Genes

19 pages, 748 KB

Open AccessEditor’s ChoiceReview

Management of MET-Driven Resistance to Osimertinib in EGFR-Mutant Non-Small Cell Lung Cancer

by Panagiotis Agisilaos Angelopoulos, Antonio Passaro, Ilaria Attili, Pamela Trillo Aliaga, Carla Corvaja, Gianluca Spitaleri, Elena Battaiotto, Ester Del Signore, Giuseppe Curigliano and Filippo de Marinis

Genes 2025, 16(7), 772; https://doi.org/10.3390/genes16070772 - 30 Jun 2025

Cited by 5 | Viewed by 5768

Abstract

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity [...] Read more.

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal–epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody–drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives. Full article

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

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17 pages, 5483 KB

Open AccessEditor’s ChoiceArticle

Genome-Wide Analysis of HIPP Gene Family in Maize Reveals Its Role in the Cadmium Stress Response

by Chunyan Gao, Zhirui Zhang, Yuxuan Zhu, Jiaxin Tian, Kaili Yu, Jinbo Hou, Dan Luo, Jian Cai and Youcheng Zhu

Genes 2025, 16(7), 770; https://doi.org/10.3390/genes16070770 - 30 Jun 2025

Cited by 4 | Viewed by 1420

Abstract

Background: Phytoremediation is an efficient approach for remediating heavy metal-contaminated soils. Heavy metal-associated isoprenylated plant proteins (HIPPs)—crucial for metal ion homeostasis—are unique to vascular plants, featuring a heavy metal-associated (HMA) domain and an isoprenylated CaaX motif. However, ZmHIPP genes have not been systematically [...] Read more.

Background: Phytoremediation is an efficient approach for remediating heavy metal-contaminated soils. Heavy metal-associated isoprenylated plant proteins (HIPPs)—crucial for metal ion homeostasis—are unique to vascular plants, featuring a heavy metal-associated (HMA) domain and an isoprenylated CaaX motif. However, ZmHIPP genes have not been systematically or functionally characterized in maize. Methods: This study characterizes ZmHIPP at the genome-wide level, including phylogenetic classification, motif/gene structure, chromosome location, gene duplication events, promoter elements, and tissue expression patterns. Cadmium (Cd) responses were evaluated by specific ZmHIPP expression and Cd accumulation in shoots and roots under Cd treatment. Results: A total of 66 ZmHIPPs were distributed unevenly across ten chromosomes, classified into five phylogenetic groups phylogenetically. Gene collinearity revealed 26 pairs of segmental duplications in ZmHIPPs. Numerous synteny genes were detected in rice and sorghum, but none in Arabidopsis, suggesting high conservation of HIPP genes in crop evolution. Transcriptomic analysis revealed tissue-specific expression patterns of ZmHIPP members in maize. Cis-acting element analysis linked several binding elements to abscisic acid, MeJA response, and MYB and MYC transcription factors. Under Cd stress, 53 out of 66 ZmHIPP genes were significantly induced, exhibiting three expression patterns. Cd exposure confirmed that the expression of ZmHIPP11, ZmHIPP30, and ZmHIPP48 was generally higher in shoots than roots, while ZmHIPP02 and ZmHIPP57 exhibited the opposite. Cd accumulation was higher in roots than shoots, peaking at 72 h (96 mg/kg) in shoots and exceeding 1000 mg/kg in roots after 120 h. Conclusions: This study not only provides fundamental genetic and molecular insights into HIPP function in maize but also identifies specific ZmHIPP genes as promising genetic resources for breeding Cd-tolerant maize, aiding in phytoremediation of Cd-contaminated soils. Full article

(This article belongs to the Special Issue Abiotic Stress in Plant: Molecular Genetics and Genomics)

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25 pages, 799 KB

Open AccessEditor’s ChoiceReview

A Review of the Diagnostic Approaches for the Detection of Antimicrobial Resistance, Including the Role of Biosensors in Detecting Carbapenem Resistance Genes

by Kaily Kao and Evangelyn C. Alocilja

Genes 2025, 16(7), 794; https://doi.org/10.3390/genes16070794 - 30 Jun 2025

Cited by 5 | Viewed by 3240

Abstract

Antimicrobial resistance (AMR) is a rapidly growing global concern resulting from the overuse of antibiotics in both agricultural and clinical settings, the lack of surveillance for resistant bacteria, and the low quality of some available antimicrobial agents. Resistant pathogens are no longer susceptible [...] Read more.

Antimicrobial resistance (AMR) is a rapidly growing global concern resulting from the overuse of antibiotics in both agricultural and clinical settings, the lack of surveillance for resistant bacteria, and the low quality of some available antimicrobial agents. Resistant pathogens are no longer susceptible to common clinical antimicrobials, which decreases the effectiveness of medicines used to treat infections caused by these organisms. Carbapenems are an important class of antibiotics due to their broad-spectrum effectiveness in treating infections caused by Gram-positive and Gram-negative organisms. Carbapenem-resistant bacteria have been found not only in healthcare but also in the environment and food supply chain, where they have the potential to spread to pathogens and infect humans and animals. Current methods of detecting AMR genes are expensive and time-consuming. While these methods, like polymerase chain reactions or whole-genome sequencing, are considered the “gold standard” for diagnostics, the development of inexpensive, rapid diagnostic assays is necessary for effective AMR detection and management. Biosensors have shown potential for success in diagnostic testing due to their ease of use, inexpensive materials, rapid results, and portable nature. Biosensors can be combined with nanomaterials to produce sensitive and easily interpretable results. This review presents an overview of carbapenem resistance, current and emerging detection methods of antimicrobial resistance, and the application of biosensors for rapid diagnostic testing for bacterial resistance. Full article

(This article belongs to the Special Issue Mobile Genetic Elements and Microbial Multidrug Resistance)

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22 pages, 2036 KB

Open AccessEditor’s ChoiceReview

Radiogenomics of Stereotactic Radiotherapy: Genetic Mechanisms Underlying Radiosensitivity, Resistance, and Immune Response

by Damir Vučinić, Ana-Marija Bukovica Petrc, Ivona Antončić, Maja Kolak Radojčić, Matea Lekić and Felipe Couñago

Genes 2025, 16(7), 732; https://doi.org/10.3390/genes16070732 - 24 Jun 2025

Cited by 4 | Viewed by 2826

Abstract

Stereotactic body radiotherapy (SBRT) delivers ablative radiation doses with sub-millimeter precision. Radiogenomic studies, meanwhile, provide insights into how tumor-intrinsic genetic factors influence responses to such high-dose treatments. This review explores the radiobiological mechanisms underpinning SBRT efficacy, emphasizing the roles of DNA damage response [...] Read more.

Stereotactic body radiotherapy (SBRT) delivers ablative radiation doses with sub-millimeter precision. Radiogenomic studies, meanwhile, provide insights into how tumor-intrinsic genetic factors influence responses to such high-dose treatments. This review explores the radiobiological mechanisms underpinning SBRT efficacy, emphasizing the roles of DNA damage response (DDR) pathways, tumor suppressor gene alterations, and inflammatory signaling in shaping tumor radiosensitivity or resistance. SBRT induces complex DNA double-strand breaks (DSBs) that robustly activate DDR signaling cascades, particularly via the ATM and ATR kinases. Tumors with proficient DNA repair capabilities often resist SBRT, whereas deficiencies in key repair genes can render them more susceptible to radiation-induced cytotoxicity. Mutations in tumor suppressor genes may impair p53-dependent apoptosis and disrupt cell cycle checkpoints, allowing malignant cells to evade radiation-induced cell death. Furthermore, SBRT provokes the release of pro-inflammatory cytokines and activates innate immune pathways, potentially leading to immunogenic cell death and reshaping the tumor microenvironment. Radiogenomic profiling has identified genomic alterations and molecular signatures associated with differential responses to SBRT and immune activation. These insights open avenues for precision radiotherapy approaches, including the use of genomic biomarkers for patient selection, the integration of SBRT with DDR inhibitors or immunotherapies, and the customization of treatment plans based on individual tumor genotypes and immune landscapes. Ultimately, these strategies aim to enhance SBRT efficacy and improve clinical outcomes through biologically tailored treatment. This review provides a comprehensive summary of current knowledge on the genetic determinants of response to stereotactic radiotherapy and discusses their implications for personalized cancer treatment. Full article

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

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10 pages, 331 KB

Open AccessEditor’s ChoiceArticle

Dopaminergic Modulation of Conscientiousness: DRD2 rs1799732 and Personality Traits in Elite Mixed Martial Arts Athletes

by Milena Lachowicz, Remigiusz Recław, Krzysztof Chmielowiec, Jolanta Chmielowiec, Kinga Łosińska, Aleksandra Suchanecka, Jolanta Masiak and Anna Grzywacz

Genes 2025, 16(6), 720; https://doi.org/10.3390/genes16060720 - 18 Jun 2025

Cited by 5 | Viewed by 1227

Abstract

Background: Personality traits, particularly Conscientiousness, are recognised as crucial psychological factors contributing to success in elite-level athletes. Emerging evidence suggests that individual differences in these traits are influenced by environmental exposure and genetic variation, especially within the dopaminergic system. The DRD2 promoter polymorphism [...] Read more.

