Genes

15 pages, 5177 KB

Open AccessArticle

Genome-Wide Identification of the DFR Gene Family in Lonicera japonica Thunb. and Response to Drought and Salt Stress

by Dandan Lu, Xiaoyu Su, Yao Sun, Lei Li, Yongliang Yu, Chunming Li, Yiwen Cao, Lina Wang, Meiyu Qiao, Hongqi Yang, Mengfan Su, Zhengwei Tan and Huizhen Liang

Genes 2025, 16(12), 1453; https://doi.org/10.3390/genes16121453 - 4 Dec 2025

Abstract

Background: Dihydroflavonol 4-reductase (DFR) is pivotal for anthocyanin biosynthesis and plays a crucial role in plant development and stress adaptation. However, a systematic characterization of the DFR gene family is lacking in Lonicera japonica Thunb. Methods: In the present study, based on genome [...] Read more.

Background: Dihydroflavonol 4-reductase (DFR) is pivotal for anthocyanin biosynthesis and plays a crucial role in plant development and stress adaptation. However, a systematic characterization of the DFR gene family is lacking in Lonicera japonica Thunb. Methods: In the present study, based on genome and transcriptome data of L. japonica, the research identified six LjDFR gene family members throughout the entire genome. Results: The LjDFR genes were located on Chr.04 and Chr.09 and the full-length coding sequences of LjDFR1-LjDFR6 were cloned. Subcellular localization analysis showed that LjDFRs are primarily found at the cell membrane and in the nucleus. Phylogenetic analysis showed closer clustering of LjDFR genes with Capsicum annuum and Camellia sinensis. Promoter analysis linked LjDFR genes to light response, hormone signaling, and stress-responses. qRT-PCR analysis demonstrated tissue-specific and stage-specific expression patterns among LjDFR members. Notably, LjDFR2 expression was significantly higher in the intensely pigmented tissues of Lonicera japonica Thunb. var. chinensis (Wats.) Bak. compared to L. japonica. Coupled with its phylogenetic proximity to the anthocyanin-related CsDFRa and CaDFR5 genes, this suggests that LjDFR2 may be positively correlated with anthocyanin accumulation. Additionally, the expression of LjDFR2 and LjDFR4 was markedly induced by both drought and salt stress, indicating their roles in abiotic stress responses. Conclusions: This research provides a foundation for further functional studies of LjDFR genes in anthocyanin biosynthesis and stress resistance and offers candidate genes for molecular breeding of L. japonica. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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15 pages, 2768 KB

Open AccessArticle

Expression and Regulation of FGF9 Gene in Chicken Ovarian Follicles and Its Genetic Effect on Laying Traits in Hens

by Yue Wang, Xinmei Shu, Yuanyuan Guo, Qingqing Wei and Yunliang Jiang

Genes 2025, 16(12), 1452; https://doi.org/10.3390/genes16121452 - 4 Dec 2025

Abstract

Objectives: Fibroblast growth factor 9 (FGF9), a crucial member of the FGF family, functions as an intercellular signaling molecule involved in angiogenesis, embryogenesis, and tissue repair. Our previous study demonstrated that FGF9 expression in chicken hierarchical granulosa cells (Post-GCs) is regulated by LSD1 [...] Read more.

Objectives: Fibroblast growth factor 9 (FGF9), a crucial member of the FGF family, functions as an intercellular signaling molecule involved in angiogenesis, embryogenesis, and tissue repair. Our previous study demonstrated that FGF9 expression in chicken hierarchical granulosa cells (Post-GCs) is regulated by LSD1 Ser54 phosphorylation and that FGF9 promotes cell proliferation. This study aims to analyze the expression and regulation of the FGF9 gene in chicken ovarian follicles and its genetic effect on laying traits in hens. Methods: Chicken FGF9 mRNA expression patterns were examined by real-time quantitative PCR (RT-qPCR). Detection of single nucleotide polymorphisms (SNPs) was performed using PCR amplification and Sanger sequencing. Transcription activity was compared using dual-luciferase reporter assay. Results: Following follicle selection, chicken FGF9 expression significantly decreased in granulosa cells (p < 0.05) while it increased in theca cells (p < 0.05). Hormonal treatments revealed differential regulation; estradiol and FSH downregulated FGF9 in both pre-hierarchical and hierarchical granulosa cells (p < 0.05), whereas progesterone exhibited opposing effects, suppressing expression in pre-hierarchical granulosa cells (Pre-GCs) but stimulating its expression in Post-GCs (p < 0.05). In theca cells, estradiol consistently inhibited FGF9 expression (p < 0.05), while FSH only affected FGF9 expression in pre-hierarchical follicles. Six SNPs in the promoter region (g.−1965G>A, g.−2177G>A, g.−2289G>A, g.−3669A>G, g.−3770A>G, g.−3906G>A) were identified, five of which (g.−1965G>A, g.−2177G>A, g.−2289G>A, g.−3669A>G, g.−3906G>A) showed significant associations with egg production traits. Notably, alleles A (g.−2289), G (g.−3669), and A (g.−3906) enhanced the transcription activity of chicken FGF9 in Pre-GCs. Conclusions: These findings provide novel insights into the expression pattern and regulatory mechanisms of chicken FGF9 during follicular development and identify some genetic markers for egg-laying traits in chickens. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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18 pages, 5482 KB

Open AccessArticle

Genome-Wide Identification of the AMT Gene Family in Wheat: Expression Profiles Under Ammonium Nutrition and Pathogen Effects

by Yanzhen Wang, Jialu Li, Xia Liu, Rui Huang, Menglin Lei, Yaoyuan Zhang and Guoqing Cui

Genes 2025, 16(12), 1451; https://doi.org/10.3390/genes16121451 - 4 Dec 2025

Abstract

Background: Ammonium nitrogen (NH₄⁺) serves as a vital nitrogen source, playing pivotal regulatory roles in plant growth, development, and high-yield formation. Ammonium transporters (AMTs), encoded by the AMT gene family, are central to NH₄⁺ transport. However, the [...] Read more.

