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Volume 16
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Genes, Volume 16, Issue 2 (February 2025) – 128 articles

Cover Story (view full-size image): The variants rs10517086 and rs1534422 are predictive of type 1 diabetes mellitus (T1DM) development and poor residual β cell function within the first year of diagnosis. However, the mechanism by which risk is conferred is unknown. Using CRISPR/Cas9, we show that both variants significantly reduce glucose-stimulated insulin secretion, increase the production of pro-inflammatory cytokines, and reduce the expression of several β cell markers and transcription factors. However, much of this appeared to be under the control of HNF1A. Analysis of human data revealed an association of rs10517086_A genotype with C-peptide in 153 individuals with T1DM, but not in 417 people with T2DM. Our data suggest that rs1534422 and rs10517086 exert multiple insults on the β cell through excessive upregulation of HNF1A and the induction of pro-inflammatory cytokines. View this paper
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21 pages, 5996 KiB  
Article
Molecular Characteristics and Role of Buffalo SREBF2 in Triglyceride and Cholesterol Biosynthesis in Mammary Epithelial Cells
by Wenbin Dao, Hongyan Chen, Yina Ouyang, Lige Huang, Xinyang Fan and Yongwang Miao
Genes 2025, 16(2), 237; https://doi.org/10.3390/genes16020237 - 19 Feb 2025
Viewed by 591
Abstract
Background/Objectives: Sterol regulatory element-binding transcription factor 2 (SREBF2) is a key transcription factor involved in regulating cholesterol homeostasis. However, its role in buffalo mammary gland lipid metabolism remains unclear. Methods: To address this, we isolated and characterized the SREBF2 gene from buffalo [...] Read more.
Background/Objectives: Sterol regulatory element-binding transcription factor 2 (SREBF2) is a key transcription factor involved in regulating cholesterol homeostasis. However, its role in buffalo mammary gland lipid metabolism remains unclear. Methods: To address this, we isolated and characterized the SREBF2 gene from buffalo mammary glands and performed an in-depth analysis of its molecular characteristics, tissue-specific expression, and functional roles in buffalo mammary epithelial cells (BuMECs). Additionally, we investigated the single nucleotide polymorphisms (SNPs) of SREBF2 in both river and swamp buffalo. Results: The coding sequence (CDS) of buffalo SREBF2 is 3327 bp long and encodes a protein of 1108 amino acid residues. Bioinformatics analysis revealed that the molecular characteristics of buffalo SREBF2 were highly similar across Bovidae species, with collinearity being observed among them. An expression profile analysis revealed that SREBF2 is expressed in all 11 tested tissues of buffalo, with its expression level in the mammary gland being higher during lactation than in the dry period. The knockdown of SREBF2 in BuMECs during lactation led to a significant reduction in the expression of genes involved in triglyceride (TAG) and cholesterol synthesis, including PI3K, AKT, mTOR, SREBF1, PPARG, INSIG1, ACACA, SCD, DGAT1, LPL, CD36, HMGCR, and SQLE. This knockdown led to a 23.53% and 94.56% reduction in TAG and cholesterol levels in BuMECs, respectively. In addition, a total of 22 SNPs were identified in both buffalo types, of which four non-synonymous substitutions (c.301G>C, c.304A>T, c.1240G>A, and c.2944G>A) were found exclusively in the SREBF2 CDS of swamp buffalo, and the assessment revealed that these substitutions had no impact on SREBF2 function. Conclusions: These findings emphasize the critical role of SREBF2 in regulating both triglyceride and cholesterol biosynthesis, providing valuable insights into its functions in buffalo mammary glands. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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10 pages, 873 KiB  
Article
The Relationship Between Genetic Variants at Loci 9p21, 6q25.1, and 2q36.3 and the Development of Cardiac Allograft Vasculopathy in Heart Transplant Patients
by Dana Dlouha, Kristyna Janouskova, Jevgenija Vymetalova, Sarka Novakova, Sarka Chytilova, Marianna Lukasova and Jaroslav A. Hubacek
Genes 2025, 16(2), 236; https://doi.org/10.3390/genes16020236 - 19 Feb 2025
Viewed by 438
Abstract
Background: Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease (CAD) that is characterized by concentric fibrous intimal hyperplasia along the length of coronary vessels, and is recognized as long-term complication after heart transplantation. The chromosomal loci 9p21, 6q25.1, and [...] Read more.
Background: Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease (CAD) that is characterized by concentric fibrous intimal hyperplasia along the length of coronary vessels, and is recognized as long-term complication after heart transplantation. The chromosomal loci 9p21, 6q25.1, and 2q36.3, represented by their respective leading variants rs10757274, rs6922269 and rs2943634, have been linked with a history of CAD by genome-wide association studies. We aimed to investigate the associations of genetic variants at the loci 9p21, 6q25.1, and 2q36.3 with CAV as genetic risk factors for early prediction. Methods: Genomic DNA was extracted from paired aortic samples of 727 heart recipients (average age 50.8 ± 12.2 years; 21.3% women) and corresponding donors (average age 39.7 ± 12.0 years; 26.1% women). The variants within the loci 9p21, 6q25.1, and 2q36.3 were genotyped using PCR-RFLP. Results: The recipients’ variants of 9p21 (OR 1.97; 95% CI, 1.21-3.19 for GG vs. +A comparison, p = 0.0056) and 2q36.3 (OR 2.46; 95% CI, 1.12–6.17 for +C vs. AA comparison, p = 0.0186) were associated with higher incidence of CAV during the first year following heart transplantation. No such association was found for donor genotypes. Conclusions: Our data suggest that variants at the locus 9p21 (rs10757274) and 2q36.3 (rs2943634) are associated with early CAV development. Full article
(This article belongs to the Special Issue Single-Nucleotide Polymorphisms: Associations, Molecular Functions, Applications and Progress (2nd Edition))
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21 pages, 4387 KiB  
Article
Exploring the Genotoxic Stress Response in Primed Orphan Legume Seeds Challenged with Heat Stress
by Andrea Pagano, Conrado Dueñas, Jr., Nicolò Bedotto, Amine Elleuch, Bassem Khemakhem, Hanen El Abed, Eleni Tani, Maria Goufa, Dimosthenis Chachalis and Alma Balestrazzi
Genes 2025, 16(2), 235; https://doi.org/10.3390/genes16020235 - 19 Feb 2025
Viewed by 582
Abstract
Background/Objectives: The increased frequency of extreme weather events related to climate change, including the occurrence of extreme temperatures, severely affects crop yields, impairing global food security. Heat stress resulting from temperatures above 30 °C is associated with poor germination performance and stand establishment. [...] Read more.
Background/Objectives: The increased frequency of extreme weather events related to climate change, including the occurrence of extreme temperatures, severely affects crop yields, impairing global food security. Heat stress resulting from temperatures above 30 °C is associated with poor germination performance and stand establishment. The combination of climate-resilient crop genotypes and tailored seed priming treatments might represent a reliable strategy to overcome such drawbacks. This work explores the potential of hydropriming as a tool to mitigate the heat-stress-mediated impact on germination performance in orphan legumes. Methods: For each tested species (Lathyrus sativus L., Pisum sativum var. arvense and Trigonella foenum-graecum L.), two accessions were investigated. Germination tests were performed at 25 °C, 30 °C, 35 °C and 40 °C to assess the heat stress tolerance threshold. Hydropriming was then applied and germination tests were performed at 40 °C to test the impact of the treatment on the seeds’ ability to cope with heat stress. An alkaline comet assay and Quantitative Real Time-Polymerase Chain Reaction were performed on embryos excised from primed and control seeds. Results: Phenotyping at the germination and seedling development stage highlighted the accession-specific beneficial impact of hydropriming under heat stress conditions. In L. sativus seeds, the alkaline comet assay revealed the dynamics of heat stress-induced DNA damage accumulation, as well as the repair patterns promoted by hydropriming. The expression patterns of genes involved in DNA repair and antioxidant response were consistently responsive to the hydropriming and heat wave conditions in L. sativus accessions. Full article
(This article belongs to the Special Issue DNA Damage Repair and Plant Stress Response)
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15 pages, 4972 KiB  
Article
Developmental Expression Patterns of miRNA in Mythimna separata Walker (Lepidotera: Noctuidae)
by Yuhan Liu, Huiman Tian, Shaoqiu Ren, Xiulin Chen, Kun Luo, Guangwei Li and Boliao Li
Genes 2025, 16(2), 234; https://doi.org/10.3390/genes16020234 - 19 Feb 2025
Viewed by 456
Abstract
Background/Objectives: miRNAs are a family of single-stranded non-coding RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) for suppression, with an average length of 22 nt. The oriental armyworm, Mythimna separata Walker, is a pest insect with long-distance migratory capability, which causes [...] Read more.
