Biology subjects

Mao, Y.

Publications and source records attributed to Mao, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

A long-read human pangenome initiative for comprehensive interpretation of nuclear-embedded mitochondrial DNA

Nuclear-embedded mitochondrial DNA segments (NUMT) preserve a record of ongoing mitochondrial-to-nuclear DNA transfer during evolution, with important implications for disease mechanisms and genome organization. Here, we developed a Pangenome Graph-based NUMT Detection (PG-NUMT) approach to improve NUMT detection sensitivity by 2.52-fold compared to short-read based approaches and comprehensively resolved seven concatenated mega-NUMTs with a maximum length of 127.7 kbp. We generated a high-resolution human NUMT map comprising 774 fixed, 280 polymorphic, and 123 pericentromeric NUMTs, alongside 74 superpopulation-stratified NUMTs. Both fixed and polymorphic NUMTs are hypermethylated and enriched within segmental duplications, whereas fixed NUMTs preferentially localize to intergenic regions and avoid transposable elements. Interestingly, NUMTs derived from the 3-end of the mtDNA D-loop are less frequently fixed in human genomes and exhibit potential cis-regulatory activity in the nuclear genome. These observations suggest that selective pressures shape the genomic features of fixed NUMTs. Seven NUMTs associated with gene expression or alternative splicing were further identified, suggesting potential modulatory functions of common NUMTs. Using 20 complete non-human primate genomes, we identified variable NUMT insertion rates across primate lineages (1.5-18.7 insertions per million years), with particularly high rates in the Pan lineage. Notably, we uncovered two NUMT-derived variable number tandem repeats (VNTRs), establishing NUMTs as a novel source of VNTRs. In summary, the integrated analysis enhances our understanding of NUMT genomic architecture, population dynamics, and evolutionary implications in human and non-human primates, establishing NUMTs as dynamic genomic components of biomedical relevance.

genomics↗

bioRxiv2026

Thermal Nano-Engineering of Ginger Extracellular Vesicles for Targeted Oral Therapy of Colitis

Plant-derived extracellular vesicles (PEVs) are promising candidates for oral drug delivery, yet their clinical translation is hindered by limited targeting precision and inconsistent systemic absorption. While surface engineering can enhance tissue accumulation, strategies that preserve biocompatibility and enable scalable production remain limited. Here, we introduce a simple thermal processing approach, boiling, to structurally reconfigure ginger EVs into functionally enhanced, thermally reassembled nanoparticles (B-GEVs). The surface architecture of B-GEVs is enriched with key vesicle trafficking regulators, including V-type proton ATPase subunit G, ARF1, and {beta}-adaptin-like protein. This specific composition drives their tissue-specific accumulation in the intestine and liver and potentiates clathrin-dependent cellular uptake in intestinal cells by 8.57-fold. Beyond superior intrinsic anti-inflammatory activity through NLRP3 inflammasome suppression, B-GEVs function as an efficient oral delivery platform. When loaded with TNF- siRNA, they enable a synergistic therapy that simultaneously modulates upstream inflammation and silences key downstream mediators, showing potent efficacy in colitis. Our findings position boiling as a natural strategy for enhancing the bioactivity and targeted oral delivery potential of ginger-derived EVs.

bioengineering↗

bioRxiv2026

Top2a-dependent neuronal regulation of social behavior and persistent rescue of social deficit through PRC2-mediated epigenetic reprogramming

Disruption of social behavior is a core feature of autism spectrum disorder (ASD), yet the molecular and cellular mechanisms governing social behavior development are not well understood. We previously identified topoisomerase II (Top2a) as a critical regulator of social behavior and restricted and repetitive behavior through antagonism of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), based mainly on pharmacological perturbations during embryogenesis in zebrafish and mouse. However, whether neuronal Top2a is genetically required for social behavior in mammals, and whether PRC2 inhibition can rescue genetically induced social deficits, remain untested. Here, we establish a neuron-specific Top2a conditional knockout mouse model and demonstrate that neuronal Top2a haploinsufficiency selectively impairs social interaction without inducing restricted and repetitive behaviors or cognitive deficits. Pharmacological inhibition of PRC2 using the EZH2 inhibitor tazemetostat, combined with elacridar to facilitated blood-brain barrier penetration, robustly rescues social deficits in Top2a conditional knockout mice. Strikingly, a one-week oral dosing regimen produced a rescue effect that persisted for up to two months after treatment cessation, far exceeding the temporal window typically observed for neuromodulatory drugs targeting neurotransmitter systems. These results showcase the unique capability of epigenetic modulatory therapy to induce durable behavioral improvements and their therapeutic potential for treating social dysfunction in neuropsychiatric disorders. Together, our results provide direct genetic evidence that neuronal Top2a governs social behavior in mice and establish the neuronal Top2a-PRC2 axis as a conserved, targetable epigenetic pathway regulating social behavior.