Background: Ammonium nitrogen (NH₄⁺) serves as a vital nitrogen source, playing pivotal regulatory roles in plant growth, development, and high-yield formation. Ammonium transporters (AMTs), encoded by the AMT gene family, are central to NH₄⁺ transport. However, the functional roles of AMT genes in wheat remain poorly understood. Methods: A comprehensive genome-wide analysis of the TaAMT gene family numbers was conducted, encompassing investigations into gene structure, protein motif composition, gene duplication events, collinearity relationships, and cis-acting regulatory elements. Furthermore, the expression patterns of distinct TaAMT members were examined under varying ammonium supply conditions and pathogen stress. Results: In this study, a total of 21 TaAMT members were identified. Additionally, all TaAMT proteins were localized to the plasma membrane. Phylogenetic analysis clustered these genes into four distinct subgroups. Comparative analyses of gene structure and conserved motifs revealed conserved domain composition and motif organization within each subgroup. Interspecific synteny analysis highlighted evolutionary conservation across species. Promoter region analysis identified multiple cis-regulatory elements associated with hormone signaling, light responsiveness, and abiotic stress adaptation. Expression profiling demonstrated that TaAMT members exhibit both tissue-specific and constitutive expression patterns across developmental stages. RT-qPCR further revealed that the expression of TaAMT members responds to varying concentrations of ammonium nitrogen supply, as well as infection stresses caused by stripe rust and powdery mildew. Conclusions: Collectively, this study uncovered the functional diversity of TaAMT members, offering novel molecular targets and theoretical foundations for breeding wheat varieties with enhanced nitrogen use efficiency and disease resistance. Full article

(This article belongs to the Section Bioinformatics)

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15 pages, 2411 KB

Open AccessArticle

Hepcidin from the Chinese Spiny Frog (Quasipaa spinosa) Integrates Membrane-Disruptive Antibacterial Activity with Macrophage-Mediated Protection Against Elizabethkingia miricola

by Fen Qiao, Xin-Yi Qian, Yi-Kai Feng and Jie Chen

Genes 2025, 16(12), 1450; https://doi.org/10.3390/genes16121450 - 4 Dec 2025

Abstract

Background/Objectives: Hepcidin is a cysteine-rich antimicrobial peptide that links iron homeostasis and innate immunity in vertebrates, but its functions in amphibians remain poorly understood. The Chinese spiny frog (Quasipaa spinosa) is an economically important species that suffers serious losses from [...] Read more.

Background/Objectives: Hepcidin is a cysteine-rich antimicrobial peptide that links iron homeostasis and innate immunity in vertebrates, but its functions in amphibians remain poorly understood. The Chinese spiny frog (Quasipaa spinosa) is an economically important species that suffers serious losses from bacterial diseases. This study aimed to identify and functionally characterize a hepcidin homolog (QsHep) from Q. spinosa, focusing on its antibacterial activity, immunomodulatory effects on primary macrophages, and protective efficacy against Elizabethkingia miricola infection. Methods: The QsHep gene was cloned and analyzed, its tissue distribution and inducible expression were examined by qRT-PCR, and the synthetic peptide was tested for antimicrobial, membrane-disruptive, and immunomodulatory activities in vitro, as well as for in vivo protection in an E. miricola infection model. Results: QsHep encodes a typical preprohepcidin with a signal peptide, prodomain, and a conserved mature peptide containing eight cysteine residues. QsHep was widely expressed, with the highest levels in liver, and was significantly upregulated in liver and spleen following bacterial challenge. Synthetic QsHep displayed broad-spectrum antibacterial activity, including strong inhibition of E. miricola, and induced dose-dependent membrane damage in E. miricola. QsHep showed no obvious cytotoxicity but significantly enhanced chemotaxis, phagocytic activity, and respiratory burst in primary macrophages. In vivo, QsHep treatment markedly improved the survival of E. miricola-infected frogs in a dose-dependent manner. Conclusions: QsHep is an amphibian hepcidin that combines membrane-disruptive antibacterial activity with the activation of macrophage effector functions and confers significant protection against bacterial infection in vivo. These findings expand our understanding of hepcidin-mediated innate immunity in amphibians and highlight QsHep as a promising peptide candidate for controlling bacterial diseases in frog aquaculture. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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18 pages, 2769 KB

Open AccessArticle

Genetic Diversity of Rhodiola quadrifida (Crassulaceae) in Altai High-Mountain Populations of Kazakhstan

by Oxana Khapilina, Ainur Turzhanova, Moldir Zhumagul, Saule Magzumova, Olesya Raiser, Damelya Tagimanova, Serik Kubentayev and Vladislav Shevtsov

Genes 2025, 16(12), 1449; https://doi.org/10.3390/genes16121449 - 3 Dec 2025

Abstract

Background: Rhodiola quadrifida (Pall.) Fisch. & C.A. Mey. (Crassulaceae) is a rare medicinal species in the Kazakh Altai, yet information on its population structure and genetic diversity remains limited. This study presents findings from an investigation of natural R. quadrifida populations. Methods: [...] Read more.

