Genes

14 pages, 3508 KiB

Open AccessArticle

Genetic Editing of Tomato Golgi-Localized Nucleotide Sugar Transporter 1.1 Promotes Immunity Against Phytophthora infestans

by Peize He, Yanling Cai, Yanzi Wang, Zhiqing Wang, Yaqing Lyu, Tao Li, Xingtan Zhang and Shaoqun Zhou

Genes 2025, 16(4), 470; https://doi.org/10.3390/genes16040470 - 21 Apr 2025

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Abstract

Background: Functional alleles of host plant susceptibility genes (S genes) can exacerbate the severity of diseases by enhancing pathogen compatibility. Genetic editing of the targeted host S genes has demonstrated remarkable efficacy in conferring broad-spectrum resistance across multiple crop species. We have previously [...] Read more.

Background: Functional alleles of host plant susceptibility genes (S genes) can exacerbate the severity of diseases by enhancing pathogen compatibility. Genetic editing of the targeted host S genes has demonstrated remarkable efficacy in conferring broad-spectrum resistance across multiple crop species. We have previously identified a Golgi-localized Nucleotide Sugar Transporter 1 homolog (SlGONST1.1) in the host plant Solanum lycopersicum as a susceptibility gene towards late blight caused by Phytophthora infestans. Methods: In this study, we performed a detailed characterization of tissue-specific and P. infestans-inducible expression patterns of this gene, and the subcellular localization of its encoded protein product. Results: Similar to phenotypes of two reported Slgonst1.1 edited lines, two newly generated genetically edited lines of SlGONST1.1 demonstrated enhanced resistance against P. infestans without obvious growth and developmental abnormality. Phytohormonal quantifications and reactive oxygen species measurements showed that an Slgonst1.1 line had lower constitutive abscisic acid contents and depleted reactive oxygen species burst induced by pathogen-associated molecular pattern. Further comparative transcriptomic analyses revealed that the expression of defense-related genes is disproportionally up-regulated in the Slgonst1.1 line. Conclusions: In summary, our findings confirmed SlGONST1.1 as a functional host susceptibility gene towards late blight and shed light on the potential molecular mechanism underlying its function. Full article

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

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11 pages, 238 KiB

Open AccessArticle

Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy

by Federica Francesca L’Erario, Annalisa Gazzellone, Ilaria Contaldo, Chiara Veredice, Marina Carapelle, Anna Gloria Renzi, Clarissa Modafferi, Marta Palucci, Pino D’Ambrosio, Elena Sonnini, Lorenzo Loberti, Arianna Panfili, Emanuela Lucci Cordisco, Pietro Chiurazzi, Valentina Trevisan, Chiara Leoni, Giuseppe Zampino, Maria Grazia Pomponi, Daniela Orteschi, Marcella Zollino and Giuseppe Marangi Show full author list Hide full author list

Genes 2025, 16(4), 469; https://doi.org/10.3390/genes16040469 - 20 Apr 2025

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Abstract

Background: Macrocephaly can be a component manifestation of several monogenic conditions, in association with intellectual disability/developmental delay (ID/DD) behaviour abnormalities, including autism spectrum disorders (ASD), and variable additional features. On the other hand, idiopathic ASD can present with developmental delay and macrocephaly. Methods: [...] Read more.

Background: Macrocephaly can be a component manifestation of several monogenic conditions, in association with intellectual disability/developmental delay (ID/DD) behaviour abnormalities, including autism spectrum disorders (ASD), and variable additional features. On the other hand, idiopathic ASD can present with developmental delay and macrocephaly. Methods: We carried out a retrospective analysis of a cohort of 78 patients who were tested from February 2017 to December 2024 by high-throughput sequencing of a panel of 27 genes (ABCC9, AKT1, AKT2, AKT3, BRWD3, DIS3L2, DNMT3A, EZH2, GPC3, GPC4, HERC1, MED12, MTOR, NFIA, NFIX, NSD1, PDGFRB, PIK3CA, PIK3R1, PIK3R2, PPP2R1A, PPP2R5D, PTEN, RAB39B, RNF135, SETD2, and TBC1D7) because of neurodevelopmental impairment, including ID/DD, ASD/behaviour abnormalities associated with macrocephaly, mimicking to a large extent idiopathic ASD. Results: Pathogenic variants leading to the diagnosis of monogenic conditions were detected in 22 patients (28%), including NSD1 (2), PTEN (16), and PPP2R5D (4). Distinctive of the PTEN-associated phenotype were true macrocephaly (100%), ASD or behaviour abnormalities (92%), mild/borderline ID (79%), and no facial dysmorphisms. Typical of the PPP2R5D-associated phenotype were relative macrocephaly (75%), a few unspecific peculiar facial characteristics (50%), and a more variable presentation of the neurodevelopmental phenotype. Conclusions: Pathogenic variants in PTEN and PPP2R5D are the most recurrent gene mutations in a patient-oriented procedure for the genetic diagnosis of apparently idiopathic ASD and behaviour abnormalities associated with macrocephaly. The clinical applicability of the presented diagnostic strategy is discussed. Full article

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

22 pages, 12266 KiB

Open AccessArticle

Physiological and Transcriptomic Analyses Unveil the Preservation Mechanism of Streptomyces albulus Ah11601 Fermentation Broth on ‘Shine Muscat’ Grapes

by Chao-Tian Lv, Huan Li and Ri-Mao Hua

Genes 2025, 16(4), 468; https://doi.org/10.3390/genes16040468 - 19 Apr 2025

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Abstract

Background/Objectives: Grapes (Vitis vinifera), particularly ‘Shine Muscat’, are prone to postharvest quality loss mainly due to poor storage tolerance. Actinomycetes are microbial resources that produce secondary metabolites that exhibit notable functional properties. Methods: This study explored the use of Streptomyces albulus [...] Read more.

Background/Objectives: Grapes (Vitis vinifera), particularly ‘Shine Muscat’, are prone to postharvest quality loss mainly due to poor storage tolerance. Actinomycetes are microbial resources that produce secondary metabolites that exhibit notable functional properties. Methods: This study explored the use of Streptomyces albulus Ah11601 fermentation broth (SFB) as a postharvest treatment to preserve ‘Shine Muscat’ grape quality during 6 days of room temperature storage using physiological, transcriptomic, and bioinformatics analyses to elucidate the underlying regulatory mechanism. Results: The results demonstrated that, compared to the control group stored at room temperature (25 °C) for 6 days (6D), the SFB-treated group (T6D) presented a significant delay in the decrease in fruit hardness and vitamin C content. Further investigations revealed that the 6D treatment significantly elevated lipoxygenase activity, MDA content, O₂⁻ generation rate, and H₂O₂ levels. In addition, both the 6D and T6D treatments significantly increased the activities of SOD and APX. Functional enrichment analysis revealed that the upregulated DEGs in the 6D group were predominantly enriched in pathways such as phenylpropanoid biosynthesis; flavonoid biosynthesis; phenylalanine metabolism; and stilbenoid, diarylheptanoid, and gingerol biosynthesis. The downregulated DEGs were enriched primarily in the endoplasmic reticulum protein processing pathway. In the T6D group, the upregulated DEGs were predominantly enriched in the zeatin biosynthesis pathway. In addition, significant alterations in the expression of genes associated with the ethylene and abscisic acid signaling pathways were detected. Conclusions: In conclusion, SFB treatment effectively mitigated the deterioration of the postharvest quality of ‘Shine Muscat’ grapes by preserving the cellular redox balance, regulating cytokinin and ethylene biosynthesis, and optimizing the regulation of ethylene and abscisic acid signaling. Full article

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

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12 pages, 10633 KiB

Open AccessReview

Splenic Diffuse Red Pulp Small B-Cell Lymphoma with Overlapping Clinical and Immunophenotypic Features with Hairy Cell Leukaemia: A Case Report and a Review of the Literature

by Mirette Hanna, Michola Trus and Erica DiMaria

Genes 2025, 16(4), 467; https://doi.org/10.3390/genes16040467 - 19 Apr 2025

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Abstract

Background: Splenic B-cell lymphomas and leukaemias include hairy cell leukaemia, splenic marginal zone lymphoma, splenic diffuse red pulp small B-cell lymphoma, and splenic B-cell lymphoma/leukaemia with prominent nucleoli. The main diagnostic challenge is to differentiate between splenic B-cell lymphomas and leukaemias due to [...] Read more.