neuroscience↗

bioRxiv2026

UBE3C retrofits the proteasome to enforce degradation of ultra-stable folds

Neurodegeneration and proteinopathies arise from mutated or misfolded proteins that form ultra-stable, proteotoxic aggregates that evade proteasomal degradation despite ubiquitylation1-8. These conditions are exacerbated by the deubiquitylase USP14 that can prematurely rescue substrates9-11. To counter these obstacles to effective proteolysis, eukaryotes evolved the highly conserved HECT-type E3 ligase UBE3C--dysregulated in neurodegeneration12,13 and overexpressed in cancers14-17--to reprogram the 26S proteasome toward heightened activity via unknown mechanisms18-25. Here we visualized functional dynamics of the human UBE3C-retrofitted proteasome enforcing degradation of a re-engineered superfolder GFP that normally escapes proteolysis, using time-resolved cryo-electron microscopy. A continuum of non-equilibrium conformations, comprising fourteen proteasome conformers orthogonally combined with four UBE3C states or three USP14 states, reveals a cryptic UBE3C-receptor site in the proteasomal lid and captures key intermediates of ubiquitin-chain elongation and branching at four linkage-specific ubiquitin-binding sites. Remarkably, UBE3C creates an extreme shortcut for ubiquitin shuttling that bypasses USP14, promotes USP14 recycling and allosterically strengthens substrate-unfolding forces of the AAA-ATPase unfoldase to ultimately surmount the unfolding energy barrier of ultra-stable proteins. These findings define the complete functional cycle of the UBE3C-reprogrammed proteasome, illuminating how UBE3C simultaneously controls USP14 and the proteasome to enforce clearance of ultra-stable folds, and establish crucial mechanistic foundations for proteolysis-targeting therapeutic discovery.

biochemistry↗

bioRxiv2026

Donor-specific assemblies enhance somatic structural variant detection in complex genomic regions

Structural variants (SVs) contribute substantially to genomic variation and disease, but detecting somatic SVs (sSVs) remains difficult due to reference bias, mosaicism, and enrichment in repetitive regions. Linear reference genomes, like GRCh38 and CHM13, do not fully capture individual genomic structure, which can obscure true somatic variation. Donor-specific assemblies (DSAs) generated from the same genome where sSVs are being assayed provide a personalized alternative, yet their performance for sSV detection has not been systematically assessed. As part of the Somatic Mosaicism across Human Tissues (SMaHT) Network, we benchmark a DSA for sSV discovery in the COLO829 melanoma cell line with a matched normal sample from the same individual. We compare sSV detection across GRCh38, CHM13, and the COLO829BL_DSA using three different sSV callers (Delly, Severus, and Sniffles2) and sequence data from multiple long-read platforms. The COLO829BL_DSA identifies 1.8-fold more manually validated sSVs than linear references, in regions both shared with GRCh38 and CHM13 and unique to the COLO829BL_DSA. Variants detected only with the COLO829BL_DSA are often found in satellite and other repeat-rich regions that are difficult to resolve using standard references. In addition, several COLO829BL_DSA-specific sSVs are located in genes, some of which are associated with cancer. Overall, these results underscore the utility of DSAs in improving sSV detection.

genomics↗

bioRxiv2026

Differential higher-order superassembly of HECT-type UBE3 ligases controlled by calcium signals

The yeast E4 ligase Hul5 transiently associates with the proteasome during heat shock and proteotoxic stress to maintain cytosolic protein quality control. Two of its human orthologs, UBE3B and UBE3C, have specialized to safeguard mitochondria and inherit Hul5 function, respectively. We determined cryo-electron microscopy structures of full-length human UBE3B and UBE3C in complex with calmodulin at 2.9-3.5 [A] in calcium-free and calcium-saturated conditions. Calmodulin acts as an inter-protomer molecular glue clamping UBE3B into ring-shaped anti-parallel homodimers or asymmetric trimers, and remodels UBE3C into a conformation competent for proteasome association. Calcium binding to calmodulin promotes disassembly of these higher-order complexes, toggling UBE3B/C from E4 to E3 activity. These findings reveal how calmodulin regulates higher-order architectures of E3/E4 ligases to rewire the ubiquitin-proteasome system via calcium signaling.