Background: Personality traits, particularly Conscientiousness, are recognised as crucial psychological factors contributing to success in elite-level athletes. Emerging evidence suggests that individual differences in these traits are influenced by environmental exposure and genetic variation, especially within the dopaminergic system. The DRD2 promoter polymorphism rs1799732, which affects dopamine D2 receptor expression, may modulate goal-directed behaviour and self-regulation traits. Methods: This study included 323 participants (141 elite mixed martial arts (MMA) athletes and 182 non-athlete controls). Participants completed the NEO Five-Factor Inventory (NEO-FFI). Genotyping for the DRD2 rs1799732 polymorphism was conducted using real-time PCR. Group comparisons and two-way ANOVA were used to assess genotype–phenotype associations and gene × environment interactions. Results: Athletes scored significantly higher on Conscientiousness than controls. A significant main effect of the DRD2 rs1799732 genotype and a genotype × group interaction were observed for Conscientiousness. Specifically, athletes with the ins/ins genotype exhibited the highest levels of Conscientiousness, whereas individuals with the del/del genotype showed the lowest scores. No significant associations were found for other personality traits. Conclusions: These findings suggest that the DRD2 promoter polymorphism rs1799732 moderates the expression of Conscientiousness, particularly under the structured and demanding conditions experienced by elite athletes. Our results support a gene × environment interaction model, highlighting the importance of considering genetic predispositions in high-performance environments. These insights may inform personalised psychological support strategies tailored to athletes’ genetic profiles, enhancing motivation, self-regulation and long-term athletic development. Full article

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

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20 pages, 1211 KB

Open AccessEditor’s ChoiceReview

Human CD36: Gene Regulation, Protein Function, and Its Role in Atherosclerosis Pathogenesis

by Monika Rac

Genes 2025, 16(6), 705; https://doi.org/10.3390/genes16060705 - 13 Jun 2025

Cited by 8 | Viewed by 4329

Abstract

Human CD36 plays an important role in ligand binding, signalling, cell adhesion, and the regulation of angiogenesis. As a scavenging receptor, it is responsible for clearing long-chain fatty acids (LCFAs) and removing approximately 50% of oxidised low-density lipoprotein (ox-LDL) from plasma. The CD36 [...] Read more.

Human CD36 plays an important role in ligand binding, signalling, cell adhesion, and the regulation of angiogenesis. As a scavenging receptor, it is responsible for clearing long-chain fatty acids (LCFAs) and removing approximately 50% of oxidised low-density lipoprotein (ox-LDL) from plasma. The CD36 gene is alternatively spliced. It has several alternative promoters and first exons. The alternative transcripts are expressed in multiple tissues, and their expression patterns are highly variable. The molecular mechanisms that regulate CD36 gene expression are complex and reflect its multifunctional role in different tissues. CD36 activity has been linked to several metabolic processes, such as inflammation, angiogenesis, phagocytosis, and energy homeostasis. CD36 plays a key role in regulating vascular and cardiovascular health and in the pathogenesis of atherosclerosis. CD36 gene mutations in the Caucasian population are rare. Hence, it is extremely difficult to recruit a statistically significant group of CAD patients with these mutations. Nevertheless, this population is largely at risk of cardiovascular disease. Atherosclerosis is a multifactorial disease, but the role of the CD36 receptor in the development of ox-LDL is extremely important. This review aims to introduce readers to issues related to the relationship between CD36 and CAD. The activity of this receptor should be considered when exploring treatment options for atherosclerosis-related complications. Full article

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

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53 pages, 1863 KB

Open AccessEditor’s ChoiceReview

The Role of Adiponectin and ADIPOQ Variation in Metabolic Syndrome: A Narrative Review

by Wiktoria Błażejewska, Justyna Dąbrowska, Joanna Michałowska and Paweł Bogdański

Genes 2025, 16(6), 699; https://doi.org/10.3390/genes16060699 - 10 Jun 2025

Cited by 9 | Viewed by 5656

Abstract

Metabolic syndrome (MetS), a significant global health concern, is characterized as a cluster of metabolic abnormalities that elevate the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Adiponectin, an adipokine secreted by adipose tissue, plays a crucial role in regulating [...] Read more.

Metabolic syndrome (MetS), a significant global health concern, is characterized as a cluster of metabolic abnormalities that elevate the risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Adiponectin, an adipokine secreted by adipose tissue, plays a crucial role in regulating glucose and lipid homeostasis while exhibiting protective effects against vascular alterations. Single-nucleotide variants (SNVs) in the ADIPOQ gene have significantly affected circulating adiponectin levels and metabolic parameters. This narrative review examines current evidence on the relationship between adiponectin, ADIPOQ gene variants, and metabolic syndrome. The findings indicate that lower adiponectin levels are associated with an increased risk of metabolic syndrome components, including elevated triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and fasting glucose levels. In conclusion, adiponectin emerges as a key regulator of metabolic homeostasis, with SNVs in the ADIPOQ gene correlating with the development of metabolic-related complications. Full article

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

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13 pages, 1150 KB

Open AccessEditor’s ChoiceReview

The Emergence of Artificial Intelligence-Guided Karyotyping: A Review and Reflection

by Lynne S. Rosenblum, Julia Holmes and Agshin F. Taghiyev

Genes 2025, 16(6), 685; https://doi.org/10.3390/genes16060685 - 31 May 2025

Cited by 3 | Viewed by 4262

Abstract

Artificial intelligence (AI) has entered the medical subspecialty of cytogenetics with the recent introduction of AI-guided karyotyping into the clinical laboratory. Karyotyping is an essential component of the cytogenetic analysis process; however, it is both labor-intensive and time-consuming. The introduction of AI algorithms [...] Read more.

Artificial intelligence (AI) has entered the medical subspecialty of cytogenetics with the recent introduction of AI-guided karyotyping into the clinical laboratory. Karyotyping is an essential component of the cytogenetic analysis process; however, it is both labor-intensive and time-consuming. The introduction of AI algorithms into karyotyping software streamlines this process to provide accurate and abundant auto-karyotyped images for laboratory professionals to review and, also, alters the paradigm for chromosome analysis. Herein, we provide an overview of the AI-guided karyotyping products currently available for clinical use, discuss their utilization in the cytogenetics laboratory, and highlight changes AI-guided karyotyping has brought for early users. Finally, we reflect on our own laboratory observations and experience to discuss issues and practices that may need to adapt to best utilize this promising new technology. Full article

(This article belongs to the Special Issue Clinical Cytogenetics: Current Advances and Future Perspectives)

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24 pages, 797 KB

Open AccessEditor’s ChoiceReview

Obesity and Heart Failure: Mechanistic Insights and the Regulatory Role of MicroRNAs

by Parul Sahu, Furkan Bestepe, Sezan Vehbi, George F. Ghanem, Robert M. Blanton and Basak Icli

Genes 2025, 16(6), 647; https://doi.org/10.3390/genes16060647 - 28 May 2025

Cited by 5 | Viewed by 3127

Abstract

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, driven by diverse pathophysiological mechanisms. Among its major risk factors, obesity has emerged as a lobal public health concern affecting individuals across all age groups. The rising prevalence of obesity significantly [...] Read more.

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, driven by diverse pathophysiological mechanisms. Among its major risk factors, obesity has emerged as a lobal public health concern affecting individuals across all age groups. The rising prevalence of obesity significantly increases the risk of cardiovascular complications, including the development and progression of HF. MicroRNAs (miRNAs), small non-coding RNA molecules, have garnered attention for their regulatory roles in cardiovascular disease, particularly through post-transcriptional modulation of gene expression. This review highlights the involvement of miRNAs in key pathological processes observed in the obese heart, including cardiac remodeling, apoptosis, angiogenesis, inflammation, mitochondrial dysfunction, and myocardial lipotoxicity. Understanding how specific miRNAs and their targets contribute to HF in the context of obesity may inform the development of novel RNA-based therapeutic strategies for cardiometabolic disease. Full article

(This article belongs to the Section RNA)

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34 pages, 9334 KB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of Deep Learning Applications with Multi-Omics Data in Cancer Research

by Flavio Sartori, Francesco Codicè, Isabella Caranzano, Cesare Rollo, Giovanni Birolo, Piero Fariselli and Corrado Pancotti

Genes 2025, 16(6), 648; https://doi.org/10.3390/genes16060648 - 28 May 2025

Cited by 23 | Viewed by 12808

Abstract

The integration of deep learning (DL) with multi-omics data has significantly advanced our understanding of biological systems, particularly in cancer research. DL enables the analysis of high-dimensional datasets and the discovery of novel disease mechanisms and biomarkers, contributing to improved patient treatment and [...] Read more.