Background: Splenic B-cell lymphomas and leukaemias include hairy cell leukaemia, splenic marginal zone lymphoma, splenic diffuse red pulp small B-cell lymphoma, and splenic B-cell lymphoma/leukaemia with prominent nucleoli. The main diagnostic challenge is to differentiate between splenic B-cell lymphomas and leukaemias due to highly overlapping clinical, morphologic, and phenotypic features in the absence of splenectomies for diagnostic purposes. Case presentation: We describe a case of a 78-year-old woman who presented with weight loss and was subsequently found to have pancytopenia, lymphocytosis, and splenomegaly. Peripheral blood smear showed a homogenous population of small- to medium-sized lymphocytes having oval nuclei, condensed chromatin, and villous cytoplasmic projections. Bone marrow showed B-cell infiltrate in a predominantly intrasinusoidal pattern. Except for cyclin D1 and BRAF, the immunophenotype was similar to that of hairy cell leukaemia. This was further supported by the lack of BRAF p.V600E mutation by polymerase chain reaction. A diagnosis of splenic diffuse red pulp small B-cell lymphoma was thus favored based on the lack of cyclin D1 expression and pattern of infiltration in the bone marrow biopsy. Conclusions: Awareness of this infrequent clinical presentation and immunophenotype of splenic diffuse red pulp small B-cell lymphoma is crucial for diagnosis and devising appropriate therapeutic strategies for the patient. Full article

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

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22 pages, 5264 KiB

Open AccessArticle

miR-143-3p Promotes T_SCM Differentiation and Inhibits Progressive T Cell Differentiation via Inhibiting ABL2 and PAG1

by Wenkai Shi, Jieming Hu, Hongqiong Wang, Huishan Zhong, Wenfeng Zhang, Jinquan Wang, Hongwei Shao, Han Shen, Huaben Bo, Changli Tao and Fenglin Wu

Genes 2025, 16(4), 466; https://doi.org/10.3390/genes16040466 - 19 Apr 2025

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Abstract

Background: Adoptive cell therapy (ACT), including CAR-T and TCR-T therapies, shows promise for cancer treatment, depending on infused T cell expansion, persistence and activity. We previously characterized four T-cell subsets (T_N, T_SCM, T_CM and T_EM) and [...] Read more.

Background: Adoptive cell therapy (ACT), including CAR-T and TCR-T therapies, shows promise for cancer treatment, depending on infused T cell expansion, persistence and activity. We previously characterized four T-cell subsets (T_N, T_SCM, T_CM and T_EM) and their miRNA profiles. Objectives: This study investigates miR-143-3p’s role in T cell differentiation. Methods: Using qPCR, we analyzed miR-143-3p expression. Target genes were validated by dual-luciferase assays. Functional assays assessed differentiation markers, proliferation, apoptosis and cytokine secretion. Results: miR-143-3p was upregulated in early-differentiated T_SCM but downregulated during progression. We confirmed ABL2 and PAG1 as direct targets suppressed by miR-143-3p. Overexpression increased early markers (LEF1, CCR7 and CD62L) while decreasing late markers (EOMES, KLRG1 and CD45RO). It also enhanced proliferation, reduced apoptosis and suppressed cytokine secretion. Conclusions: miR-143-3p promotes T_SCM differentiation and inhibits progressive differentiation by targeting ABL2/PAG1, suggesting new ACT optimization strategies. Full article

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

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30 pages, 2870 KiB

Open AccessReview

Barth Syndrome: TAFAZZIN Gene, Cardiologic Aspects, and Mitochondrial Studies—A Comprehensive Narrative Review

by Consolato M. Sergi

Genes 2025, 16(4), 465; https://doi.org/10.3390/genes16040465 (registering DOI) - 18 Apr 2025

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Abstract

Barth syndrome (BTHS) is inherited through an X-linked pattern. The gene is located on Xq28. Male individuals who inherit the TAFAZZIN pathogenic variant will have the associated condition, while female individuals who inherit the TAFAZZIN pathogenic variant generally do not experience the condition. [...] Read more.

Barth syndrome (BTHS) is inherited through an X-linked pattern. The gene is located on Xq28. Male individuals who inherit the TAFAZZIN pathogenic variant will have the associated condition, while female individuals who inherit the TAFAZZIN pathogenic variant generally do not experience the condition. There are several organs that may be affected, but striking is the cardiological involvement. Cardiovascular disease, which may be the trigger starting the diagnostic procedure in a proband, may include a range of diseases from a severely dilated heart to a hypertrophic heart in the spectrum of anomalies encountered. Left ventricular non-compaction of the heart is also occasionally encountered. This cardiac event may reveal the prognosis of the affected patients. In this narrative review, we highlight the gene’s characteristics, the reactome, the cardiological features of the cardiovascular disease observed in patients affected with BTHS, emphasize the most current studies on BTHS cardiomyopathy, and delineate the biological underlying mechanisms supporting the proposal of new therapeutic options. Full article

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13 pages, 1729 KiB

Open AccessArticle

Novel Truncating Variants in PODXL Represent a New Entity to Be Explored Among Podocytopathies

by José María García-Aznar, María Lara Besada-Cerecedo, Cristina Castro-Alonso, Milagros Sierra Carpio, Miquel Blasco, Borja Quiroga, Michal Červienka, Ricardo Mouzo, Roser Torra, Alberto Ortiz and Patricia de Sequera

Genes 2025, 16(4), 464; https://doi.org/10.3390/genes16040464 - 18 Apr 2025

Viewed by 264

Abstract

Background/Objectives: Podocalyxin is a sialoprotein mainly expressed in the kidney cortex and lung tissue, which has been described as a component of the podocyte glycocalyx. This protein promotes the reorganization of the podocyte cytoskeleton, as well as the morphogenesis and differentiation of nascent [...] Read more.

Background/Objectives: Podocalyxin is a sialoprotein mainly expressed in the kidney cortex and lung tissue, which has been described as a component of the podocyte glycocalyx. This protein promotes the reorganization of the podocyte cytoskeleton, as well as the morphogenesis and differentiation of nascent podocytes, actively participating in glomerular filtration. Previous research has suggested that PODXL haploinsufficiency leads to podocytopathy with development of focal segmental glomerulosclerosis, a disorder that has been demonstrated in Podxl-deficient animal models and proposed as a primary cause in human families affected by this condition. However, only a few families have been reported, which limits the understanding about the spectrum of phenotype and prognosis of the disease. Methods: We performed high-throughput sequencing in a cohort of young adults with CKD, describing the clinical scenario of those who harbored truncating variants in the PODXL gene and testing the families for detected variants. Results: The PODXL gene exhibited a slight deviation in loss intolerance probability and moderate deviation in the observed/expected ratio of variation, which is typically observed in dominant genes with age-dependent incomplete penetrance or variable expression. We reported four novel truncating variants in the PODXL gene, along with a collection of previously published monoallelic truncating variants. Conclusions: These findings further support evidence about genetic defects in the PODXL gene associated with a new molecular entity of podocytopathy with adult onset. Additionally, the nucleotide sequence of PODXL contains particularities that require careful analysis to interpret the effect of the variants detected in this gene. Full article

(This article belongs to the Section Genetic Diagnosis)

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16 pages, 11711 KiB

Open AccessArticle

The Solute Carrier Superfamily as Therapeutic Targets in Pancreatic Ductal Adenocarcinoma

by Sang Yeon Cho, Hyuk Soo Eun, Jaejeung Kim, Yun Dam Ko, Woo Sun Rou and Jong Seok Joo

Genes 2025, 16(4), 463; https://doi.org/10.3390/genes16040463 - 18 Apr 2025

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Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC), a challenging and malignant cancer, primarily originates from the exocrine cells of the pancreas. The superfamily of solute carrier (SLC) transporters, consisting of more than 450 proteins divided into 65 families, is integral to various cellular processes and [...] Read more.

