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Results for “single-nucleus sequencing”

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PubMed2026

Developmental and cellular vulnerabilities underlie genetic architecture of schizophrenia.

Schizophrenia (SZ) is a highly heritable neuropsychiatric condition with complex polygenic architecture. Elucidating the cellular and developmental substrates vulnerable to the genetic risk is essential for understanding the underlying neurobiological mechanisms. Here, we integrated genome-wide association study (GWAS) and whole-exome sequencing (WES) data with a developmental multi-omics atlas of the human cortex (including 5 cortical regions), comprising about 3 million single-nucleus RNA sequencing (snRNA-Seq) and single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-Seq) profiles across 8 neurodevelopmental processes, to map cell-type-specific enrichment of SZ genetic risk. Our enrichment analyses revealed that both common and rare genetic liabilities converged on broad excitatory and inhibitory neuronal classes. Across different statistical frameworks, we identified genetic enrichment within intratelencephalic (IT) projection neurons and layer 6b excitatory neurons (Ex-L6b) networks across multiple cortical regions. Stage-resolved developmental mapping in the frontal cortex showed that genetic liabilities, particularly the rare variants, are predominantly concentrated within early developmental processes, namely neurogenesis and neuronal migration. Differential expression analysis in postmortem frontal cortex snRNA-Seq datasets cross-validated the cellular substrates of the genetic liabilities. Collectively, our findings establish a high-resolution cellular and temporal framework of SZ susceptibility, implicating mature associative IT microcircuits, deep-layer thalamocortical-regulating networks, and early developmental specification windows as primary points of genetic convergence in SZ.

Journal Article↗

PubMed2026

Single-nucleus profiling reveals hepatocyte identity and immune features associated with corticosteroid response in severe alcohol-related hepatitis.

BACKGROUND & AIMS: Severe alcohol-related hepatitis (sAH) is associated with high short-term mortality. However, 30-40% of patients fail to respond to corticosteroids, the only proven pharmacological treatment. The pathophysiological mechanisms underlying sAH and the marked heterogeneity in treatment response remain incompletely understood. We aimed to define cellular changes associated with corticosteroid response in sAH and to identify baseline markers predictive of treatment outcome. METHODS: Single-nucleus RNA sequencing was performed on liver biopsies from patients with biopsy-proven sAH (n = 17), including paired baseline and day 8 biopsies in a subset of patients (n = 8). Patients were classified as corticosteroid responders (sAH-R; Lille score <0.45) or non-responders (sAH-NR; Lille score ≥0.45). Liver biopsies from patients with acute decompensation of alcohol-related cirrhosis (AD; n = 5) and healthy controls (n = 4) were included for comparison. Findings were validated using immunohistochemistry and spatial proteomics in a large multicenter validation cohort (n = 172). RESULTS: At baseline, sAH-R exhibited a significantly higher proportion of liver-infiltrating S100A8+ monocytes compared to sAH-NR, a difference that persisted at day 8. sAH livers showed a marked reduction in mature hepatocytes and an expansion of stressed and intermediate hepatocyte populations, indicating progressive loss of mature hepatocyte identity. This loss was more pronounced in sAH-NR, who also exhibited fewer cycling hepatocytes at day 8, consistent with impaired regenerative capacity. Expression of SULT2A1, a marker of mature hepatocyte identity, was significantly reduced in sAH-NR at baseline. Finally, liver biopsies with ≥50% SULT2A1-positive hepatocytes at baseline were strongly predictive of corticosteroid response. CONCLUSIONS: This study delineates distinct immune and hepatocyte changes associated with corticosteroid response in sAH. Baseline SULT2A1 expression may facilitate stratified treatment approaches in sAH. IMPACT AND IMPLICATIONS: Severe alcohol-related hepatitis (sAH) represents one of the most devastating manifestations of alcohol-related disorders. sAH is characterized by acute hepatic inflammation and high short-term mortality. Clinical management remains challenging, as corticosteroids - the only pharmacological therapy currently applied - are ineffective in a substantial proportion of patients and are associated with significant adverse effects. These limitations highlight the need for a more detailed understanding of sAH pathophysiology and for approaches that enable improved patient stratification and therapeutic decision-making. In this study, we identify distinct pre-treatment differences between corticosteroid responders and non-responders at the level of both hepatocytes and myeloid cells, providing new insight into the cellular mechanisms underlying treatment heterogeneity in sAH. Furthermore, leveraging these findings, we developed a histology-based SULT2A1 scoring system using a commercially available antibody, which predicts corticosteroid response at baseline and may support stratified treatment approaches in clinical practice.