Background/Objectives: miRNAs are a family of single-stranded non-coding RNAs that regulate gene expression by targeting messenger RNAs (mRNAs) for suppression, with an average length of 22 nt. The oriental armyworm, Mythimna separata Walker, is a pest insect with long-distance migratory capability, which causes severe loss of grains and pastures in Eastern Asia, Southeastern Asia, and Oceania. This study aims to elucidate the post-transcriptional regulatory mechanisms of miRNAs in the development of this pest. Methods: We carried out small RNA sequencing on samples from eggs, third instar larvae, pre-pupae, pupae, and adults. Results: A total of 400 miRNAs were identified, among which 40 were known and 360 were novel miRNAs. Dynamic trend analysis of miRNAs revealed that 199 miRNAs were highly expressed in eggs (profile 12), while 173 miRNAs were highly expressed in both eggs and pupae (profile 13). The results of differential expression analysis of miRNAs (DEmiR) revealed that 75 miRNAs were significantly more abundant in eggs compared to other developmental stages. Furthermore, more up-regulated miRNAs were observed than down-regulated miRNAs in adults relative to 3rd instar larvae, pre-pupae, and pupae. The core genes for miRNA biosynthesis—Pasha, Dicer1, and Ago1—were highly expressed in eggs but poorly expressed in 3rd instar larvae. KEGG enrichment analyses indicated that several genes in the pentose and glucuronate interconversion pathway, as well as the fructose and mannose metabolism pathway, were regulated by DEmiRs. Conclusions: DEmiRNAs targeted most genes of M. separata, resulting in a complex miRNA–mRNA regulation mode. Full article
(This article belongs to the Special Issue Genomics, Transcriptomics, and Proteomics of Insects)
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17 pages, 4465 KiB  
Article
Genome-Wide Analyses of the Soybean GmABCB Gene Family in Response to Salt Stress
by Hui Zou, Caiyun Fan, Xiulin Chen, Ruifeng Chen, Zhihui Sun and Xiaorong Wan
Genes 2025, 16(2), 233; https://doi.org/10.3390/genes16020233 - 19 Feb 2025
Viewed by 604
Abstract
Background: Soybean (Glycine max (L.) Merr.) is a significant economic oilseed crop, and saline-alkali soils restrict soybean yield. Identifying salt-tolerant genes is a key strategy for enhancing soybean productivity under saline-alkali conditions. The roles of the GmABCB gene family in growth, [...] Read more.
Background: Soybean (Glycine max (L.) Merr.) is a significant economic oilseed crop, and saline-alkali soils restrict soybean yield. Identifying salt-tolerant genes is a key strategy for enhancing soybean productivity under saline-alkali conditions. The roles of the GmABCB gene family in growth, development, and stress resistance remain incompletely understood. Methods: Bioinformatics approaches were employed to identify and analyze GmABCB genes. A total of 39 GmABCB genes were identified and analyzed in the soybean genome, focusing on their phylogenetic relationships, chromosomal distribution, gene structure, cis-acting elements, evolutionary history, and expression patterns under salt stress. Results: A total of 39 GmABCB genes were identified. These genes are unevenly distributed across the soybean genome, with 21 segmental duplication events identified. Several cis-acting elements associated with abiotic stress responses were identified. Conclusions: The GmABCB gene family likely regulates growth, development, and stress tolerance in soybean. Full article
(This article belongs to the Special Issue Advances in Genetics and Genomics of Plants: 2nd Edition)
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9 pages, 1324 KiB  
Article
The Survival of the Kiss: Presence and Persistence of Salivary Male DNA in Mixed Samples
by Mauro Pesaresi, Federica Alessandrini, Elena Bignozzi, Alessia Bernini Di Michele, Filomena Melchionda, Rosaria Gesuita, Valerio Onofri and Chiara Turchi
Genes 2025, 16(2), 232; https://doi.org/10.3390/genes16020232 - 19 Feb 2025
Viewed by 646
Abstract
Background/Objectives: The study of DNA transfer and persistence has become increasingly significant, driven by advancements in DNA detection sensitivity and the need for reliable forensic evidence. In forensic investigations, saliva and saliva-stained materials are recognised as valuable DNA sources, particularly in cases of [...] Read more.
Background/Objectives: The study of DNA transfer and persistence has become increasingly significant, driven by advancements in DNA detection sensitivity and the need for reliable forensic evidence. In forensic investigations, saliva and saliva-stained materials are recognised as valuable DNA sources, particularly in cases of homicide, sexual assault, and burglary, where saliva can be transferred between individuals during the criminal act. The time between the crime and sample collection is a critical factor that can influence the success of the analysis. The value of the specimens collected from the victim’s skin or mouth (perilabial and labial sites, teeth and tongue) after the crime has not been investigated with currently used highly sensitive and specific molecular methods. Methods: On the assumption that a significant loss of DNA occurred, in our study, 10 voluntary pairs were tested at different time points after intense kissing and samples were taken from the above-mentioned sites to assess the presence of the donor’s DNA. Extracted DNA was quantified using the Plexor HY System kit (Promega), and both autosomal STRs and Y-STRs were analysed. Results: The results reveal a greater persistence of male DNA on the female partner, particularly in the labial and perilabial regions, even up to 120 min after contact, in terms of both concentration and duration. Conclusions: This study emphasises the forensic importance of salivary DNA as a solid source of evidence, particularly in investigations involving mixed DNA profiles. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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31 pages, 3433 KiB  
Review
Nucleotide Excision Repair: Insights into Canonical and Emerging Functions of the Transcription/DNA Repair Factor TFIIH
by Amélie Zachayus, Jules Loup-Forest, Vincent Cura and Arnaud Poterszman
Genes 2025, 16(2), 231; https://doi.org/10.3390/genes16020231 - 19 Feb 2025
Viewed by 932
Abstract
Nucleotide excision repair (NER) is a universal cut-and-paste DNA repair mechanism that corrects bulky DNA lesions such as those caused by UV radiation, environmental mutagens, and some chemotherapy drugs. In this review, we focus on the human transcription/DNA repair factor TFIIH, a key [...] Read more.
Nucleotide excision repair (NER) is a universal cut-and-paste DNA repair mechanism that corrects bulky DNA lesions such as those caused by UV radiation, environmental mutagens, and some chemotherapy drugs. In this review, we focus on the human transcription/DNA repair factor TFIIH, a key player of the NER pathway in eukaryotes. This 10-subunit multiprotein complex notably verifies the presence of a lesion and opens the DNA around the damage via its XPB and XPD subunits, two proteins identified in patients suffering from Xeroderma Pigmentosum syndrome. Isolated as a class II gene transcription factor in the late 1980s, TFIIH is a prototypic molecular machine that plays an essential role in both DNA repair and transcription initiation and harbors a DNA helicase, a DNA translocase, and kinase activity. More recently, TFIIH subunits have been identified as participating in other cellular processes, including chromosome segregation during mitosis, maintenance of mitochondrial DNA integrity, and telomere replication. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Microorganisms, Plants and Mammalian Systems)
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12 pages, 236 KiB  
Article
Human Papilloma Virus Infection in Men: A Specific Human Virome or a Specific Pathology?
by Ivana Čulav, Mihael Skerlev, Lidija Žele Starčević, Pero Hrabač, Suzana Ljubojević Hadžavdić, Iva Bešlić and Liborija Lugović Mihić
Genes 2025, 16(2), 230; https://doi.org/10.3390/genes16020230 - 18 Feb 2025
Viewed by 556
Abstract
Background: Human papillomavirus (HPV) infections in men remain under-researched despite their critical role in disease transmission and the increasing incidence of HPV-related cancers. This study investigates the clinical and molecular characteristics of anogenital HPV infections in men, emphasizing genotype prevalence, diagnostic methods, and [...] Read more.
