Front Genet [JOURNAL]
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200 papers
Nanopore genome sequencing of strain AB001 from lesions of diseased .
Mashzhan A, Smekenov I, Bakiyev S … +4 more , Utegenova K, Kuanbay A, Kairov U, Bissenbaev A
Front Genet · 2026 · PMID 42232520 · Full text
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Multi-omics landscape and functional validation of HCCS in breast cancer: from pan-cancer immunometabolic characterization to regulating tumor proliferation.
Cheng H, Li C
Front Genet · 2026 · PMID 42232519 · Full text
BACKGROUND: Holocytochrome c synthase (HCCS) is an essential mitochondrial regulator; however, its pan-cancer significance and its direct functional role in breast cancer (BRCA) progression remain insufficiently explored...
BACKGROUND: Holocytochrome c synthase (HCCS) is an essential mitochondrial regulator; however, its pan-cancer significance and its direct functional role in breast cancer (BRCA) progression remain insufficiently explored. This study aimed to systematically characterize the pan-cancer landscape of HCCS and validate its biological impact on BRCA. METHODS: We integrated multi-omics data from 33 TCGA cancer types to investigate HCCS expression patterns, genomic alterations, and its correlation with the immune microenvironment. In breast cancer cell lines (MDA-MB-231), the effects of HCCS knockdown on cell proliferation and cell cycle distribution were assessed using CCK-8, colony formation, and flow cytometry assays. Finally, we constructed a machine learning-based prognostic signature and performed drug sensitivity analysis to evaluate its clinical relevance. RESULTS: HCCS was significantly upregulated in multiple malignancies, including BRCA, and correlated with poor patient prognosis. Pan-cancer analysis suggested that HCCS might act as a mitochondrial-immunometabolic hub involved in immune evasion. validation confirmed that HCCS is a key driver of tumor growth, as HCCS knockdown significantly inhibited cell proliferation and colony-forming ability by inducing G0/G1 phase arrest. By integrating these mechanistic findings with clinical data, we developed a robust HCCS-based prognostic model that demonstrated high predictive accuracy across independent BRCA cohorts. Furthermore, pharmacogenomic analysis identified candidate small molecules, such as MK-886 and mercaptopurine, as potential therapeutic options. CONCLUSION: Our findings transition HCCS from a computational biomarker to a functionally validated regulator of breast cancer cell survival. By linking its systemic immunometabolic impact with its direct role in cell cycle control, this study identifies HCCS as a promising therapeutic target and a reliable prognostic indicator in BRCA.
Comparative DCMS analysis reveals a novel breed-specific X-linked selection signature in Changthangi sheep.
Nath S, Illa SK, Yata VK … +2 more , Shukla R, Kolliputi N
Front Genet · 2026 · PMID 42232518 · Full text
INTRODUCTION: The X chromosome contributes to important adaptive and fitness-related traits in livestock, but it has received relatively limited attention in sheep genomics, particularly in studies of indigenous Indian b...
INTRODUCTION: The X chromosome contributes to important adaptive and fitness-related traits in livestock, but it has received relatively limited attention in sheep genomics, particularly in studies of indigenous Indian breeds. METHODS: We utilised the de-correlated composite of multiple signals (DCMS) approach, which integrates five individual statistics including FST, H1, H12, Tajima's D, and π, to identify selection signatures within breeds on the X chromosome in Changthangi (n = 29), Deccani (n = 24), and Garole (n = 26) sheep, genotyped with the Illumina OvineSNP50 BeadChip. Candidate genes and quantitative trait loci (QTLs) in significant regions (FDR <0.05) were annotated using the GALLO package, followed by prioritisation and visualisation through protein-protein interaction networks. RESULTS: Our analysis identified a significant genomic region on the X chromosome (∼55.9-57.2 Mb; ∼1.396 Mb) in Changthangi sheep, whereas no comparable signal was detected in Deccani or Garole. This region includes 31 genes, with the top-prioritized genes being , , , and . The QTL annotation indicated enrichment for traits related to milk production, body weight, and reproduction, while protein-protein interaction networks identified as a prioritized and relatively well-connected node within the candidate interval. CONCLUSION: This study identifies a breed-specific X-linked candidate selection region in Changthangi sheep and supports the view that X-linked variation may contribute to local adaptation at high altitudes. These findings highlight the value of within-breed composite approaches for investigating the X chromosome in indigenous sheep populations and provide a basis for future validation of candidate genes relevant to adaptation and breeding.
Responses and adaptations of plants to abiotic stress: transcriptional regulation of secondary metabolic pathways, metabolomics, and nanobiological approaches.
Srivastava Y, Saini N, Nishu … +6 more , Yadav S, Tripathi S, Kumar A, Yadav N, Saini M, Sangwan NS
Front Genet · 2026 · PMID 42232517 · Full text
Plants are continuously exposed to diverse abiotic stresses such as drought, salinity, extreme temperatures, and heavy metal toxicity, each of which disrupts cellular homeostasis and reactive oxygen species (ROS) generat...