Humans↗

PubMed2026

From wild to domestic: Single-cell transcriptomic perspectives on hippocampal regulation and evolution.

How domestication shapes brain evolution remains an open question. In this study, we integrated single-nucleus RNA sequencing (snRNA-seq), population genomics, and machine learning to investigate the hippocampal evolution under domestication. Across-species comparisons revealed that hippocampal cell type profiles are largely conserved across vertebrate species, while supporting the presence of adult hippocampal neurogenesis in birds. We further found that domestication and selective breeding likely influence the cellular composition and molecular regulation of the hippocampus. Our findings provide cellular evidence supporting the hypothesis that domestication affects adult hippocampal neurogenesis. Additionally, we showed that genes associated with neural progenitor cells (NPC) states and cell-marker programs are enriched for signatures of selection. Many of these genes function as regulators of neurogenesis and pathways mediating stress and fear reduction. Specifically, we identified selection at the FKBP5 promoter that may influence its expression in the NPC lineage, potentially contributing to stress-response regulation during domestication. Collectively, these results suggest that domestication is associated with hippocampal remodeling as part of an adaptive response to human-managed environments. This study provides a cellular and genetic perspective on how domestication reshapes the brain and offers a basis for further investigation into the mechanisms of neural evolution within the context of microevolution.

Animals↗

PubMed2026

Benchmarking computational decontamination of ambient RNA.

Gene expression profiling of single cells using single-cell and single-nucleus RNA sequencing (sxRNA-seq) enables researchers to characterize cellular heterogeneity and unraveling complex biological processes at unprecedented resolution. However, sxRNA-seq faces challenges due to the presence of ambient RNA, extraneous RNA molecules not originating from the cells of interest. Sample preparation is a major source of ambient RNA, where harsh conditions can lead to cell lysis and the release of intracellular RNA. This inescapable inclusion of ambient RNA can cause erroneous results and hinder downstream analyses. To address this issue, various methodologies have been developed to identify, quantify, and remove ambient RNA. Here, we rigorously evaluate 7 state-of-the-art methodologies for ambient RNA removal using simulated datasets, species-mixing experiments of varying complexities, and genotype-mixing experiments. We find that no single method performs the best across all datasets and metrics, but CellBender, DecontX and SoupX generally perform well.

ambient RNA↗

PubMed2026

Putative glioblastoma origin-like cells in the subventricular zone: isolation and characterization.

Glioblastoma (GBM) remains lethal despite maximal therapy. The adult subventricular zone (SVZ), a neural stem-cell niche, has been implicated as a potential site of origin, yet the identity and functional properties of putative GBM origin-like cells (GBM-OCs) within the SVZ remain unclear. An SVZ-restricted somatic mutation mouse model (Cre-induced EGFRvIII expression with Trp53 and Pten disruption) was established and mouse SVZ-derived cells were prospectively isolated for functional and molecular profiling. Self-renewal, multipotency, invasive potential and tumour-initiating capacity were assessed relative to control SVZ cells and matched tumour-derived tumourspheres. Whole-genome and RNA sequencing defined genomic and transcriptional alterations during early progression. Mouse GBM-OCs exhibited self-renewal and multilineage differentiation and initiated tumours only after re-implantation into the SVZ (11/29, 38%), whereas direct striatal implantation failed (0/25, 0%), indicating context-dependent tumorigenic potential associated with the SVZ microenvironment. In contrast, tumour-derived tumourspheres retained tumorigenic capacity upon implantation into both the SVZ and the striatum. During progression from mouse GBM-OCs to tumours, whole-chromosome and arm-level aneuploidies accumulated. In patients with GBM, multi-region single-nucleus RNA sequencing of tumour-free SVZ, matched tumours and tumour-free cortex identified rare neural stem cell-like, astrocyte-like and oligodendrocyte precursor-like SVZ populations transcriptionally aligned with GBM programmes. These cells showed single-nucleus RNA-inferred chromosome 7 gain and/or chromosome 10 loss signals, with concordant low-frequency copy-number alterations in the SVZ detected by exome sequencing and enriched in matched tumours. Together, these findings support the presence of SVZ-resident stem or progenitor-like populations with early GBM-associated features, consistent with putative GBM-OCs, and highlight the SVZ niche as a potential target for early detection and niche-informed therapeutic strategies.