Background: Rhodiola quadrifida (Pall.) Fisch. & C.A. Mey. (Crassulaceae) is a rare medicinal species in the Kazakh Altai, yet information on its population structure and genetic diversity remains limited. This study presents findings from an investigation of natural R. quadrifida populations. Methods: The morphometric characteristics, population age structure, and genetic diversity of the plants were analysed using PCR-based genome profiling. Genetic diversity within R. quadrifida populations was assessed using PCR primers for binding sites complementary to a specific region at the 3′ terminus of a particular tRNA. Results: The populations exhibited variations in morphological traits, age structures, and reproductive strategies. The IVA-1, IVA-2 and KOK populations represent the most mature stages, characterized by a dominance of vegetative reproduction and a disturbed age structure, with a predominance of senile and virgin individuals. In contrast, the LIN-1 and LIN-2 population is characterized by a balanced age structure, encompassing all ontogenetic groups, and a mixed reproductive system that includes both sexual and vegetative propagation. Genetic diversity, as measured by Shannon’s information index, ranged from 0.194 to 0.247, indicating low genetic diversity in R. quadrifida. Analysis of molecular variance (AMOVA) revealed significantly greater variation within populations (62%) than among populations (38%). Genetic diversity was higher in the LIN-1 and LIN-2 populations, which employs a mixed reproductive system (clonal and seeds), than in populations dominated by vegetative reproduction. Both LIN populations, characterized by a mixed reproductive system, exhibited higher genetic diversity than the KOK, IVA-1 and IVA-2 populations, where vegetative reproduction predominated. Conclusions: These results underscore the necessity for priority conservation measures, including monitoring population size and age structure in populations with low levels of seed reproduction and disturbed age structure. Additional measures include supporting in situ and ex situ conservation, such as clonal collection, seed banks, and tissue cultures, as well as restricting the harvesting of medicinal raw materials. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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22 pages, 1034 KB

Open AccessReview

The Utility of Genome-Wide Association Studies in Inherited Arrhythmias and Cardiomyopathies

by Saif Dababneh, Arya Ardehali, Jasleen Badesha and Zachary Laksman

Genes 2025, 16(12), 1448; https://doi.org/10.3390/genes16121448 - 3 Dec 2025

Abstract

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given [...] Read more.

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as SCN5A for Brugada syndrome, and MYH7 and MYBPC3 for hypertrophic cardiomyopathy, which have revolutionized diagnosis, risk stratification, and medical management. Nonetheless, issues such as variable expressivity and penetrance, low yield of genetic testing, and relative lack of disease-modifying therapies remain significant hurdles for clinical management. The revolution of genome-wide association studies GWASs has transformed our understanding of inherited arrhythmias and cardiomyopathies, shifting the view of these disorders from a monogenic Mendelian inheritance towards a more complex, often polygenic inheritance with nuanced interplay between genetics and environment. Moreover, GWASs have enabled the quantification of polygenic predisposition to disease using polygenic risk scores, which are often complementary to and independent of monogenic risk. In this review, we highlight how GWASs have transformed the field of inherited arrhythmias and cardiomyopathies, with a particular focus on the polygenic risk scores developed and their clinical utility for the four disorders which have been impacted by GWASs—hypertrophic cardiomyopathy, dilated cardiomyopathy, Brugada syndrome, and long QT syndrome. Full article

(This article belongs to the Special Issue Application of Genome-Wide Association Studies in Rare Diseases Research)

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40 pages, 1000 KB

Open AccessReview

Addiction Susceptibility: Genetic Factors, Personality Traits, and Epigenetic Interactions with the Gut Microbiome

by Alejandro Borrego-Ruiz and Juan J. Borrego

Genes 2025, 16(12), 1447; https://doi.org/10.3390/genes16121447 - 3 Dec 2025

Abstract

Despite valuable insights into the individual roles of genetic factors and personality traits, their combined contribution to addiction susceptibility remains insufficiently characterized. Within this framework, the potential influence of epigenetic mechanisms, particularly those mediated by the gut microbiome, also remains underexplored. This comprehensive [...] Read more.

Despite valuable insights into the individual roles of genetic factors and personality traits, their combined contribution to addiction susceptibility remains insufficiently characterized. Within this framework, the potential influence of epigenetic mechanisms, particularly those mediated by the gut microbiome, also remains underexplored. This comprehensive review aims to address these gaps in an integrative manner by examining: (i) the association of gene regulation with personality traits; (ii) the genetics of substance use disorders; (iii) the roles of genes and personality in addiction; and (iv) epigenetic influences on addiction, with a particular focus on the role of the gut microbiome. Genetic influences on personality act primarily via regulatory variants that modulate gene expression during neurodevelopment, shaping cognitive, emotional, and behavioral traits that contribute to individual differences. Substance use disorders share partially overlapping genetic foundations, with specific loci, heritability estimates, and causal pathways differing across substances, reflecting both shared vulnerability and substance-specific genetic influences on addiction susceptibility. Impulsivity, novelty-seeking, and stress responsiveness are heritable personality traits that interact to shape susceptibility to substance use disorders, with genetic factors modulating risk across different forms of addiction. Environmental factors, early-life stress, and social influences interact with the gut microbiome to shape neurobiological and behavioral pathways that modulate addiction risk. These interactions highlight the multifactorial nature of substance use disorders, in which epigenetic, microbial, and psychosocial mechanisms converge to influence susceptibility, progression, and maintenance of addictive behaviors. Full article

(This article belongs to the Section Neurogenomics)

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14 pages, 1555 KB

Open AccessArticle

Bridging East and West: Real-World Clinicogenomic Landscape of Metastatic NSCLC in Türkiye

by Kübra Canaslan, Emre Eken, Mehmet Bilici, Fahriye Merve Balcıoğlu, Banu Öztürk, Mehmet Çakmak, Öznur Bal, Görkem Turhan, Feyyaz Özdemir, Hayati Arvas, Zuhat Urakçı, Ebru Çiçek, Zeynep Hande Turna and Aziz Karaoğlu

Genes 2025, 16(12), 1446; https://doi.org/10.3390/genes16121446 - 3 Dec 2025

Abstract

Background/Objectives: Genomic profiling guides treatment in metastatic non-small-cell lung cancer (mNSCLC), yet country-level data from Türkiye remain limited. Methods: We retrospectively analyzed consecutive patients with mNSCLC diagnosed between January 2018 and March 2025 across tertiary centers in all seven regions. Variables included demographics, [...] Read more.