Plants are continuously exposed to diverse abiotic stresses such as drought, salinity, extreme temperatures, and heavy metal toxicity, each of which disrupts cellular homeostasis and reactive oxygen species (ROS) generation and impairs development. To survive under these adverse conditions, plants activate a complex network of transcriptional regulators that remodel primary and secondary metabolic pathways. These regulatory cascades, involving transcription factors such as AP2, WUSCHEL, MYB, bHLH, WRKY, and NAC, orchestrate the biosynthesis of key secondary metabolites, including phenolics, flavonoids, terpenoids, and alkaloids, that function as antioxidants, osmoprotectants, and signaling molecules. Advances in metabolomics have provided deeper insights into stress-induced metabolic reconfigurations, enabling high-resolution profiling of pathway metabolic fluxes and revealing novel metabolites associated with adaptive resilience and tolerance. Alongside engineering abiotic stress resistance, nanobiological approaches have emerged as innovative strategies to modulate and remediate transcriptional responses and secondary metabolite production. This review comprehends current understanding of transcriptional regulation of secondary metabolism under abiotic stress, integrates metabolomics-driven discoveries, and highlights the potential of metabolites and metabolomics-based tools to augment plant adaptive mechanisms. Together, these interconnected perspectives offer a comprehensive framework for developing stress-resilient crops in the era of climate change.
An integrative genetic and transcriptomic study reveals a causal link and candidate biomarkers between tuberculosis and asthma.
Liu Y, Li K, Guan F … +10 more , Zhang Y, Li P, Yang M, Tan H, Chen C, Guo L, Liu S, Shi M, Wang J, Liang H
Front Genet · 2026 · PMID 42232516 · Full text
INTRODUCTION: Tuberculosis, caused by , mainly affects the lungs, while asthma is a common chronic respiratory condition often linked with other health issues. Research on the connection between these two diseases is sca...
INTRODUCTION: Tuberculosis, caused by , mainly affects the lungs, while asthma is a common chronic respiratory condition often linked with other health issues. Research on the connection between these two diseases is scarce, and their relationship needs more study. METHODS: We analyzed data from the Global Burden of Disease study to compare the impact of tuberculosis and asthma worldwide from 2013 to 2023. We used two-sample Mendelian randomization to explore the causal link between tuberculosis, asthma, and lung function. Transcriptomic data from active tuberculosis and asthma patients were obtained from the Gene Expression Omnibus database for differential expression, gene co-expression network, and functional enrichment analyses. The expression patterns of the identified candidate genes were validated using quantitative PCR in an independent clinical cohort of 40 tuberculosis patients and 40 healthy controls. RESULTS: The global disease burden analysis shows that tuberculosis has a greater impact than asthma. Mendelian randomization indicates that pulmonary tuberculosis is a risk factor for asthma (Odds ratio = 1.58, 95% Confidence interval: 1.08-2.31, p = 0.018 for ebi-a-GCST90086044; Odds ratio = 1.74, 95% Confidence interval: 1.43-2.12, p < 0.001 for ebi-a-GCST90086047) and adversely affects lung function, including forced vital capacity and forced expiratory volume at one second. Transcriptome analysis reveals immune pathway activation and cellular function suppression in both diseases. Using weighted gene co-expression network analysis, five comorbidity genes: , , , , and , were identified. These genes show significant expression changes in tuberculosis patients and demonstrate high discriminatory potential in the discovery cohort, with an area under the curve of up to 1.0, supporting their further investigation as candidate biomarkers. Clinical validation confirmed these expression patterns. CONCLUSION: Tuberculosis is identified as a causal risk factor for asthma based on genetic evidence from Mendelian randomization. The five key genes, including and , represent promising candidate biomarkers, providing new insights into their comorbidity.
Multi-omics mendelian randomization integrating GWAS and eQTL data revealed potential drug target for irritable bowel syndrome.
Ke H, Chen W, Zhang Q … +9 more , Liu Z, Wei P, Li L, Yu H, Huang D, Lan C, Xu N, Pi L, Song K
Front Genet · 2026 · PMID 42232515 · Full text
INTRODUCTION: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder mainly affecting the young and female with limited therapeutic options, necessitating the identification of novel drug targets. This stud...
INTRODUCTION: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder mainly affecting the young and female with limited therapeutic options, necessitating the identification of novel drug targets. This study aimed to identify and prioritize new, genetically validated drug targets for IBS by leveraging large-scale human genetic data. METHODS: We conducted a systematic, druggable genome-wide Mendelian randomization (MR) analysis to evaluate the causal effects of 5,642 potential druggable protein-coding genes on IBS risk. The analysis integrated summary statistics from the largest available IBS genome-wide association study (GWAS), including 53,400 cases and 433,201 controls, with comprehensive blood expression quantitative trait loci (eQTL) data. Significant findings were further validated using colocalization analysis. A phenome-wide association study (PheWAS) was performed to assess the potential for on-target adverse effects. Finally, potential therapeutic compounds were predicted using the Drug Signatures Database (DSigDB) and molecular docking. RESULTS: The MR analysis identified eight genes with potential causal associations with IBS. Following rigorous validation with colocalization analysis, EP300 and P2RY14 emerged as the most promising candidate targets. Genetically predicted higher expression of both EP300 (OR: 1.128, 95% CI: 1.079-1.180) and P2RY14 (OR: 1.118, 95% CI: 1.067-1.172) was suggestively causally associated with an increased risk of IBS. The PheWAS analysis indicated that EP300 and P2RY14 did not show genome-wide significant associations with any other phenotypes. Additionally, molecular docking predicted that existing compounds, such as captopril and menadione, could effectively bind to the EP300 protein. CONCLUSION: Our study provides genetic evidence establishing EP300 and P2RY14 as promising drug targets for the treatment of IBS, laying a foundation for future drug development and repurposing efforts.