The integration of deep learning (DL) with multi-omics data has significantly advanced our understanding of biological systems, particularly in cancer research. DL enables the analysis of high-dimensional datasets and the discovery of novel disease mechanisms and biomarkers, contributing to improved patient treatment and management. This review provides a detailed overview of recent developments in deep learning models applied to genomics data, with a focus on cancer type classification, driver gene identification, survival analysis, and drug response prediction. We introduce the foundational concepts of machine and deep learning and explain the characteristics of multi-omics data, addressing a broad and interdisciplinary audience. Methods published since 2020 are systematically reviewed, including their model architectures, datasets, and key innovations. Full article

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

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14 pages, 2401 KB

Open AccessEditor’s ChoiceArticle

Identification of Novel Genetic Loci Involved in Testis Traits of the Jiangxi Local Breed Based on GWAS Analyses

by Jing-E Ma, Ke Huang, Bahareldin Ali Abdalla Gibril, Xinwei Xiong, Yanping Wu, Zhangfeng Wang and Jiguo Xu

Genes 2025, 16(6), 637; https://doi.org/10.3390/genes16060637 - 27 May 2025

Cited by 3 | Viewed by 1117

Abstract

Background: The testis, a critical reproductive organ in male animals, is responsible for sperm production and androgen secretion. Testis weight often correlates with reproductive performance, yet the genetic factors influencing testicular traits in chickens remain unclear. Methods: Previous genome-wide association studies (GWAS) have [...] Read more.

Background: The testis, a critical reproductive organ in male animals, is responsible for sperm production and androgen secretion. Testis weight often correlates with reproductive performance, yet the genetic factors influencing testicular traits in chickens remain unclear. Methods: Previous genome-wide association studies (GWAS) have identified key genes affecting testicular traits in Kangle Yellow chickens, along with the associated regulatory pathways and Gene Ontology (GO) terms, through bioinformatic analyses. In this study, we utilized the existing literature, full-length transcriptome data, and proteome analyses to select key candidate genes. Results: We identified 13 associated markers for chicken testicular traits with 262 candidate genes. Nine candidate genes were found to regulate chicken testicular traits referred to integrated analysis, including CDH3, ZFPM1, CFAP52, ST6GAL1, IGF2BP2, SPG7, CDT1, NFAT5, and OPRK1. Physical interactions among these genes were also observed, implicating mechanisms such as cell adhesion molecules and neuroactive ligand–receptor interaction. Conclusions: These findings provide a genetic basis for improving testicular traits in Chinese native chicken breeds. Full article

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

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16 pages, 809 KB

Open AccessEditor’s ChoiceReview

The Dynamic Remodeling of Plant Cell Wall in Response to Heat Stress

by Chengchen Lu, Wenfei Li, Xiaomeng Feng, Jiarui Chen, Shijie Hu, Yirui Tan and Leiming Wu

Genes 2025, 16(6), 628; https://doi.org/10.3390/genes16060628 - 24 May 2025

Cited by 9 | Viewed by 3275

Abstract

Heat stress has a significant negative impact on plant growth, development, and yield. The cell wall, a key structural feature that sets plants apart from animals, not only acts as the first physical barrier against heat stress but also plays an active role [...] Read more.

Heat stress has a significant negative impact on plant growth, development, and yield. The cell wall, a key structural feature that sets plants apart from animals, not only acts as the first physical barrier against heat stress but also plays an active role in the heat stress (HS) response through signaling pathways. The plant cell wall has a complex structural composition, including cellulose, hemicellulose, lignin, and pectin. These components not only provide mechanical support for cell growth but also constitute the material basis for plant response to environmental changes. This review summarizes recent research on how the cell wall’s structural composition affects its mechanical properties in response to stresses. It examines changes in plant cell walls under HS and the adaptive mechanisms leading to cell wall thickening. Additionally, it explores the role of cell wall integrity in sensing and transmitting HS, along with the molecular mechanisms that maintain this integrity. Finally, it addresses unresolved scientific questions regarding plant cell wall responses to HS. This review aims to provide a theoretical foundation and research direction for enhancing plant thermotolerance through genetic improvement of the cell wall. Full article

(This article belongs to the Special Issue Genetic Modification of Plant Cell Wall and Bioenergy Crop Breeding)

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17 pages, 3721 KB

Open AccessEditor’s ChoiceArticle

Comparative Genomic Analysis Across Multiple Species to Identify Candidate Genes Associated with Important Traits in Chickens

by Fuyang Zhang, Hengcong Chen, Cheng Chang, Jiamei Zhou and Hui Zhang

Genes 2025, 16(6), 627; https://doi.org/10.3390/genes16060627 - 24 May 2025

Cited by 3 | Viewed by 1821

Abstract

Background: As one of the most important poultry species worldwide, chickens provide substantial amounts of meat, eggs, and other products for human consumption. With continuous improvements in living standards, consumer demand for high-quality animal products is increasing, making it essential to understand the [...] Read more.

Background: As one of the most important poultry species worldwide, chickens provide substantial amounts of meat, eggs, and other products for human consumption. With continuous improvements in living standards, consumer demand for high-quality animal products is increasing, making it essential to understand the genetic basis of key traits such as egg production, meat quality, and disease resistance for targeted genetic improvement. Methods: In this study, a number of the candidate genes associated with important traits in chickens were screened by various comparative genomics analysis methods. To further clarify the relationship between these candidate genes and important traits in chickens, they were functionally annotated through the KOG, GO, and KEGG databases. Results: These candidate genes are mainly concentrated in the functional categories of transcription and signal transduction mechanisms and are involved in biological processes such as cyclic nucleotide biosynthesis and intracellular signaling, which involve signaling pathways such as ECM–receptor interactions and calcium signaling. Conclusions: Based on the annotation results from various databases, a functional search of the candidate genes and related literature reports, the following results were obtained: genes such as TBX22, LCORL, and GH were associated with chicken growth traits; genes such as A-FABP, H-FABP, and PRKAB2 were associated with chicken meat quality; genes such as IGF-1, SLC25A29, and WDR25 were associated with chicken reproductive traits; and genes such as C1QBP, VAV2 and IL12B were associated with chicken disease resistance traits. Overall, the findings of this study provide novel insights and candidate genes for genetic improvements in chickens, laying a foundation for future research and breeding strategies targeting key economic traits. Full article

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

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20 pages, 2416 KB

Open AccessEditor’s ChoiceArticle

Examination of Runs of Homozygosity Distribution Patterns and Relevant Candidate Genes of Potential Economic Interest in Russian Goat Breeds Using Whole-Genome Sequencing

by Tatiana E. Deniskova, Arsen V. Dotsev, Olga A. Koshkina, Anastasia D. Solovieva, Nadezhda A. Churbakova, Sergey N. Petrov, Alexey N. Frolov, Stanislav A. Platonov, Alexandra S. Abdelmanova, Maxim A. Vladimirov, Elena A. Gladyr, Igor V. Gusev, Svyatoslav V. Lebedev, Darren K. Griffin, Michael N. Romanov and Natalia A. Zinovieva

Genes 2025, 16(6), 631; https://doi.org/10.3390/genes16060631 - 24 May 2025

Cited by 4 | Viewed by 1543

Abstract

Background/Objectives: Whole-genome sequencing (WGS) data provide valuable information about the genetic architecture of local livestock but have not yet been applied to Russian native goats, in particular, the Orenburg and Karachay breeds. A preliminary search for selection signatures based on single nucleotide polymorphism [...] Read more.