Background/Objectives: Genomic profiling guides treatment in metastatic non-small-cell lung cancer (mNSCLC), yet country-level data from Türkiye remain limited. Methods: We retrospectively analyzed consecutive patients with mNSCLC diagnosed between January 2018 and March 2025 across tertiary centers in all seven regions. Variables included demographics, smoking, histology, testing modality (single-gene vs. next-generation sequencing [NGS]), targetable genomic alterations (TGAs) and co-mutations, and programmed death-ligand 1 (PD-L1) tumor proportion score. Results: Among 1023 patients (mean age 64 years; 76.4% male), tobacco exposure was frequent (mean 42.1 pack-years); 16.9% were never-smokers. NGS use increased over time, exceeding 90% by 2025. TGAs were detected in 28.3% (EGFR 16.0%, ALK 5.0%, KRAS G12C 2.6%, BRAF V600E 3.2%; ROS1, MET exon 14, HER2, NTRK ≤ 2.5%; no RET). EGFR alterations occurred in 19% of non-squamous carcinomas and 6% of squamous cell carcinomas (SCCs), suggesting an intermediate East–West pattern. Among NGS-tested samples, TP53 was the most frequent co-mutation (33.1%), followed by alterations in CDKN2A, PIK3CA, FGFR, STK11, and KEAP1. Conclusions: In this large, multicenter Turkish real-world cohort, the TGA spectrum broadly mirrors global patterns while revealing local nuances; EGFR mutations were more frequent than expected in SCC, and nationwide NGS adoption is accelerating. Limitations include retrospective design, non-centralized PD-L1 testing, and missing data. Prospective, standardized studies integrating outcomes and resistance mechanisms are warranted to refine regional precision oncology. Full article

(This article belongs to the Special Issue Genetics and Genomics of Lung Cancer)

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20 pages, 4134 KB

Open AccessArticle

TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation

by Nurgul Sikhayeva, Svetlana Volodchenko, Elena Kovzel, Aiganym Toleuzhanova, Aliya Romanova, Gulnar Tortayeva, Yelena Sagandykova, Marina Morenko, Aidos Bolatov and Ilyas Akhmetollayev

Genes 2025, 16(12), 1445; https://doi.org/10.3390/genes16121445 - 2 Dec 2025

Abstract

Background/Objectives: Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections. Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where [...] Read more.

Background/Objectives: Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections. Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted. We present a pediatric case from Kazakhstan to broaden the clinical and molecular spectrum of TYK2-related immunodeficiency and accentuate diagnostic challenges. Methods: The proband underwent clinical assessment, immunophenotyping, and biochemical analysis during episodes of active pathology and subsequent follow-up. Whole-exome sequencing (WES) was executed, followed by confirmatory Sanger sequencing and segregation analysis in first-degree kin. Functional assays for phagocyte oxidative burst and phagocytosis were conducted to exclude CGD. Results: WES identified two rare TYK2 variants (c.209_212del, pathogenic; c.2395G>A, previously reported as pathogenic in a Chinese patient with TYK2 deficiency) and a heterozygous MEFV duplication (c.761_764dup). Paternal DNA was unavailable; therefore, allelic phase could not be formally established, but the combined genotype and phenotype are consistent with autosomal recessive TYK2 deficiency. Sanger sequencing confirmed segregation of the frameshift TYK2 variant in the mother, while the clinically healthy brother carried only the wild-type allele. The missense alteration was exclusive to the proband. Conclusions: This case exemplifies the significance of contemplating TYK2 deficiency in pediatric patients with refractory mycobacterial infections, particularly in BCG-endemic locales. Genetic validation provided a definitive diagnosis, differentiating the condition from CGD and informing patient management. To our knowledge, this constitutes one of the inaugural genetically confirmed instances of TYK2 deficiency in Central Asia, enhancing regional epidemiological comprehension and emphasizing the role of molecular diagnostics in directing treatment and vaccination policies. Full article

(This article belongs to the Special Issue Genetics and Genomics of Heritable Pediatric Disorders)

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31 pages, 2851 KB

Open AccessReview

Genetic, Clinical and Neuroradiological Spectrum of MED-Related Disorders: An Updated Review

by Alessandro Fazio, Roberta Leonardi, Lorenzo Aliotta, Manuela Lo Bianco, Gennaro Anastasio, Giuseppe Messina, Corrado Spatola, Pietro Valerio Foti, Stefano Palmucci, Antonio Basile, Martino Ruggieri and Emanuele David

Genes 2025, 16(12), 1444; https://doi.org/10.3390/genes16121444 - 2 Dec 2025

Abstract

Background/Objectives: The Mediator (MED) complex is an essential regulator of RNA polymerase II transcription. There is increasing evidence that pathogenic variants in several MED subunits are the cause of neurodegenerative and neurodevelopmental phenotypes, collectively referred to as “MEDopathies”. This review aims to summarize [...] Read more.