Precision diagnosis of -associated encephalopathies and epilepsy: optimizing variants classification and molecular subregional effects.
Liu WH, Li QL, Li HP … +4 more , Wen QR, Zhang SQ, Ding Y, Meng H
Front Genet · 2026 · PMID 42232514 · Full text
BACKGROUND: variants are associated with a broad spectrum of epileptic phenotypes ranging from mild idiopathic generalized epilepsy to severe developmental and epileptic encephalopathy (DEE). To date, the majority of th...
BACKGROUND: variants are associated with a broad spectrum of epileptic phenotypes ranging from mild idiopathic generalized epilepsy to severe developmental and epileptic encephalopathy (DEE). To date, the majority of the identified variants are missense. Evaluating the pathogenicity of missense variants is a great challenge in genetics. This study aimed to explore reliable biological tools to optimize pathogenic classification of variants, thereby improving precision diagnosis of -associated encephalopathies and epilepsy. METHODS: The dataset of disease-associated and control missense variants was curated. The location of these variants was visualized, to analyze the molecular subregional effects. The performance of 34 algorithms in evaluating the pathogenicity of variants was systematically analyzed, including accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Matthews correlation coefficient (MCC), F-score, and the area under the receiver operating characteristic curve (AUC). RESULT: A total of 61 GABRA1 missense variants were analyzed, including 30 pathogenic/likely pathogenic variants from patients with -associated epilepsies and 31 benign/likely benign controls from the gnomAD database. The pathogenicity and phenotypes of these variants showed significant domain dependence: all transmembrane variants caused severe developmental and epileptic encephalopathy (DEE), the extracellular domain had the highest phenotypic heterogeneity, and the phenotype distribution differed significantly between functionally critical regions and other regions (P = 0.01), indicating a molecular subregional effect. We evaluated 34 commonly used algorithms, which varied considerably in performance. Ensemble and deep learning algorithms showed superior overall performance, with MetaLR and PrimateAI achieving the highest accuracy (0.9167) and AlphaMissense yielding the best AUC (0.9644). Tools like M-CAP and CADD_phred had low specificity. All tools except fathmm-XF showed highly significant score differences between groups (P < 0.0001), and high-performance tools presented a clear bimodal distribution with minimal overlap. CONCLUSION: Ensemble learning and deep learning algorithms are highly effective for predicting the pathogenicity of missense variants. These computational tools provide reliable support for the pathogenicity assessment of variants in clinical genetic diagnosis.
Multi-omics integration identifies ARID1B linking cuproptosis-immune crosstalk with atherosclerotic plaque progression.
Hu X, Wei K, Pang P … +2 more , Chang W, Huang L
Front Genet · 2026 · PMID 42227004 · Full text
BACKGROUND: Atherosclerosis is a long-term inflammatory disorder of the arterial wall, characterized by lipid deposition and infiltration of immune cells. Recent studies suggest that cuproptosis may participate in the pr...
BACKGROUND: Atherosclerosis is a long-term inflammatory disorder of the arterial wall, characterized by lipid deposition and infiltration of immune cells. Recent studies suggest that cuproptosis may participate in the progression of atherosclerosis. METHODS: Multiple scRNA-seq and bulk RNA-seq datasets were integrated to systematically characterize cuproptosis patterns in atherosclerosis. Differential expression analysis based on cuproptosis scores identified cuproptosis-modulating genes, which were further refined using least absolute shrinkage and selection operator, decision tree, and XGBoost algorithms. CellChat analysis explored the effect of ARID1B expression on intercellular communication, while immune infiltration patterns were assessed via single-sample gene set enrichment analysis. ApoE mice served as the model of atherosclerosis to confirmed relationships among cuproptosis, ARID1B expression, and immune infiltration in plaques. RESULTS: Cuproptosis activity was significantly elevated in atherosclerotic tissues compared with normal arteries, with macrophages exhibiting the highest cuproptosis scores. Distinct expression profiles of cuproptosis-related genes, together with divergent immune infiltration landscapes, were observed between the high and low cuproptosis score atherosclerosis groups. ARID1B was identified as a gene discriminating cuproptosis status in atherosclerosis pathology, with significantly reduced expression in the disease group. Functional enrichment analyses suggested that ARID1B-associated networks were mainly involved in immune cell adhesion, activation, and differentiation. validation further confirmed that ARID1B expression was significantly reduced in the atherosclerosis group, which was associated with prominent T cell and macrophage infiltration. CONCLUSION: Cuproptosis-related gene ARID1B may reshape immune infiltration patterns in atherosclerosis, positioning it as a promising therapeutic target.
