significantly improved compared with the previous version, providing a solution for large protein complex structure modeling through divide-and-conquer assembly strategy, and is expected to provide new insights and an effective tool for drug development, vaccine design, etc. The web server of DeepAssembly2 is freely available at http://zhanglab-bioinf.com/DeepAssembly/.

bioinformatics↗

A multi-tissue developmental gene expression atlas towards understanding the biological basis of phenotypes in sheep

Sheep (Ovis aries) represents one of the most important livestock species for animal protein and wool production worldwide. However, little is known about the genetic and biological basis of ovine phenotypes, particularly for those of high economic value and environmental impact. Here, by generating and integrating 1,413 RNA-seq samples from 51 distinct tissues across 14 developmental time points, representing early prenatal, late prenatal, neonate, lamb, juvenile, adult, and elderly stages, we built a high-resolution developmental Gene Expression Atlas (dGEA) in sheep. We observed dynamic patterns of gene expression and regulatory networks across tissues and developmental stages. When harnessing this resource for interpreting genomic associations of 48 monogenetic and 12 complex traits in sheep, we found that genes upregulated at prenatal developmental stages played more important roles in shaping these phenotypes than those upregulated at postnatal stages. For instance, genetic associations of crimp number, mean staple length (MSL), and individual birth weight were significantly enriched in the prenatal rather than postnatal skin and immune tissues. By comprehensively integrating fine-mapping results and the sheep dGEA, we identified several key genes associated with complex traits in sheep, such as SOX9 (associated with MSL), GNRHR (associated with litter size at birth), and PRKDC (associated with live weight). These results provide novel insights into the gene regulatory and developmental architecture underlying ovine phenotypes. The dGEA (https://sheepdgea.njau.edu.cn/) will serve as an invaluable resource for sheep developmental biology, genetics, genomics, and selective breeding.

genetics↗