Background: Pancreatic ductal adenocarcinoma (PDAC), a challenging and malignant cancer, primarily originates from the exocrine cells of the pancreas. The superfamily of solute carrier (SLC) transporters, consisting of more than 450 proteins divided into 65 families, is integral to various cellular processes and represents a promising target in precision oncology. As therapeutic targets, SLC transporters are explored through an integrative analysis. Materials and Methods: The expression profiles of SLCs were systematically analyzed using mRNA data from The Cancer Genome Atlas (TCGA) and protein data from the Human Protein Atlas (HPA). Survival analysis was examined to evaluate the prognostic significance of SLC transporters for overall survival (OS) and disease-specific survival (DSS). Genetic alterations were examined using cBioPortal, while structural studies were performed with AlphaFold and AlphaMissense to predict functional impacts. Furthermore, Gene Set Enrichment Analysis (GSEA) was carried out to identify oncogenic pathways linked to SLC transporter expression. Results: SLC transporters were significantly upregulated in tumors relative to normal tissues. Higher expression levels of SLC39A10 (HR = 1.89, p = 0.0026), SLC22B5 (HR = 1.84, p = 0.0042), SLC55A2 (HR = 2.15, p = 0.00023), and SLC30A6 (HR = 1.90, p = 0.003) were strongly associated with unfavorable OS, highlighting their connection to poor prognosis in PDAC. GSEA highlighted that these four transporters are significantly involved in key oncogenic pathways, such as epithelial–mesenchymal transition (EMT), TNF-α signaling, and angiogenesis. Conclusions: The study identifies four SLCs as therapeutic targets in PDAC, highlighting their crucial role in essential metabolic pathways. These findings lay the groundwork for developing next-generation metabolic anti-cancer treatment to improve survival for PDAC patients. Full article

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

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14 pages, 2794 KiB

Open AccessArticle

Comprehensive Analysis of Ghd7 Variations Using Pan-Genomics and Prime Editing in Rice

by Jiarui Wang, Shihang Liu, Jisong Pu, Jun Li, Changcai He, Lanjing Zhang, Xu Zhou, Dongyu Xu, Luyao Zhou, Yuting Guo, Yuxiu Zhang, Yang Wang, Bin Yang, Pingrong Wang, Xiaojian Deng and Changhui Sun

Genes 2025, 16(4), 462; https://doi.org/10.3390/genes16040462 - 17 Apr 2025

Viewed by 184

Abstract

The Ghd7 gene in rice plays a crucial role in determining heading date, plant height, and grain yield. However, the variations in Ghd7 and their functional implications across different rice accessions are not fully understood. Based on the release of a large amount [...] Read more.

The Ghd7 gene in rice plays a crucial role in determining heading date, plant height, and grain yield. However, the variations in Ghd7 and their functional implications across different rice accessions are not fully understood. Based on the release of a large amount of rice genome data in recent years, we investigated Ghd7 through pan-genome analysis of 372 diverse rice varieties and figured out the structural variations (SVs) in the Ghd7 locus. However, due to the high cost of pan-genomes, most genomes are based on next-generation sequencing (NGS) data now. Therefore, we developed a method for identifying SVs using NGS data and Polymerase Chain Reaction (PCR) based on the results of pan-genome analysis and identified 977 accessions carrying such SVs of Ghd7. Furthermore, we identified 46 single-nucleotide polymorphisms (SNPs) and one insertion-deletion (InDel) in the coding region of Ghd7. They are classified into 49 haplotypes. Notably, a splice-site mutation in haplotype H6 causes aberrant mRNA splicing. Using prime editing (PE) technology, we successfully restored the functional of Ghd7 in Yixiang 1B (YX1B), delaying the heading date by approximately 16 days. This modification synchronized the heading date between YX1B and the restorer line Yahui 2115 (YH2115R), enhancing the hybrid rice seed production efficiency. In conclusion, our findings highlight the potential of integrating pan-genomics and precision gene editing to accelerate crop improvement and enhance agronomic traits. Full article

(This article belongs to the Collection Feature Papers: 'Plant Genetics and Genomics' Section)

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10 pages, 866 KiB

Open AccessArticle

Genetic Profiling and Performance Optimization in Elite Combat Sport Athletes: A Cross-Sectional Study Based on Total Genetic Score Analysis

by Andrea Pagliaro, Anna Alioto, Alessia Boatta, Giuseppe Messina, Patrik Drid, Paolo Milazzo, Cristina Cortis, Andrea Fusco, Sonya Vasto, Patrizia Proia and Sara Baldassano

Genes 2025, 16(4), 461; https://doi.org/10.3390/genes16040461 - 17 Apr 2025

Viewed by 508

Abstract

Background/Objectives: The interplay between genetics and athletic performance has garnered significant attention, particularly regarding performance-enhancing polymorphisms (PEPs) and their role in determining key traits that are critical for athletic success. Therefore, this study investigates the genetic predispositions related to peroxisome proliferator-activated receptor alpha [...] Read more.

Background/Objectives: The interplay between genetics and athletic performance has garnered significant attention, particularly regarding performance-enhancing polymorphisms (PEPs) and their role in determining key traits that are critical for athletic success. Therefore, this study investigates the genetic predispositions related to peroxisome proliferator-activated receptor alpha (PPARα), angiotensin converting enzyme (ACE), and creatine kinase muscle-type (CKM) gene variants and their potential influence on elite point-fighting (PF) athletes. Methods: A total of 24 elite PF athletes (12 women and 12 men; age = 22.1 ± 5.8 years; body mass = 66.1 ± 15.4 kg; and height = 173.0 ± 9.5 cm, BMI = 21.8 ± 3.2 kg·m⁻²) participated in the study. Saliva samples were collected for DNA extraction and genotyping, analyzing the prevalence of key genetic markers, including the D allele and ID genotype for the ACE variant, the G allele and GG genotype for PPARα, and the A allele and AA genotype for CKM. Results: Genotyping revealed a high prevalence of key genetic markers among participants, with the D allele (58.33%) and ID genotype (66.67%) for the ACE variant, the G allele (77.08%) and GG genotype (54.17%) for PPARα, and the A allele (77.08%) with an AA genotype (62.50%) for CKM. The Total Genetic Score (TGS) analysis indicated a mixed-oriented genetic predisposition across the sample. Conclusions: Although PF athletes showed mixed aerobic/anaerobic genetic profiles, their training routines were primarily strength-oriented, suggesting a possible misalignment between genetic predispositions and their current training approach. These findings offer preliminary insights into the genetic characteristics of elite PF athletes and may inform future investigations into the potential role of genetic information in guiding training strategies. Full article

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

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21 pages, 6764 KiB

Open AccessArticle

Genome-Wide Identification and Expression Pattern Analysis of SBP Gene Family in Neolamarckia cadamba

by Linhan Tang, Keying Li, Chuqing Cai, Wenjun Wu, Guichen Jian, Ziming Lei, Changcao Peng and Jianmei Long

Genes 2025, 16(4), 460; https://doi.org/10.3390/genes16040460 - 17 Apr 2025

Viewed by 153

Abstract

Background: SQUAMOSA promoter-binding protein (SBP) genes encode a group of plant-specific transcription factors that play crucial roles in plant growth, development, and stress responses. To date, SBP genes have been reported in a number of plant species, but the SBP gene family [...] Read more.

Background: SQUAMOSA promoter-binding protein (SBP) genes encode a group of plant-specific transcription factors that play crucial roles in plant growth, development, and stress responses. To date, SBP genes have been reported in a number of plant species, but the SBP gene family has not been identified in Neolamarckia cadamba, an important fast-growing species referred to as a ‘miracle tree’ and recognized for its potential medicinal value in Southeast Asia. Methods: Bioinformatics approaches were employed to conduct a comprehensive analysis of the NcSBP gene family, including investigations into physicochemical characteristics, phylogenetic relationships, gene structure, chromosomal localization, conserved motifs, cis-acting elements, and expression patterns. Results: A total of 27 NcSBP members were identified in the N. cadamba genome, encoding proteins ranging from 148 to 1038 amino acids in length, with molecular weights between 16,714.34 and 114,331.61 Da. They were classified into eight clades according to phylogenetic analysis, and unevenly distributed across 17 chromosomes, with 4 tandem gene duplication pairs and 27 fragment duplication events. In addition, cis-acting elements associated with hormone and light responses were most presented in the promoters of NcSBP genes. The transcript levels of NcSBP were investigated through RNA-seq and qRT-PCR, indicating distinct expression patterns across various tissues and under different hormone and stress conditions. Conclusions: In summary, this study comprehensively identified and characterized the SBP gene family in N. cadamba, providing a significant foundation for further functional investigation into NcSBP genes. Full article

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

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10 pages, 885 KiB

Open AccessCase Report

Loose Anagen Hair Associated with Wooly Hair Caused by a Heterozygous, Intronic KRT71 Variant

by Elizabeth Phillippi, Marcelo Melo, Kelly N. Messingham and Hatem El-Shanti

Genes 2025, 16(4), 459; https://doi.org/10.3390/genes16040459 - 17 Apr 2025

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Abstract

Background: Loose anagen hair syndrome is a recently described genetic form of non-scarring alopecia that occurs in children and is due to poorly anchored hair shafts during the anagen phase. It can occur alone or in association with hair pathology or complex systemic [...] Read more.