Background/Objectives: The Mediator (MED) complex is an essential regulator of RNA polymerase II transcription. There is increasing evidence that pathogenic variants in several MED subunits are the cause of neurodegenerative and neurodevelopmental phenotypes, collectively referred to as “MEDopathies”. This review aims to summarize current knowledge on the genetic basis, clinical manifestations, and neuroradiological features of MED-related disorders. Methods: We undertook a narrative synthesis of the literature focusing on the MED subunits most commonly associated with neurological disorders, including MED1, MED8, MED11, MED12/MED12L, MED13/MED13L, MED14, MED17, MED20, MED23, MED25, MED27, and CDK8. Sources included peer-reviewed genetic, clinical, and imaging studies, supplemented by relevant case reports and cohort analyses. In addition, representative facial phenotypes associated with selected MED variants (MED11, MED12, MED13, MED13L, MED25) were visualized for educational purposes using artificial intelligence-based image generation derived from standardized clinical descriptors. Results: All MEDopathies show converging clinical patterns: global developmental delay/intellectual disability, hypotonia, epilepsy, speech disorders, and behavioral comorbidity. Non-neurological involvement, such as craniofacial or cardiac anomalies, is subunit-specific. Neuroradiological features include callosal abnormalities (agenesis, thinning, dysmorphia), delayed or hypomyelination, progressive cerebral and cerebellar atrophy, basal ganglia signaling changes, pontine hypoplasia, and, in MED27 deficiency, a “hot cross bun” sign. Gene-specific constellations emphasize catastrophic infantile progression (MED11), X-linked syndromes with callosal defects (MED12/MED12L), language-dominant phenotypes (MED13), and syndromic intellectual disability with systemic features (MED13L). Conclusions: The growing spectrum of MEDopathies argues for their recognition as a unified nosological group with overlapping clinical and radiological signatures. Characteristic MRI constellations may serve as diagnostic clues and guide targeted molecular testing. Future directions include longitudinal imaging to describe disease progression and the integration of genomic data with curated clinical radiological datasets to refine genotype-phenotype correlations. Full article

(This article belongs to the Collection Study on Genotypes and Phenotypes of Pediatric Clinical Rare Diseases)

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20 pages, 888 KB

Open AccessReview

Role of Genetic and Epigenetic Biomarkers in Treatment-Resistant Depression: A Literature Review

by Petra Sulić, Andrea Ražić Pavičić, Biljana Đapić Ivančić, Tamara Božina, Nada Božina and Maja Živković

Genes 2025, 16(12), 1443; https://doi.org/10.3390/genes16121443 - 2 Dec 2025

Abstract

Background: Treatment-resistant depression (TRD) affects up to 30–40% of patients with major depressive disorder and remains a major therapeutic challenge. Genetic and epigenetic factors are increasingly recognized as key contributors to both vulnerability and treatment response. Methods: We conducted a narrative review of [...] Read more.

Background: Treatment-resistant depression (TRD) affects up to 30–40% of patients with major depressive disorder and remains a major therapeutic challenge. Genetic and epigenetic factors are increasingly recognized as key contributors to both vulnerability and treatment response. Methods: We conducted a narrative review of studies published between 2021 and 2025, focusing exclusively on DNA- and RNA-based biomarkers of TRD. Twelve studies met the inclusion criteria, covering candidate gene analyses, genome-wide association studies (GWAS), neuroimaging–genetic approaches, and microRNA profiling. Results: Genetic investigations consistently implicate neuroplasticity-related genes (BDNF, NTRK2, PTEN, SYN1, MAPK1, and GSK3B) in the risk of TRD and its relapse. Variants in glutamatergic receptor genes (GRIN2A, GRIN2B, GRIA2, GRIA3) were predicted to result in a rapid and sustained response to ketamine. Genomic approaches further demonstrated that composite genetic panels outperform single-variant predictors. In parallel, microRNAs such as miR-1202, miR-16, miR-135, miR-124, miR-223, and miR-146a emerged as dynamic biomarkers of treatment response, particularly in cohorts treated with ketamine or electroconvulsive therapy. Conclusions: DNA- and RNA-based biomarkers provide promising avenues for improving the understanding and management of TRD. Their integration into clinical frameworks could support patient stratification, individualized treatment selection, and real-time monitoring of therapeutic efficacy. Future research should prioritize replication, methodological harmonization, and longitudinal validation to facilitate the translation of findings into precision psychiatry. Full article

(This article belongs to the Special Issue Psychiatric Pharmacogenomics)

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28 pages, 1621 KB

Open AccessReview

From Metabolic to Epigenetic Memory: The Impact of Hyperglycemia-Induced Epigenetic Signature on Kidney Disease Progression and Complications

by Sara Cannito, Ida Giardino, Maria D’Apolito, Alessandra Ranaldi, Francesca Scaltrito, Massimo Pettoello-Mantovani and Annamaria Piscazzi

Genes 2025, 16(12), 1442; https://doi.org/10.3390/genes16121442 - 2 Dec 2025

Abstract

Chronic kidney disease is a significant global health burden and a leading cause of cardiovascular morbidity and mortality. Diabetes mellitus is the primary cause of kidney disease, driving the progression of both micro- and macrovascular complications. Sustained hyperglycemia initiates a cascade of deleterious [...] Read more.