Background: Human papillomavirus (HPV) infections in men remain under-researched despite their critical role in disease transmission and the increasing incidence of HPV-related cancers. This study investigates the clinical and molecular characteristics of anogenital HPV infections in men, emphasizing genotype prevalence, diagnostic methods, and lesion variability. Methods: A cross-sectional study was conducted on 70 men aged 18–65 years with clinically diagnosed anogenital HPV infection. Lesions were characterized by morphology and location. HPV DNA was analyzed using INNO-LiPA (INNOvative Line Probe Assay), Hybrid Capture II (HC II), and polymerase chain reaction (PCR) assays to determine genotype distribution. Associations between clinical features and HPV genotypes were assessed using multivariate statistical analyses. Results: Lesions varied in morphology, with verrucous (52.86%) and papular (30%) types being the most common. Localization patterns showed predominance on the penis radix (34.29%) and shaft (27.14%). Molecular testing revealed HPV DNA in 88.57% of the cases using INNO-LiPA, compared to 45% and 40% with HC II and PCR, respectively. Low-risk (LR) genotypes, particularly HPV6, dominated single infections, comprising 68.57% of the cases, while high-risk (HR) genotypes accounted for 20%. Mixed LR and HR infections were observed in 14.29% of the lesions, with greater diversity noted in distal genital regions. Notably, condyloma plana and lesions on the inner prepuce exhibited a higher prevalence of HR and mixed infections. Age and lesion duration showed trends toward older patients and longer disease duration in cases involving perianal and extragenital condylomas, though these findings were not statistically significant. No direct correlation between lesion type or localization and specific genotypes was identified, underscoring the heterogeneity of HPV clinical manifestations in men. Conclusions: Anogenital HPV infections in men exhibit significant heterogeneity in lesion morphology, localization, and genotype distribution. HR HPV genotypes were detected in a notable proportion of benign lesions, underscoring their potential role in disease progression. INNO-LiPA proved superior in diagnostic accuracy, highlighting the need for standardized and cost-effective diagnostic approaches for men. Further research is crucial to elucidate HPV’s clinical impact in men and inform prevention and treatment strategies. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
29 pages, 5146 KiB  
Article
Unveiling Racial Disparities in Localized Prostate Cancer: A Systems-Level Exploration of the lncRNA Landscape
by Rebecca A. Morgan, E. Starr Hazard, Stephen J. Savage, Chanita Hughes Halbert, Sebastiano Gattoni-Celli and Gary Hardiman
Genes 2025, 16(2), 229; https://doi.org/10.3390/genes16020229 - 17 Feb 2025
Viewed by 698
Abstract
Background/Objectives: Prostate cancer (PC) is the most common non-cutaneous cancer in men globally, and one which displays significant racial disparities. Men of African descent (AF) are more likely to develop PC and face higher mortality compared to men of European descent (EU). The [...] Read more.
Background/Objectives: Prostate cancer (PC) is the most common non-cutaneous cancer in men globally, and one which displays significant racial disparities. Men of African descent (AF) are more likely to develop PC and face higher mortality compared to men of European descent (EU). The biological mechanisms underlying these differences remain unclear. Long non-coding RNAs (lncRNAs), recognized as key regulators of gene expression and immune processes, have emerged as potential contributors to these disparities. This study aimed to investigate the regulatory role of lncRNAs in localized PC in AF men relative to those of EU and assess their involvement in immune response and inflammation. Methods: A systems biology approach was employed to analyze differentially expressed (DE) lncRNAs and their roles in prostate cancer (PC). Immune-related pathways were investigated through over-representation analysis of lncRNA–mRNA networks. The study also examined the effects of vitamin D supplementation on lncRNA expression in African descent (AF) PC patients, highlighting their potential regulatory roles in immune response and inflammation. Results: Key lncRNAs specific to AF men were identified, with several being implicated for immune response and inflammatory processes. Notably, 10 out of the top 11 ranked lncRNAs demonstrated strong interactions with immune-related genes. Pathway analysis revealed their regulatory influence on antigen processing and presentation, chemokine signaling, and ribosome pathways, suggesting their critical roles in immune regulation. Conclusions: These findings highlight the pivotal role of lncRNAs in PC racial disparities, particularly through immune modulation. The identified lncRNAs may serve as potential biomarkers or therapeutic targets to address racial disparities in PC outcomes. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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18 pages, 4025 KiB  
Brief Report
Identification of Ziziphus jujuba cv. Dongzao DNA Demethylase ZjROS1 Gene Family and Construction of CRISPR/Cas9-Mediated Gene-Editing Vector
by Jiaqi Wang, Huiran Wang, Jiayi Zhai, Fulun Zhu, Yufeng Ren, Jun Zhou, Zhikai Zhang, Lan Luo and Wendi Xu
Genes 2025, 16(2), 228; https://doi.org/10.3390/genes16020228 - 17 Feb 2025
Viewed by 445
Abstract
DNA methylation is one of the earliest and most extensively studied epigenetic regulatory mechanisms. The ROS1 (Repressor of Silencing 1) gene was first discovered in Arabidopsis thaliana, and it is a DNA demethylase that can remove 5-methylcytosine from DNA, thereby affecting DNA [...] Read more.
DNA methylation is one of the earliest and most extensively studied epigenetic regulatory mechanisms. The ROS1 (Repressor of Silencing 1) gene was first discovered in Arabidopsis thaliana, and it is a DNA demethylase that can remove 5-methylcytosine from DNA, thereby affecting DNA methylation levels and gene expression. Objectives: The objective of this study was to investigate the role of ROS1 in the development and maturation of Ziziphus jujuba cv. “Dongzao” fruit. Methods: We cloned the ROS1 gene and conducted bioinformatics and expression characteristics analyses on it. Results: Three ROS1 genes, named ZjROS1-1~3, was identified, and each member protein was localized in the nucleus, cytoskeleton, chloroplast, and vacuole. The promoter contained cis-elements such as light response, plant hormone signal transduction, and stress response cis-elements, and it interacted with many proteins such as CMT, MET, and ZDP. The results of the real-time fluorescence quantitative PCR show that ZjROS1 has specific expression patterns in different tissues of Z. jujuba cv. Dongzao, and the expression of ZjROS1-2 in flowers and fruits is high. At the same time, CRISPR/Cas9 technology was used to construct a gene-editing vector for ZjROS1, which provided a basis for the subsequent genetic transformation. Conclusions: In this study, the biological function of ZjROS1 was clarified and a gene-editing vector was constructed, which provided a theoretical basis for the regulation mechanism of demethylase ZjROS1 in the fruit ripening and development of Z. jujuba cv. Dongzao. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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11 pages, 3831 KiB  
Brief Report
Expanding the Clinical Spectrum Associated with the Recurrent Arg203Trp Variant in PACS1: An Italian Cohort Study
by Stefano Pagano, Diego Lopergolo, Alessandro De Falco, Camilla Meossi, Sara Satolli, Rosa Pasquariello, Rosanna Trovato, Alessandra Tessa, Claudia Casalini, Lucia Pfanner, Guja Astrea, Roberta Battini and Filippo M. Santorelli
Genes 2025, 16(2), 227; https://doi.org/10.3390/genes16020227 - 16 Feb 2025
Viewed by 572
Abstract
Background/Objectives: Schuurs–Hoeijmakers syndrome (SHMS), also known as PACS1 neurodevelopmental disorder, is a rare condition characterized by intellectual disability, distinctive craniofacial abnormalities, and congenital malformations. SHMS has already been associated with variants in the PACS1 gene in 63 patients. In this study, we [...] Read more.