Background: Loose anagen hair syndrome is a recently described genetic form of non-scarring alopecia that occurs in children and is due to poorly anchored hair shafts during the anagen phase. It can occur alone or in association with hair pathology or complex systemic phenotypes. Methods: We report a mother and daughter with loose anagen hair syndrome that is associated with wooly hair, although it shows variable expressivity. We studied the family using genomic sequencing and identified an intronic variant in their KRT71 that segregates in an autosomal dominant pattern and is suspected to affect splicing in the tail domain of this hair follicle keratin. We studied this variant with a minigene experimental approach. Results: We provide experimental evidence that the identified intronic variant affects splicing in the tail domain, which is critical to the biomechanical properties of the keratin intermediate filaments. We demonstrate that it affects splicing by adding 12 bases to the mature transcript and consequently four amino acids to the peptide. Conclusion: We suspect that this variant is responsible for the poorly anchored and finely curled hair in the mother and daughter, which leads to a proposed diagnosis of autosomal dominant wooly hair, as well as loose anagen hair syndrome. We thus expand the variant spectrum of KRT71 and its associated phenotypes to include both disorders. Full article

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

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18 pages, 2729 KiB

Open AccessArticle

Genetic Features of Tumours Arising in the Context of Suspected Hereditary Cancer Syndromes with RAD50, RAD51C/D, and BRIP1 Germline Mutations, Results of NGS-Reanalysis of BRCA/MMR-Negative Families

by Mónica Arranz-Ledo, Mar Infante, Enrique Lastra, Amaya Olaverri, Marta Orozco, Lucia C. Mateo, Noemí Martínez, Lara Hernández and Mercedes Durán

Genes 2025, 16(4), 458; https://doi.org/10.3390/genes16040458 - 16 Apr 2025

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Abstract

Background and Objectives: Despite the well-established role of the BRCA and mismatch repair (MMR) genes in DNA damage repair pathways, a substantial proportion of familial cancer cases still lack pathogenic variants in those genes. Next Generation Sequencing (NGS) panels have emerged as a [...] Read more.

Background and Objectives: Despite the well-established role of the BRCA and mismatch repair (MMR) genes in DNA damage repair pathways, a substantial proportion of familial cancer cases still lack pathogenic variants in those genes. Next Generation Sequencing (NGS) panels have emerged as a powerful tool to identify hereditary cancer at-risk individuals and subsequently provide them with accurate management. Materials and Methods: Families harbouring PVs in RAD50, RAD51C, RAD51D, and BRIP1 were identified by analysing a cancer-predisposing genes panel using Ion S5 system technology. A retrospective cohort of 155 families tested only for the BRCAs of MMR genes were reanalysed, prompted by an increase in familial cases or new cancer diagnoses among index cases. Results: We identified 40 families through molecular reanalysis (33 with Hereditary Breast and Ovarian Cancer (HBOC) and 7 with Lynch Syndrome (LS)), with positive test results among 155 families lacking BRCA or MMR mutations. The most frequently mutated genes after ATM and CHEK2 were BRIP1, RAD51D, and RAD51C with 16, 13, and 9 positive families, respectively. The phenotype–genotype correlations not only revealed ovarian and HER-negative breast cancer predispositions but also other cancer types, particularly lung and gastric, and individuals with a second or third distinct cancer episode. Conclusions: Broader ranges of malignancies, including gastric, lung, and bladder, have been identified among BRIP1, RAD51D, and RAD51C positive families. The results generated using NGS provide a comprehensive genetic landscape in each patient that could explain the diversity of phenotypes shown in PV families that, combined with non-genetic factors, might enable accurate surveillance and personalized treatments. NGS reanalysis doubled our diagnostic yield and was a good strategy to identify hereditary cancer families that would otherwise be overlooked. Full article

(This article belongs to the Special Issue Genetics, Molecular Profiling, and Precision Medicine in Gastric and Esophagogastric Cancer)

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13 pages, 6996 KiB

Open AccessArticle

Decoding the Mitochondrial Genome of the Tiger Shrimp: Comparative Genomics and Phylogenetic Placement Within Caridean Shrimps

by Zhengfei Wang, Weijie Jiang, Jingxue Ye, Huiwen Wu, Yan Wang and Fei Xiong

Genes 2025, 16(4), 457; https://doi.org/10.3390/genes16040457 - 16 Apr 2025

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Abstract

Background/Objectives: Freshwater shrimps of the family Atyidae, particularly the hyperdiverse genus Caridina, are keystone decomposers in tropical aquatic ecosystems and valuable aquaculture resources. However, their evolutionary relationships remain unresolved due to conflicting morphological and molecular evidence. Here, we sequenced and characterized the complete [...] Read more.

Background/Objectives: Freshwater shrimps of the family Atyidae, particularly the hyperdiverse genus Caridina, are keystone decomposers in tropical aquatic ecosystems and valuable aquaculture resources. However, their evolutionary relationships remain unresolved due to conflicting morphological and molecular evidence. Here, we sequenced and characterized the complete mitochondrial genome of Caridina mariae (Tiger Shrimp), aiming to (1) elucidate its genomic architecture, and (2) reconstruct a robust phylogeny of Caridea using 155 decapod species to address long-standing taxonomic uncertainties. Methods: Muscle tissue from wild-caught C. mariae (voucher ID: KIZ-2023-001, Guangdong, China) was subjected to Illumina NovaSeq 6000 sequencing (150 bp paired-end). The mitogenome was assembled using MITObim v1.9, annotated via MITOS2, and validated by PCR. Phylogenetic analyses employed 13 protein-coding genes under Bayesian inference (MrBayes v3.2.7; 10⁶ generations, ESS > 200) and maximum likelihood (RAxML v8.2.12; 1000 bootstraps), with Harpiosquilla harpax as the outgroup. The best-fit substitution model (MtZoa + F + I + G4) was selected via jModelTest v2.1.10. Results: The 15,581 bp circular mitogenome encodes 37 genes (13 PCGs, 22 tRNAs, and 2 rRNAs) and an A + T-rich control region (86.7%). Notably, trnS1 lacks the dihydrouracil arm—a rare structural deviation in Decapoda. The 13 PCGs exhibit moderate nucleotide skew (AT = 0.030; GC = −0.214), while nad5, nad4, and nad6 show significant GC-skew. Phylogenomic analyses strongly support (PP = 1.0; BS = 95) a novel sister-group relationship between Halocaridinidae and Typhlatyinae, contradicting prior morphology-based classifications. The monophyly of Penaeoidea, Astacidea, and Caridea was confirmed, but Eryonoidea and Crangonoidea formed an unexpected clade. Conclusions: This study provides the first mitogenomic framework for C. mariae, revealing both conserved features (e.g., PCG content) and lineage-specific innovations (e.g., tRNA truncation). The resolved phylogeny challenges traditional Caridea classifications and highlights convergent adaptation in freshwater lineages. These findings offer molecular tools for the conservation prioritization of threatened Caridina species and underscore the utility of mitogenomics in decapod systematics. Full article

(This article belongs to the Special Issue Molecular Evolution, Mitochondrial Genomics and Mitochondrial Genome Expression in Animals: 2024–2025)

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20 pages, 5422 KiB

Open AccessArticle

IL-6 Affects Liver Metabolic Abnormalities Caused by Silicon Exposure by Regulating the PKC/YY1 Signaling Pathway

by Hui Zhao, Huihui Tao, Jian Gao, Jingjing Wang, Guangliang Hui, Ye Zhu, Jialin Wang, Xuansheng Ding and Yong Dai

Genes 2025, 16(4), 456; https://doi.org/10.3390/genes16040456 - 16 Apr 2025

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Abstract

Background: This study aims to investigate the impact of coal dust (silicon dioxide) exposure on dyslipidemia and its underlying mechanisms, with a focus on the association between coal dust exposure and hepatic metabolic disorders. Methods: Clinical data were collected from 5433 coal mine [...] Read more.

Background: This study aims to investigate the impact of coal dust (silicon dioxide) exposure on dyslipidemia and its underlying mechanisms, with a focus on the association between coal dust exposure and hepatic metabolic disorders. Methods: Clinical data were collected from 5433 coal mine workers to compare the incidence of dyslipidemia between the dust-exposed group and the non-exposed group. A mouse model of silicon dioxide exposure was established to observe hepatic fat accumulation and pathological changes. Liver tissue sequencing was performed to screen for key differential genes. In vitro cell experiments were utilized to identify the molecular mechanisms underlying hepatocyte metabolic abnormalities induced by silicon dioxide exposure. Results: Clinical data revealed that 69.2% of miners in the dust-exposed group developed dyslipidemia, which was higher than the 30.7% in the non-exposed group. Animal data showed that silicon dioxide exposure led to hepatic fat deposition and pathological damage, with the degree of injury positively correlated with exposure time. Liver sequencing identified a significant upregulation of the FMO3 (flavin monooxygenase 3) gene in mouse liver tissue following silicon dioxide exposure, accompanied by enhanced inflammatory responses. Mechanistic studies demonstrated that silicon dioxide activates Kupffer cells to secrete IL-6 (interleukin-6), which induces high expression of FMO3 in hepatocytes through the PKC/YY1 signaling pathway, thereby disrupting lipid metabolism. Conclusions: Silicon dioxide exposure can promote the upregulation of FMO3 expression in hepatocytes by activating Kupffer cells to release IL-6 via the PKC/YY1 pathway, ultimately leading to lipid metabolic disorders and dyslipidemia Full article

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

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15 pages, 6105 KiB

Open AccessArticle

Inferring the Degree of Relatedness and Kinship Types Using an All-in-One Marker Set

by Ran Li, Yu Zang, Jiajun Liu, Enlin Wu, Riga Wu and Hongyu Sun

Genes 2025, 16(4), 455; https://doi.org/10.3390/genes16040455 - 15 Apr 2025

Viewed by 188

Abstract

Background/Objectives: Kinship inference is commonly adopted in various forensic applications, but previous studies have often lacked precision. Methods: In this study, a new method for the nomenclature of kinship types, i.e., kinship chain (KC), was proposed, and then, six types of identity by [...] Read more.

