Genes

13 pages, 803 KiB

Open AccessArticle

Transcriptomic Approach in Understanding Fabry Nephropathy: A Review of the Literature and Proof-of-Concept

by Nika Breznik, Tina Levstek, Bojan Vujkovac, Andreja Cokan Vujkovac and Katarina Trebušak Podkrajšek

Genes 2025, 16(5), 601; https://doi.org/10.3390/genes16050601 (registering DOI) - 19 May 2025

Abstract

Background/Objectives: Fabry nephropathy (FN) is a progressive complication of Fabry disease that significantly affects patient outcomes. However, the molecular mechanisms underlying FN are not yet fully understood. Recent advances in transcriptomics have opened new perspectives for the identification of early changes in gene [...] Read more.

Background/Objectives: Fabry nephropathy (FN) is a progressive complication of Fabry disease that significantly affects patient outcomes. However, the molecular mechanisms underlying FN are not yet fully understood. Recent advances in transcriptomics have opened new perspectives for the identification of early changes in gene expression associated with the development and progression of the disease. Methods: This study includes a systematic review of transcriptomic findings in chronic kidney disease, with a particular focus on FN, and presents a proof-of-concept RNA sequencing analysis of peripheral blood samples from six Fabry patients with progressive nephropathy and six age- and sex-matched control subjects. Results: The analysis identified 41 differentially expressed genes (DEGs), all of which were upregulated in Fabry patients. Enrichment analysis revealed significant involvement in immune-related pathways, including neutrophil degranulation, interferon, and cytokine signaling. Cell type enrichment revealed that neutrophils and other immune cells are key players in this process. Conclusions: These results suggest that immune and inflammatory mechanisms play a central role in the pathogenesis of FN. The identified DEGs are involved in pro-fibrotic signaling and immune system activation and shed light on possible mechanisms underlying fibrosis, podocyte injury, and kidney damage. This study contributes to a deeper understanding of FN and may facilitate in the identification of early biomarkers for diagnosis and disease monitoring. Full article

(This article belongs to the Section Genetic Diagnosis)

22 pages, 1670 KiB

Open AccessReview

Signaling Pathways in Gliomas

by Paulina Stachyra and Ludmiła Grzybowska-Szatkowska

Genes 2025, 16(5), 600; https://doi.org/10.3390/genes16050600 (registering DOI) - 19 May 2025

Abstract

Changes in cell signaling pathways, which in normal conditions determine the maintenance of cell homeostasis and the correctness of its basic processes, may cause the transformation of a normal cell into a cancer cell. Alterations in cellular metabolism leading to oncogenesis are considered [...] Read more.

Changes in cell signaling pathways, which in normal conditions determine the maintenance of cell homeostasis and the correctness of its basic processes, may cause the transformation of a normal cell into a cancer cell. Alterations in cellular metabolism leading to oncogenesis are considered to be a hallmark of cancer cells. Therefore, a thorough understanding of cellular enzymes affecting metabolism and respiration, as well as intracellular pathways connected with them, seems crucial. These changes may be both prognostic and predictive factors, especially in terms of using molecularly targeted therapies. Aberrations in the pathways responsible for cell growth and angiogenesis are considered particularly important in the process of oncogenesis. Gliomas are the most common primary malignant tumors of the brain. The most important molecular disorders determining their particularly malignant nature are aberrations in the pathways responsible for cell growth and angiogenesis, such as the PI3K/Akt or RAS/MAPK/ERK signaling pathway, as well as excessive activity of enzymes, like hexokinases, which play a key role in glycolysis, autophagy, and apoptosis. The multitude of alterations detected in glioma cells, high heterogeneity, and the immunosuppressive environment within the tumor are the main features causing failures in the attempts to implement modern therapies. Full article

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

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18 pages, 10821 KiB

Open AccessArticle

Combined Analysis of Transcriptomes and Metabolomes Reveals That MeJA-Mediated Flavonoid Biosynthesis Is Crucial for Pigment Deposition in Naturally Colored Green Cotton Fibers

by Shuangquan Xie, Kailu Chen, Rui Tang, Xuechi Li, Yuxin Wei, Yijie Cheng, Shouwu Tang, Wengang Chen, Quanliang Xie, Zhuang Meng, Asigul Ismayil, Xiang Jin, Fei Wang, Haifeng Liu and Hongbin Li

Genes 2025, 16(5), 599; https://doi.org/10.3390/genes16050599 (registering DOI) - 19 May 2025

Abstract

Background: Green cotton fibers (GCFs) are valued for their natural coloration and eco-friendly properties, but their pigmentation mechanisms remain unclear, limiting their wider application in the textile industry. This study aims to uncover the key regulatory genes and metabolic pathways involved in [...] Read more.

Background: Green cotton fibers (GCFs) are valued for their natural coloration and eco-friendly properties, but their pigmentation mechanisms remain unclear, limiting their wider application in the textile industry. This study aims to uncover the key regulatory genes and metabolic pathways involved in GCF coloration. Methods: We conducted transcriptome and metabolome profiling of green and white cotton fibers at different developmental stages to identify differences in gene expression and metabolite accumulation related to pigmentation. Results: Transcript analysis revealed significant enrichment in α-linolenic acid metabolism, flavonoid biosynthesis and phenylpropane metabolism pathways during late pigmentation stages. Key genes in methyl jasmonate (MeJA) biosynthesis and flavonoid biosynthesis (LOX, JMT, ANS, C4H, DFR, F3H) were upregulated. The MYB transcription factor showed the most significant increase during fiber development. Metabolomic analysis identified 12 metabolites that accumulated specifically in green fibers. MeJA treatment promoted the expression of MYB genes and flavonoid biosynthesis genes (DFRs, ANSs, F3H, C4H), as well as the accumulation of Luteolin, Gallocatechin, Cyanidin and Chrysanthemum metabolites. Conclusions: Our study demonstrates that MeJA-mediated flavonoid biosynthesis, regulated by MYB transcription factors, is the central pathway controlling pigment deposition in GCFs. These findings provide valuable insights for developing improved colored cotton materials. Full article

(This article belongs to the Special Issue 5Gs in Crop Genetic and Genomic Improvement: 2nd Edition)

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9 pages, 1332 KiB

Open AccessCase Report

The Expression of a Germline Fusion Gene Involving a Protein-Coding and a Long Non-Coding RNA Gene Results in Severe Brain Malformations

by Lukas Kaufmann, Christine Beichler, Jasmin Blatterer, Ingrid Janisch, Bence Csapó, Elisabeth Schreiner, Sarah Verheyen, Jochen B. Geigl and Christian Windpassinger

Genes 2025, 16(5), 598; https://doi.org/10.3390/genes16050598 (registering DOI) - 18 May 2025

Abstract

In the present study, an exceptional germline gene fusion involving the protein-coding MN1 gene and the long non-coding RNA (lncRNA) gene CPMER was detected as the genetic cause of severe cerebral abnormalities with unfavorable prognosis in a male fetus at 14 weeks of [...] Read more.

In the present study, an exceptional germline gene fusion involving the protein-coding MN1 gene and the long non-coding RNA (lncRNA) gene CPMER was detected as the genetic cause of severe cerebral abnormalities with unfavorable prognosis in a male fetus at 14 weeks of gestation. Quantitative and qualitative RNA analyses indicate the expression of C-terminally truncated MN1 proteins. MN1 proteins lacking the C-terminal amino acids have been previously described to cause an ultra-rare syndrome with brain malformations due to a gain-of-function effect. To the best of our knowledge, this is the first study reporting a germline gene fusion of a protein-coding gene and an lncRNA gene linked to a functional, but neomorphic, protein associated with severe phenotypic abnormalities. The results of our study are not only relevant for the genotype–phenotype correlation of MN1 but should especially raise awareness for potentially disease-associated protein expressions in germline gene fusions involving lncRNAs. Full article

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

10 pages, 2006 KiB

Open AccessArticle

RiceReceptor: The Cell-Surface and Intracellular Immune Receptors of the Oryza Genus

by Baihui Jin, Jian Dong, Xiaolong Hu, Na Li, Xiaohua Li, Dawei Long and Xiaoni Wu

Genes 2025, 16(5), 597; https://doi.org/10.3390/genes16050597 (registering DOI) - 18 May 2025

Abstract

Introduction: Rice, a cornerstone of global food security, faces escalating demands for enhanced yield and disease resistance. We collected 300 high-quality genomes, representing both cultivated (Oryza sativa indica, O. sativa japonica, and O. sativa aus) and wild species ( [...] Read more.