Background/Objectives: Whole-genome sequencing (WGS) data provide valuable information about the genetic architecture of local livestock but have not yet been applied to Russian native goats, in particular, the Orenburg and Karachay breeds. A preliminary search for selection signatures based on single nucleotide polymorphism (SNP) genotype data in these breeds was not informative. Therefore, in this study, we aimed to address runs of homozygosity (ROHs) patterns and find the respective signatures of selection overlapping candidate genes in Orenburg and Karachay goats using the WGS approach. Methods: Paired-end libraries (150 bp reads) were constructed for each animal. Next-generation sequencing was performed using a NovaSeq 6000 sequencer (Illumina, Inc., San Diego, CA, USA), with ~20X genome coverage. ROHs were identified in sliding windows, and ROH segments shared by at least 50% of the samples were considered as ROH islands. Results: ROH islands were identified on chromosomes CHI3, CHI5, CHI7, CHI12, CHI13, and CHI15 in Karachay goats; and CHI3, CHI11, CHI12, CHI15, and CHI16 in Orenburg goats. Shared ROH islands were found on CHI12 (containing the PARP4 and MPHOSPH8 candidate genes) and on CHI15 (harboring STIM1 and RRM1). The Karachay breed had greater ROH length and higher ROH number compared to the Orenburg breed (134.13 Mb and 695 vs. 78.43 Mb and 438, respectively). The genomic inbreeding coefficient (F_ROH) varied from 0.032 in the Orenburg breed to 0.054 in the Karachay breed. Candidate genes associated with reproduction, milk production, immunity-related traits, embryogenesis, growth, and development were identified in ROH islands in the studied breeds. Conclusions: Here, we present the first attempt of elucidating the ROH landscape and signatures of selection in Russian local goat breeds using WGS analysis. Our findings will pave the way for further insights into the genetic mechanisms underlying adaption and economically important traits in native goats. Full article

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

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21 pages, 1811 KB

Open AccessEditor’s ChoiceReview

Impact of Heavy Metal and Resistance Genes on Antimicrobial Resistance: Ecological and Public Health Implications

by Carlos G. Sánchez-Corona, Luis Uriel Gonzalez-Avila, Cecilia Hernández-Cortez, Jorge Rojas-Vargas, Graciela Castro-Escarpulli and Hugo G. Castelán-Sánchez

Genes 2025, 16(6), 625; https://doi.org/10.3390/genes16060625 - 24 May 2025

Cited by 15 | Viewed by 5046

Abstract

Heavy metals (HMs) are widespread pollutants that can exert selection pressure on microbial populations due to their toxicity and persistence, leading to the evolution of heavy metal resistance genes (HMRGs). These genes are part of the resistome, and their spread often occurs via [...] Read more.

Heavy metals (HMs) are widespread pollutants that can exert selection pressure on microbial populations due to their toxicity and persistence, leading to the evolution of heavy metal resistance genes (HMRGs). These genes are part of the resistome, and their spread often occurs via mobile genetic elements that allow co-selection with antibiotic and biocide resistance genes. Such processes have an impact on microbial biodiversity, biogeochemical cycling and public health in agriculture, industry and urban areas. The selection pressure exerted by HM promotes the spread of multidrug-resistant strains and thus increases ecological and health risks. This review discusses the interaction between HMRGs and genetic determinants such as virulence genes that influence biofilm formation, cellular homeostasis and oxidative stress. It also discusses the dual role of HMRGs in promoting ecological functions such as bioremediation while potentially limiting them by reducing microbial diversity. Understanding such interactions contributes significantly to targeting different systems to overcome the challenges associated with antimicrobial resistance (AMR). Full article

(This article belongs to the Special Issue Advances in Molecular Microbiology, Genetics, and Bioinformatics of Multiple-Drug-Resistant Bacteria in Public Health)

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16 pages, 15842 KB

Open AccessEditor’s ChoiceArticle

Analysis of Codon Usage Bias of 30 Chloroplast Genomes in Ulva (Ulvophyceae, Chlorophyta)

by Jiao Fang, Liming Qin, Hongni Liu and Zhangfeng Hu

Genes 2025, 16(5), 608; https://doi.org/10.3390/genes16050608 - 21 May 2025

Cited by 5 | Viewed by 1115

Abstract

Background: Ulva is a globally distributed genus with ecological and economic significance, yet the codon usage bias of the Ulva chloroplast genome remains poorly understood. Methods: We assessed the Ulva chloroplast genome codon usage patterns and their drivers by analyzing 30 genomes across [...] Read more.

Background: Ulva is a globally distributed genus with ecological and economic significance, yet the codon usage bias of the Ulva chloroplast genome remains poorly understood. Methods: We assessed the Ulva chloroplast genome codon usage patterns and their drivers by analyzing 30 genomes across 16 Ulva species. Results: The nucleotide composition analysis demonstrated that Ulva chloroplast genomes are rich in A/T, and prefer to use codons that ended with A/T. The relative synonymous codon usage analysis suggested that related species have similar codon usage patterns. A total of 25 high-frequency codons and 7–14 optimal codons were identified in these chloroplast genomes. The ENC values ranged from 31.40 to 32.76, all of which are less than 35, illustrating a strong codon bias of the Ulva genus. Our comparative analyses suggested that natural selection played the main role in the formation of the codon usage bias. Furthermore, the correlation analysis indicated that an influence of the base composition and gene expression levels on the codon usage bias. Conclusions: This study provides the first comprehensive analysis of the codon usage patterns in Ulva chloroplast genomes, improving our understanding of the genetics and evolution of these economically and ecologically important macroalgae. Full article

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

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22 pages, 1670 KB

Open AccessEditor’s ChoiceReview

Signaling Pathways in Gliomas

by Paulina Stachyra and Ludmiła Grzybowska-Szatkowska

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

Cited by 3 | Viewed by 2648

Abstract

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

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

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

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53 pages, 1175 KB

Open AccessEditor’s ChoiceReview

Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy

by Pierre Bougnères and Catherine Le Stunff

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

Cited by 3 | Viewed by 6204

Abstract

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

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

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

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25 pages, 4439 KB

Open AccessEditor’s ChoiceArticle

Genetic Diversity and Metabolic Profile of Tibetan Medicinal Plant Saussurea obvallata

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

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

Cited by 4 | Viewed by 1386

Abstract

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

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

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

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23 pages, 418 KB

Open AccessEditor’s ChoiceSystematic Review

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

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

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

Cited by 3 | Viewed by 4463

Abstract

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

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

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

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17 pages, 688 KB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 6 | Viewed by 4670

Abstract

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

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

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

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17 pages, 17046 KB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 3 | Viewed by 1578

Abstract

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

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

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

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34 pages, 1707 KB

Open AccessEditor’s ChoiceReview

Natural Bioproducts with Epigenetic Properties for Treating Cardiovascular Disorders

by Olaia Martínez-Iglesias, Vinogran Naidoo, Iván Carrera, Lola Corzo and Ramón Cacabelos

Genes 2025, 16(5), 566; https://doi.org/10.3390/genes16050566 - 10 May 2025

Cited by 2 | Viewed by 2360

Abstract

Cardiovascular disorders (CVDs) are the leading cause of mortality worldwide, highlighting an urgent need for innovative therapeutic strategies. Recent advancements highlight the potential of naturally derived bioproducts with epigenetic properties to offer protection against CVDs. These compounds act on key epigenetic mechanisms, DNA [...] Read more.

Cardiovascular disorders (CVDs) are the leading cause of mortality worldwide, highlighting an urgent need for innovative therapeutic strategies. Recent advancements highlight the potential of naturally derived bioproducts with epigenetic properties to offer protection against CVDs. These compounds act on key epigenetic mechanisms, DNA methylation, histone modifications, and non-coding RNA regulation to modulate gene expression essential for cardiovascular health. This review explores the effects of various bioproducts, such as polyphenols, flavonoids, and other natural extracts, on these epigenetic modifications and their potential benefits in preventing and managing CVDs. We discuss recent discoveries and clinical applications, providing insights into the epigenetic regulatory mechanisms of these compounds as potential epidrugs, naturally derived agents with promising therapeutic prospects in epigenetic therapy for CVDs. Full article

(This article belongs to the Section Epigenomics)

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13 pages, 17357 KB

Open AccessEditor’s ChoiceArticle

Comparative Mitochondrial Genomic and Phylogenetic Study of Eight Species of the Family Lonchodidae (Phasmatodea: Euphasmatodea)

by Ting Luo, Qianwen Zhang, Siyu Pang, Yanting Qin, Bin Zhang and Xun Bian

Genes 2025, 16(5), 565; https://doi.org/10.3390/genes16050565 - 10 May 2025

Cited by 3 | Viewed by 1230

Abstract

Background: Lonchodidae is the largest family within the order Phasmatodea, and although many studies have been conducted on this family, the monophyly of the family has not been established. Methods: Eight mitogenomes from Lonchodidae, including the first complete mitogenomes of four genera, were [...] Read more.