Background/Objectives: Kinship inference is commonly adopted in various forensic applications, but previous studies have often lacked precision. Methods: In this study, a new method for the nomenclature of kinship types, i.e., kinship chain (KC), was proposed, and then, six types of identity by state (IBS) scores were calculated for simulated and real families using four types of markers. Finally, several Bayesian network (BN)-based classifiers were constructed to investigate the efficiency of the kinship inference. Results: A total of 7, 22, 58, and 3 KCs were obtained for common first-, second-, and third-degree relatives and unrelated pairs, respectively. High accuracies could be achieved in distinguishing between related and unrelated pairs after combining the four types of genetic markers, with an accuracy of >99.99% for all 7 KCs of first-degree relationships and ~99% for 14 out of 22 KCs of second-degree relatives. When comparing relationships of the same degree, the accuracies were 99.28%, 42.31%, and 15.82% for first-, second-, and third-degree relationships, respectively. When it came to differentiating unspecific relationships, the overall accuracy was over 80%. All the results were validated on real family data. Conclusions: With the new nomenclature method of kinship types and the combination of autosomal and non-autosomal genetic markers, kinship inference can be realized with high accuracy and precision, which will be helpful in complex forensic cases, such as the identification of mass disaster victims. Full article

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

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18 pages, 1347 KiB

Open AccessArticle

Population-Specific Differences in Pathogenic Variants of Genes Associated with Monogenic Parkinson’s Disease

by Victor Flores-Ocampo, Amanda Wei-Yin Lim, Natalia S. Ogonowski, Luis M. García-Marín, Jue-Sheng Ong, Dennis Yeow, Claudia Gonzaga-Jauregui, Kishore R. Kumar and Miguel E. Rentería

Genes 2025, 16(4), 454; https://doi.org/10.3390/genes16040454 - 15 Apr 2025

Viewed by 341

Abstract

Background: Parkinson’s disease (PD) is a genetically complex neurodegenerative disorder. Up to 15% of cases are considered monogenic. However, research on monogenic PD has largely focused on populations of European ancestry, leaving gaps in our understanding of genetic variability in other populations. This [...] Read more.

Background: Parkinson’s disease (PD) is a genetically complex neurodegenerative disorder. Up to 15% of cases are considered monogenic. However, research on monogenic PD has largely focused on populations of European ancestry, leaving gaps in our understanding of genetic variability in other populations. This study addresses this gap by analysing the allele frequencies of pathogenic and likely pathogenic variants in known monogenic PD genes across eight global populations, using data from the gnomAD database. Methods: We compiled a list of 27 genes associated with Mendelian PD from the Online Mendelian Inheritance in Man (OMIM) database, and identified pathogenic and likely pathogenic variants using ClinVar. We then performed pairwise comparisons of allele frequencies across populations included in the gnomAD database. Variants with significant frequency differences were further assessed using in silico pathogenicity predictions. Results: We identified 81 variants across 17 genes with statistically significant allele frequency differences between at least two populations. Variants in GBA1 were the most prevalent among monogenic PD-related genes, followed by PLA2G6, ATP13A2, VPS13C, and PRKN. GBA1 exhibited the greatest variability in allele frequencies, particularly the NM_000157.4:c.1226A>G (p.Asn409Ser) variant. Additionally, we observed significant population-specific differences in PD-related variants, such as the NM_032409.3:c.1040T>C (p.Leu347Pro) variant in PINK1, which was most prevalent in East Asian populations. Conclusions: Our findings reveal substantial population-specific differences in the allele frequencies of pathogenic variants linked to monogenic PD, emphasising the need for broader genetic studies beyond European populations. These insights have important implications for PD research, genetic screening, and understanding the pathogenesis of PD in diverse populations. Full article

(This article belongs to the Special Issue Genetics of Parkinson’s Disease Around the World)

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16 pages, 1058 KiB

Open AccessArticle

Association of ABC Efflux Transporter Genetic Variants and Adverse Drug Reactions and Survival in Patients with Non-Small Lung Cancer

by Cecilia Souto Seguin, Giovana Fernanda Santos Fidelis, Carolina Dagli-Hernandez, Pedro Eduardo Nascimento Silva Vasconcelos, Mariana Vieira Morau, Yasmim Gabriele Matos, Maurício Wesley Perroud, Jr., Eder de Carvalho Pincinato and Patricia Moriel

Genes 2025, 16(4), 453; https://doi.org/10.3390/genes16040453 - 15 Apr 2025

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Abstract

Background/Objectives: Lung cancer has a high mortality rate worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent. Carboplatin and paclitaxel are key treatments for NSCLC; however, adverse drug reactions (ADRs) pose significant challenges. This study examined the impact of genetic variations [...] Read more.

Background/Objectives: Lung cancer has a high mortality rate worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent. Carboplatin and paclitaxel are key treatments for NSCLC; however, adverse drug reactions (ADRs) pose significant challenges. This study examined the impact of genetic variations in ABCB1 and ABCC2 genes on the incidence of ADRs and survival in NSCLC patients treated with carboplatin and paclitaxel. Methods: Variants were identified using RT-PCR, and ADRs classified according to the Common Toxicity Criteria for Adverse Events, Version 4.03. Results: The ABCB1 rs1128503 (c.1236C>T) CC genotype was associated with a higher chance of nausea (OR: 3.5, 95% CI 1.367–9.250, p = 0.0093), vomiting (OR: 13.553, 95% CI 1.705–107.723, p = 0.0137), and a higher risk of death in CT or TT genotypes (HR: 1.725, 95% CI 1.036–2.871, p = 0.0361). The ABCC2 rs717620 (c.-24C>T) TT genotype was associated with increased ALP levels (OR: 14.6, 95% CI 1.234–174.236, p = 0.0335). The ABCB1 rs2032582 non-CC genotypes (TT+AA+TA+CA+CT) were associated with an increased risk of death (HR: 1.922, 95% CI 1.093–3.377, p = 0.0232). Patients with hypocalcemia (HR: 2.317, 95% IC 1.353–3.967, p = 0.022), vomiting (HR: 3.047, 95% IC 1.548–5.997, p = 0.0013), and diarrhea (HR: 2.974, 95% IC 1.590–5.562, p = 0.0006) were associated with lower overall survival. Conclusions: The data suggest that ABCB1 variants may influence gastrointestinal ADRs and patient survival, highlighting the importance of pharmacogenomics in predicting ADRs and drug resistance. This approach offers more precise pharmacotherapy, reduces ADRs, and enhances the patients’ quality of life and survival. Full article

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

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19 pages, 10518 KiB

Open AccessArticle

Deciphering Gut Microbiome in Colorectal Cancer via Robust Learning Methods

by Huiye Han, Ying Li, Youran Qi, Stefano Mangiola and Wodan Ling

Genes 2025, 16(4), 452; https://doi.org/10.3390/genes16040452 - 15 Apr 2025

Viewed by 314

Abstract

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and is closely linked to the gut microbiota. Identifying reproducible and generalizable microbial signatures holds significant potential for enhancing early detection and advancing treatment for this deadly disease. Methods: This study [...] Read more.