biochemistry↗

bioRxiv2026

Gangliosides GM3 And GD3 Modulate Insulin Aggregation Pathways and Reduce Cytotoxicity Through Structural Remodeling

Insulin amyloid aggregation is a key pathological and pharmaceutical concern, particularly in the context of Type-2 Diabetes (T2D), where amyloid deposition of protein can impair therapeutic efficacy and contribute to cell death leading to local tissue damage. Although gangliosides--glycosphingolipids containing sialic acid residues--are known to modulate amyloid formation in neurodegenerative disorders, their influence on insulin aggregation remains largely unexplored. In this study, we investigate the effects of gangliosides GM3 and GD3 on insulin aggregation. Using Thioflavin-T (ThT) based fluorescence kinetics, Fourier Transform Infrared (FTIR) spectroscopy, Circular Dichroism (CD) spectroscopy, Small Angle X-ray Scattering (SAXS), Nuclear Magnetic Resonance (NMR) spectroscopy, and Transmission Electron Microscopy (TEM), the aggregation pathway, changes in the secondary structure and morphology of insulin aggregates have been characterized. Our results show that both GM3 and GD3 lipids accelerated insulin aggregation in a concentration-dependent manner while steering the pathway away from classical fibril formation, producing short, beaded structures distinct from the extended fibrils observed under lipid-free conditions. CD and FTIR data analyses revealed that insulin in the presence of gangliosides formed non-fibrillar intermediates with distinct secondary structures: {beta}-sheet-rich globular clusters in presence of GD3 and -helical intermediates in GM3-treated samples. Cytotoxicity assays further demonstrated that ganglioside-induced aggregates are significantly less toxic to cells when compared to insulin-only aggregates. Furthermore, ganglioside-bound insulin oligomers retain seeding capacity, suggesting that they can nucleate further aggregation despite their non-fibrillar morphology. These findings underscore the role of gangliosides in modulating insulin amyloid polymorphism and toxicity, offering new insights into their potential impact on the pathology of T2D and treatment strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/703542v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@5bf40eorg.highwire.dtl.DTLVardef@f400ddorg.highwire.dtl.DTLVardef@164dcd8org.highwire.dtl.DTLVardef@def4e7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGangliosides GD3 and GM3 accelerate insulin aggregation, forming non-fibrillar assemblies. C_LIO_LIGanglioside-bound insulin aggregates are less cytotoxic than fibrillar aggregates. C_LIO_LIDespite altered morphology, ganglioside-bound aggregates retain seeding ability. C_LI

biophysics↗

bioRxiv2026

Global brain activity links subcortical degeneration to cortical tau progressively across Braak regions over early Alzheimer disease stages

Alzheimers disease (AD) is characterized by early tau pathology in subcortical neuromodulatory nuclei, followed by progressive cortical tau accumulation; however, the mechanisms linking subcortical dysfunction to cortical tau pathology remain unclear. Using multimodal neuroimaging data from the ADNI cohort, we examined how infra-slow (< 0.1 Hz) global brain (i.e., gBOLD) activity is related to the volume of the nucleus basalis of Meynert (NbM) and cortical tau accumulations in the early stages of AD. NbM degeneration was associated with reduced gBOLD activity and spatially co-localized tau accumulation, appearing in early Braak regions during the preclinical stage, i.e., cognitively unimpaired participants with abnormal CSF markers, and extending to more advanced Braak areas during the prodromal stage, i.e., mild cognitive impairment (MCI) subjects. Our findings suggest that infra-slow gBOLD activity serves as a functional neural mediator linking subcortical degeneration to cortical tau pathology, highlighting a potential functional pathway linking subcortical and cortical pathology in early AD.