Chronic kidney disease is a significant global health burden and a leading cause of cardiovascular morbidity and mortality. Diabetes mellitus is the primary cause of kidney disease, driving the progression of both micro- and macrovascular complications. Sustained hyperglycemia initiates a cascade of deleterious molecular and cellular events, including mitochondrial dysfunction, inflammation, oxidative stress, and dysregulated apoptosis and autophagy, which collectively contribute to the progression of renal injury. Beyond these well-established mechanisms, a compelling body of evidence highlights the pivotal role of epigenetic alterations (such as DNA methylation, histone post-translational modifications, and non-coding RNAs) in mediated long-term kidney damage. The interplay between transcriptional and epigenetic regulation underlies the phenomenon of the “metabolic memory”, wherein cellular dysfunction persists even after glycemic control is achieved. This review synthesizes the current knowledge on mechanisms sustaining metabolic and epigenetic memory, with a particular focus on the epigenetic machinery that establishes and maintains these signals, a concept increasingly termed “epigenetic memory.” Given their reversible nature, epigenetic determinants are emerging as promising biomarkers and a compelling therapeutic avenue. Targeting these “epifactors” offers a novel strategy to halt progression to end-stage renal disease, thereby paving the way for precision medicine approaches in diabetes-related renal disease. Full article

(This article belongs to the Section Epigenomics)

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13 pages, 1306 KB

Open AccessReview

Plant-Derived miRNAs as Potential Cross-Kingdom Cancer Regulators

by Aizhan Rakhmetullina, Zuzanna Lubas and Piotr Zielenkiewicz

Genes 2025, 16(12), 1441; https://doi.org/10.3390/genes16121441 - 2 Dec 2025

Abstract

MicroRNAs (miRNAs) are key posttranscriptional regulators of gene expression that influence cancer initiation, progression, and therapeutic response. While most studies have focused on endogenous miRNAs, emerging evidence has highlighted the role of plant-derived miRNAs as exogenous dietary regulators capable of cross-kingdom gene modulation. [...] Read more.

MicroRNAs (miRNAs) are key posttranscriptional regulators of gene expression that influence cancer initiation, progression, and therapeutic response. While most studies have focused on endogenous miRNAs, emerging evidence has highlighted the role of plant-derived miRNAs as exogenous dietary regulators capable of cross-kingdom gene modulation. This review summarises current knowledge regarding plant-derived miRNAs and their ability to regulate human cancer-related genes. Experimental findings indicate that plant miRNAs can withstand gastrointestinal digestion, enter the circulation, and regulate the expression of oncogenes, tumour suppressors, long noncoding RNAs, and immune checkpoint molecules via canonical RNA-induced silencing mechanisms. Specific examples include miR-156a, miR-159a-3p, miR-166a, miR-167e-5p, miR-171, miR-395e, miR-2911, miR-4995 and miR-5754, which exhibit anticancer activities across various cancer types and modulate key signalling pathways in mammalian cells, highlighting their potential as cross-kingdom regulators with therapeutic relevance. In addition to these characterised miRNAs, certain plant groups, which are rich in bioactive compounds, remain unexplored as sources of functional miRNAs, representing a promising avenue for future research. Collectively, these studies underscore the ability of plant-derived miRNAs to modulate mammalian gene expression and suggest their potential as diet-based or synthetic therapeutic agents. Further investigations into their bioavailability, target specificity, and functional relevance could inform innovative strategies for cancer prevention, integrating nutritional, molecular biological, and therapeutic approaches. Full article

(This article belongs to the Special Issue Function and Regulatory Mechanism of MicroRNAs in Cancers)

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12 pages, 378 KB

Open AccessArticle

Host Immunogenetics and Chronic HCV Infection Shape Atopic Risk in Pediatric Beta-Thalassemia: A Genotype–Phenotype Study

by Caterina Cuppari, Alessio Mancuso, Laura Colavita, Clelia Cusmano, Valeria Tallarico, Valerio Caruso, Roberto Chimenz, Mimma Caloiero, Mariarosa Calafiore, Antonina La Mazza and Luciana Rigoli

Genes 2025, 16(12), 1440; https://doi.org/10.3390/genes16121440 - 2 Dec 2025

Abstract

Background: Pediatric patients with beta-thalassemia (BT) face unique immunologic challenges due to chronic transfusions and viral exposure. Hepatitis C virus (HCV), a common infection in polytransfused individuals, may influence immune polarization. However, the combined effect of chronic HCV and host immunogenetics on allergic [...] Read more.

Background: Pediatric patients with beta-thalassemia (BT) face unique immunologic challenges due to chronic transfusions and viral exposure. Hepatitis C virus (HCV), a common infection in polytransfused individuals, may influence immune polarization. However, the combined effect of chronic HCV and host immunogenetics on allergic sensitization remains incompletely understood. Objective: To assess total serum IgE levels and allergic manifestations in HCV-positive vs. HCV-negative BT patients, and explore associations with common polymorphisms in IL10, TLR7, IL4, and IFNG genes Methods: This cross-sectional observational study enrolled 46 BT patients (37 HCV-positive, 9 HCV-negative) and 50 healthy controls. Clinical allergy history, total IgE levels (ELISA), and skin prick tests (SPT) for aeroallergens were collected. Genotyping for IL10 −1082, TLR7 rs179008, IL4 −589, and IFNG +874 polymorphisms was performed. Associations between genotypes, HCV status, and IgE levels were analyzed descriptively due to small sample size Results: HCV-positive BT patients had lower mean IgE levels (18.73 ± 4.2 IU/mL) and fewer reported allergic symptoms (21.6%) compared to HCV-negative counterparts (118.76 ± 7.9 IU/mL; 55.5%). The IL10 −1082 AA and TLR7 rs179008 TT genotypes were more common in the HCV-positive group and were associated with lower IgE levels. No associations were noted for IL4 or IFNG variants. Splenectomy appeared to further modify IgE levels in HCV-negative patients. Due to limited power and absence of multivariate analysis, findings are exploratory. These preliminary observations may inform future studies of immune deviation in chronically infected pediatric cohorts. Conclusions: Chronic HCV infection may contribute to immune tolerance and reduced allergic expression in BT patients, potentially modulated by IL10 and TLR7 genotypes. Further studies with functional immune profiling and larger cohorts are required. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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18 pages, 11393 KB