Background: Lonchodidae is the largest family within the order Phasmatodea, and although many studies have been conducted on this family, the monophyly of the family has not been established. Methods: Eight mitogenomes from Lonchodidae, including the first complete mitogenomes of four genera, were sequenced and annotated to explore their features and phylogenetic relationships. Results: The total length ranged from 15,942–18,021 bp, and the mitogenome consisted of 13 protein-coding genes (PCGs), 22 tRNA genes, 2 rRNA genes, and a control region (CR). atp8 had the highest A + T content in Lonchodidae, except for Neohirasea stephanus and Asceles clavatus, in which the highest A + T contents were detected in nad6. The phylogenetic trees were reconstructed via Bayesian inference (BI) and maximum likelihood (ML) based on the PCG123 and PCG12 datasets. As the phylogenetic trees show, Necrosciinae is recognized as monophyletic, but the monophyly of Lonchodinae has not been supported. Gene deletion and rearrangement have occurred mainly in Lonchodidae and Aschiphasmatidae. The most common reason for gene rearrangements was tandem duplication random loss (TDRL), but trnI of Stheneboea repudiosa inverted into the CR. In addition, genes within the same family or genus share related sequences and conserved gene blocks. Conclusions: we expanded the mitochondrial genomic data for this family, thereby establishing a foundational dataset for future studies. 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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28 pages, 708 KB

Open AccessEditor’s ChoiceReview

The Role of Artificial Intelligence in Identifying NF1 Gene Variants and Improving Diagnosis

by Vasiliki Sofia Grech, Kleomenis Lotsaris, Theano Eirini Touma, Vassiliki Kefala and Efstathios Rallis

Genes 2025, 16(5), 560; https://doi.org/10.3390/genes16050560 - 7 May 2025

Cited by 4 | Viewed by 3302

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene, typically diagnosed during early childhood and characterized by significant phenotypic heterogeneity. Despite advancements in next-generation sequencing (NGS), the diagnostic process remains challenging due to the gene’s complexity, [...] Read more.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene, typically diagnosed during early childhood and characterized by significant phenotypic heterogeneity. Despite advancements in next-generation sequencing (NGS), the diagnostic process remains challenging due to the gene’s complexity, high mutational burden, and frequent identification of variants of uncertain significance (VUS). This review explores the emerging role of artificial intelligence (AI) in enhancing NF1 variant detection, classification, and interpretation. A systematic literature search was conducted across PubMed, IEEE Xplore, Google Scholar, and ResearchGate to identify recent studies applying AI technologies to NF1 genetic analysis, focusing on variant interpretation, structural modeling, tumor classification, and therapeutic prediction. The review highlights the application of AI-based tools such as VEST3, REVEL, ClinPred, and NF1-specific models like DITTO and RENOVO-NF1, which have demonstrated improved accuracy in classifying missense variants and reclassifying VUS. Structural modeling platforms like AlphaFold contribute further insights into the impact of NF1 mutations on neurofibromin structure and function. In addition, deep learning models, such as LTC neural networks, support tumor classification and therapeutic outcome prediction, particularly in NF1-associated complications like congenital pseudarthrosis of the tibia (CPT). The integration of AI methodologies offers substantial potential to improve diagnostic precision, enable early intervention, and support personalized medicine approaches. However, key challenges remain, including algorithmic bias, limited data diversity, and the need for functional validation. Ongoing refinement and clinical validation of these tools are essential to ensure their effective implementation and equitable use in NF1 diagnostics. Full article

(This article belongs to the Section Bioinformatics)

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21 pages, 1417 KB

Open AccessEditor’s ChoiceReview

Non-Invasive Preimplantation Genetic Testing

by Daniela N. Bakalova, Luis Navarro-Sánchez and Carmen Rubio

Genes 2025, 16(5), 552; https://doi.org/10.3390/genes16050552 - 30 Apr 2025

Cited by 3 | Viewed by 7949

Abstract

To minimise the influence of chromosomal abnormalities during IVF treatment, embryos can be screened before transfer using preimplantation genetic testing. This typically involves an invasive trophectoderm biopsy at the blastocyst stage, where 4–8 cells are collected and analysed. However, emerging evidence indicates that, [...] Read more.

To minimise the influence of chromosomal abnormalities during IVF treatment, embryos can be screened before transfer using preimplantation genetic testing. This typically involves an invasive trophectoderm biopsy at the blastocyst stage, where 4–8 cells are collected and analysed. However, emerging evidence indicates that, as embryos develop in vitro in culture media, they release cell-free DNA into the media, providing an alternative source of genetic material that can be accessed non-invasively. Spent blastocyst media samples that contain embryo cell-free DNA demonstrate high informativity rates and ploidy concordance when compared with the corresponding trophectoderm, inner cell mass, or whole blastocyst results. However, optimising this non-invasive approach requires several changes to embryo culture protocols, including additional embryo washes to tackle contamination and extending embryo culture time to maximise the amount of cell-free DNA released into the culture media. In this review, we discuss this novel non-invasive approach for aneuploidy detection and embryo prioritisation, as well as the current data and future prospects for utilising cell-free DNA analysis to identify structural rearrangements and single gene disorders. Full article

(This article belongs to the Special Issue Current Advances and Future Perspectives on Preimplantation Genetic Testing)

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21 pages, 7303 KB

Open AccessEditor’s ChoiceReview

Updates on the Regulatory Framework of Edited Organisms in Brazil: A Molecular Revolution in Brazilian Agribusiness

by Nicolau B. da Cunha, Jaim J. da Silva Junior, Amanda M. M. Araújo, Ludmila R. de Souza, Michel L. Leite, Gabriel da S. Medina, Gustavo R. Rodriguez, Renan M. dos Anjos, Júlio C. M. Rodrigues, Fabrício F. Costa, Simoni C. Dias, Elíbio L. Rech and Giovanni R. Vianna

Genes 2025, 16(5), 553; https://doi.org/10.3390/genes16050553 - 30 Apr 2025

Cited by 6 | Viewed by 4265

Abstract

Genome editing technologies have revolutionized the production of microorganisms, plants, and animals with phenotypes of interest to agriculture. Editing previously sequenced genomes allows for the punctual, discreet, precise, and accurate alteration of DNA for genetic analysis, genotyping, and phenotyping, as well as the [...] Read more.

Genome editing technologies have revolutionized the production of microorganisms, plants, and animals with phenotypes of interest to agriculture. Editing previously sequenced genomes allows for the punctual, discreet, precise, and accurate alteration of DNA for genetic analysis, genotyping, and phenotyping, as well as the production of edited organisms for academic and industrial purposes, among many other objectives. In this context, genome editing technologies have been causing a revolution in Brazilian agriculture. Thanks to the publication of Normative Resolution No. 16 (in Portuguese Resolução Normativa No. 16-RN16) in 2018, Brazilian regulatory authorities have adapted to the new genetic manipulation technologies available to the scientific community. This review aims to describe the effects of updates to the regulatory framework for edited organisms in Brazil and to point out their impacts on research and development of emerging technologies in the Brazilian agricultural sector. The implementation of RN16 rationalized the regulatory aspects regarding the production, manipulation, exploration and commercial release of edited organisms and led to the faster, cheaper and safer obtaining of edited technologies, which are more productive and better adapted to different environmental conditions in Brazil. Full article

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

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36 pages, 1680 KB

Open AccessEditor’s ChoiceReview

Genotoxicity in Unconventional Mammalian Models of Wild, Urban, and Agricultural Ecosystems: A Systematic Review Under the One Health Approach

by Nora Bibiana M. Gorla, Mariela Nieves and Daniela Marisol Ferré

Genes 2025, 16(5), 525; https://doi.org/10.3390/genes16050525 - 29 Apr 2025

Cited by 2 | Viewed by 2731

Abstract

Background/Objectives: This systematic review evaluates unconventional mammalian models from wild, agricultural, and urban/domestic ecosystems for genotoxicity assessment under the One Health framework. Non-human primates (NHPs), cattle, and domestic dogs are analyzed as sentinel species due to their distinct environmental niches, unique human interactions, [...] Read more.