Single-cell RNA sequencing unveils macrophage heterogeneity and cell-cell interactions in hepatocellular carcinoma progression.
Tang Y, Li J, Huang L
Front Genet · 2026 · PMID 42227003 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) represents a major global health burden, characterized by complex metabolic reprogramming and immunological dysregulation. This study aimed to elucidate the molecular mechanisms...
BACKGROUND: Hepatocellular carcinoma (HCC) represents a major global health burden, characterized by complex metabolic reprogramming and immunological dysregulation. This study aimed to elucidate the molecular mechanisms underlying HCC progression using integrative multi-omics analyses, with a specific focus on macrophage heterogeneity and intercellular communication networks in the tumor microenvironment. METHODS: We performed comprehensive bioinformatic analyses integrating gene expression profiling, DNA methylation data, and single-cell RNA sequencing (scRNA-seq) datasets from publicly available databases. Single-cell transcriptomic data (GSE149614) were processed using Seurat for quality control, dimensionality reduction, and cell type annotation. Macrophage subpopulation diversity was assessed through Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis. Intercellular communication networks were reconstructed using CellPhoneDB and CellChat to identify Signaling axes that act as primary mediators of macrophage-hepatocyte/fibroblast crosstalk in HCC. Functional enrichment analyses were conducted via Gene Ontology and KEGG pathway analyses. The diagnostic and prognostic potential of genes whose expression or methylation status predicts HCC stage, metastasis risk, and patient survival was evaluated through Receiver Operating Characteristic curve analysis and survival modeling. Expression patterns of genes whose dysregulation directly disrupts immunometabolic crosstalk between macrophages and tumor cells, whose dysregulation increases the risk of hepatocellular carcinoma progression by promoting an immunosuppressive microenvironment and enhancing tumor cell proliferation and invasion were experimentally validated using quantitative real-time PCR (qRT-PCR) in two hepatocellular carcinoma cell lines (HepG2 and Huh7) obtained from American Type Culture Collection. RESULTS: Single-cell analysis revealed profound cellular heterogeneity within the HCC microenvironment, identifying six transcriptionally distinct macrophage subpopulations (M1-M6) with unique immunometabolic signatures. M2-like subsets were enriched in extracellular matrix organization and integrin-mediated signaling pathways, supporting their pro-fibrotic and immunosuppressive roles. Intercellular communication network analysis identified the SPP1-CD44/ITGAV signaling axis as a dominant pathway mediating macrophage-hepatocyte and macrophage-fibroblast interactions. APOA2 demonstrated differential expression between normal and tumor tissues, with its downregulation strongly correlated with promoter methylation (Spearman ρ = -0.31, P = 9.11 × 10). Although APOA2 showed limited diagnostic performance (AUC = 0.552), APOA2-low tumors exhibited trends toward poorer clinical outcomes across multiple survival metrics. Integration of metabolomic and transcriptomic data revealed associations between APOA2 silencing, altered serum metabolite profiles, and enhanced macrophage activation, establishing a metabolic-immune-epigenetic cascade that promotes tumor fibrogenesis and progression. qRT-PCR validation in HCC cell lines confirmed differential expression of Genes encoding core components of the SPP1-CD44/ITGAV signaling axis that regulate macrophage-tumor crosstalk and whose expression levels correlate with higher histological grade and increased metastatic risk in hepatocellular carcinoma in aggressive Huh7 cells (3.2-fold and 2.8-fold respectively, P < 0.001), while APOA2 was downregulated (0.35-fold, P < 0.001), corroborating bioinformatic predictions. CONCLUSION: This study unveils Macrophages that orchestrate the majority of intercellular signaling interactions in the HCC microenvironment orchestrating the immunometabolic landscape of HCC through the SPP1-integrin signaling network. The identification of functionally distinct macrophage subpopulations and the metabolic-immune-epigenetic axis involving APOA2 provides novel mechanistic insights into HCC pathogenesis and identifies genes and signaling axes whose pharmacological inhibition can reverse immunosuppression and block HCC progression for precision intervention strategies.
Deep learning for genomic insights into athletic performance in sports education.
Dong B, Lv Q
Front Genet · 2026 · PMID 42222603 · Full text
INTRODUCTION: This study proposes a deep learning based framework to investigate genomic factors influencing athletic performance in sports education. Traditional approaches often face challenges in modeling the high dim...