Introduction: Rice, a cornerstone of global food security, faces escalating demands for enhanced yield and disease resistance. We collected 300 high-quality genomes, representing both cultivated (Oryza sativa indica, O. sativa japonica, and O. sativa aus) and wild species (O. rufipogon, O. glaberrima, and O. barthii). Methods: Leveraging HMMER, NLR-Annotator, and OrthoFinder, we systematically identified 148,077 leucine-rich repeat (LRR) and 143,459 nucleotide-binding leucine-rich repeat (NLR) genes, with LRR receptor-like kinases (LRR-RLKs) dominating immune receptor proportions, followed by coiled-coil domain containing (CNL)-type NLRs and LRR receptor-like proteins (LRR-RLPs). Results: Benchmarking Universal Single-Copy Orthologs (BUSCO) assessments confirmed robust genome quality (average score: 94.78). Strikingly, 454 TIR-NB-LRR (TNL) genes—typically rare in monocots—were detected, challenging prior assumptions. Phylogenetic analysis with Arabidopsis TNLs highlighted five O. glaberrima genes clustering with dicot TNLs; these genes featured truncated PLN03210 motifs fused to nucleotide-binding adaptor shared by APAF-1, R proteins, and CED-4 (NB-ARC) and LRR domains. Conclusions: By bridging structural genomics, evolutionary dynamics, and domestication-driven adaptation, this work provides a foundation for targeted breeding strategies and advances functional studies of plant immunity in rice. Full article

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

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15 pages, 7733 KiB

Open AccessArticle

ABA-Insensitive 5 (ABI5) Is Involved in ABA-Induced Dormancy via Activating PavCIG1/2 Expression in Sweet Cherries

by Jiyuan Wang, Li Wang, Muhammad Usman, Jie Zhu, Songtao Jiu, Ruie Liu and Caixi Zhang

Genes 2025, 16(5), 596; https://doi.org/10.3390/genes16050596 (registering DOI) - 18 May 2025

Abstract

Background/Objectives: In perennial plants, developing floral buds survive winter through entering a dormant state, which is induced by low temperature and abscisic acid (ABA). ABA performs vital functions in the dormancy process. ABA-insensitive 5 (ABI5) transcription factor is a key regulator in the [...] Read more.

Background/Objectives: In perennial plants, developing floral buds survive winter through entering a dormant state, which is induced by low temperature and abscisic acid (ABA). ABA performs vital functions in the dormancy process. ABA-insensitive 5 (ABI5) transcription factor is a key regulator in the ABA signaling pathway. However, little is known about the regulation of ABI5 in the winter dormancy of sweet cherries. Methods: We identified the sweet cherry ABI5 gene and its expression changes using gene cloning and qRT-PCR. Additionally, we validated the interaction between PavABI5 and PavCIG1/2 using Yeast One-Hybrid and Dual-Luciferase Assays. Results: In this study, we identified a basic leucine zipper (bZIP) family gene ABI5 from the sweet cherry, which was closely related to PduABI5 from Prunus dulcis, PpABI5 from Prunus persica, PmABI5 from Prunus mume, and ParABI5 from Prunus armeniaca, through phylogenetic tree analysis. The seasonal expression pattern showed that the PavABI5 level was increased during the winter dormancy stage and induced by exogenous ABA. Specifically, we found that the expression of cherry cold-induced genes (PavCIG1/2) was positively correlated with PavABI5 expression. Furthermore, PavABI5 directly bound to the ABRE elements in the PavCIG1/2 promoters to activate their expression. We further confirmed that the dormancy-associated MADS-box (DAM) genes DAM4 and DAM5 function downstream of the ABA signaling pathway to regulate bud dormancy in sweet cherries. Conclusions: Our findings suggest a putative regulatory model of ABA-mediated bud-dormancy with PavABI5. Full article

(This article belongs to the Section Genes & Environments)

18 pages, 3532 KiB

Open AccessArticle

Transcriptomic Profiling of Paulownia fortunei (Seem.) Hemsl. Roots in Response to Chromium and Copper Stress

by Jiang Su, Xinfeng Pan, Kanghua Xian, Chuanming Fu, Jinxiang He, Baojun Liu, Jinhan Sang and Ningzhen Huang

Genes 2025, 16(5), 595; https://doi.org/10.3390/genes16050595 (registering DOI) - 18 May 2025

Abstract

Background: Soil heavy metal pollution by chromium (Cr) and copper (Cu) is a global environmental concern. Methods: This study evaluated Cr/Cu accumulation in Paulownia fortunei tissues and analyzed its root transcriptome under Cr and Cu stress to elucidate molecular response mechanisms. Results: Findings [...] Read more.

Background: Soil heavy metal pollution by chromium (Cr) and copper (Cu) is a global environmental concern. Methods: This study evaluated Cr/Cu accumulation in Paulownia fortunei tissues and analyzed its root transcriptome under Cr and Cu stress to elucidate molecular response mechanisms. Results: Findings revealed significantly higher Cr and Cu accumulation capacity in roots compared to stems and leaves. Transcriptome sequencing identified 6017 and 2265 differentially expressed genes (DEGs) under Cr and Cu stress, respectively. These DEGs were primarily involved in redox reactions, stress responses, transcriptional regulation, transmembrane transport, and metabolism. Quantitative PCR of 20 selected genes validated dynamic expression changes under stress. Weighted Gene Co-expression Network Analysis (WGCNA) identified distinct co-expression modules associated with Cr and Cu. Hub gene analysis implicated Pfo_020668 and Pfo_019190 in Cr response, while Pfo_010312 and Pfo_000197 may enhance Cu tolerance via cell wall polysaccharide synthesis regulation. Pathways related to pyruvate metabolism and proteasome were significantly enriched under Cr stress, whereas amino acid metabolism pathways were prominent under Cu stress. Conclusions: Differentially expressed transporter genes suggest potential roles in heavy metal uptake and transport. This transcriptomic analysis provides novel insights into P. fortunei’s molecular responses to Cr and Cu stress, offering a foundation for utilizing this species in soil phytoremediation efforts. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Adaptive Evolution in Trees)

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12 pages, 3115 KiB

Open AccessArticle

The First Mitochondrial Genome of Family Xylococcidae (Hemiptera, Coccomorpha) and Its Phylogenetic Implications

by Xiaxia Zhao, Yuang Li, Han Xu and Sanan Wu

Genes 2025, 16(5), 594; https://doi.org/10.3390/genes16050594 (registering DOI) - 17 May 2025

Viewed by 63

Abstract

Background: The mitochondrial genome has been used for understanding higher-level phylogenetic relationships within Coccomorpha. we sequenced and analyzed the first mitochondrial genome of Xylococcus castanopsis Wu & Huang, 2017 to elucidate its genomic features and phylogenetic position. Methods: The complete mitogenome was assembled [...] Read more.