Background/Objectives: Schuurs–Hoeijmakers syndrome (SHMS), also known as PACS1 neurodevelopmental disorder, is a rare condition characterized by intellectual disability, distinctive craniofacial abnormalities, and congenital malformations. SHMS has already been associated with variants in the PACS1 gene in 63 patients. In this study, we describe 10 new Italian SHMS patients all harboring the common de novo p.(Arg203Trp) variant. Methods: The 10 patients we studied were evaluated by clinical geneticists and child neurologists and a detailed description of clinical features was recorded. Data were then coded using the Human Phenotype Ontology (HPO) terms. The recurrent p.(Arg203Trp) variant in PACS1 was identified by clinical exome sequencing or whole exome sequencing in trio using standard methodologies. To facilitate mutation identification, we designed a new PCR-RFLP strategy adopting the endonuclease DpnII. Results: We define a detailed clinical phenotyping in patients with intellectual disability and facial characteristics (thick eyebrows, down-slanting palpebral fissures, ocular hypertelorism, low-set ears, a thin upper lip, and a wide mouth) that can help clinicians form a more efficient diagnosis of SHMS even through neuroimaging and neuropsychological evaluation. Conclusions: Our series of 10 newly affected Italian children highlights specific clinical features that may help clinicians recognize and better manage this syndrome, contributing to precision medicine approaches in medical genetics. Full article
(This article belongs to the Section Genetic Diagnosis)
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17 pages, 2352 KiB  
Article
Characterization of the Complete Mitochondrial Genome of Dwarf Form of Purpleback Flying Squid (Sthenoteuthis oualaniensis) and Phylogenetic Analysis of the Family Ommastrephidae
by Wenjuan Duo, Lei Xu, Mohd Johari Mohd Yusof, Yingmin Wang, Seng Beng Ng and Feiyan Du
Genes 2025, 16(2), 226; https://doi.org/10.3390/genes16020226 - 15 Feb 2025
Viewed by 553
Abstract
Background: The Ommastrephidae family of cephalopods is important in marine ecosystems as both predators and prey. Species such as Todarodes pacificus, Illex argentinus, and Dosidicus gigas are economically valuable but are threatened by overfishing and environmental changes. The genus Sthenoteuthis, [...] Read more.
Background: The Ommastrephidae family of cephalopods is important in marine ecosystems as both predators and prey. Species such as Todarodes pacificus, Illex argentinus, and Dosidicus gigas are economically valuable but are threatened by overfishing and environmental changes. The genus Sthenoteuthis, especially S. oualaniensis, shows significant morphological and genetic variation, including medium-sized and dwarf forms found in the South China Sea. Methods: Specimens of S. oualaniensis were collected from the South China Sea, their genomic DNA sequenced, and phylogenetic relationships analyzed using mitochondrial genomes from various Ommastrephidae species. Results: The study presents the complete mitochondrial genome of the dwarf form of S. oualaniensis (20,320 bp) and compares it with the medium-sized form, revealing a typical vertebrate structure with 13 protein-coding genes, 21 tRNA genes, and 2 rRNA genes, along with a strong AT bias. Nucleotide composition analysis shows a 12% genetic divergence between the two forms, suggesting a recent common ancestor and potential cryptic speciation, with all protein-coding genes exhibiting purifying selection based on Ka/Ks ratios below 1. Conclusions: The mitochondrial genome of the dwarf form of S. oualaniensis shows a close evolutionary relationship with the medium-sized form and a 12% genetic divergence, suggesting potential cryptic speciation. These findings underscore the importance of mitochondrial analysis in understanding speciation and guiding future conservation efforts. 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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18 pages, 2370 KiB  
Review
Chromatin Remodulator CHD4: A Potential Target for Cancer Interception
by Krishnendu Goswami, Karthikkumar Venkatachalam, Surya P. Singh, Chinthalapally V. Rao and Venkateshwar Madka
Genes 2025, 16(2), 225; https://doi.org/10.3390/genes16020225 - 15 Feb 2025
Viewed by 898
Abstract
Cancer initiation and progression are associated with numerous somatic mutations, genomic rearrangements, and structure variants. The transformation of a normal cell into a cancer cell involves spatio-temporal changes in the regulation of different gene networks. The accessibility of these genes within the cell [...] Read more.
Cancer initiation and progression are associated with numerous somatic mutations, genomic rearrangements, and structure variants. The transformation of a normal cell into a cancer cell involves spatio-temporal changes in the regulation of different gene networks. The accessibility of these genes within the cell nucleus is manipulated via nucleosome remodeling ATPases, comprising one of the important mechanisms. Here, we reviewed studies of an ATP-dependent chromatin remodulator, chromodomain helicase DNA-binding 4 (CHD4), in cancer. Multiple domains of CHD4 are known to take part in nucleosome mobilization and histone binding. By binding with other proteins, CHD4 plays a vital role in transcriptional reprogramming and functions as a key component of Nucleosome Remodeling and Deacetylase, or NuRD, complexes. Here, we revisit data that demonstrate the role of CHD4 in cancer progression, tumor cell proliferation, DNA damage responses, and immune modulation. Conclusively, CHD4-mediated chromatin accessibility is essential for transcriptional reprogramming, which in turn is associated with tumor cell proliferation and cancer development. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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20 pages, 6224 KiB  
Article
The Impact of the Competition on miRNA, Proteins, and Metabolites in the Blood Exosomes of the Yili Horse
by Xinxin Yuan, Xinkui Yao, Yaqi Zeng, Jianwen Wang, Wanlu Ren, Tongliang Wang, Xueyan Li, Lipin Yang, Xixi Yang and Jun Meng
Genes 2025, 16(2), 224; https://doi.org/10.3390/genes16020224 - 15 Feb 2025
Viewed by 657
Abstract
Purpose: Horse racing may cause stress-induced physiological changes and tissue damage in horses, but the changes in miRNA expression, protein expression, and metabolic substances in the plasma exosomes of the Yili horse after racing are still unclear. This study detected miRNA, protein expression, [...] Read more.
Purpose: Horse racing may cause stress-induced physiological changes and tissue damage in horses, but the changes in miRNA expression, protein expression, and metabolic substances in the plasma exosomes of the Yili horse after racing are still unclear. This study detected miRNA, protein expression, and metabolic substances in the plasma exosomes of Yili horses before and after competition, providing new insights for post-race recovery and care of Yili horses. Method: Eight three-year-old Yili horses that had undergone training were selected as the research subjects, with four horses that had not competed as the control group and four horses that had participated in the competition for half an hour as the training group. Extract whole blood and separate plasma from two groups of horses, and then extract plasma exosomes; MiRNAs, proteins, and metabolites in extracellular vesicles were detected and analyzed using miRNAomics, proteomics, and metabolomics. P Result: After the competition, the levels of miRNAs related to the cytoplasm and nucleus in Yili horse plasma exosomes increased, and miRNAs related to the transcription and transcriptional regulation of biological processes significantly increased. The levels of proteins related to the cytoplasm and nucleus also increased, and the levels of proteins related to cell signaling function increased, carbohydrates and their metabolites were significantly reduced. Conclusions: The competition process causes significant changes in the miRNA, proteomics, and metabolomics of plasma exosomes in the Yili horses, which are mainly related to metabolic regulation. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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16 pages, 297 KiB  
Article
Genetic Variants in RASSF1 (rs2073498), SERPINE1 (rs1799889), and EFNA1 (rs12904) Are Associated with Susceptibility in Mexican Patients with Colorectal Cancer: Clinical Associations and Their Analysis In Silico
by César de Jesús Tovar-Jácome, Clara Ibet Juárez-Vázquez, Martha Patricia Gallegos-Arreola, José Elías García-Ortiz, María Eugenia Marín-Contreras, Tomás Daniel Pineda-Razo, Ignacio Mariscal-Ramírez, Oscar Durán-Anguiano, Aldo Antonio Alcaraz-Wong, Rubria Alicia González-Sánchez, Marina Lizbeth Mundaca-Rodríguez, Miriam Yadira Godínez-Rodríguez, Marlín Corona-Padilla and Mónica Alejandra Rosales-Reynoso
Genes 2025, 16(2), 223; https://doi.org/10.3390/genes16020223 - 15 Feb 2025
Viewed by 571
Abstract
Background/Objectives: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Variants in genes that regulate processes such as apoptosis and angiogenesis play a significant role in CRC. The objective of this study is to investigate the possible association between RASSF1 [...] Read more.