INTRODUCTION: This study proposes a deep learning based framework to investigate genomic factors influencing athletic performance in sports education. Traditional approaches often face challenges in modeling the high dimensionality and complex genotype phenotype relationships inherent in genomic data. METHODS: To address these issues, the proposed framework integrates three core components: a formalized problem formulation, a Genomic Athletic Predictor, and a Constrained Optimization Refinement mechanism with uncertainty aware prediction. The method models the genomic feature space and athletic performance metrics under manifold informed constraints, while explicitly incorporating uncertainty quantification to enhance reliability. The Genomic Athletic Predictor consists of a Manifold Informed Constraint Encoder, an Agent Driven Genomic Planner, and an Uncertainty Guided Athletic Forecaster, enabling structured representation learning and robust performance prediction. RESULTS AND DISCUSSION: Experimental evaluations conducted on two large scale cohort datasets demonstrate that the proposed framework consistently outperforms classical regression models, ensemble learning methods, and advanced neural network baselines. The model achieves superior results across multiple evaluation metrics, including Pearson correlation, RMSE, R, and MAE, while maintaining moderate computational complexity. Ablation studies further confirm the complementary contributions of manifold constraints and uncertainty modeling in improving predictive stability and biological plausibility. These findings highlight the effectiveness of integrating deep learning, domain constraints, and uncertainty aware modeling for genomic based athletic performance prediction, offering practical implications for personalized training, talent identification, and data driven optimization in sports education.
Retraction: Corrigendum: Cytokinins: a genetic target for increasing yield potential in the CRISPR era.
Frontiers Editorial Office
Front Genet · 2026 · PMID 42222602 · Full text
[This retracts the article DOI: 10.3389/fgene.2024.1360528.].
[This retracts the article DOI: 10.3389/fgene.2024.1360528.].
Retraction: Cytokinins: a genetic target for increasing yield potential in the CRISPR era.
Frontiers Editorial Office
Front Genet · 2026 · PMID 42222601 · Full text
[This retracts the article DOI: 10.3389/fgene.2022.883930.].
[This retracts the article DOI: 10.3389/fgene.2022.883930.].
m5C and m6A cooperatively stabilize EPHB4 to drive lymphatic metastasis in gastric cancer.
Zhang Y, He R, Lin X … +1 more , Ye J
Front Genet · 2026 · PMID 42222600 · Full text
BACKGROUND: Gastric cancer remains a major cause of cancer-related mortality worldwide, and lymph node metastasis is a major determinant of recurrence and poor prognosis. However, the molecular basis of lymphatic dissemi...
BACKGROUND: Gastric cancer remains a major cause of cancer-related mortality worldwide, and lymph node metastasis is a major determinant of recurrence and poor prognosis. However, the molecular basis of lymphatic dissemination, particularly the epitranscriptomic regulation of metastasis-related genes, remains unclear. We investigated whether RNA modifications promote gastric cancer lymphatic metastasis by regulating EPHB4, a receptor tyrosine kinase implicated in lymphangiogenesis and nodal spread. METHODS: We integrated transcriptome sequencing of gastric cancer tissues, bioinformatic database analyses, and immunohistochemical validation to identify EPHB4 as a metastasis-associated gene. gain- and loss-of-function assays and an hindfoot lymphatic metastasis mouse model were used to assess the role of EPHB4 in metastatic behavior. Mechanistic studies, including RNA stability assays, RIP, MeRIP-qPCR, dual-luciferase reporter assays, RIPiT, co-immunoprecipitation, and confocal microscopy, were performed to determine how NSUN2/YBX1-mediated mC regulation and IGF2BP1-associated mA recognition affect EPHB4 mRNA. RESULTS: Transcriptome sequencing identified EPHB4 as significantly upregulated in lymph node-positive gastric cancer. Database analyses and immunohistochemistry further supported the association of high EPHB4 expression with poor clinical outcome. Functionally, EPHB4 promoted lymphatic metastasis and enhanced migration and invasion of gastric cancer cells . Mechanistically, NSUN2, YBX1, and IGF2BP1 each increased EPHB4 expression by stabilizing its mRNA. NSUN2 deposited mC marks on EPHB4 transcripts that were recognized by YBX1, whereas IGF2BP1 preferentially bound mA-modified EPHB4 RNA and supported its stability. Mutational mapping and dual-luciferase assays identified functional mC- and mA-associated sites within EPHB4 mRNA. YBX1 and IGF2BP1 also physically interacted, co-occupied EPHB4 transcripts, and reciprocally enhanced m5C- and m6A-associated EPHB4 RNA enrichment. CONCLUSION: These findings reveal a cooperative epitranscriptomic mechanism in which NSUN2/YBX1-mediated mC signaling and IGF2BP1-associated mA recognition converge on EPHB4 mRNA to promote gastric cancer lymphatic metastasis, highlighting the NSUN2-YBX1-IGF2BP1-EPHB4 axis as a potential therapeutic target.
Tumor ecosystem subtyping of breast cancer based on somatic mutations and network propagation reveals distinct prognostic and genomic landscapes.
Ding K, Zhu Z, Huo Z … +4 more , Li H, Chen H, Wang S, Yang L
Front Genet · 2026 · PMID 42222599 · Full text
INTRODUCTION: Breast cancer is the most common malignancy in women worldwide, exhibiting high heterogeneity that complicates diagnosis, treatment, and prognosis. While somatic mutations stably reveal genetic characterist...