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and is closely linked to the gut microbiota. Identifying reproducible and generalizable microbial signatures holds significant potential for enhancing early detection and advancing treatment for this deadly disease. Methods: This study integrated various publicly available case-control datasets to identify microbial signatures for CRC. Alpha and beta diversity metrics were evaluated to characterize differences in gut microbial richness, evenness, and overall composition between CRC patients and healthy controls. Differential abundance analysis was conducted using ANCOM-BC and LEfSe to pinpoint individual taxa that were enriched or depleted in CRC patients. Additionally, sccomp, a Bayesian machine learning method from single-cell analysis, was adapted to provide a more robust validation of compositional differences in individual microbial markers. Results: Gut microbial richness is significantly higher in CRC patients, and overall microbiome composition differs significantly between CRC patients and healthy controls. Several taxa, such as Fusobacterium and Peptostreptococcus, are enriched in CRC patients, while others, including Anaerostipes, are depleted. The microbial signatures identified from the integrated data are reproducible and generalizable, with many aligning with findings from previous studies. Furthermore, the use of sccomp enhanced the precision of individual microbial marker identification. Conclusions: Biologically, the microbial signatures identified from the integrated data improve our understanding of the gut microbiota’s role in CRC pathogenesis and may contribute to the development of translational targets and microbiota-based therapies. Methodologically, this study demonstrates the effectiveness of adapting robust techniques from single-cell research to improve the precision of microbial marker discovery. Full article

(This article belongs to the Special Issue Advances in Bioinformatics and Environmental Health)

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17 pages, 7485 KiB

Open AccessArticle

Identification and Expression Analysis of Chalcone Synthase Gene Family in Tartary Buckwheat

by Qinghai Wang, Yanhua Jia, Xin Lin, Lu Tan, Hanmei Du and Anhu Wang

Genes 2025, 16(4), 451; https://doi.org/10.3390/genes16040451 - 14 Apr 2025

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Abstract

Background: Chalcone synthase (CHS) functions as a pivotal and initiating enzyme in the flavonoid biosynthesis pathway within plants, playing a crucial role in the accumulation and metabolic processes of flavonoids. Despite its importance, there has been no comprehensive analysis or detailed description of [...] Read more.

Background: Chalcone synthase (CHS) functions as a pivotal and initiating enzyme in the flavonoid biosynthesis pathway within plants, playing a crucial role in the accumulation and metabolic processes of flavonoids. Despite its importance, there has been no comprehensive analysis or detailed description of the CHS gene family members specifically in Tartary buckwheat. Methods: Based on a comprehensive analysis using multiple bioinformatics approaches and quantitative real−time PCR (qRT−PCR) technology, this study systematically identified and characterized the CHS gene family members from the complete genome sequence of Tartary buckwheat. Results: In this study, we identified a total of 14 FtCHS genes (FtCHS1−FtCHS14) in Tartary buckwheat. Analysis of gene structure and protein motifs showed that most FtCHS genes consist of two exons and a single intron, featuring conserved Chal−sti−synt_N and Chal−sti−synt_C domains. Phylogenetic studies suggested that FtCHS genes can be categorized into four primary groups: Groups I, II, III, and IV. Further analysis of the promoter regions revealed that the FtCHS family genes contain multiple cis−acting elements that respond to light, plant hormones, stress, and developmental cues. By combining phylogenetic analysis with gene expression data, we found that the genes in Group II (FtCHS3, FtCHS4, FtCHS5, and FtCHS6) exhibit significantly elevated expression levels specifically in flowers. Conclusions: Our study indicated that FtCHS is a gene superfamily comprising at least four functional members. The expression patterns of these FtCHS genes suggest their probable involvement in flower−related biological processes in Tartary buckwheat. This work provides fundamental insights into the comprehensive understanding of the functional roles of the CHS gene family in Tartary buckwheat. Full article

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

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15 pages, 7280 KiB

Open AccessArticle

Assembly and Comparative Analysis of the Complete Mitochondrial Genomes of Smilax glabra and Smilax zeylanica

by Guojian Liao, Wenjing Liang, Haixia Yu, Kun Zhang, Linxuan Li, Shixin Feng, Lisha Song, Cuihong Yang, Lingyun Wan, Dongqiang Zeng, Zhanjiang Zhang and Shugen Wei

Genes 2025, 16(4), 450; https://doi.org/10.3390/genes16040450 - 14 Apr 2025

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Abstract

Background: Smilax glabra (S. glabra) and Smilax zeylanica (S. zeylanica), two medicinally important species within the genus Smilax, have been widely used in Traditional Chinese Medicine (TCM) for the treatment of rheumatism, traumatic injuries, and related ailments. Despite their medicinal [...] Read more.

Background: Smilax glabra (S. glabra) and Smilax zeylanica (S. zeylanica), two medicinally important species within the genus Smilax, have been widely used in Traditional Chinese Medicine (TCM) for the treatment of rheumatism, traumatic injuries, and related ailments. Despite their medicinal significance, research on the mitochondrial DNA (mtDNA) of Smilax species remains limited. Methods: We utilized NovaSeq 6000 and PromethION sequencing platforms to assemble the complete mitochondrial genomes of Smilax glabra and Smilax zeylanica, and conducted in-depth comparative genomic and evolutionary analyses. Results: The complete mitochondrial genomes of S. glabra and S. zeylanica were assembled and annotated, with total lengths of 535,215 bp and 471,049 bp, respectively. Both genomes encode 40 unique protein-coding genes (PCGs), composed of 24 core and 16 non-core genes, alongside multiple tRNA and rRNA genes. Repetitive element analysis identified 158 and 403 dispersed repeats in S. glabra and S. zeylanica, respectively, as well as 123 and 139 simple sequence repeats (SSRs). RNA editing site predictions revealed C-to-U conversions in both species. Additionally, chloroplast-to-mitochondrial DNA migration analysis detected 34 homologous fragments in S. glabra and 28 homologous fragments in S. zeylanica. Phylogenetically, S. glabra and S. zeylanica cluster within the Liliales order and Smilacaceae family, closely related to Lilium species. Collinearity analysis indicated numerous syntenic blocks between Smilax and three other Liliopsida species, though gene order was not conserved. Conclusions: This study presents high-quality mitochondrial genome assemblies for S. glabra and S. zeylanica, providing valuable insights into molecular identification and conservation efforts of these traditional medicinal plants. Full article

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

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13 pages, 5188 KiB

Open AccessArticle

Reduction in Liver Cancer Risk by Quercetin via Modulation of Urate Levels: Insights from Drug-Target Mendelian Randomization

by Zhengwen Li, Yue Wang, Kaichuan Yang, Chujie Li and Ming Zhang

Genes 2025, 16(4), 449; https://doi.org/10.3390/genes16040449 - 13 Apr 2025

Viewed by 363

Abstract

Background: Quercetin, a dietary flavonoid and a widely used supplement, has hepatoprotective properties. Given its urate-lowering effects and epidemiological evidence linking elevated serum urate levels to liver cancer risk, we tested whether quercetin reduces liver cancer risk via modulation of urate levels by [...] Read more.

Background: Quercetin, a dietary flavonoid and a widely used supplement, has hepatoprotective properties. Given its urate-lowering effects and epidemiological evidence linking elevated serum urate levels to liver cancer risk, we tested whether quercetin reduces liver cancer risk via modulation of urate levels by bioinformatics methods. Methods: We employed drug-target Mendelian randomization using genome-wide association study summary statistics from public databases (e.g., MRC-IEU) to assess genetic associations, and integrated these findings with GEO datasets (such as GSE138709 and GSE179443) and immune infiltration analyses using tools like xCell, TIMER. Results: Our analyses identified ABCG2-mediated urate elevation as a causal risk factor for hepatocellular carcinoma (OR = 1.001, p < 0.01), cholangiocarcinoma (OR = 3.424, p < 0.01), and liver fibrosis (OR = 2.528, p < 0.01). Single-cell transcriptomics revealed elevated ABCG2 expression in cholangiocarcinoma endothelial cells, while immune infiltration analysis showed significant associations between ABCG2 expression and both endothelial cell and macrophage infiltration. Survival analysis further indicated that ABCG2 was not associated with poor prognosis in cholangiocarcinoma or hepatocellular carcinoma. Conclusions: Considering quercetin’s multifaceted interactions with BCRP/ABCG2, our findings support its potential use as a preventive dietary supplement for hepatic diseases rather than as an adjunctive therapy for established liver cancer. Full article

(This article belongs to the Section Bioinformatics)

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16 pages, 2171 KiB

Open AccessArticle

G0S2 Promotes PD-L1 Expression in Monocytes and Influences the Efficacy of PD-1 Inhibitors in Hepatocellular Carcinoma

by Xuanshuang Du, Wenwen Zhang, Sujuan Sun, Chenghao Liu, Yuanying He, Fengling Luo, Hongyan Wu and Min Liu