neuroscience↗

bioRxiv2026

BiHiTo: Biomolecular Hierarchy-inspired Tokenization

Three-dimensional atomic arrangements of biomolecules are key to demystifying biological functions. The rapid expansion of accessible structural data, driven by advances in AI for science, highlights the critical challenge of efficiently modeling large-scale biomolecular structures, which are high-dimensional systems shaped by biological assembly principles. To address this, we introduce BiHiTo, a multi-level Biomolecular Hierarchy-inspired Tokenizer that intrinsically mimics natural biological assembly hierarchies. Specifically, we design a multi-codebook quantizer that mirrors the natural hierarchy of biomolecular structure, enabling simultaneous capture of representations spanning atomic motifs to global conformational variations. This hierarchical alignment markedly improves the biological interpretability and reconstruction fidelity of biomolecular structure.Extensive experiments demonstrate that BiHiTo delivers state-of-the-art performance and robust generalization across molecular dynamics trajectories and macromolecular complexes, facilitating advances in structure generation and dynamic conformation exploration. In the reconstruction of the CASP14 and OOD test set FastFolding protein multi-conformation data, our method achieves a 17% and 51% reduction in RMSD compared to Bio2Token, respectively.

molecular biology↗

bioRxiv2026

Joint Segmental Duplication Co-option Drives Human-specific Transcriptional Readthrough and Expression Fine-tuning of NPEPPS-TBC1D3

Segmental duplication (SD) is a major driver of functional changes in evolution and disease. Many genes embedded within SDs, such as NPEPPS and TBC1D3, display substantial copy number variation (CNV) across individuals. Yet, the precise identification of the functional copies and their transcriptional outputs remains largely unstudied. Focusing on NPEPPS and TBC1D3, we illustrate human-specific expression fine-tuning mechanisms associated with readthrough transcripts. We identified a human-specific NPEPPS-TBC1D3 digenic genomic structure that originated from a joint SD pair and became fixed across populations. Experiments demonstrate that this structure generates NPEPPS-TBC1D3 readthrough transcripts, which are the predominant isoforms of TBC1D3 expression in various cell types, fine-tuning its protein level. Furthermore, a human-specific hypomethylation signal within an upstream CpG island of NPEPPS precisely pinpoints the expressed TBC1D3 paralog. Moreover, we reveal transcriptional readthrough events are [~]3-fold enriched for joint-SD-associated transcriptional readthrough (JSDTR) and identify 109 JSDTR gene pairs, including neurodevelopmentally important pairs and clinically interesting SERF1A/B-SMN1/2. Taken together, our findings comprehensively describe an example of how a joint SD event shaped evolution and suggest that JSDTR is a broad mechanism for the emergence of new functions.

genetics↗

bioRxiv2025

Kilohertz-rate two-photon voltage imaging of population dynamics in vivo

Understanding how neural circuits compute requires capturing voltage dynamics across large neuronal populations with millisecond resolution in vivo. However, two-photon voltage imaging remains fundamentally limited by a trade-off among imaging speed, field of view, and excitation efficiency. We introduce HS2PM, a hybrid scanning two-photon microscope that overcomes this bottleneck, enabling kilohertz-rate imaging over a 650 x 524 m2 field of view at single-cell resolution while preserving the photon efficiency of single-point excitation. HS2PM stably records deep-layer membrane potentials from over 160 neurons simultaneously, with minimal photobleaching and phototoxicity. It resolves both spikes and subthreshold voltage dynamics in vivo, revealing how these jointly shape sensory adaptation and population coding. Beyond voltage imaging, HS2PM supports high-speed fluorescence lifetime and vascular flow imaging, establishing a multimodal platform for dissecting fast circuit dynamics with precision previously inaccessible to optical methods.

neuroscience↗

bioRxiv2025

Multimodal Data Fusion Reveals Morpho-Genetic Variations in Human Cortical Neurons Associated with Tumor Infiltration

We introduce LetsACT (Light-Electron-Transcriptome synergistic ACTomography), a multimodal integration platform that overcomes the limitations of single-modality data acquisition and analysis of human brain cells while synergistically leveraging the strengths of each modality. Our approach enables the rapid sample preparation, cell injection, imaging, and multimodal integration of large-scale human neuronal datasets at single-cell resolution. By generating initial laser-scanning-microscopy based optical reconstruction of neuron morphologies followed by refining them using electron-microscopy derived morphological priors, we have assembled one of the largest human cortical morphology datasets to date: 8,398 neurons from 58 donors, with high cortical coverage. This platform is then applied to studying morphological impact of tumor infiltration. Pyramidal neurons in glioma-infiltrated tissues display clear volume shrinkage in somas and branches, tapering from the soma to nearby dendritic compartments. By integrating these morphological variations with spatial and bulk transcriptomic profiles, we find that glioblastoma tissues exhibit dysregulation of 15.29% of genes, including overexpression of TERT, whereas infiltrated tissues show 7.74% gene dysregulation, characterized by overexpression of tumor suppressors such as CDKN2A and TP53. Our analysis implies that pyramidal neurons observed in these infiltrated tissues may involve an active defense instead of undergoing passive apoptosis. Our finding also indicates that LetsACT establishes a valuable resource for the large-scale, comprehensive morpho-genetic analysis of human tissues.