Background: The mitochondrial genome has been used for understanding higher-level phylogenetic relationships within Coccomorpha. we sequenced and analyzed the first mitochondrial genome of Xylococcus castanopsis Wu & Huang, 2017 to elucidate its genomic features and phylogenetic position. Methods: The complete mitogenome was assembled using NOVOPlasty and annotated with MITOS. We analyzed genome organization, codon usage, and tRNA structures. Phylogenetic relationships were reconstructed using 13 protein-coding genes from 19 scale insect species with Bayesian Inference and Maximum Likelihood methods. Result: The mitochondrial genome is 16,363 bp in size and contains the typical 37 mitochondrial genes, with an A + T content of 89.2%. All protein-coding genes start with the ATN and end with TAA/TAG or a single T- residue. Sixteen tRNAs exhibit the typical cloverleaf structure, while the remaining six lack either the dihydrouridine (DHU) or TΨC (T) arm. Gene rearrangements occur only in individual tRNAs and transpositions between the gene clusters trnS2-ND1 and trnL1-rrnL-trnV-rrnS. Phylogenetic analysis consistently place Xylococcidae as a sister group to all scale insects except Matsucoccidae. Conclusions: This study provides the first complete mitogenome for Xylococcidae, revealing characteristic gene rearrangements. Phylogenetic reconstruction resolves the phylogenetic position of Xylococcidae as a distinct lineage sister to all scale insects except Matsucoccidae, providing critical evolutionary insights. Full article

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

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25 pages, 1824 KiB

Open AccessArticle

Genetic Diversity and Metabolic Profile of Tibetan Medicinal Plant Saussurea obvallata

by Shengnan Zhang, Sujuan Wang, Shiyan Wang, Hao Su and Ji De

Genes 2025, 16(5), 593; https://doi.org/10.3390/genes16050593 (registering DOI) - 17 May 2025

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Abstract

Background/Objectives: Saussurea obvallata (DC.) Edgew., Asteraceae, is a traditional medicinal herbnative to the Qinghai–Tibet Plateau (QTP). Pharmacological investigationshave validated its pharmacological effects in anti-tumor, anti-inflammatory, heat-clearing, detoxifying, and analgesia. S. obv is presently facing habitat fragmentation and population decline. Therefore, we analyzed its [...] Read more.

Background/Objectives: Saussurea obvallata (DC.) Edgew., Asteraceae, is a traditional medicinal herbnative to the Qinghai–Tibet Plateau (QTP). Pharmacological investigationshave validated its pharmacological effects in anti-tumor, anti-inflammatory, heat-clearing, detoxifying, and analgesia. S. obv is presently facing habitat fragmentation and population decline. Therefore, we analyzed its genetic and chemical diversity to provide a scientific basis for the conservation and sustainable use of S. obv. Methods: Seven populations of S. obv were sampled from Xizang, China. The genetic diversity was analyzed using inter-simple sequence repeat (ISSR) markers, and metabolites were identified by ultra-high-performance liquid chromatography-tandem-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS). Correlation analysis among genetic diversity, differential metabolites, and climatic factors were performed by R. Results: The genetic diversity among and within populations were both lowly and significantly correlated with geographical distance, showing a decreasing trend from east to west of the QTP. A total of 110 compounds were identified, including flavonoids, phenylpropanoids, lipids, fatty acids, terpenoids, alkaloids, etc. The metabolite contents among populations varied greatly and were related to environmental factors, mainly annual mean temperature and temperature fluctuation. The genetic diversity had little effect on the metabolic differences. Conclusions: These findings provided valuable baseline information for the conservation and pharmacological utilization of S. obv. Meanwhile, further research is necessary for the efficacy evaluation of anti-inflammatory, anti-tumor, radiation protection, and scar removal both in vitro and in vivo. Full article

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

14 pages, 719 KiB

Open AccessArticle

Pharmacogenetic Profiling of Genes Associated with Outcomes of Chemotherapy in Omani Healthy Controls

by Nahad Al-Mahrouqi, Nada Al Shuaili, Shoaib Al-Zadjali, Anoopa Pullanhi, Hamida Al-Barwani, Aida Al-Kindy, Hadeel Al-Sharqi, Khalid Al-Baimani, Mansour Al-Moundhri and Bushra Salman

Genes 2025, 16(5), 592; https://doi.org/10.3390/genes16050592 (registering DOI) - 17 May 2025

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Abstract

Background/Objectives: Pharmacogenomic screening plays a crucial role in optimizing chemotherapy outcomes and minimizing toxicity. Characterizing the baseline distribution of genetic variants in specific populations is essential to inform the prioritization of drug–gene combinations for clinical implementation. The objective of this study was to [...] Read more.

Background/Objectives: Pharmacogenomic screening plays a crucial role in optimizing chemotherapy outcomes and minimizing toxicity. Characterizing the baseline distribution of genetic variants in specific populations is essential to inform the prioritization of drug–gene combinations for clinical implementation. The objective of this study was to investigate the distribution of pharmacogenetic variants in 36 genes related to the fluoropyrimidine (FP) pathway among healthy Omani individuals, forming a foundation for future studies in cancer patients receiving FP-based chemotherapy. Methods: Ninety-eight healthy Omani participants aged ≥18 years were recruited at the Sultan Qaboos Comprehensive Cancer Care and Research Center. Whole-blood samples were collected, and genomic DNA was extracted. Targeted next-generation sequencing was performed using a custom Ion AmpliSeq panel covering coding exons and splice-site regions of 36 genes involved in FP metabolism and response. Results: A total of 999 variants were detected across the 36 genes, with 63.3% being heterozygous. The ABCC4 gene had the highest mutation frequency (76 mutations), while DHFR and SMUG1 had the lowest (<10 mutations). In DPYD, four functionally significant variants were found at frequencies ranging from 1 to 8.2% of the population. Missense mutations were also observed in MTHFR and UGT1A1. Three actionable variants in DPYD and MTHFR, associated with 5-fluorouracil and/or capecitabine response, were identified. Additionally, 27 novel single-nucleotide polymorphisms of unknown clinical significance were detected. Conclusions: This study reveals key pharmacogenetic variants in the Omani population, underscoring the importance of integrating pharmacogenomic testing into routine care to support safer, more personalized chemotherapy in the region. Full article

(This article belongs to the Section Pharmacogenetics)

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19 pages, 3463 KiB

Open AccessArticle

Characterizing the Social Epigenome in Mexican Patients with Early−Onset Psychosis

by David Ruiz-Ramos, José Jaime Martínez-Magaña, Isela Esther Juárez-Rojop, Germán Alberto Nolasco-Rosales, Fernanda Sosa-Hernández, Juan Daniel Cruz-Castillo, Josefa Cavazos, Adriana Callejas, Patricia Zavaleta-Ramírez, José Antonio Zorrilla-Dosal, Nuria Lanzagorta, Humberto Nicolini, Janitza L. Montalvo-Ortiz, David C. Glahn and Alma Delia Genis-Mendoza

Genes 2025, 16(5), 591; https://doi.org/10.3390/genes16050591 (registering DOI) - 17 May 2025

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Abstract

Background: Psychosis is one of the leading causes of disability worldwide. Individuals with early−onset psychosis (EOP) tend to experience a worse prognosis and shorter life expectancy. The etiology of EOP remains unclear, but epigenetic mechanisms are known to serve as the interface between [...] Read more.

Background: Psychosis is one of the leading causes of disability worldwide. Individuals with early−onset psychosis (EOP) tend to experience a worse prognosis and shorter life expectancy. The etiology of EOP remains unclear, but epigenetic mechanisms are known to serve as the interface between environmental exposures and biological processes to better understand its etiology. Objectives: We characterized the sociodemographic and clinical characteristics, as well as genome-wide epigenetic markers, in Mexican patients with EOP. Methods: We estimated epigenetic age, performed an epigenome−wide association study, and finally developed an epigenetic risk score (MRS) to predict manifestations of psychosis. Results: We found that patients with EOP have a higher epigenetic age using Wu’s clock (p = 0.015). Moreover, accelerated epigenetic age was correlated with chronological age (PedBE clock, p = 0.046), global functioning (Wu’s clock, p = 0.027), and psychiatric admissions (DNAmTL, p = 0.038). In addition, we observed that a reduction in years of schooling is associated with an increase on epigenetic age (Levine’s clock, β = 5.07, p = 0.001). In our epigenome-wide association study, we identified eight CpGs associated with EOP. Noteworthy, a psychosis−methylation risk score (EOP−MRS) was associated with panic disorder (β = 1.36, p = 0.03), as well as auditory (β = 1.28, p = 0.04) and visual (β = 1.22, p = 0.04) hallucinations. Conclusions: Years of education have an impact on epigenetic age. Additionally, our study suggests associations of DNA methylation with EOP. Finally, we developed an MRS that associates clinical manifestations of psychosis. Full article

(This article belongs to the Section Neurogenomics)

54 pages, 1065 KiB

Open AccessReview

Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy

by Pierre Bougnères and Catherine Le Stunff

Genes 2025, 16(5), 590; https://doi.org/10.3390/genes16050590 (registering DOI) - 17 May 2025

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Abstract

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal [...] Read more.