Animals↗

PubMed2025

Cell-type-specific defense priming and NHP-dependent systemic immunity against Pectobacterium in Chinese cabbage.

Defense priming is an effective strategy for mounting the defensive capacity of plants. Primed plants undergo minimal changes, enabling rapid, robust responses to subsequent pathogen attack. The cell-type-specific mechanisms underlying priming and systemic immunity remain unclear. Using single-nucleus RNA sequencing (snRNA-seq), we reveal how primed Chinese cabbage coordinates N-hydroxypipecolic acid (NHP)-dependent systemic immunity against Pectobacterium carotovorum. NHP accumulates as a phloem-mobile priming signal. snRNA-seq identified a priming-specific epidermal cell state transition and transcriptional cascade: BrWRKY18-1 activates BrWRKY33-1 expression during priming, initiating NHP-dependent systemic immunity. At post-challenge primed state, pathogenesis-related genes (PRs), such as BrPR3, BrPR4-1, and BrPR4-2, are predominantly expressed in systemic tissues to inhibit infection. Notably, the functionality of these PR genes in immunity necessitates their expression in all cells to effectively enhance defensive resistance. This NHP-transcription factor-PR axis couples mobile signaling to systemic immunity, elucidating cell-type-specific defense priming.

Plant Immunity↗

PubMed2026

Single-nucleus transcriptomics reveals cell type-specific remodeling and epilepsy-associated microglia.

Temporal lobe epilepsy (TLE) is the most common acquired epilepsy, causing refractory seizures and cognitive deficits. We performed single-nucleus RNA sequencing on hippocampal tissue from mice 3 and 6 weeks following pilocarpine-induced status epilepticus, a robust model of TLE. Epilepsy samples showed reductions in Cck and Lamp5-Lhx6 interneuron subclusters, alongside increases in Cajal-Retzius cells, dentate granule (DG) cell precursors, and a mature DG cell subcluster. Among glia, an astrocyte subcluster and a markedly expanded microglia sublcuster were increased. We term this microglia population epilepsy-associated microglia (EAM). The transcriptomic profile of EAM overlaps with microglia described in models of Alzheimer's disease and traumatic brain injury, including enrichment of Myo1e and Igf1. EAM display amoeboid morphology, can be found in clumps around pyramidal and granule cell body layers, and exhibit enlarged vesicles and mitochondria. Cell-cell interaction analysis predicts DG cells as their primary interaction partners. This dataset defines transcriptomic programs underlying key cellular alterations in TLE, enabling mechanistic dissection of epileptogenesis.

TLE↗

PubMed2026

A single-nucleus transcriptome atlas of soybean anthers.

Anther development is crucial for plant sexual reproduction. However, a high-resolution, cell-type-specific transcriptomic atlas of this process is lacking for the legume crop soybean (Glycine max). Here, we construct a comprehensive transcriptional atlas of developing soybean anthers using single-nucleus RNA sequencing (snRNA-seq). We identify and characterize nine distinct cell types spanning both somatic and reproductive lineages. Our analysis reveals robust transcriptional continuity across anther developmental stages and dynamic reprogramming during key transitions. Notably, the shift from diploid meiocytes to haploid unicellular microspores is marked by the induction of previously inactive genes, despite an overall reduction in transcript abundance. Subsequently, within bicellular microspores, generative and vegetative cell lineages exhibit sharply divergent transcriptional programs: generative cells specialize in mRNA export and turnover, whereas vegetative cells up-regulate translational machinery. Evolutionary analysis further indicates that generative-cell-specific genes are subject to more relaxed purifying selection compared to those specific to vegetative cells. Functional validation using mutants generated by CRISPR/Cas9-mediated genome editing and EMS mutagenesis reveals the essential roles of OSD1A and PKSA in pollen development and fertility. This high-resolution atlas provides fundamental insights into the transcriptional regulation of soybean anther development and serves as a valuable resource for manipulating male fertility to advance hybrid breeding programs. The data are available at https://databases.genedenovo.com/pollen.