Open AccessArticle

What Do Single-Cell Models Already Know About Perturbations?

by Andreas Bjerregaard, Iñigo Prada-Luengo, Vivek Das and Anders Krogh

Genes 2025, 16(12), 1439; https://doi.org/10.3390/genes16121439 - 2 Dec 2025

Abstract

Background: Virtual cells are embedded in widely used single-cell generative models. Nonetheless, the models’ implicit knowledge of perturbations remains unclear. Methods: We train variational autoencoders on three gene expression datasets spanning genetic, chemical, and temporal perturbations, and infer perturbations by differentiating [...] Read more.

Background: Virtual cells are embedded in widely used single-cell generative models. Nonetheless, the models’ implicit knowledge of perturbations remains unclear. Methods: We train variational autoencoders on three gene expression datasets spanning genetic, chemical, and temporal perturbations, and infer perturbations by differentiating decoder outputs with respect to latent variables. This yields vector fields of infinitesimal change in gene expression. Furthermore, we probe a publicly released scVI decoder trained on the

CELL \times GENE

Discover Census (

\sim 5.7

M mouse cells) and score genes by the alignment between local gradients and an empirical healthy-to-disease axis, followed by a novel large language model-based evaluation of pathways. Results: Gradient flows recover known transitions in Irf8 knockout microglia, cardiotoxin-treated muscle, and worm embryogenesis. In the pretrained Census model, gradients help identify pathways with stronger statistical support and higher type 2 diabetes relevance than an average expression baseline. Conclusions: Trained single-cell decoders already contain rich perturbation-relevant information that can be accessed by automatic differentiation, enabling in-silico perturbation simulations and principled ranking of genes along observed disease or treatment axes without bespoke architectures or perturbation labels. Full article

(This article belongs to the Special Issue Machine Learning in Cancer and Disease Genomics)

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19 pages, 3312 KB

Open AccessArticle

Global Transcriptome Analysis Reveals the Molecular Mechanism Underlying Seed Physical Dormancy Formation in Medicago sativa

by He Li, Xiaoying Kang, Xu Li, Feng Yuan, Zeng-Yu Wang and Maofeng Chai

Genes 2025, 16(12), 1438; https://doi.org/10.3390/genes16121438 - 1 Dec 2025

Abstract

Seed physical dormancy, also known as hard-seededness, is a characteristic commonly found in higher plants, which functions to prevent water and oxygen from passing through the impermeable seed coat. Background: Notably, seed dormancy has emerged as a critical factor in the domestication [...] Read more.

Seed physical dormancy, also known as hard-seededness, is a characteristic commonly found in higher plants, which functions to prevent water and oxygen from passing through the impermeable seed coat. Background: Notably, seed dormancy has emerged as a critical factor in the domestication of leguminous plants. Alfalfa (Medicago sativa L.) is a globally cultivated high-quality legume forage crop, while the seeds from different varieties maintain varying degrees of hard-seededness. However, the molecular mechanisms underlying physical dormancy in alfalfa seeds remain poorly understood. In particular, the regulatory mechanisms at the transcriptomic level remain unclear, which has hindered the breeding process of varieties with low hard-seededness. Methods: In this study, we performed global transcriptome analysis to discover the genes specifically expressed in the alfalfa seed coat and provide insights into alfalfa seeds’ physical dormancy domestication traits. RNA sequencing was performed on various alfalfa tissues, including roots, stems, leaves, flowers, and seed coats. Results: This analysis led to the identification of 4740 seed coat-specific expressed genes, including key genes such as KNOX4 (a class II KNOTTED-like homeobox gene), qHs1 (encoding endo-1,4-β-glucanase), GmHs1-1 (encoding a calcineurin-like metallophosphoesterase), and KCS12 (β-ketoacyl-CoA synthase). In addition, several seed coat-specific transcription factor families were identified, including ERF, B3, and NAC, among others. Furthermore, a comparison of gene expression profiles between seeds with and without physical dormancy revealed 60 upregulated and 197 downregulated genes associated with physical dormancy. Crucially, functional enrichment analysis demonstrated that these genes are predominantly associated with lipid metabolism pathways, particularly those involved in the formation of “monolayer-surrounding lipid storage bodies.” Conclusions: This key finding suggests that the establishment of physical dormancy is closely linked to the biosynthesis and deposition of specialized lipid-based layers in the seed coat, which likely constitute the primary barrier to water penetration. Our study thus provides fundamental insights and a valuable genetic resource for future functional studies aimed at deciphering and manipulating physical dormancy in alfalfa. Full article

(This article belongs to the Special Issue Genetics and Breeding of Forage)

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17 pages, 1677 KB

Open AccessReview

Molecular Cargo of Exosomes in Prostate Cancer: A Multi-Omics Perspective on Liquid Biopsies

by Roxana Andra Coman, Andreea Nutu, Stefan Strilciuc, Liviuta Budisan and Ioana Berindan-Neagoe

Genes 2025, 16(12), 1437; https://doi.org/10.3390/genes16121437 - 1 Dec 2025

Abstract

Prostate cancer is one of the most common cancers affecting men, and finding better ways to detect and monitor it remains a top priority in oncology. In recent years, scientists have focused their attention on different classes of extracellular bodies, among them the [...] Read more.