INTRODUCTION: Breast cancer is the most common malignancy in women worldwide, exhibiting high heterogeneity that complicates diagnosis, treatment, and prognosis. While somatic mutations stably reveal genetic characteristics of tumor cells, their application in breast cancer subtyping remains underexplored. METHODS: A total of 2,526 breast cancer patients from Memorial Sloan Kettering Cancer Center were classified into different tumor ecosystem subtypes (TESs) based on somatic mutation profiles using a network propagation algorithm. RESULTS: The prognosis of breast cancer patients in TES 1 was significantly better than that of those in TES 2. Immunological characterization further revealed that the tumor microenvironment contained significantly more tumor immune cells in TES 1 than in TES 2, and that TES 2 had lower response to immunotherapy but was more sensitive to chemotherapeutic agents. Moreover, our tumor ecosystem subtyping method effectively classified patients across 20 cancer cohorts with good generalization. CONCLUSION: This study proposes a stable, reproducible, and clinically applicable subtyping strategy based on somatic mutation data for tumor ecosystem subtyping, which can be used to guide personalized treatment for breast cancer patients and promote the development of precision medicine.
Overexpression of the gene enhances resistance against heat stress in cotton ( L.).
Iqbal S, Hafeez A, Shehzad S … +8 more , Bilal S, Imran M, Chang MS, Khan MN, Rasool G, Fang L, Zafar MM, Razzaq A
Front Genet · 2026 · PMID 42222598 · Full text
INTRODUCTION: Cotton is widely known as "white gold" due to its significant contribution to the global agricultural economy. Among the species, the allotetraploid cottons and are the most extensively cultivated due to...
INTRODUCTION: Cotton is widely known as "white gold" due to its significant contribution to the global agricultural economy. Among the species, the allotetraploid cottons and are the most extensively cultivated due to their superior fiber yield and quality. However, rapid climatic fluctuations have intensified abiotic stresses, posing serious challenges to cotton production. Of these stresses, elevated temperature has emerged as one of the most damaging factors affecting cotton growth and productivity. METHODS: In the current research, a genome-wide investigation of the filamentation temperature-sensitive H () gene family was conducted to identify stress-responsive candidates. This analysis highlighted as a promising gene of interest. The candidate gene was confirmed through polymerase chain reaction (PCR) and found on a 1% agarose gel. Subsequently, was successfully introduced in the cotton cultivar Ghauri genotype using an -mediated transformation approach. RESULTS: The observed transformation effectiveness as well as seed germination index were 1.89% and 71.42%, accordingly. Transcriptional profiling of the introduced gene was performed in the T0, T1, and T2 generations using quantitative real-time PCR, revealing consistently elevated expression levels. Compared with non-transgenic plants, transgenic cotton lines exhibited approximately 5.59-fold, 5.55-fold, and 5.45-fold increases in expression in the T0, T1, and T2 generations, respectively. DISCUSSION: Overall, the identification of family genes, followed by functional validation through genetic transformation, provides a valuable strategy for developing stress-resilient cotton cultivars and supports future efforts toward sustainable cotton production under adverse environmental conditions.
Clinical characterization and molecular analysis of X-linked juvenile retinoschisis in a northern Chinese cohort.
Sun H, Shi J, Wang J … +4 more , Yang S, Liu X, Jin P, Zheng Z
Front Genet · 2026 · PMID 42211025 · Full text
PURPOSE: This study aims to explore the clinical features and genetic findings associated with X-linked juvenile retinoschisis (XLRS) in affected patients. METHODS: This study included 16 patients with XLRS from 13 unrel...
PURPOSE: This study aims to explore the clinical features and genetic findings associated with X-linked juvenile retinoschisis (XLRS) in affected patients. METHODS: This study included 16 patients with XLRS from 13 unrelated families between 2016 and 2024. Genomic DNA from peripheral blood leukocytes of the probands were subjected to whole-exome sequencing or direct sequence. Comprehensive analyses of molecular genetic profiles and detailed ophthalmic evaluations were performed. RESULTS: We identified 12 retinoschisin 1 () variants, and five of them were novel. Missense variants (7/9, 75%) in the discoidin domain were the most common mutations. All 16 patients aged 4-45 years old were males, and the mean visual acuity was 0.58 ± 0.49 (Log MAR). The funduscopic observations were consistent with typical XLRS presentations. Notably, distinctive clustered pigmentation exhibited 75% penetrance (3/4 cases) in individuals harboring the novel Q43* mutation. Optical coherence tomography revealed macular schisis in 27 eyes (87.1%), peripheral schisis in six eyes (19.35%), and retinal atrophic changes in five eyes (16.13%). Schisis predominantly affected the inner nuclear layer (27/31, 87.10%). Additionally, other less common abnormalities included asymmetric schisis in patients with the R182C variant, presenting with schisis in one eye and a relatively normal fellow eye. Furthermore, two individuals with the Q43* nonsense mutation exhibited mild electroretinogram abnormalities with a preserved b-to-a amplitude ratio. Given these findings, larger multicenter studies are warranted to validate the observed associations. CONCLUSION: This study comprehensively analyzed the genetic and clinical features of XLRS in a northern Chinese cohort. Five novel variants were identified, expanding the known mutational spectrum and enriching the clinical manifestation. Distinct pigment clusters (Q43*) and asymmetric schisis (R182C) appeared consistently within our limited cohort carrying specific mutations, which may potentially facilitate the diagnosis of XLRS.