Glycine max↗

PubMed2026

Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains.

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain"). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to α-synuclein pathology. Like the human brain, pathogenic α-synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.

alpha-Synuclein↗

PubMed2026

Single-cell profiling decodes patagium development in gliding mammal.

The gliding patagium represents a key adaptation for mammalian flight, but its cellular development remains unexplored. Using single-nucleus RNA sequencing of embryonic flying squirrel patagium and dorsal skin, we construct a single-cell atlas of patagium development and identify two distinct fibroblast subpopulations (Fp2 and Fr) highly enriched in the patagium. These fibroblasts are characterized by the patagium upregulation of Wnt5a, Fgf7, and Fgf10, and are associated with patagium morphogenesis through dermal-epidermal putative communication interactions between dermal fibroblasts (Fp2 and Fr) and epithelial basal keratinocytes. Specifically, Fp2 fibroblasts are potentially involved in distal dermal condensation and epithelial thickening together with elevated Wnt5a expression, while both Fp2 and Fr fibroblasts could play a role in epithelial polarization and thickening through Fgf7 and Fgf10, as suggested by ex vivo assays. Our data suggest that gliding patagium development results from the co-option of conserved WNT and FGF signaling pathways within a specialized fibroblast-epithelial context, illustrating how modifications of conserved developmental programs give rise to derived morphological traits.

Animals↗

PubMed2026

Cell-type signatures of Alzheimer's disease shared across population groups.

Genomic studies at single-cell resolution have identified several cell types associated with clinical and pathological traits in Alzheimer's disease1-9, but have not examined associations that are shared across populations. To bridge this gap, here we use single-nucleus RNA sequencing and assay for transposase-accessible chromatin with sequencing to profile cortical and subcortical regions in post-mortem brain-tissue samples from Latin, white (excluding Latin) and African American (excluding Latin) individuals. Using discrete and continuous dissections of molecular programs, we identify cell-type-specific clusters associated with Alzheimer's disease in a region-specific manner across all three population groups, including microglial (GPNMB+ and CD74+ subgroups), astrocytic (SERPINH1+, CD44+ and WIF1+ subgroups) and neuronal (SST+ GABAergic and superficial-layer glutamatergic) signatures. We also report continuous gene-expression factors in astrocytes and oligodendrocytes that are not captured by discrete cluster assignments, but which show strong associations with disease phenotypes; these factors are enriched for genes associated with annotated functions such as lipid processing and neurotransmitter reuptake. Finally, we find that molecular programs reveal six distinct subgroups of individuals with cognitive impairment that span all three populations, are not captured by neuropathology, and are instead distinguished by molecular signatures that are not universally present but are nonetheless associated with ante-mortem impairment. Overall, our study identifies key cell types and gene programs implicated in Alzheimer's disease that are shared across population groups, and underscores how representative sampling can capture both shared signatures and disease heterogeneity, thereby enabling better prioritization of key cell types for further investigation.

Female↗

PubMed2026

Decoding the landscape of cell-type-specific co-expressed transcription factors in soybean.

Soybean (Glycine max) is an essential source of protein and oil with high nutritional value for human and animal consumption. To enhance our understanding of soybean biology, it is essential to have accurate information regarding the expression of each of its protein-coding genes. Here, we present Tabula Glycine max, a soybean single-cell resolution transcriptome atlas. This atlas comprises single-nucleus RNA-sequencing data from ten different G. max organs and morphological structures constituting the entire soybean plant. These nuclei are grouped into 156 different clusters based on their transcriptomic profiles. The breadth of various organs, tissues and cell types represented in Tabula Glycine max reveals that the pattern of co-expressed transcription factor genes is sufficient to define most cell types based on their function and organ of origin. Defining cell-type-specific co-expressed transcription factor genes offers a new perspective to engineer cell-type-specific programmes and enhance the biology of unique soybean cell types. This cellular resolution and breadth make the Tabula Glycine max an exceptional resource for the plant and soybean communities.

Journal Article↗

PubMed2026

Genetics-Informed Mapping Identifies a CRIM1-Associated Endocardial Inflammatory Remodeling State in Acute Myocardial Infarction.