Background/Objectives: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Variants in genes that regulate processes such as apoptosis and angiogenesis play a significant role in CRC. The objective of this study is to investigate the possible association between RASSF1 (rs2073498), SERPINE1 (rs1799889), EFNA1 (rs12904), and RAD51 (rs1801320) variants and clinicopathological characteristics of Mexican patients with CRC. Methods: DNA of peripheral blood samples was obtained from 631 individuals (349 patients and 282 control individuals). The RASSF1 (rs2073498), SERPINE1 (rs1799889), EFNA1 (rs12904), and RAD51 (rs1801320) variants were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The association was calculated using the odds ratio (OR) test. p-values were adjusted by the Bonferroni test (0.0125). In silico analysis programs, including Combined Annotation Dependent Depletion (CADD), Polymorphism Phenotyping-2 (PolyPhen-2), and Gene Expression Profiling Interactive Analysis (GEPIA), were conducted to predict the functional impact of these variants. Results: Patients carrying the G/A genotype of the RASSF1 (rs2073498) variant showed an association with CRC characteristics, including TNM stages and tumor location (OR > 2.5, p = 0.001). Regarding the SERPINE1 (rs1799889) variant, patients carrying the 5G/4G genotype showed an association between TNM stages and tumor location in the rectum (OR > 1.5, p ≤ 0.05). Patients with the G/G genotype for the EFNA1 (rs12904) variant showed an association with TNM stages and rectal tumor location (OR > 2.0, p = 0.001). The RAD51 (rs1801320) variant had no association with colorectal cancer. Conclusions: RASSF1 (rs2073498), SERPINE1 (rs1799889), and EFNA1 (rs12904) variants significantly influence colorectal cancer risk. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
15 pages, 7417 KiB  
Article
Identification and Expression Patterns of Critical Genes Related to Coat Color in Cashmere Goats
by Dubala Wu, Jing Fan, Yue Pang, Binhong Wen, Wei Li, Guanghao Yang, Huiyu Cheng, Jiahui Shi, Ting Wang, Sile Hu, Chun Li, Bin Liu, Jun Yin and Jianghong Wu
Genes 2025, 16(2), 222; https://doi.org/10.3390/genes16020222 - 14 Feb 2025
Viewed by 608
Abstract
Background/Objectives: Research on cashmere goat coat color is crucial for optimizing cashmere goat breeds and increasing their economic value. To identify key genes associated with the formation of cashmere goat coat color and to provide molecular markers for breeding purposes, three healthy, 3-year-old [...] Read more.
Background/Objectives: Research on cashmere goat coat color is crucial for optimizing cashmere goat breeds and increasing their economic value. To identify key genes associated with the formation of cashmere goat coat color and to provide molecular markers for breeding purposes, three healthy, 3-year-old does with similar weights and distinct coat colors—white, black, and light brown—were selected. Methods: Skin samples were collected for transcriptome sequencing, and bioinformatics methods were applied to screen for differentially expressed genes (DEGs) in the skin of cashmere goats with varying coat colors. Real-time fluorescence quantitative PCR (qRT-PCR) and immunofluorescence were subsequently conducted to examine the expression patterns of these DEGs. Results: The results showed that a total of 1153 DEGs were identified across the three groups of cashmere goats. According to GO and KEGG analyses, these DEGs were involved in key biological processes and structures, such as the melanin biosynthetic process (GO:0042438), melanosome membrane (GO:0033162), and melanin biosynthesis from tyrosine (GO:0006583). Employing Cytoscape, a gene interaction network was plotted, highlighting a compact network of DEGs associated with coat color formation. Critical genes identified included TYRP1, TYR, DCT, ASIP, PMEL, LOC102180584, MLANA, TSPAN10, TRPM1, CLDN16, AHCY, LOC106503350, and LOC102175263. qRT-PCR and fluorescence immunohistochemistry further determined that TYRP1, TYR, DCT, and PMEL expression levels were high in black goats (BGs), while ASIP and AHCY expression levels were high in white goats (WGs). The expression levels of these six genes in light brown goats (RGs) were intermediate between those in BGs and WGs. Conclusions: TYRP1, TYR, DCT, and PMEL were believed to play pivotal roles in the formation of black coat color, while ASIP and AHCY regulated the formation of white coat color in cashmere goats. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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17 pages, 3232 KiB  
Article
Retinal Disease Variability in Female Carriers of RPGR Variants Associated with Retinitis Pigmentosa: Clinical and Genetic Parameters
by Sena A. Gocuk, Thomas L. Edwards, Jasleen K. Jolly, Fred K. Chen, David C. Sousa, Myra B. McGuinness, Terri L. McLaren, Tina M. Lamey, Jennifer A. Thompson and Lauren N. Ayton
Genes 2025, 16(2), 221; https://doi.org/10.3390/genes16020221 - 13 Feb 2025
Viewed by 631
Abstract
Objectives: We sought to investigate the visual function, retinal features, and genotype–phenotype correlations of an Australian cohort of RPGR carriers. Methods: In this cross-sectional study, we evaluated RPGR carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between [...] Read more.
Objectives: We sought to investigate the visual function, retinal features, and genotype–phenotype correlations of an Australian cohort of RPGR carriers. Methods: In this cross-sectional study, we evaluated RPGR carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between 2022 and 2023 in Melbourne. Visual acuity tests, fundus-tracked microperimetry, and retinal imaging were performed. RPGR carriers were classified into four retinal phenotypes (normal, radial, focal pigmentary retinopathy, and male pattern phenotype) and compared against healthy controls. Genotype–phenotype relationships in the RPGR carriers were investigated. Results: Thirty-five female RPGR carriers and thirty healthy controls were included in this study. The median ages were 40 and 48.5 years for RPGR carriers and controls, respectively (p = 0.26). Most RPGR carriers (89%) had a genetic diagnosis. Best-corrected visual acuity (BCVA), low luminance visual acuity, retinal sensitivity, central inner retinal thickness (IRT, 1°), and photoreceptor complex (PRC) thickness across the central 1–7° of the retina differed between phenotypes of RPGR carriers. On average, RPGR carriers with ORF15 variants (n = 25 carriers) had reduced LLVA, a greater IRT at 1°, and thinner PRC thickness at 7° from the fovea (all p < 0.05) compared to those with exon 1–14 variants. Conclusions: Female RPGR carriers with severe retinal phenotypes had significantly decreased visual function and changes in retinal structure in comparison to both the controls and carriers with mild retinal disease. BCVA, LLVA, retinal sensitivity, and retinal thickness are biomarkers for detecting retinal disease in RPGR carriers. The genetic variant alone did not influence retinal phenotype; however, RPGR carriers with ORF15 variants exhibited reduced retinal and visual measurements compared to those with exon 1–14 variants. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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26 pages, 56274 KiB  
Review
Chemical Evolution of Life on Earth
by Lei Lei and Zachary Frome Burton
Genes 2025, 16(2), 220; https://doi.org/10.3390/genes16020220 - 13 Feb 2025
Viewed by 1510
Abstract
Background/Objectives: The origin of genes and genetics is the story of the coevolution of translation systems and the genetic code. Remarkably, the history of the origin of life on Earth was inscribed and preserved in the sequences of tRNAs. Methods: Sequence [...] Read more.