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD. Methods: This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis. Results: In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation. Conclusions: Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons. Full article

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

11 pages, 237 KiB

Open AccessArticle

Association Between Genetically Predicted Memory and Self-Reported Foreign Language Proficiency

by Meruert B. Yerdenova, Gaukhar K. Datkhabayeva, Manzura K. Zholdassova, Altyngul T. Kamzanova, Zukhra M. Sadvakassova, Amal Bouzid, Poorna Manasa Bhamidimarri, Rifat Hamoudi, Ekaterina A. Semenova, Andrey K. Larin, Nikolay A. Kulemin, Edward V. Generozov, Tim Rees, Almira M. Kustubayeva and Ildus I. Ahmetov

Genes 2025, 16(5), 589; https://doi.org/10.3390/genes16050589 (registering DOI) - 17 May 2025

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Abstract

Background: Foreign language proficiency is a complex trait that reflects an individual’s ability to effectively understand and use a non-native language, shaped by both genetic and environmental factors. The aim of this study was to establish the relationship between genetically determined memory capacity [...] Read more.

Background: Foreign language proficiency is a complex trait that reflects an individual’s ability to effectively understand and use a non-native language, shaped by both genetic and environmental factors. The aim of this study was to establish the relationship between genetically determined memory capacity and self-reported foreign language proficiency in 129 children (63 males, 66 females, age 14.2 ± 3.9) and 128 adults (90 males, 38 females, age 29.8 ± 8.2). Methods: Seven single nucleotide polymorphisms (SNPs) previously linked with memory function were used in a polygenic analysis (CAMTA1 rs4908449, CLSTN2 rs6439886, COMT rs4680, CPEB3 rs11186856, SCN1A rs10930201, SNAP25 rs3746544, and WWC1 rs17070145). Self-reported foreign language proficiency was evaluated using a single-item question. Children’s level of immersion in foreign languages was divided into three categories: linguistic school, non-linguistic school with extra foreign language courses, and non-linguistic school without additional foreign language courses. Results: We found that genetically predicted memory capacity (i.e., number of memory-increasing alleles) was positively associated with self-reported foreign language proficiency in children (p = 0.0078 adjusted for age, sex, ethnicity, verbal IQ, and level of immersion in foreign languages). When combined, genetically predicted memory capacity, age, sex, ethnicity, verbal IQ, and level of immersion in foreign languages explained 31.5% (p < 0.0001) of the variance in children’s self-reported foreign language proficiency. The association between genetically predicted memory capacity and self-reported foreign language proficiency was replicated in adults (p = 0.0158 adjusted for age, sex, and ethnicity). Conclusions: Foreign language proficiency may partly depend on the presence of a high number of memory-increasing alleles in both children and adults. Full article

(This article belongs to the Section Neurogenomics)

11 pages, 858 KiB

Open AccessCase Report

Cumulative Effects of Genetic Variants Detected in a Child with Early-Onset Non-Syndromic Obesity Due to SIM-1 Gene Mutation

by Giovanni Luppino, Malgorzata Wasniewska, Mara Giordano, Giorgia Pepe, Letteria Anna Morabito, Debora Porri, Tommaso Aversa and Domenico Corica

Genes 2025, 16(5), 588; https://doi.org/10.3390/genes16050588 (registering DOI) - 17 May 2025

Viewed by 96

Abstract

Background: Single-minded homolog 1 (SIM1) gene mutations with autosomal dominant inheritance have been related to hyperphagia and early-onset severe obesity. SIM1 is implicated in the development of hypothalamic nuclei, which play a crucial role in energy homeostasis. The development of melanocortin [...] Read more.

Background: Single-minded homolog 1 (SIM1) gene mutations with autosomal dominant inheritance have been related to hyperphagia and early-onset severe obesity. SIM1 is implicated in the development of hypothalamic nuclei, which play a crucial role in energy homeostasis. The development of melanocortin neural circuits in the hypothalamus is promoted by other factors such as Semaphorine 3 (SEMA3) and its receptors, such as PLXNA1-4 and NRP1-2. Loss-of-function across multiple SEMA3/NRP/PLXNA genes can collectively contribute to obesity onset. Case Description: A 3-year-old male was referred for the first time to Outpatient pediatric endocrinology due to early-onset and progressive severe obesity and hyperphagia. He presented neurobehavior disorders and partial diabetes insipidus. At age 6, the child was diagnosed with obesity-related complications, including hyperinsulinemia, impaired glucose tolerance, hypercholesterolemia, hepatic steatosis, and hypovitaminosis. The NGS analysis revealed four variants related to obesity: SIM1, SEMA3C, PLXNA4, and CREBBP gene mutations. Conclusions: The case presents the association of SIM-1 gene mutation with other obesity-related variants. The interactive and cumulative effects of the identified variants could coexist in the determination of severe obesity through abnormalities in the development and function of hypothalamic melanocortin circuits related to energy homeostasis. Although the pathogenic mutation of the SIM1 gene plays the main role, the complex clinical picture may be related to the possible cumulative effect of the other genetic mutations. Full article

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

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15 pages, 1375 KiB

Open AccessArticle

Comparative Transcriptome Analysis Elucidates the Desiccation Stress Adaptation in Sargassum muticum

by Wei Cao, Mingyi Zhang, Nan Wu, Yanxin Zheng, Xiaodong Li, Haiying Han, Tao Yu, Zhongxun Wu, Pei Qu and Bo Li

Genes 2025, 16(5), 587; https://doi.org/10.3390/genes16050587 (registering DOI) - 16 May 2025

Viewed by 46

Abstract

Background/Objectives: Desiccation profoundly influences the distribution and abundance of intertidal seaweeds, necessitating robust molecular adaptations. Sargassum muticum is a brown seaweed inhabiting intertidal rocky substrates. During low tides, this species undergoes periodic aerial exposure. Such environmental conditions necessitate robust physiological mechanisms to mitigate [...] Read more.

Background/Objectives: Desiccation profoundly influences the distribution and abundance of intertidal seaweeds, necessitating robust molecular adaptations. Sargassum muticum is a brown seaweed inhabiting intertidal rocky substrates. During low tides, this species undergoes periodic aerial exposure. Such environmental conditions necessitate robust physiological mechanisms to mitigate desiccation stress. Yet, the molecular basis of this adaptation remains poorly understood. Methods: To investigate desiccation-responsive genes and elucidate the underlying mechanisms of adaptation, we exposed S. muticum to 6 h of controlled desiccation stress in sterilized ceramic trays, simulating natural tidal conditions, and performed comparative transcriptome analysis using RNA-seq on the Illumina NovaSeq 6000 platform. Results: High-quality sequencing identified 66,192 unigenes, with 1990 differentially expressed genes (1399 upregulated and 591 downregulated). These differentially expressed genes (DEGs) were categorized into regulatory genes—including mitogen-activated protein kinase (MAPK), calmodulin, elongation factor, and serine/threonine-protein kinase—and functional genes, such as heat shock protein family members (HSP20, HSP40, and HSP70), tubulin (TUBA and TUBB), and endoplasmic reticulum homeostasis-related genes (protein disulfide-isomerase A6, calreticulin, and calnexin). Gene Ontology (GO) enrichment highlighted upregulated DEGs in metabolic processes like glutathione metabolism, critical for oxidative stress mitigation, while downregulated genes were linked to transport functions, such as ammonium transport, suggesting reduced nutrient uptake during dehydration. KEGG pathway analysis revealed significant enrichment in “protein processing in endoplasmic reticulum” and “MAPK signaling pathway-plant”, implicating endoplasmic reticulum stress response and conserved signaling cascades in desiccation adaptation. Validation via qRT-PCR confirmed consistent expression trends for key genes, reinforcing the reliability of transcriptomic data. Conclusions: These findings suggest that S. muticum undergoes extensive biological adjustments to mitigate desiccation stress, highlighting candidate pathways for future investigations into recovery and tolerance mechanisms. Full article

(This article belongs to the Special Issue Abiotic Stress in Plants: Molecular Genetics and Genomics—2nd Edition)

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13 pages, 2257 KiB

Open AccessArticle

Genetic Diversity Among Wild and Cultured Bighead Carp (Hypophthalmichthys nobilis) in the Middle Yangtze River by Microsatellite Markers

by Junru Wang, Qi Lei, Hanjun Jiang, Jun Liu, Xiaomu Yu, Xusheng Guo and Jingou Tong

Genes 2025, 16(5), 586; https://doi.org/10.3390/genes16050586 (registering DOI) - 16 May 2025

Viewed by 35

Abstract

Background: Bighead carp (Hypophthalmichthys nobilis), a vital species in China’s freshwater ecosystems and aquaculture, has experienced significant population declines due to habitat degradation and intensive farming. Methods: In this study, eight polymorphic microsatellite markers were utilized to examine the genotypes and [...] Read more.