-associated congenital myopathy with tremor: further delineation of the clinical and pathological phenotype in the first Italian case.
Velardo D, Alberti C, Gagliardi D … +13 more , Del Bo R, Ciscato P, Napoli L, Zanotti S, Ripolone M, Croce MG, Cosentino G, Tumminello G, Locatelli M, Comi GP, Corti S, Ravaglia S, Ronchi D
Front Genet · 2026 · PMID 42211024 · Full text
The gene, mapping to chromosome 12q23.2, encodes the slow myosin binding protein-C (sMyBP-C), a sarcomeric accessory protein, expressed mainly in slow skeletal muscle fibers, that aids in the regulation of actomyosin cr...
The gene, mapping to chromosome 12q23.2, encodes the slow myosin binding protein-C (sMyBP-C), a sarcomeric accessory protein, expressed mainly in slow skeletal muscle fibers, that aids in the regulation of actomyosin cross-bridges and provides thick filament stability. Biallelic molecular defects in are associated with a lethal congenital form of myopathy (Lethal congenital contracture syndrome 4); meanwhile, heterozygous damaging variants lead to a form of distal arthrogryposis (distal arthrogryposis type 1B) and an early-onset congenital myopathy with tremor (congenital myopathy-16, CMYO16). To date, only 20 cases have been documented, all presenting a mild axial-proximal myopathy consistently coupled with a distinctive tremor phenotype. We report the case of a young Italian woman presenting with mild axial and proximal weakness, associated with a high-frequency postural tremor affecting the limbs and tongue, with apparent exacerbation of symptoms after hormonal stimulation. Laboratory tests showed normal creatine kinase levels. Electromyography revealed diffuse mild myopathic changes. Muscle MRI was substantially normal. Polygraphic tremor analysis confirmed the presence of a postural tremor at a frequency of 10-11 Hz. Muscle biopsy showed selective type 1 fiber hypotrophy. Clinical exome sequencing revealed the heterozygous c.788T>G p.(Leu263Arg) variant in exon 11 in the gene. This variant has been previously reported in multiple independent subjects displaying skeletal muscle weakness and myogenic tremor. Our case helps further define the phenotypic spectrum of this disorder, providing additional clinical and pathologically relevant insides, including the possible influence of hormonal stimulation and a detailed characterization of muscle biopsy findings. Knowledge of this myopathic phenotype may allow identification of individuals with variants without arthrogryposis.
miR-379-5p promotes ovarian granulosa cell apoptosis in primary ovarian insufficiency by targeting KNDC1 and PEG10.
Luo J, Zhang F, Feng Y … +4 more , You F, Yang D, Wu Z, Zeng L
Front Genet · 2026 · PMID 42205180 · Full text
BACKGROUND: Primary ovarian insufficiency (POI) is a heterogeneous disorder characterized by premature decline in ovarian function in women of reproductive age, yet its molecular mechanisms remain incompletely elucidated...
BACKGROUND: Primary ovarian insufficiency (POI) is a heterogeneous disorder characterized by premature decline in ovarian function in women of reproductive age, yet its molecular mechanisms remain incompletely elucidated. MicroRNAs (miRNAs), as crucial post-transcriptional regulators, may play a crucial role in the onset and progression of POI. Our research sought to elucidate the regulatory roles and mechanisms of key miRNAs and their target genes in ovarian granulosa cells (GCs) from POI patients. METHODS: Based on POI-related mRNA and miRNA microarray datasets obtained from GEO database, we employed bioinformatics methods to identify differentially expressed genes (DEGs) and performed functional enrichment analyses. The interactions between miRNAs and target genes were validated using dual-luciferase reporter assays. In POI cell models, following transfection with miRNA mimics or inhibitors using a lipid-based reagent, we assessed their effects on cell proliferation, apoptosis, and cell cycle progression using CCK-8 assays, flow cytometry, real-time quantitative PCR (qRT-PCR), and Western blotting. Finally, rescue experiments were conducted to further validate the underlying mechanism. RESULTS: This study identified 590 DEGs and 610 differentially expressed miRNAs (DEMs) from microarray datasets, which were primarily enriched in processes including cell cycle regulation, chromosome segregation, and tubulin binding. Notably, miR-379-5p was significantly upregulated in the POI group. Intersection analysis of DEGs and predicted miR-379-5p targets identified two key genes, Kinase Non-catalytic C-lobe Domain Containing 1 (KNDC1) and Paternally Expressed Gene 10 (PEG10). Experimental validation confirmed that miR-379-5p was highly expressed in the POI GCs and directly targeted and suppressed the expression of KNDC1 and PEG10. miR-379-5p mimics reduced cell viability, increased apoptosis, and induced G0/G1 phase arrest. Conversely, miR-379-5p inhibition or KNDC1/PEG10 overexpression reversed these phenotypic changes. CONCLUSION: This study revealed elevated miR-379-5p expression in POI GCs, which induced cell cycle arrest and apoptosis by suppressing the expression of KNDC1 and PEG10. These findings provide a theoretical basis for understanding POI pathogenesis and for developing targeted therapeutic strategies centered on miR-379-5p.