Background/Objectives: This systematic review evaluates unconventional mammalian models from wild, agricultural, and urban/domestic ecosystems for genotoxicity assessment under the One Health framework. Non-human primates (NHPs), cattle, and domestic dogs are analyzed as sentinel species due to their distinct environmental niches, unique human interactions, and species-specific traits. In conjunction with this, evidence is presented about the in vitro use of cells of these mammals for the genotoxicological evaluation of different chemical substances, such as veterinary drugs, environmental pollutants, and pesticides. The synthesis focuses on standardized genetic toxicology assays (e.g., chromosomal aberrations, micronucleus, comet assay) aligned with Organization for Economic Cooperation and Development (OECD) guidelines. Methods: A structured search of international literature identified studies employing OECD-compliant genotoxicity assays in NHPs, cattle, dogs, and others not listed in OECD. Data was categorized by species, assay type, chemical class evaluated, environmental context (wild, agricultural, urban), and merits of the papers. Results: NHPs, despite their phylogenetic proximity to humans, show limited genotoxicity data in contrast to biomedical research, which has been constrained by ethical concerns and fieldwork logistics. Cattle emerge as robust models in agricultural settings due to the abundance of studies on the genotoxic capacity of pesticides, veterinary drug, and environmental biomonitoring, with direct implications for food safety. Domestic dogs are recognized as powerful sentinels for human health due to shared exposomes, physiological similarities (e.g., shorter cancer latency), and reduced lifestyle confounders; however, genotoxicity studies in dogs remain sparse compared to chemical exposure monitoring or cancer research. Conclusions: This review advocates for expanded, integrated use of these models to address genotoxic threats across ecosystems, which would benefit both animal and human health. In the application of biomonitoring studies with sentinel animals, a critical gap persists: the frequent lack of integration between xenobiotic quantification in environmental and biological samples, along with genotoxicity biomarkers evaluation in sentinel populations, which hinders comprehensive environmental risk assessment. Full article

(This article belongs to the Collection Feature Papers in ‘Animal Genetics and Genomics’)

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19 pages, 1979 KB

Open AccessEditor’s ChoiceReview

Epigenetic Regulation of Human Vascular Calcification

by Lova Prasadareddy Kajuluri, Yugene Young Guo, Sujin Lee, Michael Christof and Rajeev Malhotra

Genes 2025, 16(5), 506; https://doi.org/10.3390/genes16050506 - 28 Apr 2025

Cited by 7 | Viewed by 2395

Abstract

Vascular diseases present a significant threat to human health worldwide. Atherosclerosis is the most prevalent vascular disease, accounting for the majority of morbidity and mortality globally. Vascular calcification is a dynamic pathological process underlying the development of atherosclerotic plaques and involves the phenotypic [...] Read more.

Vascular diseases present a significant threat to human health worldwide. Atherosclerosis is the most prevalent vascular disease, accounting for the majority of morbidity and mortality globally. Vascular calcification is a dynamic pathological process underlying the development of atherosclerotic plaques and involves the phenotypic transformation of vascular smooth muscle cells (VSMCs) into osteogenic cells. Specifically, the phenotypic switch in VSMCs often involves modifications in gene expression due to epigenetic changes, including DNA methylation, histone modification, and non-coding RNAs. Understanding the role of these epigenetic changes in regulating the pathophysiology of vascular calcification, along with the proteins and pathways that mediate these changes, will aid in identifying new therapeutic candidates to enhance vascular health. This review discusses a comprehensive range of epigenetic modifications and their implications for vascular health and the development of vascular calcification. Full article

(This article belongs to the Special Issue Epigenetics in Human Development and Diseases)

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26 pages, 2266 KB

Open AccessEditor’s ChoiceReview

Single Amino Acid Supplementation in Inherited Metabolic Disorders: An Evidence-Based Review of Interventions

by Elvira Verduci, Martina Tosi, Carlo Dionisi Vici and Marco Spada

Genes 2025, 16(5), 502; https://doi.org/10.3390/genes16050502 - 27 Apr 2025

Cited by 2 | Viewed by 3177

Abstract

Background/Objectives: Inherited metabolic disorders (IMDs) are a group of genetic conditions affecting metabolic pathways. The treatment of some IMDs requires the dietary restriction of specific amino acids. IMDs may also necessitate the supplementation of one or more amino acids due to factors such [...] Read more.

Background/Objectives: Inherited metabolic disorders (IMDs) are a group of genetic conditions affecting metabolic pathways. The treatment of some IMDs requires the dietary restriction of specific amino acids. IMDs may also necessitate the supplementation of one or more amino acids due to factors such as reduced dietary intake, impaired synthesis, defective transport or absorption, or increased utilization. This literature review aims to evaluate the most recent evidence regarding amino acid supplementation in IMDs, considering not only the prevention of amino acid deficiency and toxic accumulation but also the competition with other toxic metabolites. Methods: A systematic search strategy was developed and applied to PubMed/Medline and Scopus databases to identify relevant studies. Amino acids were categorized into six groups: branched-chain amino acids, aromatic amino acids, sulfur amino acids, urea cycle amino acids, other essential amino acids, and other non-essential amino acids. Results: A total of 24 rare IMDs were evaluated. A final number of 99 selected articles were assessed based on the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. Although this work represents a preliminary non-systematic review, it highlights the need for further studies and data collection. Conclusions: Future research must establish the plasma amino acid levels that indicate the need for supplementation, specify the appropriate dosages (g/day or mg/kg/day), determine the optimal treatment duration, and, crucially, define the target plasma ranges to be maintained for effective management of IMDs. Full article

(This article belongs to the Special Issue Inborn Errors of Metabolism (IEMs): Advances in Diagnosis and Treatment)

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25 pages, 28238 KB

Open AccessEditor’s ChoiceArticle

Analysis of Kallikrein 6, Acetyl-α-Tubulin, and Aquaporin 1 and 2 Expression Patterns During Normal Human Nephrogenesis and in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

by Nela Kelam, Marin Ogorevc, Ivona Gotovac, Ivana Kuzmić Prusac, Katarina Vukojević, Mirna Saraga-Babić and Snježana Mardešić

Genes 2025, 16(5), 499; https://doi.org/10.3390/genes16050499 - 27 Apr 2025

Cited by 4 | Viewed by 1156

Abstract

Background/Objectives: The human kallikrein-related peptidase 6 (KLK6), a serine protease with trypsin-like properties, belongs to the 15-member kallikrein (KLK) gene family and is predominantly recognized for its role in oncogenesis, neurodegenerative disorders, and skin conditions. Aquaporins (AQPs) are integral membrane [...] Read more.

Background/Objectives: The human kallikrein-related peptidase 6 (KLK6), a serine protease with trypsin-like properties, belongs to the 15-member kallikrein (KLK) gene family and is predominantly recognized for its role in oncogenesis, neurodegenerative disorders, and skin conditions. Aquaporins (AQPs) are integral membrane proteins that facilitate water transport across cell membranes. AQP1 is constitutively active in the kidneys and plays a crucial role in reabsorbing filtered water, while AQP2 is regulated by vasopressin and is essential for maintaining body fluid homeostasis. The primary objective of the present study is to investigate the spatio-temporal expression patterns of KLK6, AQP1, and AQP2 throughout normal human nephrogenesis and congenital kidney and urinary tract (CAKUT) abnormalities: duplex kidneys, horseshoe kidneys, and dysplastic kidneys. Methods: An immunofluorescence analysis of KLK6, AQP1, and AQP2 was performed on 37 paraffin-embedded fetal kidney samples. The area percentage of KLK6 in the kidney cortex was calculated in normal developing samples during developmental phases 2, 3, and 4 and compared with CAKUT samples. Results: KLK6 exhibits distinct spatiotemporal expression patterns during human kidney development, with consistent localization in proximal tubules. Its subcellular positioning shifts from the basolateral cytoplasm in early phases to the apical cytoplasm in later stages, which may be strategically positioned to act on its substrate in either the peritubular space or the tubular fluid. KLK6 expression followed a quadratic trajectory, peaking at Ph4. This marked increase in the final developmental phase aligns with its strong expression in mature kidneys, suggesting a potential role in proximal tubule differentiation and functional maturation through facilitating extracellular matrix remodeling and activating proteinase-activated receptors, modulating the signaling pathways that are essential for tubular development. In duplex kidneys, structural abnormalities such as ureteral obstruction and hydronephrosis may upregulate KLK6 as part of a reparative response, while its downregulation could impair epithelial remodeling and cytoskeletal integrity, exacerbating dysplastic phenotypes. Conclusions: These findings highlight the potential of KLK6 involvement in normal kidney development and the pathology of CAKUT. Full article

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

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20 pages, 1122 KB

Open AccessEditor’s ChoiceReview

Epitranscriptomic Role of m6A in Obesity-Associated Disorders and Cancer Metabolic Reprogramming

by Sujun Yan, Weijing Wen, Zhe Mo, Simeng Gu and Zhijian Chen

Genes 2025, 16(5), 498; https://doi.org/10.3390/genes16050498 - 27 Apr 2025

Cited by 2 | Viewed by 2365

Abstract

The global rise in obesity and its associated metabolic disorders underscores the need for a deeper investigation into their underlying molecular mechanisms. While genetic factors are well-established contributors, recent research has increasingly focused on epigenetic regulators, particularly N6-methyladenosine (m⁶A)—the most prevalent [...] Read more.