Background: Bighead carp (Hypophthalmichthys nobilis), a vital species in China’s freshwater ecosystems and aquaculture, has experienced significant population declines due to habitat degradation and intensive farming. Methods: In this study, eight polymorphic microsatellite markers were utilized to examine the genotypes and genetic diversity of 320 individuals of bighead carp populations located in the middle Yangtze River. This included four wild populations (ZX, DTH, SS, WH) and six cultured populations (HH, XZ, CH, QC, CD, HG). Results: Wild populations exhibited significantly higher genetic diversity (mean Na = 12.25 ± 0.63, Ho = 0.802 ± 0.063) than cultured groups (mean Na = 8.85 ± 1.21, He = 0.779 ± 0.032). Low differentiation (Fst < 0.05) among wild populations indicated high connectivity with low genetic structure, whereas cultured populations CH and HG showed moderate-to-high differentiation (Fst = 0.156–0.293). Bayesian analysis (K = 7) revealed a distinct clustering of wild populations, while cultured stocks exhibited admixed genetic ancestries. Bottleneck tests confirmed recent genetic bottlenecks in three cultured populations. Conclusions: Wild bighead carp populations retain a critical genetic diversity, serving as reservoirs for conservation, while intensive aquaculture practices threaten genetic integrity through allele loss and inbreeding. Full article

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

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11 pages, 368 KiB

Open AccessReview

Pontocerebellar Hypoplasia Type 1 and Associated Neuronopathies

by Mario Škarica, Gyula Acsadi and Sasha A. Živković

Genes 2025, 16(5), 585; https://doi.org/10.3390/genes16050585 - 15 May 2025

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Abstract

Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH [...] Read more.

Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders. Full article

(This article belongs to the Section Neurogenomics)

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24 pages, 418 KiB

Open AccessSystematic Review

Understanding Glycogen Storage Disease Type IX: A Systematic Review with Clinical Focus—Why It Is Not Benign and Requires Vigilance

by Egidio Candela, Giulia Montanari, Andrea Zanaroli, Federico Baronio, Rita Ortolano, Giacomo Biasucci and Marcello Lanari

Genes 2025, 16(5), 584; https://doi.org/10.3390/genes16050584 - 15 May 2025

Viewed by 81

Abstract

Background/Objectives: Glycogen storage disease type IX (GSD IX) is a group of inherited metabolic disorders caused by phosphorylase kinase deficiency affecting the liver or muscle. Despite being relatively common among GSDs, GSD IX remains underexplored. Methods: A systematic review of GSD IX was [...] Read more.

Background/Objectives: Glycogen storage disease type IX (GSD IX) is a group of inherited metabolic disorders caused by phosphorylase kinase deficiency affecting the liver or muscle. Despite being relatively common among GSDs, GSD IX remains underexplored. Methods: A systematic review of GSD IX was conducted per PRISMA guidelines using SCOPUS and PubMed, registered with PROSPERO. Inclusion focused on human clinical studies published up to 31 December 2024. Results: A total of 400 patients with GSD IX were analyzed: 274 IXa (mean age at diagnosis 5.1 years), 72 IXc (mean age at diagnosis 4.9 years), 39 IXb (mean age at diagnosis 4.2 years), and 15 IXd (mean age at diagnosis 44.9 years). Hepatomegaly was commonly reported in types IXa, IXb, and especially IXc (91.7%), but was rare in IXd. Elevated transaminases were frequently observed in types IXa, IXb, and particularly IXc, while uncommon in IXd. Fasting hypoglycemia was occasionally observed in types IXa and IXb, more frequently in IXc (52.7%), and was not reported in IXd. Growth delay or short stature was observed in a substantial proportion of patients with types IXa (43.8%), IXb, and IXc, but was rare in IXd. Muscle involvement was prominent in IXd, with all patients showing elevated CPK (mean 1011 U/L). Neurological involvement was infrequently reported in types IXa and IXc. Conclusions: This systematic review includes the most extensive clinical case history of GSD IX described in the literature. The clinical spectrum of GSD IX varies widely among subtypes, with IXc being the most aggressive. While liver forms are generally present in early childhood, muscle-type IXd shows delayed onset and milder symptoms, often leading to diagnostic delays. For diagnosis, it is essential not to underestimate key clinical features such as hepatic involvement and hypoglycemia in a child under 5 years of age. Other manifestations, including the as-yet unexplored systemic involvement of bone and kidney, remain insufficiently understood and require further investigation. Next-generation sequencing has improved diagnostic precision over traditional biopsy. Dietary management, including uncooked cornstarch, Glycosade^®, and high-protein intake, remains the cornerstone of treatment. However, there is a paucity of well-designed, evidence-based studies to determine the most effective therapeutic approach. Despite its historically perceived benign course, the broad phenotypic variability of GSD IX, including progressive liver involvement and potential neurological complications, highlights its substantial clinical relevance and underscores the need for accurate diagnostic classification and long-term multidisciplinary follow-up. Full article

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

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22 pages, 2262 KiB

Open AccessArticle

Genome-Wide Association Studies and Candidate Genes for Egg Production Traits in Layers from an F₂ Crossbred Population Produced Using Two Divergently Selected Chicken Breeds, Russian White and Cornish White

by Natalia A. Volkova, Michael N. Romanov, Alan Yu. Dzhagaev, Polina V. Larionova, Ludmila A. Volkova, Alexandra S. Abdelmanova, Anastasia N. Vetokh, Darren K. Griffin and Natalia A. Zinovieva

Genes 2025, 16(5), 583; https://doi.org/10.3390/genes16050583 - 15 May 2025

Viewed by 62

Abstract

Background/Objectives: Finding single nucleotide polymorphisms (SNPs) and candidate genes that influence the expression of key traits is essential for genomic selection and helps improve the efficiency of poultry production. Here, we aimed to conduct a genome-wide association study (GWAS) for egg production [...] Read more.

Background/Objectives: Finding single nucleotide polymorphisms (SNPs) and candidate genes that influence the expression of key traits is essential for genomic selection and helps improve the efficiency of poultry production. Here, we aimed to conduct a genome-wide association study (GWAS) for egg production traits in an F₂ resource population of chickens (Gallus gallus). Methods: The examined F₂ population was produced by crossing two divergently selected breeds with contrasting phenotypes for egg performance traits, namely Russian White (of higher egg production) and Cornish White (of lower egg production). Sampled birds (n = 142) were genotyped using the Illumina Chicken 60K SNP iSelect BeadChip. Results: In the course of the GWAS analysis, we were able to clarify significant associations with phenotypic traits of interest and economic value by using 47,432 SNPs after the genotype dataset was filtered. At the threshold p < 1.06 × 10⁻⁶, we found 23 prioritized candidate genes (PCGs) associated with egg weight at the age of 42–52 weeks (FGF14, GCK), duration of egg laying (CNTN4), egg laying cycle (SAMD12) and egg laying interval (PHF5A, AKR1B1, CALD1, ATP7B, PIK3R4, PTK2, PRKCE, FAT1, PCM1, CC2D2A, BMS1, SEMA6D, CDH13, SLIT3, ATP10B, ISCU, LRRC75A, LETM2, ANKRD24). Moreover, two SNPs were co-localized within the FGF14 gene. Conclusions: Based on our GWAS findings, the revealed SNPs and candidate genes can be used as genetic markers for egg weight and other performance characteristics in chickens to attain genetic enhancement in production and for further genomic selection. Full article

(This article belongs to the Special Issue Genetic Breeding of Poultry)

14 pages, 641 KiB

Open AccessReview

Genetic Aspects of Tooth Agenesis

by Clarissa Modafferi, Ilaria Tucci, Francesco Maria Bogliardi, Elena Gimondo, Pietro Chiurazzi, Elisabetta Tabolacci and Cristina Grippaudo

Genes 2025, 16(5), 582; https://doi.org/10.3390/genes16050582 - 15 May 2025

Viewed by 140

Abstract

Tooth agenesis is among the most prevalent congenital anomalies affecting human dentition, characterized by the developmental absence of one or more teeth. This condition may be present in either syndromic or non-syndromic forms, with significant implications for oral function, aesthetics, and craniofacial development. [...] Read more.