neuroscience↗

bioRxiv2025

Tibetan near-complete pangenome reveals complex variants underlying high-altitude adaptation

Genomic diversity in indigenous populations offers critical insights into human evolution and population-specific adaptation. Here, we generated 70 near-complete, fully phased genome assemblies from 35 high-altitude Tibetan trios and identified 4.55 million small variants and 63,031 structural variants (SVs) absent from the current global pangenome reference. Comparative analyses with a 595 globally diverse long-read genome dataset revealed 207 previously uncharacterized Tibetan-enriched SVs spanning 275 genes implicated in high-altitude physiological adaptation. Genotyping these SVs in 1,164 Tibetan and Han individuals with 88 physiological traits reveals five variants significantly associated with cardiopulmonary and hematological phenotypes central to hypoxia adaptation. We further map 2.45 Gb of archaic hominin sequences in Tibetans and uncover 18 previously unrecognized introgressed regions enriched in Tibetans with genes related to hematopoiesis and lung function. These regions harbor five Tibetan-enriched SVs, indicating that archaic introgression contributed SVs relevant to human adaptation. Together, these findings reveal substantial uncharacterized genomic diversity in Tibetans and highlight a previously underappreciated role of SVs and archaic SVs in shaping human evolution and high-altitude adaptation.

genomics↗

bioRxiv2025

Integron-associated structures underlie the accumulation of antibiotic resistance genes on plasmids beyond cassette arrays

Rising multidrug-resistant (MDR) bacteria threatens global public health. While antibiotic selection preserves MDR plasmids, how mobile genetic elements (MGEs) drive the antibiotic resistance gene (ARG) accumulation to form complex plasmid architectures remain elusive. Here, we demonstrate that MDR plasmid evolution follows a hierarchical scheme, where progressive combinations of integrons, IS26, and ISCR elements drive stepwise increases in ARG load. The combination of all these three MGEs were significantly linked to the highest ARG load on plasmids. In the presence of integrons or ISCR elements, ARG numbers in plasmids are strongly and positively correlated with IS26 copy numbers. Such correlations were further validated by Escherichia coli plasmids collected from human and pig wastewater. We propose an integron-IS26-ISCR (3I) framework with four MDR plasmid evolutionary stages of increasing ARG accumulation potential. The "3I" framework refines predictions of MDR plasmid emergence and spread, providing universal genetic markers for cost-effective surveillance.

microbiology↗

bioRxiv2025

OS2CR-Diff: A Self-Refining Diffusion Framework for CD8 Imputation from One-Step Inference to Conditional Representation

Stain imputation in multiplex immunofluorescence (mIF) imaging addresses the challenge of missing or damaged biomarker channels by reconstructing target biomarker images from a limited set of available stains. This approach offers a faster and more efficient alternative to full-panel staining, enabling detailed analysis of the tumour microenvironment. Existing One-Step Inference Models (OSIMs), primarily based on generative adversarial networks (GAN) or autoencoders, often generate suboptimal images with significant artifacts or reduced signal intensity. These limitations impair visual interpretability and reliability of the downstream immunotherapy response assessment. The challenge is further amplified when imputing cytoplasmic biomarkers such as CD8 from commonly used stains such as DAPI, due to the limited spatial correlation and the inherently complex structure of cytoplasmic signals. To address these limitations, we propose a self-refining diffusion model, OS2CR-Diff, which utilises the results from OSIMs as additional conditional representations. Unlike prior studies that rely on a single or limited conditional inputs, OS2CR-Diff incorporates three conditional inputs: the OSIM-imputed target biomarker image, OSIM-imputed complementary biomarker images, and non-antibody-stained images. Furthermore, we propose a feature fusion module that employs a cross-gated attention mechanism to effectively integrate these inputs, enabling context-aware feature refinement and improving the quality and reliability of imputed biomarker images. We evaluated OS2CR-Diff for CD8 biomarker imputation on mIF images of melanoma tissues. Our method out-performed state-of-the-art methods, achieving a 73.4% increase in the Structural Similarity Index Measure (SSIM), a 28.9% gain in the Peak Signal-to-Noise Ratio (PSNR), a 61.2% improvement in Mean Absolute Error (MAE), and significantly lower false positive rates compared to OSIM.