The global rise in obesity and its associated metabolic disorders underscores the need for a deeper investigation into their underlying molecular mechanisms. While genetic factors are well-established contributors, recent research has increasingly focused on epigenetic regulators, particularly N6-methyladenosine (m⁶A)—the most prevalent internal RNA modification in eukaryotes. This post-transcriptional modification plays a crucial role in RNA metabolism by regulating mRNA stability, splicing, nuclear export, and translation efficiency. Notably, emerging evidence implicates m⁶A in both adipogenesis and metabolic dysregulation. In this review, we systematically examine three key dimensions: (1) the molecular mechanisms of m⁶A modification, including writers, erasers, and readers, in obesity; (2) dysregulated m⁶A patterns in obesity-related pathologies, such as type 2 diabetes (T2D), insulin resistance, metabolic dysfunction-associated steatotic liver disease (MASLD), and the glycolysis in cancer cells; and (3) the therapeutic potential of targeting m⁶A and the regulators. By critically assessing recent advancements, we highlight m⁶A’s dual role as both a metabolic sensor and a disease modulator, offering novel insights into potential strategies for combating obesity-related metabolic syndromes. Full article

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

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17 pages, 1138 KB

Open AccessEditor’s ChoiceArticle

Unravelling the Genotype of the Apical Variant of Hypertrophic Cardiomyopathy in a Swedish Cohort

by Antheia Kissopoulou, Rada Ellegård, Eva Ingemarsdotter Fernlund, Jan-Erik Karlsson, Henrik Green and Cecilia Gunnarsson

Genes 2025, 16(5), 494; https://doi.org/10.3390/genes16050494 - 26 Apr 2025

Cited by 3 | Viewed by 2043

Abstract

Background: Apical hypertrophic cardiomyopathy (ApHCM) is a distinct variant of hypertrophic cardiomyopathy (HCM). Few studies have focused on the genetic determinants of this subtype. We aimed to investigate the genetic basis of apical hypertrophy in a Swedish cohort. Methods–Results: Longitudinal data on 58 [...] Read more.

Background: Apical hypertrophic cardiomyopathy (ApHCM) is a distinct variant of hypertrophic cardiomyopathy (HCM). Few studies have focused on the genetic determinants of this subtype. We aimed to investigate the genetic basis of apical hypertrophy in a Swedish cohort. Methods–Results: Longitudinal data on 58 unrelated index patients with ApHCM from the Southeast healthcare region in Sweden from 2010 to 2024 were assessed retrospectively. Additionally, the original raw data from genetic testing were re-evaluated using AI-based Emedgene software. Patients were 47 ± 14 years old, and 60% males. A total of 72.4% had the pure apical type and the remaining had the mixed phenotype, dominant distal. In the cohort, 50/58 (86.2%) underwent genetic testing, of whom 7/50 (14%) were considered genotype positive for a pathogenic/likely pathogenic variant, mainly in MYH7 (43%) and in the non-sarcomeric ALPK3 gene (28.6%). A re-evaluation of the original data from genetic testing identified a previously unreported variant in the skeletal muscle α-actin (ACTA1) gene. Overall, 21 of 58 patients (36.2%) had HCM-related events during their disease course: 10% had a stroke, and 12% had heart failure. Atrial fibrillation was present in 41.4% and non-sustained ventricular tachycardia occurred in 29.3% of the patients. Apical aneurysm was observed in 17.2% of cases. Patients with a positive genotype were more likely to have a positive family history of HCM compared to those with a negative genotype (p = 0.020). Conclusions: In ApHCM, a positive genotype was found less frequently compared to classic HCM. Only 14% of patients with ApHCM were found to be genotype positive, indicating that apical hypertrophy represents a genetically unique population with low risk of mortality. Nevertheless, patients with ApHCM faced higher rates of atrial fibrillation, ventricular arrhythmias, and apical aneurysms. Full article

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

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12 pages, 243 KB

Open AccessEditor’s ChoiceReview

Y-STR Databases—Application in Sexual Crimes

by Rita Costa, Jennifer Fadoni, António Amorim and Laura Cainé

Genes 2025, 16(5), 484; https://doi.org/10.3390/genes16050484 - 25 Apr 2025

Cited by 7 | Viewed by 2773

Abstract

Background/Objectives: The Y chromosome is a crucial tool in forensic genetics due to its unique characteristics, such as its haploid inheritance and lack of recombination. Y-STRs (short tandem repeats on the Y chromosome) are widely used for identifying male genetic profiles in DNA [...] Read more.

Background/Objectives: The Y chromosome is a crucial tool in forensic genetics due to its unique characteristics, such as its haploid inheritance and lack of recombination. Y-STRs (short tandem repeats on the Y chromosome) are widely used for identifying male genetic profiles in DNA mixtures, especially in sexual assault cases where high levels of female DNA hinder autosomal analysis. This study evaluates the applicability of Y-STRs in forensic investigations, addressing their limitations and the impact of advanced technologies, such as rapidly mutating Y-STRs (RM Y-STRs). Methods: A comprehensive literature review was conducted to analyze existing knowledge on the application of Y-STRs in sexual crimes. The study also examines the role of population databases, such as YHRD, in estimating haplotype frequencies and enhancing forensic reliability. Results: Y-STR analysis proves essential for male DNA identification in complex mixtures, with RM Y-STRs enhancing discriminatory power. However, limitations persist, particularly in cases involving closely related male lineages. The population database coverage remains insufficient in regions like Cape Verde, affecting forensic reliability. Case studies demonstrate Y-STR effectiveness in solving cold cases and sexual crimes, reinforcing the need for expanded databases and methodological advancements. Conclusions: Y-STRs play a fundamental role in forensic genetics, particularly in sexual assault investigations. Their integration with advanced sequencing technologies and expanded databases is critical for improving forensic accuracy. Ethical considerations regarding genetic data privacy and potential discrimination must be addressed through clear regulations and forensic best practices. Full article

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

20 pages, 586 KB

Open AccessEditor’s ChoiceReview

Advancing Depression Management Through Biomarker Discovery with a Focus on Genetic and Epigenetic Aspects: A Comprehensive Study on Neurobiological, Neuroendocrine, Metabolic, and Inflammatory Pathways

by Jelena Milic, Sladjana Jovic and Rosa Sapic

Genes 2025, 16(5), 487; https://doi.org/10.3390/genes16050487 - 25 Apr 2025

Cited by 9 | Viewed by 6601

Abstract

Introduction: Depression is a pervasive global health issue, affecting millions worldwide and causing significant disability. Despite its prevalence, current diagnostic and treatment approaches often yield suboptimal outcomes. The complexity of depression, characterized by diverse causes and symptoms, highlights the urgent need for advanced [...] Read more.

Introduction: Depression is a pervasive global health issue, affecting millions worldwide and causing significant disability. Despite its prevalence, current diagnostic and treatment approaches often yield suboptimal outcomes. The complexity of depression, characterized by diverse causes and symptoms, highlights the urgent need for advanced diagnostic tools and personalized therapies. Biomarkers, particularly genetic and epigenetic depression biomarkers, offer promise in uncovering the biological mechanisms underlying depression, potentially revolutionizing its management. Aim: Primary aim: To identify biomarkers associated with depressive disorders, with a focus on genetic and epigenetic biomarkers. Secondary aim: To optimize the current classification of biomarkers associated with different types of depressive disorders, with a focus on genetic and epigenetic biomarkers. Methods: We integrated findings with strategic keywords extracted from relevant studies, conducting a thorough literature review across the Google Scholar, PubMed, and Web of Science databases. Lastly, final reference inclusion had stringent criteria: recent, diverse peer-reviewed articles in English, all study designs, ensuring up-to-date coverage of genetic and epigenetic depression biomarker research. Results: The review reveals the classification of genetic and epigenetic biomarkers in regard to the type of biomarker, the system of the human body it derives from, and the sampling entity. All of the findings show promise in diagnosing depression, with the potential of predicting treatment outcomes and guiding personalized therapeutic approaches. We defined the significant correlations between genetic and epigenetic biomarker profiles and clinical parameters such as symptom severity and treatment response, thereby enhancing diagnostic accuracy and guiding treatment strategies tailored to individual patient needs across diverse depressive subtypes and treatment responses. Conclusion: Identifying biomarkers associated with depressive disorders, with a focus on genetic and epigenetic biomarkers, represents a critical step toward improving diagnostic precision and treatment efficacy. By elucidating the complex biological underpinnings of depression, this study contributes to the development of targeted therapies that address the diverse needs of individuals affected by this debilitating group of disorders. Future research should focus on validating these genetic and epigenetic biomarkers in larger cohorts and clinical trials to facilitate their clinical implementation and enhance patient outcomes. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Influences on Depression: Emerging Therapies and Biomarkers)

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13 pages, 268 KB

Open AccessEditor’s ChoiceReview

Interrelation of Oxidative Stress and Genetics in Pathophysiology of Obesity and Obesity-Related Conditions

by Emina Čolak and Lepša Žorić

Genes 2025, 16(5), 489; https://doi.org/10.3390/genes16050489 - 25 Apr 2025

Cited by 3 | Viewed by 1059

Abstract

Obesity is a medical condition influenced by many factors and manifested by the excessive accumulation of fat. It is well documented that oxidative stress plays a significant role in the development of obesity and its related diseases. The antioxidant system’s enzymes, such as [...] Read more.