Tooth agenesis is among the most prevalent congenital anomalies affecting human dentition, characterized by the developmental absence of one or more teeth. This condition may be present in either syndromic or non-syndromic forms, with significant implications for oral function, aesthetics, and craniofacial development. This narrative review aims to provide a comprehensive overview of tooth agenesis, defining its classification, genetic underpinnings, epidemiological aspects, phenotypic features, and therapeutic approaches. Recent advances in genetic research have identified numerous causative genes, notably EDA, MSX1, WNT10A, and PAX9, each associated with specific patterns of missing teeth and involved in isolated and/or syndromic forms. Additionally, genes such as TSPEAR, LRP6, PITX2, and GREM2 contribute to varying degrees of severity and tooth distribution, often blurring the lines between syndromic and isolated cases. The genotype-phenotype correlations underscore the complexity of the underlying molecular pathways involved in odontogenesis. From a therapeutic perspective, the management of tooth agenesis requires a multidisciplinary approach, often involving orthodontic, prosthetic, and surgical interventions tailored to the severity of tooth loss and patient age. Early diagnosis represents a crucial role in treatment planning, facilitating timely intervention during growth and enhancing long-term outcomes. In conclusion, tooth agenesis remains a complex clinical condition with a strong genetic basis. A patient-centered and interdisciplinary strategy is essential to address both functional and psychosocial needs. Full article

(This article belongs to the Special Issue Genetic, Epigenetic and Environmental Factors in Dental Development and Pathologies: Genes, Interactions and Dental Development)

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14 pages, 638 KiB

Open AccessSystematic Review

Genetic Determinants of Colonic Diverticulosis—A Systematic Review

by Piotr Nehring and Adam Przybyłkowski

Genes 2025, 16(5), 581; https://doi.org/10.3390/genes16050581 - 15 May 2025

Viewed by 122

Abstract

Background: Colonic diverticulosis is a common condition, particularly in the elderly population. While dietary habits, obesity, smoking, and physical inactivity contribute to its pathogenesis, emerging evidence highlights a genetic predisposition affecting extracellular matrix (ECM) remodeling, inflammation, and connective tissue integrity. The aim [...] Read more.

Background: Colonic diverticulosis is a common condition, particularly in the elderly population. While dietary habits, obesity, smoking, and physical inactivity contribute to its pathogenesis, emerging evidence highlights a genetic predisposition affecting extracellular matrix (ECM) remodeling, inflammation, and connective tissue integrity. The aim of this systematic review was to summarize genetic determinants of colonic diverticulosis. Methods: The PubMed^® database was searched for original studies in humans. The inclusion criteria were named genetic factor and confirmed diverticulosis. Patients with diverticulitis and diverticular diseases were excluded from this review. Results: Out of 137 publications, 10 articles met the inclusion criteria: six large association studies (GWAS) and four cross-sectional studies. The genes regulating ECM turnover, including TIMP1, MMP3, and MMP9, are involved in diverticulosis development. The TIMP1 (rs4898) T allele has been associated with increased susceptibility, potentially due to its role in ECM remodeling. Similarly, MMP3 (rs3025058) and MMP9 (rs3918242) polymorphisms contribute to altered collagen degradation. The COL3A1 (rs3134646) variant coding modified collagen type III may promote diverticular formation. Other genes, such as ARHGAP15 (rs4662344, rs6736741), affect cytoskeletal dynamics. Identified in GWAS studies, gene candidates may be grouped into blood group and immune system-related genes (ABO, HLA-DQA1, HLA-H, OAS1, TNFSF13, FADD), extracellular matrix and connective tissue genes (COL6A1, COLQ, EFEMP1, ELN, HAS2, TIMP2), signaling and cell communication (BMPR1B, WNT4, RHOU, PHGR1, PCSK5), nervous system and neurodevelopment (BDNF, CACNB2, GPR158, SIRT1, SCAPER, TRPS1), metabolism and transporters (SLC25A28, SLC35F3, RBKS, PPP1R14A, PPP1R16B), lipids and cholesterol (LDAH, LYPLAL1, STARD13), transcription and gene regulation (ZBTB4, UBTF, TNRC6B), apoptosis (FADD, PIAS1), and poorly characterized genes (C1TNF7, ENSG00000224849, ENSG00000251283, LINC01082, DISP2, SNX24, THEM4, UBL4B, UNC50, WDR70, SREK1IP1). Conclusions: There are a number of gene variants that probably predispose to colonic diverticulosis. Detailed characterization of the multigene background of diverticulosis will enable appropriate therapeutic or preventive interventions in the future. Full article

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

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18 pages, 9166 KiB

Open AccessArticle

Analysis of Multi-Target Synergistic Mechanism of Coix Seed Therapy for Herpes Zoster Based on Machine Learning and Network Pharmacology

by Zhiqin Song, Lin Yang, Jing He, Yuchao Li, Ningxian Yang, Min Yang and Mingkai Wu

Genes 2025, 16(5), 580; https://doi.org/10.3390/genes16050580 - 14 May 2025

Viewed by 145

Abstract

Objective: To explore the efficacy and mechanism of Coix seeds in treating herpes zoster (HZ) using an integrated computational approach. Methods: Network pharmacology, molecular docking, and machine learning were employed. Disease-related targets were collected from multiple databases, and intersection targets with Coix seed [...] Read more.

Objective: To explore the efficacy and mechanism of Coix seeds in treating herpes zoster (HZ) using an integrated computational approach. Methods: Network pharmacology, molecular docking, and machine learning were employed. Disease-related targets were collected from multiple databases, and intersection targets with Coix seed were analyzed via PPI, GO, and KEGG enrichment. A “TCM-Ingredient-Target” network was constructed using Cytoscape. Molecular docking and dynamics simulations were performed for validation. Results: Fifty-five overlapping targets were identified, with core targets including TNF, EGF, and GAPDH. Enrichment analysis revealed key pathways such as inflammation and immune regulation. Molecular docking confirmed strong binding affinity between active compounds and targets. Conclusions: This study demonstrates that Coix seed exerts anti-HZ effects through multi-target mechanisms, providing a theoretical basis for developing novel multi-pathway treatment strategies. Full article

(This article belongs to the Special Issue 5Gs in Crop Genetic and Genomic Improvement: 2nd Edition)

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20 pages, 2786 KiB

Open AccessArticle

Genome-Wide Identification of the Polygalacturonase Gene Family and Its Potential Association with Abscission Zone in Capsicum annuum L.

by Lei He, Chen Lu, Xi Yan, Sha Yang, Peng Zhou, Wei Lai and Jianwen He

Genes 2025, 16(5), 579; https://doi.org/10.3390/genes16050579 - 14 May 2025

Viewed by 90

Abstract

Background: Polygalacturonase (PG) genes regulate plant organ abscission by degrading pectin in the cell wall. However, their association with pedicel abscission susceptibility in pepper remains poorly understood. Methods: 47 CaPG genes were identified were identified in the ‘Zunla1’ genome and characterized [...] Read more.