Genes 2025, 16(4), 448; https://doi.org/10.3390/genes16040448 - 13 Apr 2025

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Abstract

Background: Hepatocellular carcinoma (HCC) is a prevalent and highly lethal form of liver cancer, with limited effective treatment options, particularly in the advanced stages. Immunotherapy using PD-1 inhibitors has emerged as a promising treatment modality, yet a substantial proportion of patients exhibit resistance [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a prevalent and highly lethal form of liver cancer, with limited effective treatment options, particularly in the advanced stages. Immunotherapy using PD-1 inhibitors has emerged as a promising treatment modality, yet a substantial proportion of patients exhibit resistance or fail to respond to such therapies. This study aimed to elucidate the role of G0/G1 Switch 2 (G0S2) in regulating PD-L1 expression in monocytes within the HCC tumor microenvironment and to investigate its impact on the efficacy of PD-1 inhibitors. Methods: Gene expression data among HCC patients treated with PD-1 inhibitors were obtained from the HCC single-cell sequencing database; immunohistochemistry was performed to detect G0S2 expression in liver cancer tissues and adjacent non-tumorous tissues of HCC patients; flow cytometry was utilized to analyze the expression of G0S2, PD-L1, CD206, and CD14 in PBMCs from HCC patients; and CD8⁺T cell proliferation and IFN-γ secretion were used to evaluate the impact of G0S2 knockdown. Results: Utilizing single-cell sequencing data from HCC patients, we identified that G0S2 expression was significantly elevated in the non-responders (NR) compared to responders (R) to PD-1 inhibitor therapy. The immunohistochemical analysis confirmed higher levels of G0S2 in HCC tumor tissues and adjacent non-tumorous tissues, while the flow cytometry revealed the increased expression of G0S2, PD-L1, and CD206 in peripheral blood mononuclear cells (PBMCs) from NR patients compared to R patients and healthy controls. The functional experiments involving the knockdown of G0S2 in the THP-1 monocyte cell line resulted in a significant reduction in PD-L1 expression and a concomitant increase in CD8⁺T cell proliferation and IFN-γ production. Conclusions: These findings indicate that G0S2 facilitates the upregulation of PD-L1 in monocytes, thereby suppressing T cell activity and contributing to resistance against PD-1 inhibitors in HCC. The high expression of G0S2 in peripheral blood monocytes offers a non-invasive and easily detectable biomarker for predicting the efficacy of PD-1 inhibitor therapy. Consequently, targeting G0S2 may enhance the responsiveness to immunotherapy in HCC patients, providing a new avenue for optimizing treatment strategies and improving patient outcomes. Full article

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

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19 pages, 6155 KiB

Open AccessArticle

Complete Mitochondrial Genome of Two Amathusiini Species (Lepidoideae: Nymphalidae: Satyrinae): Characterization, Comparative Analyses, and Phylogenetic Implications

by Qinghui Shi, Xinyue Wang, Jianhong Xing, Xiaoyun Xu, Gang Sun and Juncheng Zhang

Genes 2025, 16(4), 447; https://doi.org/10.3390/genes16040447 - 12 Apr 2025

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Abstract

Background: The Satyrinae subfamily represents a taxonomically critical group within Nymphalidae, characterized by its remarkable species diversity. Despite its evolutionary significance, the phylogenetic relationships among tribal and subtribal lineages remain poorly resolved. Although mitochondrial genomes have become crucial molecular markers in [...] Read more.

Background: The Satyrinae subfamily represents a taxonomically critical group within Nymphalidae, characterized by its remarkable species diversity. Despite its evolutionary significance, the phylogenetic relationships among tribal and subtribal lineages remain poorly resolved. Although mitochondrial genomes have become crucial molecular markers in Lepidoptera phylogenetics, their potential remains underutilized in the systematics of Satyrinae. Notably, Amathusiini exhibits a particular paucity, with only two congeneric representatives having been comprehensively sequenced to date. Methods: We employed high-throughput sequencing to assemble the complete mitochondrial genomes of two Amathusiini species, Discophora sondaica and Aemona amathusia. Our study revealed novel evolutionary insights through comparative genomics, which encompassed all available Satyrinae mitochondrial genomes. Additionally, we conducted phylogenetic reconstruction using maximum likelihood and Bayesian inference approaches, utilizing the most extensive dataset to date. Results: The closed, circular mitochondrial genomes measure 15,333 bp for D. sondaica and 15,423 bp for A. amathusia, maintaining the ancestral lepidopteran architecture: 13 protein-coding genes (PCGs), 22 tRNAs, 2 rRNAs, and an AT-rich control region. Comparative analyses of 71 mitochondrial genomes revealed strong evolutionary conservation across multiple parameters: nucleotide composition (AT content range: 77.9–81.8%), codon usage bias (ENC = 30.83–37.55), tRNA secondary structures, and control region organization. All PCGs showed purifying selection signals (Ka/Ks < 1.0), with atp8 exhibiting the highest evolutionary rate (Ka/Ks = 0.277). Phylogenetic reconstructions yielded congruent tribal-level topologies with strong nodal support: ((Satyrini + Melanitini) + (Amathusiini + Elymniini) + Zetherini), confirming a sister relationship between Amathusiini and Elymniini. Within Satyrini, five subtribes formed monophyletic groups: Ypthimina, Erebiina, Maniolina, Satyrina, and Melanargiina, arranged as ((Ypthimina + (Erebiina + Maniolina)) + (Satyrina + Melanargiina)). Mycalesina, Lethina, and Parargina comprised a well-supported clade (BS = 100%; PP = 1.0), though internal relationships required further resolution due to Lethina’s polyphyly. Conclusions: This study provides novel insights into mitochondrial genomic evolution within the Satyrinae subfamily while elucidating the efficacy of mitogenomic data for resolving deep phylogenetic relationships within this ecologically significant subfamily. Our findings establish critical genome baselines for further systematic research and underscore essential pathways for refining subtribal-level taxonomy through integrative molecular approaches. Full article

(This article belongs to the Special Issue Mitochondrial DNA Replication and Transcription)

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30 pages, 1379 KiB

Open AccessReview

Role of MicroRNAs in Acute Myeloid Leukemia

by Aneta Wiśnik, Dariusz Jarych, Kinga Krawiec, Piotr Strzałka, Natalia Potocka, Magdalena Czemerska, Aleksandra Sałagacka-Kubiak, Agnieszka Pluta, Agnieszka Wierzbowska and Izabela Zawlik

Genes 2025, 16(4), 446; https://doi.org/10.3390/genes16040446 - 11 Apr 2025

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Abstract

MicroRNA (miRNA), a significant class of regulatory non-coding RNA (ncRNA), can regulate the expression of numerous protein-coding messenger RNAs (mRNAs). miRNA plays an important part in shaping the human transcriptome. So far, in the human genome, about 2500 miRNAs have been found. Acute [...] Read more.

MicroRNA (miRNA), a significant class of regulatory non-coding RNA (ncRNA), can regulate the expression of numerous protein-coding messenger RNAs (mRNAs). miRNA plays an important part in shaping the human transcriptome. So far, in the human genome, about 2500 miRNAs have been found. Acute myeloid leukemia (AML) belongs to a malignant clonal disorder of hematopoietic stem cells and is characterized by the uncontrolled clonal proliferation of abnormal progenitor cells in the bone marrow and blood. For the past several years, significant scientific attention has been attracted to the role of miRNAs in AML, since alterations in the expression levels of miRNAs may contribute to AML development. This review describes the main functions of non-coding RNA classes and presents miRNA biogenesis. This study aims to review recent reports about altered microRNA expression and their influence on AML cell survival, cell cycle, and apoptotic potential. Additionally, it summarizes the correlations between miRNAs and their target mRNAs in AML and outlines the role of particular miRNAs in AML subtypes according to ELN recommendations. Full article

(This article belongs to the Special Issue RNA Interference Pathways)

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18 pages, 4338 KiB

Open AccessArticle

Whole-Genome Insights into the Genetic Basis of Conformation Traits in German Black Pied (DSN) Cattle

by Amelie Mandel, Monika Reißmann, Gudrun A. Brockmann and Paula Korkuć

Genes 2025, 16(4), 445; https://doi.org/10.3390/genes16040445 - 10 Apr 2025

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Abstract

Background: The German Black Pied Dairy (DSN) cattle is an endangered dual-purpose breed considered an ancestor of the modern Holstein population. DSN is known for its high milk yield, favorable milk composition, and good meat quality. Maintaining a functional body structure is essential [...] Read more.