Identification of two genes associated with recurrence in Paget's disease and construction of a predictive model.
Chen Y, Chen Y, Wan Y … +5 more , Guo W, Huang B, Long Q, He Y, Cha P
Front Genet · 2026 · PMID 42205179 · Full text
BACKGROUND: Mammary Paget's disease (MPD) and extramammary Paget's disease (EMPD) exhibit distinct clinical behaviors, yet the underlying molecular drivers of prognosis remain poorly characterized. This study aimed to id...
BACKGROUND: Mammary Paget's disease (MPD) and extramammary Paget's disease (EMPD) exhibit distinct clinical behaviors, yet the underlying molecular drivers of prognosis remain poorly characterized. This study aimed to identify key prognostic genes and construct a predictive model for Paget's disease (PD). METHODS: RNA sequencing was performed on MPD and EMPD tissues. Hub genes were screened using weighted gene co-expression network analysis (WGCNA). Their prognostic value was validated via time dependent receiver operating characteristic (ROC) curves, Kaplan-Meier survival analysis, and Decision curve analysis (DCA) in internal and external cohorts. A risk-score model was subsequently developed based on the identified genes. RESULTS: RNA-seq analysis revealed distinct functional profiles between MPD and EMPD, with recurrence in MPD associated with developmental and differentiation pathways, while EMPD recurrence was linked to immune and inflammatory processes. WGCNA identified KLF13 and TIA1 as hub genes. In the internal cohort, both genes were significantly overexpressed in patients with recurrence (KLF13: 22.74 ± 3.41 vs. 15.36 ± 4.91, P < 0.001; TIA1: 11.69 ± 2.48 vs. 7.74 ± 1.62, P < 0.001). And the KLF13 and TIA1 were also validated by qPCR in the internal cohort. The genes also demonstrated prognostic validity in an independent Chinese PD cohort. A risk-score model incorporating KLF13 and TIA1 effectively stratified patients into high- and low-risk groups with distinct outcomes in both internal and external validation sets. Moreover, we knocked down TIA1 expression in MDA-MB-231 cells, and both and results demonstrated that TIA1 functions as an oncogene. CONCLUSION: KLF13 and TIA1 are robust prognostic biomarkers in PD. The developed risk-score model provides a valuable tool for predicting recurrence and personalizing patient management. In addition, both and findings confirmed that TIA1 functions as an oncogene.
Multivariate GWAS reveals shared genetic basis of common oral diseases.
Ma X, Zheng X
Front Genet · 2026 · PMID 42205178 · Full text
BACKGROUND: Oral diseases, including dental caries, periodontitis, pulpitis, and temporomandibular disorders (TMD), impose a substantial global burden affecting billions of individuals and costing an estimated USD 390 bi...
BACKGROUND: Oral diseases, including dental caries, periodontitis, pulpitis, and temporomandibular disorders (TMD), impose a substantial global burden affecting billions of individuals and costing an estimated USD 390 billion annually. Despite their frequent clinical co-occurrence, the extent to which these conditions share a common genetic basis remains unclear. METHODS: We analyzed genome-wide association study (GWAS) summary statistics from up to 500,000 Finnish participants. Genome-wide and regional genetic correlations were quantified using High-Definition Likelihood. Genomic Structural Equation Modelling was applied to identify a latent common oral genetic factor (COF). A multivariate GWAS of the COF was conducted, followed by SuSiE fine-mapping. Integrative gene and pathway analyses were performed using cTWAS and MAGMA, and spatial mapping was conducted using embryonic tooth-germ atlases. RESULTS: We identified extensive shared heritability across all four oral diseases. A latent COF captured the majority of this genetic overlap. Multivariate GWAS of the COF identified 104 genome-wide significant single-nucleotide polymorphisms aggregated into 96 independent loci, which were largely novel compared to single-trait analyses. Fine-mapping refined these to 53 high-confidence causal variants enriched in immune-regulatory and odontogenic pathways. CPSF1 and SLC20A2 emerged as top-ranked genes, with tissue-specific effects mapped to coronary artery and cultured fibroblasts, respectively. Spatial projection localized genetic risk to follicular and mesenchymal compartments, consistent with developmental tissue differentiation patterns. CONCLUSION: These findings reveal a shared and developmentally rooted genetic architecture underlying common oral diseases. The results highlight convergent molecular mechanisms and provide a foundation for precision-based, integrated prevention strategies that move beyond traditional single-disease frameworks.
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