Background: Polygalacturonase (PG) genes regulate plant organ abscission by degrading pectin in the cell wall. However, their association with pedicel abscission susceptibility in pepper remains poorly understood. Methods: 47 CaPG genes were identified were identified in the ‘Zunla1’ genome and characterized by structural, evolutionary, and comparative genomic analyses. Their expression profiles across various tissues and fruit development stages were examined using transcriptome data. Ethephon treatment and qRT-PCR were employed to assess gene responses during ethylene-induced pedicel abscission. Results: The 47 CaPG genes were distributed across 12 chromosomes, with CaPG1 to CaPG5 unanchored. Most proteins were hydrophilic, nuclear-localized, and had promoters enriched in light-responsive elements. Collinearity analysis revealed limited segmental duplication, and Ka/Ks values indicated strong purifying selection. Phylogenetic and collinearity analyses showed that CaPG genes are more closely related to those in tomato than in Arabidopsis or maize. Expression profiling revealed tissue- and stage-specific patterns, with 21 CaPG genes associated with pedicel abscission susceptibility. Ethephon treatment enhanced abscission and upregulated several CaPG genes. Conclusions: This study offers insights into the CaPG gene family’s structure, evolution, and function. Specific CaPG genes likely contribute to ethylene-mediated pedicel abscission, providing potential targets for improving fruit-retention traits in pepper. Full article

(This article belongs to the Special Issue Molecular Adaptation and Evolutionary Genetics in Plants)

17 pages, 688 KiB

Open AccessReview

Gene–Diet Interactions in Diabetes Mellitus: Current Insights and the Potential of Personalized Nutrition

by Angeliki Kapellou, Effie Salata, Dimitrios Miltiadis Vrachnos, Sevastiani Papailia and Spiros Vittas

Genes 2025, 16(5), 578; https://doi.org/10.3390/genes16050578 - 14 May 2025

Viewed by 144

Abstract

Type 2 diabetes mellitus (T2DM) remaina significant global health challenge, with its increasing prevalence and associated complications contributing to high morbidity and economic burden. Genetic factors play a crucial role in T2DM susceptibility, yet individual responses to dietary interventions vary widely, emphasizing the [...] Read more.

Type 2 diabetes mellitus (T2DM) remaina significant global health challenge, with its increasing prevalence and associated complications contributing to high morbidity and economic burden. Genetic factors play a crucial role in T2DM susceptibility, yet individual responses to dietary interventions vary widely, emphasizing the importance of gene–diet (G × D) interactions. This review synthesizes the current literature on the genetic basis of T2DM and the role of G × D interactions in shaping individual responses to diet. We examine the genetics implication in T2DM risk and modulation by dietary factors, with a focus on the potential of Nutrigenetics in guiding personalized nutrition (PN) strategies. Moreover, the clinical implications of these interactions for the personalized prevention and management of T2DM are explored, highlighting the promise of tailoring dietary recommendations based on genetic profiles. Critical research gaps, including the need for diverse and longitudinal studies, the integration of multi-omic data, and the inclusion of digital health technologies in PN are discussed. Finally, future directions for the field are outlined, advocating for more inclusive, large-scale studies to optimize PN approaches for diverse populations and improve the efficacy of T2DM prevention and management. This review underscores the potential of an individualized, genetically informed dietary approach in modulating the global burden of T2DM. Full article

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

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17 pages, 5019 KiB

Open AccessArticle

PAX3 Regulatory Signatures and Gene Targets in Melanoma Cells

by Stephen P. G. Moore, Shripushkar Ganesh Krishnan, Rutu Jaswanth Kothari, Noah B. Prince, Colin Kenny, Chao Zhang and Deborah Lang

Genes 2025, 16(5), 577; https://doi.org/10.3390/genes16050577 - 14 May 2025

Viewed by 283

Abstract

Background/Objectives: PAX3 is a transcription factor that drives melanoma progression by promoting cell growth, migration, and survival, while inhibiting cellular terminal differentiation. However, known PAX3 target genes are limited and cannot fully explain the wide impact of PAX3 function. The PAX3 protein can [...] Read more.

Background/Objectives: PAX3 is a transcription factor that drives melanoma progression by promoting cell growth, migration, and survival, while inhibiting cellular terminal differentiation. However, known PAX3 target genes are limited and cannot fully explain the wide impact of PAX3 function. The PAX3 protein can regulate DNA through two separate binding domains, the Paired Domain (PD) and Homeodomain (HD), which bind different DNA motifs. It is not clear if these two domains bind and work together to regulate genes and if they promote all or only a subset of downstream cellular events. Methods: PAX3 direct downstream targets were identified using Cleavage Under Targets & Release Using Nuclease (CUT&RUN) assays in SK-MEL-5 melanoma cells. PAX3-binding genomic regions were identified through MACS2 peak calling, and peaks were categorized based on the presence of PD and/or HD binding sites (or neither) through HOMER motif analysis. The peaks were further characterized as Active, Primed, Poised, Repressed, or Closed based on ATAC-seq data and CUT&RUN for histone Post-Translational Modifications H3K4me1, H3K4me3, H3K27me3, and H3K27Ac. Results: This analysis revealed that most of the PAX3 binding sites in the SK-MEL-5 cell line were primarily through the PD and connected to Active genes. Surprisingly, PAX3 does not commonly act as a repressor in SK-MEL-5 cells. Pathway analysis identified genes involved with transcription, RNA modification, and cell growth. Peaks located in distal enhancer elements were connected to genes involved in neuronal growth, function, and signaling. Conclusions: Our results reveal novel PAX3 regulatory regions and putative genes in a melanoma cell line, with a predominance of PAX3 PD binding on active sites. Full article

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

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13 pages, 3873 KiB

Open AccessArticle

Establishment of Reference Measurement Procedure for TP53 R175H/R248W Detection and a Novel Preparation Method for ctDNA Reference Material

by Yanru Tang, Chunyan Niu, Jiejie Zhang, Lianhua Dong and Jingya Yang

Genes 2025, 16(5), 576; https://doi.org/10.3390/genes16050576 - 14 May 2025

Viewed by 133

Abstract

Background/Aims: Circulating tumor DNA (ctDNA) is becoming a valuable cancer biomarker for clinical decision-making. Nevertheless, the lack of quality control materials to assess the reliability of test results remains a challenge. This study aimed to establish digital PCR (dPCR) assays for detecting TP53 [...] Read more.

Background/Aims: Circulating tumor DNA (ctDNA) is becoming a valuable cancer biomarker for clinical decision-making. Nevertheless, the lack of quality control materials to assess the reliability of test results remains a challenge. This study aimed to establish digital PCR (dPCR) assays for detecting TP53 variants (R175H and R248W) and develop a preparation method for ctDNA reference materials to improve detection reliability. Methods: Two dPCR assays targeting TP53-R175H and TP53-R248W variants were developed and validated for repeatability, sensitivity, and linearity. Additionally, a ctDNA reference material preparation protocol was developed by digesting nucleosomes from cultured cancer cell lines with micrococcal nuclease, followed by magnetic beads purification. The size distribution and quality of the generated ctDNA fragments was analyzed, and the developed dPCR assays were applied to detect the variants in the ctDNA samples. Results: The dPCR assays demonstrated high repeatability (RSD of 0.16% to 7.65%) and excellent linearity (R² values of 1.0000 and 0.9981) across variant allele frequencies of 50%–0.1%. The limits of detection (LOD) and quantification (LOQ) were 0.143% (R175H) and 0.092% (R248W). The ctDNA reference materials exhibited single dominant peaks at 128 bp (R175H) and 143 bp (R248W). The dPCR assays successfully detected variants in these reference materials, confirming their applicability for ctDNA samples. onclusion: Firstly, accurate measurement procedures for TP53-R175H and TP53-R248W variants based on dPCR were established in this study. Furthermore, a protocol for preparing ctDNA reference material was established here. By digesting nucleosomal DNA derived from cancer cell lines with micrococcal nuclease, this method can closely mimic the properties of clinical ctDNA. The dPCR method and ctDNA reference material preparation approach established here could be used in ctDNA detection and for improving its reliability. Full article

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

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17 pages, 2313 KiB

Open AccessArticle

Mapping Inherited Genetic Variation with Opposite Effects on Autoimmune Disease and Four Cancer Types Identifies Candidate Drug Targets Associated with the Anti-Tumor Immune Response

by Junyu Chen, Michael P. Epstein, Joellen M. Schildkraut and Siddhartha P. Kar

Genes 2025, 16(5), 575; https://doi.org/10.3390/genes16050575 - 14 May 2025

Viewed by 168

Abstract

Background: Germline alleles near genes encoding certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying [...] Read more.