bioinformatics↗

bioRxiv2025

Butyrate rescues chlorpyrifos-induced social deficits through inhibition of class I histone deacetylases

Chlorpyrifos (CPF) is a widely used organophosphate pesticide effective through inhibiting acetylcholinesterase, which leads to the accumulation of acetylcholine and continuous nerve stimulation. In addition to its well-known acute toxicity, exposure to CPF has also been linked to chronic conditions such as an increasing risk of autism spectrum disorder (ASD) and adverse effects on gut health, including disturbances to the gut microbiome and metabolism. However, the underlying mechanism of CPFs contribution to ASD remains unclear, and the roles of the gut microbiome and gut metabolites in CPF-induced neurodevelopmental toxicity remain elusive. Using a high-throughput social behavior assay, we found that embryonic exposure to CPF induced lasting social deficits in zebrafish. Through a small-scale screen of common health beneficial gut microbiome metabolites, we discovered that butyrate effectively rescued CPF-induced social deficits. RNA sequencing of zebrafish brain tissues revealed that early exposure to CPF induced a lasting suppression of neuronal genes, including many ASD risk genes, and elevated expression of circadian genes. Butyrate partially reversed the suppression of key neuronal genes. Butyrate is a non-selective inhibitor of histone deacetylases (HDACs). Through a series of loss-of-function experiments utilizing CRISPR-Cas9-induced knockouts and selective chemical inhibitors, we found that the class I HDAC, HDAC1, most likely mediates butyrates rescue effect. Metabolomics analysis detected changes in several nitrogen metabolism-related pathways in the zebrafish gut following CPF exposure. Metagenomics analysis revealed an increase in abundance of the denitrifying bacteria Pseudomonas and a reduction in the nitric oxide-sensitive bacteria Aeromonas in the CPF-exposed zebrafish gut microbiome. Our results connect CPF-exposure with changes in the gut microbiome, metabolome, epigenetics, gene expression, and behavior, inspiring a novel hypothesis for the underlying molecular mechanisms of CPF-induced neurodevelopmental toxicity. In the long run, our findings may help elucidate how CPF exposure contributes to autism risk and inspire therapeutic developments.

neuroscience↗

bioRxiv2025

A spatially-resolved human brain proteome atlas for understanding function and disease

While the brain performs specialized functions across distinct regions, the spatial organization of the human brain proteome remains largely uncharted. Here we present a comprehensive spatially-resolved proteome atlas of the human brain, analyzing over two thousand MRI- guided locations across four individuals. Proteome analysis integrated with transcriptomics reveals extensive post-transcriptional regulation, with cortical regions showing markedly higher protein diversity than transcript. Unsupervised molecular clustering defines distinct brain territories that transcend anatomical boundaries, instead reflecting metabolic demands and functional specialization patterns. Application to epilepsy brain tissue uncovered disrupted astrocyte metabolism, protein homeostasis and therapeutic targets including the seizure-associated purinergic receptor P2RX7. This resource bridges molecular and systems neuroscience to accelerate neurological drug discovery.

neuroscience↗

bioRxiv2025

A Population-scale Single-cell Spatial Transcriptomic Atlas of the Human Cortex

The genetic and spatial determinants of cell type diversity in human cerebral cortices remain poorly defined. Here, we present a population-level single-cell spatial transcriptomic atlas of human cortices from 71 donors across the lifespan. We identified 906 layer-specific genes showing conserved and divergent laminar expression patterns between humans and other species. Spatial analysis revealed neuronal vulnerability and glial activation during aging, together with a decline in the proportion of superficial SST neurons and their interactions with other cells. Disease-associated genes exhibited high cell-type and layer-specific expression, implicating the pathogenic role of spatially specific gene expression. Spatial cis-eQTL analysis identified regulatory variants linked to genes related to diseases like Tourette syndrome. Cross-species comparison demonstrated glial expansion in the human cortex, accompanied by enhanced neuron-glia communication via the neuregulin signaling. Together, we provide a comprehensive single-cell atlas of the human cortex that is essential for understanding aging, evolution, and disease pathogenesis.

neuroscience↗