Background: The German Black Pied Dairy (DSN) cattle is an endangered dual-purpose breed considered an ancestor of the modern Holstein population. DSN is known for its high milk yield, favorable milk composition, and good meat quality. Maintaining a functional body structure is essential for ensuring sustained performance across multiple lactations in dual-purpose breeds like DSN. This study aims to identify candidate genes and genetic regions associated with conformation traits in DSN cattle through genome-wide association studies (GWAS). Methods: The analysis utilized imputed whole-genome sequencing data of 1852 DSN cows with conformation data for 19 linear traits and four composite scores derived from these traits. GWAS was performed using linear mixed models. Results: In total, we identified 118 sequence variants distributed across 24 quantitative trait locus (QTL) regions comprising 74 positional candidate genes. Among the most significant findings were variants associated with “Rump width” on chromosome 21 and “Teat length” on chromosome 22, with AGBL1 and SRGAP3 identified as the most likely candidate genes. Additionally, a QTL region on chromosome 15 linked to “Central ligament” contained 39 olfactory receptor genes, and a QTL region on chromosome 23 associated with “Hock quality” included eight immune-related genes, notably, BOLA and TRIM family members. Conclusions: Selective breeding for favorable alleles of the investigated conformation traits may contribute to DSN’s longevity, robustness, and overall resilience. Hence, continuous focus on healthy udders, feet, and legs in herd management contributes to preserving DSN’s positive traits while improving conformation. Full article

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

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11 pages, 1516 KiB

Open AccessArticle

Development of a BiAD Sensor for Locus-Specific Detection of Cellular Histone Acetylation Dynamics by Fluorescence Microscopy

by Anja R. Köhler, Nicole Gutekunst, Annika Harsch, Pavel Bashtrykov and Albert Jeltsch

Genes 2025, 16(4), 444; https://doi.org/10.3390/genes16040444 - 10 Apr 2025

Viewed by 247

Abstract

Background: Dynamic changes in histone acetylation play crucial roles during cellular differentiation and disease development, but their detection in living cells is still a challenging task. Objectives: Here, we developed a Bimolecular Anchor Detector (BiAD) sensor for the detection of locus-specific changes in [...] Read more.

Background: Dynamic changes in histone acetylation play crucial roles during cellular differentiation and disease development, but their detection in living cells is still a challenging task. Objectives: Here, we developed a Bimolecular Anchor Detector (BiAD) sensor for the detection of locus-specific changes in histone acetylation in living cells by fluorescence microscopy. Methods: We used the BRD9 bromodomain cloned as tandem double domain (2xBRD9-BD) as a reader of histone acetylation. It was integrated into a dual-color BiAD chassis that was previously described by us. Results: We identified the gene body of TTC34 as a potential target for our sensor, because it contains dense histone acetylation and 392 local sequence repeats. Using a binding-deficient mutant of 2xBRD9-BD as a negative control, we established a successful readout of histone acetylation at the TTC34 locus. A single-domain reader did not function, indicating the requirement for the double reader to enhance the affinity and specificity of the chromatin interaction via avidity effects. With this sensor, we could detect dynamic increases in histone acetylation at the TTC34 locus after the treatment of cells with the histone deacetylase inhibitor Trichostatin A for 6 h indicating the applicability of the sensor for single-cell epigenome studies. Conclusions: Our data demonstrate that active chromatin modifications can be detected by BiAD sensors using 2xBRD9-BD as a reader. This complements the toolkit of the available BiAD sensors and documents the modularity of BiAD sensors. Full article

(This article belongs to the Special Issue 15th Anniversary of Genes: Feature Papers in the “Molecular Genetics and Genomics” Section)

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14 pages, 1029 KiB

Open AccessReview

Current Trends in Liquid Biopsy Tracking Resistance in Molecular Breast Cancer-Targeted Therapies

by Richard Tancredi, Navid Sobhani, Martina Catalano, Giandomenico Roviello and Daniele Generali

Genes 2025, 16(4), 443; https://doi.org/10.3390/genes16040443 - 9 Apr 2025

Viewed by 389

Abstract

Breast cancer (BC) is the most commonly occurring type of cancer in women, being a major cancer-related cause of mortality worldwide. With the advancement in current therapeutic options, including hormone therapy and targeted therapies, there is a need for more accurate and less [...] Read more.

Breast cancer (BC) is the most commonly occurring type of cancer in women, being a major cancer-related cause of mortality worldwide. With the advancement in current therapeutic options, including hormone therapy and targeted therapies, there is a need for more accurate and less invasive options to monitor cancer progression in patients. Liquid biopsy has evolved rapidly, being able to detect small quantities of nucleic acids or cell-free DNA in the blood of BC patients. This method addresses three major issues of needle biopsy: firstly, it is more permissive by being less invasive and does not require needling the organs; secondly, it covers for the heterogeneous nature of the tumor of origin, which could lead to an otherwise inaccurate representation of the cancer-driving mutations; thirdly, it better represents the type of tumor that the primary tumor is going to evolve into before it starts to metastasize. This current review will address the current advancements in liquid biopsy in the context of BC, highlighting the pros and challenges. Full article

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

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33 pages, 2811 KiB

Open AccessReview

The microRNA Pathway of Macroalgae: Its Similarities and Differences to the Plant and Animal microRNA Pathways

by Jessica Webb, Min Zhao, Alexandra H. Campbell, Nicholas A. Paul, Scott F. Cummins and Andrew L. Eamens

Genes 2025, 16(4), 442; https://doi.org/10.3390/genes16040442 - 9 Apr 2025

Viewed by 413

Abstract

In plants and animals, the microRNA (miRNA) class of small regulatory RNA plays an essential role in controlling gene expression in all aspects of development, to respond to environmental stress, or to defend against pathogen attack. This well-established master regulatory role for miRNAs [...] Read more.

In plants and animals, the microRNA (miRNA) class of small regulatory RNA plays an essential role in controlling gene expression in all aspects of development, to respond to environmental stress, or to defend against pathogen attack. This well-established master regulatory role for miRNAs has led to each protein-mediated step of both the plant and animal miRNA pathways being thoroughly characterized. Furthermore, this degree of characterization has led to the development of a suite of miRNA-based technologies for gene expression manipulation for fundamental research or for use in industrial or medical applications. In direct contrast, molecular research on the miRNA pathway of macroalgae, specifically seaweeds (marine macroalgae), remains in its infancy. However, the molecular research conducted to date on the seaweed miRNA pathway has shown that it shares functional features specific to either the plant or animal miRNA pathway. In addition, of the small number of seaweed species where miRNA data is available, little sequence conservation of individual miRNAs exists. These preliminary findings show the pressing need for substantive research into the seaweed miRNA pathway to advance our current understanding of this essential gene expression regulatory process. Such research will also generate the knowledge required to develop novel miRNA-based technologies for use in seaweeds. In this review, we compare and contrast the seaweed miRNA pathway to those well-characterized pathways of plants and animals and outline the low degree of miRNA sequence conservation across the polyphyletic group known as the seaweeds. Full article

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

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27 pages, 2084 KiB

Open AccessReview

MTHFR Gene Polymorphisms: A Single Gene with Wide-Ranging Clinical Implications—A Review

by Antoni F. Araszkiewicz, Krzysztof Jańczak, Paweł Wójcik, Bartłomiej Białecki, Szymon Kubiak, Michał Szczechowski and Danuta Januszkiewicz-Lewandowska

Genes 2025, 16(4), 441; https://doi.org/10.3390/genes16040441 - 8 Apr 2025

Viewed by 822

Abstract

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a process essential for the methylation of homocysteine to methionine. Polymorphisms in the MTHFR gene can reduce enzyme activity, disrupting the folate cycle and leading to hyperhomocysteinemia. The two most common [...] Read more.

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a process essential for the methylation of homocysteine to methionine. Polymorphisms in the MTHFR gene can reduce enzyme activity, disrupting the folate cycle and leading to hyperhomocysteinemia. The two most common polymorphisms associated with this gene are 667C>T (rs1801133) and 1298A>C (rs1801131). Background: This review provides a comprehensive summary of the current knowledge regarding MTHFR polymorphisms, with a particular focus on their potential impact on disease susceptibility. We hope this review will serve as a valuable resource for understanding the significance of MTHFR polymorphisms and their complex relationships with various diseases. Methods: For this review, we prioritized recent evidence, focusing on reviews and meta-analyses published between 2015 and 2025, sourced from PubMed and Google Scholar. Results: We explore the connection between these polymorphisms and a broad spectrum of medical conditions, including cardiovascular diseases and oxidative stress pathology; neurological and psychiatric disorders, such as Autism Spectrum Disorder, Alzheimer’s disease, Schizophrenia, and Major Depressive Disorder; fertility, pregnancy, and neonatal complications, including recurrent pregnancy loss, pre-eclampsia, preterm birth, low birth weight, and neural tube defects; metabolic disorders, such as diabetes mellitus, inflammatory bowel disease, and non-alcoholic fatty liver disease; and oncological conditions, including breast, prostate, and ovarian cancers; as well as leukemia, and autoimmune diseases, particularly rheumatoid arthritis. Conclusions: While some diseases have a well-established association with MTHFR polymorphisms, others require further investigation. Our analysis highlights the crucial role of environmental factors, such as ethnic background and dietary folate intake, in influencing study outcomes. Full article

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

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