Background: Germline alleles near genes encoding certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetics. Methods: Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. Results: Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with p < 5 × 10⁻⁸ associated with at least one of the cancer types at p < 10⁻³ and one of the autoimmune/autoinflammatory diseases at p < 10⁻³. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping led variants to nearest genes as putative functional targets and focusing on immune-related genes implicated 32 genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (IRF1, IKZF1, SPI1, SH2B3, LAT) was each strongly correlated (Spearman’s ρ > 0.5) with at least one intra-tumor T/myeloid cell infiltration marker (CD4, CD8A, CD11B, CD45) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via the expression of quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable. Conclusions: We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3 and LAT as possible targets for cancer immunotherapy. Full article

(This article belongs to the Special Issue Genetics of Cancer Immunology)

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17 pages, 2090 KiB

Open AccessArticle

The Analysis of Autosomal STRs Draws the Current Genetic Map and Evolutionary History of Northernmost South America

by Julie Moncada Madero, Fernanda Mogollón Olivares, Dayana Suárez Medellín, Alejandra Coronel Guzmán, Andrea Casas-Vargas and William Usaquén Martínez

Genes 2025, 16(5), 574; https://doi.org/10.3390/genes16050574 - 14 May 2025

Viewed by 245

Abstract

Objectives: To analyze Colombia’s current human population, we employed a population genetics approach enriched by genealogical, demographic, cultural, and historical data to learn about its evolutionary history and to elucidate ethnic belonging and relationship patterns between its various population groups. Materials and Methods: [...] Read more.

Objectives: To analyze Colombia’s current human population, we employed a population genetics approach enriched by genealogical, demographic, cultural, and historical data to learn about its evolutionary history and to elucidate ethnic belonging and relationship patterns between its various population groups. Materials and Methods: This study relied on ten autosomal microsatellite markers (STRs) from 1364 individuals surveyed throughout the country. Aside from employing descriptive population genetics, substructure, and distance analysis, this investigation evaluated genealogical, demographic, cultural, and historical data gathered from fieldwork surveys. Results: We present a genetic diversity and ethnic belonging map of Colombia that suggests a nine-population classification (under Afro-descendant, Native American, and Admixed ethnicity labels) that reveals traces of evolutionary processes discussed in the light of the recent literature based on modern molecular markers. Colombia’s genetic trace from Africa varies among territories, as shown here by two differentiated Afro ancestral components, Chocó and San Andrés, in addition to the Afro admixture category. Some Native American peoples like the Wayúu, Zenú, Ticuna, Huitoto, and Cocama have a genetic configuration that remains relatively preserved. Nevertheless, other self-determined indigenous peoples who remain in their ancestral territories exhibit genetic introgression that is also reflected by their acculturation levels such as the Pijaos, Kankuamos, and Mokaná. The population classified as European admixture also shows an ancestral component that seems to be more fixed throughout neighboring territories but whose fluctuation depends on its specific demographic histories. Conclusions: This study combines STRs, a targeted sampling strategy, and advanced analytical tools to explore Colombia’s genetic diversity and evolutionary history. Locally, these findings enhance the understanding of genetics in a post-conflict society, crucial for human identification. Globally, they contribute to human population genetics, helping address evolutionary questions using data from diverse human ancestries and geographies. Full article

(This article belongs to the Section Population and Evolutionary Genetics and Genomics)

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18 pages, 17046 KiB

Open AccessArticle

Olig1/2 Drive Astrocytic Glioblastoma Proliferation Through Transcriptional Co-Regulation of Various Cyclins

by Yu Tian, Ziwu Wang, Mengge Sun, Jialin Li, Wenhui Zheng, Feihong Yang and Zhuangzhi Zhang

Genes 2025, 16(5), 573; https://doi.org/10.3390/genes16050573 - 13 May 2025

Viewed by 137

Abstract

As the most aggressive primary brain tumor, glioblastoma (GBM) is considered incurable due to its molecular heterogeneity and therapy resistance. Identifying key regulatory factors in GBM is critical for developing effective therapeutic strategies. Based on the analysis of TCGA data, we confirmed a [...] Read more.

As the most aggressive primary brain tumor, glioblastoma (GBM) is considered incurable due to its molecular heterogeneity and therapy resistance. Identifying key regulatory factors in GBM is critical for developing effective therapeutic strategies. Based on the analysis of TCGA data, we confirmed a robust co-expression and correlation of OLIG1 and OLIG2 in human GBM. However, their roles in the astrocytic GBM subtype remain unclear. In this study, we first establish an astrocytic-featured GBM mouse model by introducing PiggyBac-driven hEGFRvIII plasmids and demonstrate that both OLIG1 and OLIG2 are highly expressed within this context. Next, using CRISPR/Cas9 technology to knockout Olig1/2, we found that astrocyte differentiation markers such as GFAP, SOX9, and HOPX were preserved, but tumor cell proliferation was significantly diminished. Mechanistically, CUT&Tag-seq revealed that OLIG1/2 directly binds to the promoter region of various cyclins (Cdk4, Ccne2, Ccnd3, and Ccnd1), where an enrichment of the active histone marker H3K4me3 was observed, indicating transcriptional activation of the genes. Notably, Olig1/2 knockout did not suppress tumor initiation or migration, suggesting that their primary role is to amplify proliferation rather than to drive tumorigenesis. This study defines Olig1 and Olig2 as master regulators of GBM proliferation through various cyclins, thereby offering a novel therapeutic target. Full article

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

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15 pages, 2359 KiB

Open AccessArticle

The Effects of Ferulic Acid on the Growth Performance, Immune Function, Antioxidant Capacity, and Intestinal Microbiota of Broiler Chickens

by Xianguo Yi, Quanchao Ma, Zhili Li, Yuli Hu, Haigang Wu, Rui Wang, Xuyang Sun, Enen Wang, Chaofeng Ma and Qingmin Qin

Genes 2025, 16(5), 572; https://doi.org/10.3390/genes16050572 - 13 May 2025

Viewed by 129

Abstract

Objectives: Ferulic acid is a natural and safe herbal feed additive. This study aims to evaluate the effects of ferulic acid on the growth performance, anti-inflammatory and antioxidant capacities, immune function, and intestinal microbiota of broiler chickens. Methods: A total of 320 broiler [...] Read more.

Objectives: Ferulic acid is a natural and safe herbal feed additive. This study aims to evaluate the effects of ferulic acid on the growth performance, anti-inflammatory and antioxidant capacities, immune function, and intestinal microbiota of broiler chickens. Methods: A total of 320 broiler chickens, aged 14 days, were randomly divided into four groups: a blank control group (MA group), a low-concentration ferulic acid group (BM group, 10 mg/kg), a medium-concentration ferulic acid group (CM group, 30 mg/kg), and a high-concentration ferulic acid group (DM group, 90 mg/kg) after a 14-day acclimatization period. The experiment lasted for 28 days, and the chickens were dissected on day 29. Results: The results showed that compared to the MA group, the feed-to-meat ratio in the CM and DM groups was significantly reduced. The activity of duodenal trypsin in the CM and DM groups was significantly enhanced, and the activity of pancreatic protease in the DM group was significantly increased. The serum levels of urea nitrogen, creatinine, and triglycerides were significantly elevated in the CM and DM groups. The serum malondialdehyde (MDA) levels in the BM, CM, and DM groups were significantly reduced, while the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were significantly increased in the CM and DM groups. The serum interleukin-2 (IL-2) levels in the BM group were significantly decreased, while interferon-gamma (IFN-γ) levels in the CM group and complement component 3 (C-3) levels in the DM group were significantly increased. The mRNA expression levels of TLR4, MyD88, NF-κB, TNF-α, NLRP3, IL-1β, and IL-18 in the jejunum of the DM group were significantly reduced. The diversity of cecal microbiota in the ferulic acid groups changed, with a certain degree of increase in the relative abundance of Spirulina and Ruminococcus. The relative abundance of Escherichia coli in the DM group significantly increased, altering the metabolic function of the cecal microbiota in broiler chickens. Conclusions: The above results indicate that ferulic acid, as a novel feed additive for broiler chickens, has an impact on the growth performance, anti-inflammatory and antioxidant capacity, immune function, and intestinal microbiota of broiler chickens. Full article

(This article belongs to the Special Issue Genetic Breeding of Poultry)

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