Background/Objectives: The origin of genes and genetics is the story of the coevolution of translation systems and the genetic code. Remarkably, the history of the origin of life on Earth was inscribed and preserved in the sequences of tRNAs. Methods: Sequence logos demonstrate the patterning of pre-life tRNA sequences. Results: The pre-life type I and type II tRNA sequences are known to the last nucleotide with only a few ambiguities. Type I and type II tRNAs evolved from ligation of three 31 nt minihelices of highly patterned and known sequence followed by closely related 9 nt internal deletion(s) within ligated acceptor stems. The D loop 17 nt core was a truncated UAGCC repeat. The anticodon and T 17 nt stem-loop-stems are homologous sequences with 5 nt stems and 7 nt U-turn loops that were selected in pre-life to resist ribozyme nucleases and to present a 3 nt anticodon with a single wobble position. The 7 nt T loop in tRNA was selected to interact with the D loop at the “elbow”. The 5′-acceptor stem was based on a 7 nt truncated GCG repeat. The 3′-acceptor stem was based on a complementary 7 nt CGC repeat. In pre-life, ACCA-Gly was a primitive adapter molecule ligated to many RNAs, including tRNAs, to synthesize polyglycine. Conclusions: Analysis of sequence logos of tRNAs from an ancient Archaeon substantiates how the pre-life to life transition occurred on Earth. Polyglycine is posited to have aggregated complex molecular assemblies, including minihelices, tRNAs, cooperating molecules, and protocells, leading to the first life on Earth. Full article
(This article belongs to the Section Population and Evolutionary Genetics and Genomics)
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17 pages, 2875 KiB  
Article
Genetic Regulation of Chlorophyll Biosynthesis in Pepper Fruit: Roles of CaAPRR2 and CaGLK2
by Huagang Sun, Yiyue Zhang, Lingkui Zhang, Xiang Wang, Kang Zhang, Feng Cheng and Shumin Chen
Genes 2025, 16(2), 219; https://doi.org/10.3390/genes16020219 - 13 Feb 2025
Viewed by 642
Abstract
Background: Pepper (Capsicum annuum L.) is a widely cultivated vegetable crop worldwide, with its rich fruit colors providing unique visual traits and economic value. This study investigated the genetic basis of the immature green fruit color by constructing a F2 segregating [...] Read more.
Background: Pepper (Capsicum annuum L.) is a widely cultivated vegetable crop worldwide, with its rich fruit colors providing unique visual traits and economic value. This study investigated the genetic basis of the immature green fruit color by constructing a F2 segregating population derived from a cross between yellow fruit C20 and green fruit C62 parent lines. Methods: Bulked segregant analysis sequencing (BSA-seq) was performed to identify genomic regions associated with fruit color. Candidate genes were pinpointed through functional annotation and genetic variation analysis, supported by SNP markers, genotype analysis, and transcriptome profiling. Results: Two genomic regions associated with fruit color were identified on chromosomes 1 (14.55–20.85 Mb) and 10 (10.15–22.85 Mb), corresponding to previously reported loci pc1 and pc10.1. Two chlorophyll synthesis-related genes, CaAPRR2 and CaGLK2, were identified as candidate regulators of fruit color. Mutations in these genes include a premature stop codon in both CaGLK2 and CaAPRR2. The mutation of CaAPRR2 and CaGLK2 jointly regulate the yellow fruit trait in pepper, with CaGLK2 being the major gene and CaAPRR2 being the minor gene. Transcriptome analysis showed that the expression levels of the two genes increased during the green ripening stage of the parent fruits, with higher expression levels of CaGLK2. Conclusions: This study identifies CaGLK2 and CaAPRR2 as key regulators of immature green fruit color in pepper, with CaGLK2 playing a predominant role. These findings provide a theoretical foundation and data support for elucidating the molecular regulatory mechanisms of fruit color and advancing marker-assisted breeding in pepper. Full article
(This article belongs to the Special Issue Vegetable Genomes and Genetic Breeding)
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11 pages, 3061 KiB  
Article
Copy Number Variations of the NSMF Gene and Their Associations with Growth Traits in Three Chinese Sheep Breeds
by Xiukai Cao, Yongqi Liu, Jie Cheng, Chen Ling, Jinlin Huang and Wei Sun
Genes 2025, 16(2), 218; https://doi.org/10.3390/genes16020218 - 13 Feb 2025
Viewed by 533
Abstract
Background/Objectives: Copy number variations (CNVs) are a significant source of genetic variation and have been shown to influence growth traits in livestock. This study aimed to validate previous CNV candidates within the NSMF gene (XM_015093798.1) and identify novel CNV markers for molecular breeding [...] Read more.
Background/Objectives: Copy number variations (CNVs) are a significant source of genetic variation and have been shown to influence growth traits in livestock. This study aimed to validate previous CNV candidates within the NSMF gene (XM_015093798.1) and identify novel CNV markers for molecular breeding in sheep. Methods: Using quantitative PCR (qPCR), we genotyped NSMF CNVs (chr3: 586,001–601,000) and assessed their associations with growth traits in three Chinese sheep breeds: Chaka sheep (CKS, n = 312), Hu sheep (HS, n = 67), and Small-tailed Han sheep (STHS, n = 70). Results: Our results revealed significant differences in NSMF CNV genotype frequencies across the three breeds, with the highest proportion of deletions observed in STHS (98.44%) and CKS (90.57%), while HS exhibited a higher frequency of duplications (14.06%). No significant associations were observed between NSMF CNV genotype and CKS growth traits (p-value > 0.05). However, the CNV could markedly affected cannon circumference in HS (p-value = 0.021), with individuals carrying the normal genotype showing a larger cannon circumference. Additionally, a marginally significant association was found between the CNV and body diagonal length in HS (p-value = 0.050). Conclusions: Future investigations employing larger cohorts of Hu sheep are warranted to definitively establish the utility of NSMF CNVs as genetic markers for growth traits in Hu sheep breeding programs. Full article
(This article belongs to the Special Issue Advances in Cattle, Sheep, and Goats Molecular Genetics and Breeding)
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14 pages, 1210 KiB  
Article
Utilizing Target Sequences with Multiple Flanking Protospacer Adjacent Motif (PAM) Sites Reduces Off-Target Effects of the Cas9 Enzyme in Pineapple
by Haiyan Shu, Aiping Luan, Hidayat Ullah, Junhu He, You Wang, Chengjie Chen, Qing Wei, Rulin Zhan and Shenghe Chang
Genes 2025, 16(2), 217; https://doi.org/10.3390/genes16020217 - 13 Feb 2025
Viewed by 646
Abstract
Background/Objectives: CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats)-associated protein 9 is now widely used in agriculture and medicine. Off-target effects can lead to unexpected results that may be harmful, and these effects are a common concern in both research and therapeutic applications. Methods: [...] Read more.
Background/Objectives: CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats)-associated protein 9 is now widely used in agriculture and medicine. Off-target effects can lead to unexpected results that may be harmful, and these effects are a common concern in both research and therapeutic applications. Methods: In this study, using pineapple as the gene-editing material, eighteen target sequences with varying numbers of PAM (Protospacer-Adjacent Motif) sites were used to construct gRNA vectors. Fifty mutant lines were generated for each target sequence, and the off-target rates were counted. Results: Selecting sequences with multiple flanking PAM sites as editing targets resulted in a lower off-target rate compared to those with a single PAM site. Target sequences with two 5′-NGG (“N” represents any nucleobase, followed by two guanine “G”) PAM sites at the 3′ end exhibited greater specificity and a higher probability of binding with the Cas9 protein than those only with one 5′-NGG PAM site at the 3′ end. Conversely, although the target sequence with a 5′-NAG PAM site (where “N” is any nucleobase, followed by adenine “A” and guanine “G”) adjacent and upstream of an NGG PAM site had a lower off-target rate compared to sequences with only an NGG PAM site, their off-target rates were still higher than those of sequences with two adjacent 5′-NAG PAM sites. Among the target sequences of pineapple mutant lines (AcACS1, AcOT5, AcCSPE6, AcPKG11A), more deletions than insertions were found. Conclusions: We found that target sequences with multiple flanking PAM sites are more likely to bind with the Cas9 protein and induce mutations. Selecting sequences with multiple flanking PAM sites as editing targets can reduce the off-target effects of the Cas9 enzyme in pineapple. These findings provide a foundation for improving off-target prediction and engineering CRISPR-Cas9 complexes for gene editing. Full article
(This article belongs to the Section Epigenomics)
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19 pages, 1738 KiB  
Review
Mosaicism in Short Tandem Repeat Disorders: A Clinical Perspective
by Rose M. Doss, Susana Lopez-Ignacio, Anna Dischler, Laurel Hiatt, Harriet Dashnow, Martin W. Breuss and Caroline M. Dias
Genes 2025, 16(2), 216; https://doi.org/10.3390/genes16020216 - 13 Feb 2025
Viewed by 906
Abstract
Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that are highly mutable both in the germline and somatic tissue. As short tandem repeats are unstable, they can [...] Read more.
Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that are highly mutable both in the germline and somatic tissue. As short tandem repeats are unstable, they can expand, contract, and acquire and lose epigenetic marks in somatic tissue. This means within an individual, the genotype and epigenetic state at these loci can vary considerably from cell to cell. This somatic mosaicism may play a key role in clinical pathogenesis, and yet, our understanding of mosaicism in driving clinical phenotypes in short tandem repeat disorders is only just emerging. This review focuses on these three relatively well-studied examples where, given the advent of new technologies and bioinformatic approaches, a critical role for mosaicism is coming into focus both with respect to cellular physiology and clinical phenotypes. Full article
(This article belongs to the Special Issue Genomic Mosaicism in Human Development and Diseases)
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31 pages, 1209 KiB  
Review
Interspecies Blastocyst Complementation and the Genesis of Chimeric Solid Human Organs
by Elena Bigliardi, Anala V. Shetty, Walter C. Low and Clifford J. Steer
Genes 2025, 16(2), 215; https://doi.org/10.3390/genes16020215 - 12 Feb 2025
Viewed by 1062
Abstract
Solid organ transplantation remains a life-saving treatment for patients worldwide. Unfortunately, the supply of donor organs cannot meet the current need, making the search for alternative sources even more essential. Xenotransplantation using sophisticated genetic engineering techniques to delete and overexpress specific genes in [...] Read more.
Solid organ transplantation remains a life-saving treatment for patients worldwide. Unfortunately, the supply of donor organs cannot meet the current need, making the search for alternative sources even more essential. Xenotransplantation using sophisticated genetic engineering techniques to delete and overexpress specific genes in the donor animal has been investigated as a possible option. However, the use of exogenous tissue presents another host of obstacles, particularly regarding organ rejection. Given these limitations, interspecies blastocyst complementation in combination with precise gene knockouts presents a unique, promising pathway for the transplant organ shortage. In recent years, great advancements have been made in the field, with encouraging results in producing a donor-derived organ in a chimeric host. That said, one of the major barriers to successful interspecies chimerism is the mismatch in the developmental stages of the donor and the host cells in the chimeric embryo. Another major barrier to successful chimerism is the mismatch in the developmental speeds between the donor and host cells in the chimeric embryos. This review outlines 19 studies in which blastocyst complementation was used to generate solid organs. In particular, the genesis of the liver, lung, kidney, pancreas, heart, thyroid, thymus and parathyroids was investigated. Of the 19 studies, 7 included an interspecies model. Of the 7, one was completed using human donor cells in a pig host, and all others were rat–mouse chimeras. While very promising results have been demonstrated, with great advancements in the field, several challenges continue to persist. In particular, successful chimerism, organ generation and donor contribution, synchronized donor–host development, as well as ethical concerns regarding human–animal chimeras remain important aspects that will need to be addressed in future research. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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16 pages, 517 KiB  
Article
Comprehensive Genomic Analysis of Meyerozyma guilliermondii CECT13190: An Outstanding Biocontrol Agent
by Javier Vicente, José María Alonso de Robador, Beatriz Pintos and Arancha Gomez-Garay
Genes 2025, 16(2), 214; https://doi.org/10.3390/genes16020214 - 12 Feb 2025
Viewed by 716
Abstract
Background/Objectives: Biocontrol agents (BCAs) are gaining attention as sustainable alternatives to chemical pesticides. Understanding their molecular mechanisms is crucial for improving plant protection. This study investigates the genomic features of Meyerozyma guilliermondii CECT13190, a promising BCA, to identify key genes involved in its [...] Read more.
Background/Objectives: Biocontrol agents (BCAs) are gaining attention as sustainable alternatives to chemical pesticides. Understanding their molecular mechanisms is crucial for improving plant protection. This study investigates the genomic features of Meyerozyma guilliermondii CECT13190, a promising BCA, to identify key genes involved in its biocontrol abilities. Methods: Whole-genome sequencing of M. guilliermondii was performed, followed by bioinformatics analysis to identify genes and pathways related to biocontrol, including gene copy number variation (CNV) analysis. Gene ontology (GO) analysis was conducted to examine gene functions, and a comparative proteomics approach assessed the presence and role of proteins in the secretome of M. guilliermondii. Results: Genomic analysis revealed key biocontrol-related pathways. CNV analysis indicated a direct correlation between gene amplification and competitive fitness, with seven genes showing gains and five genes showing losses. GO analysis identified categories such as enzymes, transcription factors, ribosomal and proteasomal complexes, transporters, membrane proteins, RNA processing, and stress-response-related proteins. Secretome analysis identified HSP70 and HSP90 as potential effectors involved in biocontrol activity. Conclusions: This study provides insights into the genomic features of M. guilliermondii and its biocontrol potential. The identification of genes involved in the stress response and the secretome highlights the multifaceted mechanisms through which M. guilliermondii antagonizes plant pathogens. Practical outcomes include the identification of candidate genes and proteins, such as HSP70 and HSP90, which can be targeted to enhance biocontrol efficiency in agricultural applications. Additionally, the observed CNVs offer a potential avenue for strain improvement programs to optimize competitiveness and efficacy in field conditions. Full article
(This article belongs to the Section Bioinformatics)
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11 pages, 754 KiB  
Article
The Association Between Promoter Tandem Repeat Polymorphism (pVNTR) and CYP2C9 Gene Expression in Human Liver Samples
by Abelardo D. Montalvo, Yan Gong, Joseph M. Collins and Danxin Wang
Genes 2025, 16(2), 213; https://doi.org/10.3390/genes16020213 - 11 Feb 2025
Viewed by 739
Abstract
CYP2C9 metabolizes approximately 20% of clinically administered drugs. Several single-nucleotide polymorphisms (SNPs) of CYP2C9 (e.g., *2, *3, *8, and rs12777823) are used as biomarkers to predict CYP2C9 activity. However, a large proportion of variability in CYP2C9 expression remains unexplained. Background/Objectives: We previously identified [...] Read more.