BACKGROUND Acute myocardial infarction (AMI) reflects inherited susceptibility and inflammatory remodeling, but the cellular contexts linking genetic risk to disease remain unclear. MATERIAL AND METHODS We integrated a meta-transcriptome-wide association study (TWAS) with a human cardiac single-nucleus RNA-sequencing atlas contained 11 individuals (5 AMI and 6 donor) to identify genetics-informed cellular programs. Composite program states were defined by global score quartiles. A fixed 5-gene panel was evaluated for nucleus-level endocardial low-transcriptional-state (Endo_LTS) vs endocardial high-transcriptional-state (Endo_HTS) discrimination within the AMI endocardium using 5-fold leave-1-patient-out cross-validation. Functional follow-up used CRIM1 silencing in hypoxia-treated human induced pluripotent stem cell (hiPSC)-derived endocardial endothelial-like cells and complementary peripheral blood analyses. RESULTS The endocardium exhibited the most prominent infarction-associated increase in TWAS-anchored program activity, with expansion of program-high states and higher CytoTRACE scores. A consensus 5-gene panel (RPS8, PLEC, CFDP1, CRIM1, TNS2) was identified. Among 2163 AMI endocardial nuclei from 5 patients, the state classifier included 364 Endo_LTS and 751 Endo_HTS nuclei; 1048 Endo_MTS nuclei were excluded. Pooled out-of-fold ROC-AUCs ranged from 0.665 to 0.831. The panel also showed discriminatory value in an independent peripheral-blood AMI-vs-control cohort. CRIM1 was prioritized as a candidate linked to the remodeling program. CRIM1 silencing attenuated ACTA2/alpha-SMA, vimentin, LDHA, CCL2, and VEGFA and partially restored CD31, whereas TGF-ß remained elevated. CONCLUSIONS These findings identify a genetics-informed endocardial inflammatory remodeling state in AMI and define a 5-gene surrogate of its activated state. CRIM1 is prioritized as a candidate linked to selected inflammatory, metabolic, and structural outputs. Persistent TGF-b elevation after CRIM1 silencing argues against a simple linear regulatory model and indicates that further mechanistic validation is required.

Humans↗

PubMed2026

A longitudinal single-cell and spatial multiomic atlas of pediatric high-grade glioma.

Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities with adult glioma, it comprises distinct disease entities. In this study, we longitudinally profile a molecularly diverse cohort of 16 pHGG patients through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of neoplastic and microenvironmental features during disease progression and treatment. We define a set of core pHGG neoplastic cell states and observe differential tumor-myeloid interactions between malignant cell phenotypes. We find that essential neuromodulators and the interferon response are upregulated post-therapy, implicating them as malignant cell-intrinsic targets. We observe an increase in oligodendrocytes upon progression and that they coordinate spatial motifs with proneural tumor cells. This multiomic atlas of longitudinal pHGG captures features of therapy response and provides a scalable reference for the study of pediatric brain tumors.

Humans↗

PubMed2026

Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance mechanism to imipridone therapy.

BACKGROUND: Imipridone ONC201 is the first FDA-approved therapy for H3K27-altered diffuse midline glioma; however, clinical responses remain limited. Defining tumor-intrinsic determinants and microenvironmental, extrinsic factors that shape sensitivity or resistance to imipridones will identify actionable therapeutic opportunities and inform improved clinical strategies. METHODS: To identify mechanisms of imipridone resistance, we obtained postmortem brain tissue from DMG patients who had received imipridones and/or standard care. Single-nucleus RNA and open-chromatin sequencing were performed on N = 22 cases. Immunofluorescence-based myeloid phenotyping was performed on N = 46 cases. Mitochondrial copy-number analysis was performed on N = 19 cases. Validation of imipridone sensitivity, its effect on mitochondrial density, and its synergy with inhibition of mitochondrial biogenesis were assessed in DMG primary cells. RESULTS: We established a single-cell RNA/open-chromatin atlas from postmortem DMG cases and found imipridone treatment resulting in regressed mesenchymal transition, reduced myeloid-derived suppressive cells, and reversed aberrant H3K27-altered enhancer activity. Resistant tumors showed increased mitochondrial density, turnover, and membrane potential. Mitochondrial biogenesis and PPARGC1A emerged as resistance biomarkers and actionable targets. CONCLUSIONS: These studies implicate mitochondrial biogenesis as a biomarker of imipridone resistance and a focus for the development of combinatorial strategies to provide effective therapeutic options for a challenging pediatric brain tumor.