Prostate cancer is one of the most common cancers affecting men, and finding better ways to detect and monitor it remains a top priority in oncology. In recent years, scientists have focused their attention on different classes of extracellular bodies, among them the small ones called exosomes. Exosomes are nanoscale extracellular vesicles (30–200 nm) released into body fluids, where they transport molecular cargo reflective of their cell of origin. Instead of serving as liquid biopsies themselves, exosomes present in accessible fluids such as plasma and urine can be analyzed as part of minimally invasive liquid biopsy strategies without the need for surgery or tissue sampling. In prostate cancer, exosomes are not just passive carriers: they actively influence how cancer grows, spreads, and responds to treatment. Exosomes can be extracted from simple fluid samples, opening the door to faster, safer, and more personalised approaches to diagnosis and care. Exosome content is analysed for the molecular profiling of tumours, including genomics, transcriptomics, proteomics, and metabolomics. This has led to the discovery of new biomarkers that may help detect prostate cancer earlier, predict its aggressiveness, and monitor the effectiveness of treatment. This review synthesizes current multi-omics data on exosomal cargo in prostate cancer, highlighting diagnostic, prognostic, and therapeutic implications as well as existing challenges to clinical translation. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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19 pages, 1128 KB

Open AccessArticle

Barriers, Limitations, and Experiences with Clinical Trials—Treatment in Rare Diseases with Prader–Willi Syndrome as an Example

by Merlin G. Butler, Spencer Silvey and Harold J. P. van Bosse

Genes 2025, 16(12), 1436; https://doi.org/10.3390/genes16121436 - 1 Dec 2025

Abstract

Background/Objectives: Developing and implementing clinical trials for rare diseases is complicated by the incomplete understanding of the varied genotype and subsequent phenotypic differences of a condition, particularly when low numbers of subjects are enrolled in a study. Moreover, a small-scale clinical study [...] Read more.

Background/Objectives: Developing and implementing clinical trials for rare diseases is complicated by the incomplete understanding of the varied genotype and subsequent phenotypic differences of a condition, particularly when low numbers of subjects are enrolled in a study. Moreover, a small-scale clinical study may indicate a positive outcome but have too small of a sampling population to adequately evaluate unwanted outcomes. Prader–Willi syndrome (PWS) is one such genetic disorder with varied subtypes and heterogeneity, where little progress has been made in treatment discoveries. Recently, the FDA approved diazoxide choline for treating key features of hyperphagia and obesity associated with PWS based on clinical trial experience. Diazoxide choline activates the ATP-sensitive potassium channel (KATP) of pancreatic beta cells, inhibiting the release of insulin. One of the subunits of KATP is the protein Kir6.2, the gene product of KCNJ11. Methods: Web-based programs and datasets were used to study the gene and protein functional enrichments of Kir6.2 and KCNJ11, including shared gene and/or protein–protein interactions, and biological processes and functions. Results: Four essential domains of related functions were identified: (1) apoptosis, protein degradation, and inflammation; (2) the coupling of G proteins needed for KATP channel activation; (3) glucose metabolism and control; and (4) the maintenance of intracellular ionic homeostasis. Conclusions: Cellular metabolism in the pancreas is linked to membrane excitability by KATP, which regulates insulin production, energy production and storage, appetite regulation, and fatty acid synthesis. As such, diazoxide choline may influence several biological systems beyond pancreatic and metabolic functions. Full article

(This article belongs to the Special Issue Molecular Basis in Rare Genetic Disorders)

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12 pages, 2887 KB

Open AccessArticle

Gene Regulation in Comorbid Migraine and Myogenic Temporomandibular Disorder Pain

by Ran Tao, Sufang Liu, Hui Maltezos and Feng Tao

Genes 2025, 16(12), 1435; https://doi.org/10.3390/genes16121435 - 1 Dec 2025

Abstract

Background/Objectives: Previous studies have demonstrated an association between migraine headache and temporomandibular joint disorders (TMDs), with a higher prevalence of TMD symptoms in patients with migraine. Methods: In this study, we conducted RNA sequencing to identify differentially expressed genes (DEGs) in the spinal [...] Read more.

Background/Objectives: Previous studies have demonstrated an association between migraine headache and temporomandibular joint disorders (TMDs), with a higher prevalence of TMD symptoms in patients with migraine. Methods: In this study, we conducted RNA sequencing to identify differentially expressed genes (DEGs) in the spinal trigeminal nucleus caudalis of mice with migraine-like pain and/or myogenic TMD. Results: We observed 204 upregulated and 274 downregulated genes in the comorbid migraine and TMD group compared to the control group. We identified 15 ferroptosis-related DEGs enriched in the pathways of neurodegeneration, cellular homeostasis, interleukin signaling, and pain response. Gene Ontology analysis highlighted the involvement of neuroinflammatory response and monoamine transmembrane transporter activity, while Gene Set Enrichment analysis showed enrichment in chemokine signaling, cell cycle, and calcium signaling pathways. Immune infiltration analysis identified M0 macrophages, immature dendritic cells, neutrophils, and eosinophils as key responders. Hub genes in the protein–protein interaction network included Gm7536, Rpl17, Rpl22l1, Rpl14, Rps8, Rps29, Rpl35, Gm4889, Gm11808, Rps27rt, Rps12-ps3, Rpl10-ps3, Gm9843, Oas1c, Il1b, and Serpine1, indicating their synergistic roles in such orofacial pain comorbidity. Conclusions: Our results suggest that the comorbid migraine and TMD can regulate gene expressions involving ferroptosis and immune cell responses and the identified DEGs could be targeted to develop novel therapies for this painful comorbidity. Full article

(This article belongs to the Section Neurogenomics)

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