CYP2C9 metabolizes approximately 20% of clinically administered drugs. Several single-nucleotide polymorphisms (SNPs) of CYP2C9 (e.g., *2, *3, *8, and rs12777823) are used as biomarkers to predict CYP2C9 activity. However, a large proportion of variability in CYP2C9 expression remains unexplained. Background/Objectives: We previously identified a variable number tandem repeat (pVNTR) polymorphism in the CYP2C9 promoter. The short repeat (pVNTR-S) showed reduced transcriptional activity in reporter gene assays and was associated with decreased CYP2C9 mRNA expression. However, because pVNTR-S is in high linkage disequilibrium (LD) with CYP2C9*3 in the European population, whether pVNTR-S directly impacts CYP2C9 expression remains unclear. The objective of this study was to clarify the association between the pVNTR-S and CYP2C9 mRNA expression in human liver samples and to assess its impact on CYP2C9 expression independently of known CYP2C9 biomarkers. Methods: Gene expression was measured by real-time qPCR. SNPs and pVNTRs were genotyped using SNapShot assays and fragment analysis, respectively. Associations between CYP2C9 and the pVNTR-S or SNPs were analyzed using multiple linear regression. Results: Our results showed that pVNTR-S was associated with lower CYP2C9 expression (34% reduction, p-value = 0.032) in human liver samples (n = 247), while the known CYP2C9 biomarkers (CYP2C9*2, *3, *8, or rs12777823) were not. These results suggest that pVNTR-S reduces CYP2C9 expression independently of known biomarkers. Therefore, pVNTR-S may explain additional variability in CYP2C9 expression when present alone or in conjunction with other CYP2C9 alleles. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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11 pages, 4573 KiB  
Case Report
Clinical and Genetic Heterogeneity of HCM: The Possible Role of a Deletion Involving MYH6 and MYH7
by Giancarlo Mancuso, Marina Marsan, Paola Neroni, Consolata Soddu, Francesco Lai, Laura Serventi, Milena Cau, Alessandra Coiana, Federica Incani, Stefania Murru and Salvatore Savasta
Genes 2025, 16(2), 212; https://doi.org/10.3390/genes16020212 - 10 Feb 2025
Viewed by 819
Abstract
Background/Objectives: Pediatric hypertrophic cardiomyopathy (HCM) is the most common genetic myocardial disorder in children and a leading cause of sudden cardiac death (SCD) among the young. Its phenotypic variability, driven by incomplete penetrance and variable expressivity, presents significant challenges in diagnosis and clinical [...] Read more.
Background/Objectives: Pediatric hypertrophic cardiomyopathy (HCM) is the most common genetic myocardial disorder in children and a leading cause of sudden cardiac death (SCD) among the young. Its phenotypic variability, driven by incomplete penetrance and variable expressivity, presents significant challenges in diagnosis and clinical management. Methods: In this study, we report a unique case of a 16-month-old female diagnosed with HCM caused by a rare genetic deletion. Molecular analysis was performed using a multigene panel and chromosomal microarray analysis (CMA). Results: Molecular tests identified a 30 kb deletion encompassing the MYH6 and MYH7 genes. These genes are critical components of sarcomeric architecture, with known associations to HCM and other cardiomyopathies. Conclusions: This case underscores the clinical and genetic heterogeneity of HCM, highlighting the importance of considering genomic deletions involving key sarcomeric genes in the diagnostic evaluation. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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3 pages, 129 KiB  
Editorial
Editorial for the “Non-Coding RNAs in Human Health and Disease” Special Issue
by Sujay Paul
Genes 2025, 16(2), 211; https://doi.org/10.3390/genes16020211 - 9 Feb 2025
Viewed by 704
Abstract
Numerous non-coding RNA (ncRNA) species, including miRNAs, siRNAs, piRNAs, circRNAs, and lncRNAs, have displayed a substantial correlation with human diseases, and may serve as prospective targets for gene therapy and diagnostic biomarkers [...] Full article
(This article belongs to the Special Issue Non-coding RNAs in Human Health and Disease)
21 pages, 13634 KiB  
Article
Neuronal Network Activation Induced by Forniceal Deep Brain Stimulation in Mice
by Bin Tang, Zhenyu Wu, Qi Wang and Jianrong Tang
Genes 2025, 16(2), 210; https://doi.org/10.3390/genes16020210 - 9 Feb 2025
Viewed by 1198
Abstract
Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both [...] Read more.
Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both dementia patients and animal models of neurological diseases. Previously, we have reported the beneficial memory effects of chronic forniceal DBS in mouse models of intellectual disability disorders. In Rett syndrome and CDKL5 deficiency disorder models, DBS strengthens hippocampal synaptic plasticity, reduces dentate inhibitory transmission or increases adult hippocampal neurogenesis that aids memory. However, the underlying neuronal circuitry mechanisms remain unknown. This study we explored the neural network circuits involved in forniceal DBS treatment. Methods: We used acute forniceal DBS-induced expression of c-Fos, an activity-dependent neuronal marker, to map the brain structures functionally connected to the fornix. We also evaluated the mouse behavior of locomotion, anxiety, and fear memory after acute forniceal DBS treatment. Results: Acute forniceal DBS induces robust activation of multiple structures in the limbic system. DBS-induced neuronal activation extends beyond hippocampal formation and includes brain structures not directly innervated by the fornix. Conclusions: Acute forniceal DBS activates multiple limbic structures associated with emotion and memory. The neural circuits revealed here help elucidate the neural network effect and pave the way for further research on the mechanism by which forniceal DBS induces benefits on cognitive impairments. Full article
(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)
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15 pages, 2918 KiB  
Article
Putative Biomarkers for Prognosis, Epithelial-to-Mesenchymal Transition, and Drug Response in Cell Lines Representing Oral Squamous Cell Carcinoma Progression
by Mohamad Z. Hamoui, Shuaa Rizvi, Hilal Arnouk and Cai M. Roberts
Genes 2025, 16(2), 209; https://doi.org/10.3390/genes16020209 - 9 Feb 2025
Viewed by 1194
Abstract
Background/Objectives: Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer and accounts for over 50,000 new cancer cases annually in the United States. The survival rates are markedly different for localized OSCC versus metastatic disease, for which [...] Read more.
Background/Objectives: Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer and accounts for over 50,000 new cancer cases annually in the United States. The survival rates are markedly different for localized OSCC versus metastatic disease, for which the five-year survival rate is only 39%. Depending on its pathology and stage at diagnosis, the treatment may involve surgery, radiation, targeted therapy, or conventional chemotherapy. However, there is an unmet need for reliable biomarkers to predict the treatment response or link therapeutic efficacy to tumor progression. We sought to assemble a panel of OSCC tumor progression biomarkers that correlated with the epithelial-to-mesenchymal transition (EMT) and the response to cytotoxic drugs. Methods: We used four cell lines that represented the stepwise progression from normal oral mucosa to dysplastic, invasive, and metastatic OSCC lesions and performed a quantitative analysis via Western blot for putative markers. EMT phenotypes were assessed using wound healing migration assays. Live cell imaging was used to assess drug effectiveness over time. Results: The expression of stratifin, a tumor suppressor gene, is inversely correlated with both tumor progression steps and the expression of the EMT marker N-cadherin. Conversely, the E-cadherin and fibronectin expression was markedly decreased in the advanced-stage OSCC lines. In addition, metastatic Detroit 562 cells exhibited resistance to cell death following docetaxel treatment and showed clear migratory behavior. Conclusions: We describe a molecular signature of advanced and drug-resistant OSCC tumors which encompasses multiple markers, warranting further investigation to establish their utility in predicting clinical outcomes and guiding the treatment options for patients afflicted with oral cancer. Full article
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Review
Bidirectional Interplay Among Non-Coding RNAs, the Microbiome, and the Host During Development and Diseases
by Shanshan Nai, Jiaxian Song, Wenting Su and Xiaoqian Liu
Genes 2025, 16(2), 208; https://doi.org/10.3390/genes16020208 - 8 Feb 2025
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Abstract
It is widely known that the dysregulation of non-coding RNAs (ncRNAs) and dysbiosis of the gut microbiome play significant roles in host development and the progression of various diseases. Emerging evidence has highlighted the bidirectional interplay between ncRNAs and the gut microbiome. This [...] Read more.
It is widely known that the dysregulation of non-coding RNAs (ncRNAs) and dysbiosis of the gut microbiome play significant roles in host development and the progression of various diseases. Emerging evidence has highlighted the bidirectional interplay between ncRNAs and the gut microbiome. This article aims to review the current understanding of the molecular mechanisms underlying the crosstalk between ncRNAs, especially microRNA (miRNA), and the gut microbiome in the context of development and diseases, such as colorectal cancer, inflammatory bowel diseases, neurological disorders, obesity, and cardiovascular disease. Ultimately, this review seeks to provide a foundation for exploring the potential roles of ncRNAs and gut microbiome interactions as biomarkers and therapeutic targets for clinical diagnosis and treatment, such as ncRNA mimics, antisense oligonucleotides, and small-molecule compounds, as well as probiotics, prebiotics, and diets. Full article
(This article belongs to the Special Issue The Role of RNA Regulation in Development and Disease)
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