Humans↗

PubMed2026

Alignment-free integration of single-nucleus ATAC-seq across species with sPYce.

Changes in gene regulation largely contribute to differences in cellular identities and phenotypes between species. Single-nucleus assays for transposase-accessible chromatin with sequencing (snATAC-seq) are an efficient strategy to identify putative gene regulatory elements and provide new insight into evolutionary divergence of regulatory programmes. However, no dedicated framework exists to integrate and compare snATAC-seq data across species, while methods designed for single-cell gene expression data have serious limitations. Here we present sPYce, a cross-species snATAC-seq integration method that relies on sequence composition similarities through k-mer histograms of regulatory regions, removing the need for genome alignments to anchor data from different species. sPYce can embed datasets from multiple species into the same mathematical space and permits further downstream analysis steps. We benchmarked sPYce against existing approaches on two publicly available datasets spanning more than 160 myr of evolution, showing that it successfully uncovers conserved cellular programmes while preserving biologically relevant species-specific differences. By comparing cerebellar development in mice and opossums, sPYce identifies regulatory divergence in granule cell differentiation programmes, particularly driven by nuclear factor 1. As an easy-to-use, alignment-free cross-species snATAC-seq integration approach, sPYce opens new perspectives to compare gene regulatory evolution across species.

Animals↗

PubMed2026

Positional grammar of transcription factor binding partitions developmental and stress-response regulation in plants.

Understanding how transcription factor binding site (TFBS) position influences gene regulation remains a fundamental challenge in plants. Here, we integrate conserved multiDAP TFBS maps for 244 transcription factors (TFs) with single-nucleus chromatin accessibility, cell type-resolved gene expression, and hormone-response datasets across Brassicaceae species to determine how TFBS position relates to regulatory function. Although conserved TFBSs are enriched near transcription start sites (TSSs), TSS-proximal accessibility poorly predicts cell type-specific expression. Instead, cell type-specific expression correlates best with conserved TFBSs embedded in cell type-restricted chromatin, with TF family-specific distributions across distal promoters and introns. In contrast, TSS-proximal TFBSs in broadly accessible chromatin are associated with rapid transcriptional responses to abiotic and biotic stress hormones. Coding sequence TFBSs mark a distinct regulatory context in which the same DNA sequence encodes both amino acid sequence and TF motifs, including evidence that CDS-localized ABR1 binding may contribute to repression during hormone response. Finally, distal upstream regions contain conserved multi-family TF clusters with enhancer-like features overlapping rare cell type-specific accessible chromatin and enriched near genes controlling embryonic, meristematic, and hormone-dependent developmental patterning. Together, these results support a positional grammar in which TFBS position and chromatin context jointly partition developmental, stress-responsive, and repressive regulatory output in plants.

Transcription Factors↗

PubMed2025

Combined somatic mutation and transcriptome analysis reveals region-specific differences in clonal architecture in human cortex.

The human cerebral cortex is specialized into regions, but little is known about how human cellular lineages shape cortical regional variation and neuronal cell-type distribution during development. Here, we map single-cell lineages of human cortical regions and neuronal subtypes using >1,000 somatic single-nucleotide variants (sSNVs) identified from deep bulk whole-genome sequencing and analyzed over 25 regions and >72,000 single cells. In the fronto-parietal cortex, sSNVs are rarely restricted, marking neuron-generating clones that disperse into neighboring regions. In contrast, the primary visual cortex harbors 30%-70% more sSNVs than the neighboring secondary visual cortex. Clones at this border exhibit more restricted dispersion, suggesting late developmental lineage segregation. Single-nucleus sSNV and whole-transcriptome analysis reveal glutamatergic neuron clones with modest regional restrictions that share low-mosaic sSNVs with some GABAergic neurons, suggesting a recent dorsal cortical progenitor. Our analysis reveals human-specific cortical lineage patterns, regional differences in clonal patterns, and late divergence of some glutamatergic/GABAergic lineages.

Humans↗