Obesity is a medical condition influenced by many factors and manifested by the excessive accumulation of fat. It is well documented that oxidative stress plays a significant role in the development of obesity and its related diseases. The antioxidant system’s enzymes, such as catalase, superoxide dismutase, glutathione peroxidase, paroxonase, etc., play a significant role in maintaining the oxidant–antioxidant balance in living organisms. Genetic variants of antioxidant system genes may affect the antioxidant system and its efficacy, which can lead to increased oxidative stress and higher risk for the development of obesity and its comorbidities. This review is focused on genetic variants such as single nucleotide polymorphisms of some antioxidant enzymes, ROS generators and transcription factors, and their impact on increased oxidative stress and the development of obesity and medical conditions related to obesity, like insulin resistance and metabolic syndrome. Full article

(This article belongs to the Special Issue Molecular Genetics in Obesity and Metabolic Syndrome)

18 pages, 5921 KB

Open AccessEditor’s ChoiceArticle

Functional Equivalence of Insulin and IGF-1 in the In Vitro Culture of Chicken Primordial Germ Cells

by Xin Liu, Jun Wu, Yixiu Peng, Guangzheng Liu, Kai Jin, Yingjie Niu, Jiuzhou Song, Wei Han, Guohong Chen, Bichun Li and Qisheng Zuo

Genes 2025, 16(5), 481; https://doi.org/10.3390/genes16050481 - 24 Apr 2025

Cited by 2 | Viewed by 1201

Abstract

Background: Chicken Primordial Germ Cells (PGCs) are one of the few germ cells that can be cultured for a long time in vitro, but challenges remain such as low culture efficiency and unclear roles of nutrient factors and signaling pathways. Method: In this [...] Read more.

Background: Chicken Primordial Germ Cells (PGCs) are one of the few germ cells that can be cultured for a long time in vitro, but challenges remain such as low culture efficiency and unclear roles of nutrient factors and signaling pathways. Method: In this study, protein kinase B (AKT) pathway activator insulin-like growth factor 1 (IGF-1) was screened for its ability to promote cell proliferation by transcriptome results using various inhibitors of pathway activation. The effects of IGF-1 on PGCs were evaluated through EdU assays, qRT-PCR, flow cytometry, and migration experiments. Results: This study systematically examined the effects of insulin and IGF-1 on the proliferation, cell cycle, ferroptosis, migration capacity, and establishment efficiency of PGCs. The findings demonstrated that IGF-1 exhibited comparable effects to insulin and could effectively replace insulin in PGC culture systems. Conclusions: The research results are expected to provide a solid theoretical basis for optimizing the chicken PGC cultivation system and promoting its practical application. Full article

(This article belongs to the Special Issue Developmental Biology and Genetics in Chicken Embryo Germ Cell)

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21 pages, 1323 KB

Open AccessEditor’s ChoiceReview

Autism Spectrum Disorder: Genetic Mechanisms and Inheritance Patterns

by Ilaria La Monica, Maria Rosaria Di Iorio, Antonia Sica, Francesca Rufino, Chiara Sotira, Lucio Pastore and Barbara Lombardo

Genes 2025, 16(5), 478; https://doi.org/10.3390/genes16050478 - 23 Apr 2025

Cited by 6 | Viewed by 17526

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that first develops in early childhood and is characterized by restricted interests, activities, and behaviors, as well as difficulties with social interactions and communication. ASD arises from a complex interaction between environmental factors and genetic [...] Read more.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that first develops in early childhood and is characterized by restricted interests, activities, and behaviors, as well as difficulties with social interactions and communication. ASD arises from a complex interaction between environmental factors and genetic inheritance, influenced by epigenetic mechanisms. With an estimated heritability of 70–90%, ASD is highly familial, indicating that genetic factors play a significant role in its development. This shows how hundreds of genetic variants contribute to ASD, whose risk effects are highly variable and are often related to other conditions; these genetic alterations are at different levels, which include single gene mutations, monogenic disorders, genomic variants, and chromosomal abnormalities. Copy number variants (CNVs) appear to contribute significantly to understanding the pathogenesis of this complex disease. In some cases, single CNVs in genomic DNA are pathogenic and causative, supporting the hypothesis that some sporadic cases of ASD may result from rare mutations with significant clinical impact. However, in many cases, there are common genomic variants that increase the risk of developing ASD but are insufficient by themselves to determine an ASD phenotype, and rare genomic variants, of various sizes, inherited from a parent or de novo, that can be associated with the ASD phenotype. Therefore, the aim of this review is to deepen the concept of ASD inheritance through the two-hit theory of CNVs, in which the concomitant presence of two alterations could determine the clinical phenotypes, the concept of incomplete penetrance for inherited CNVs with pathogenic clinical significance, and the presence of compound heterozygosity. These aspects represent important mechanisms underlying the pathogenesis of autism, contributing to a better elucidation for the understanding of the genetic contribution to the ASD phenotype. Full article

(This article belongs to the Special Issue Genetic Insights into Neurodevelopmental Disorders)

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16 pages, 11711 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 2 | Viewed by 1746

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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21 pages, 6764 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 3 | Viewed by 888

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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18 pages, 2729 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 4 | Viewed by 2872

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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18 pages, 1347 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 2 | Viewed by 3403

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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19 pages, 10518 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 4 | Viewed by 2162

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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30 pages, 1379 KB

Open AccessEditor’s ChoiceReview

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

Cited by 2 | Viewed by 4427

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 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 3 | Viewed by 1084

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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33 pages, 2811 KB

Open AccessEditor’s ChoiceReview

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

Cited by 3 | Viewed by 1823

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 KB

Open AccessEditor’s ChoiceReview

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

Cited by 11 | Viewed by 18680

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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19 pages, 5741 KB

Open AccessEditor’s ChoiceArticle

GC Content in Nuclear-Encoded Genes and Effective Number of Codons (ENC) Are Positively Correlated in AT-Rich Species and Negatively Correlated in GC-Rich Species

by Douglas M. Ruden

Genes 2025, 16(4), 432; https://doi.org/10.3390/genes16040432 - 5 Apr 2025

Cited by 4 | Viewed by 1663

Abstract

Background/Objectives: Codon usage bias affects gene expression and translation efficiency across species. The effective number of codons (ENC) and GC content influence codon preference, often displaying unimodal or bimodal distributions. This study investigates the correlation between ENC and GC rankings across species and [...] Read more.

Background/Objectives: Codon usage bias affects gene expression and translation efficiency across species. The effective number of codons (ENC) and GC content influence codon preference, often displaying unimodal or bimodal distributions. This study investigates the correlation between ENC and GC rankings across species and how their relationship affects codon usage distributions. Methods: I analyzed nuclear-encoded genes from 17 species representing six kingdoms: one bacteria (Escherichia coli), three fungi (Saccharomyces cerevisiae, Neurospora crassa, and Schizosaccharomyces pombe), one archaea (Methanococcus aeolicus), three protists (Rickettsia hoogstraalii, Dictyostelium discoideum, and Plasmodium falciparum),), three plants (Musa acuminata, Oryza sativa, and Arabidopsis thaliana), and six animals (Anopheles gambiae, Apis mellifera, Polistes canadensis, Mus musculus, Homo sapiens, and Takifugu rubripes). Genes in all 17 species were ranked by GC content and ENC, and correlations were assessed. I examined how adding or subtracting these rankings influenced their overall distribution in a new method that I call Two-Rank Order Normalization or TRON. The equation, TRON = SUM(ABS((GC rank₁:GC rank_N) − (ENC rank₁:ENC rank_N))/(N²/3), where (GC rank₁:GC rank_N) is a rank-order series of GC rank, (ENC rank₁:ENC rank_N) is a rank-order series ENC rank, sorted by the rank-order series GC rank. The denominator of TRON, N²/3, is the normalization factor because it is the expected value of the sum of the absolute value of GC rank–ENC rank for all genes if GC rank and ENC rank are not correlated. Results: ENC and GC rankings are positively correlated (i.e., ENC increases as GC increases) in AT-rich species such as honeybees (R² = 0.60, slope = 0.78) and wasps (R² = 0.52, slope = 0.72) and negatively correlated (i.e., ENC decreases as GC increases) in GC-rich species such as humans (R² = 0.38, slope = −0.61) and rice (R² = 0.59, slope = −0.77). Second, the GC rank–ENC rank distributions change from unimodal to bimodal as GC content increases in the 17 species. Third, the GC rank+ENC rank distributions change from bimodal to unimodal as GC content increases in the 17 species. Fourth, the slopes of the correlations (GC versus ENC) in all 17 species are negatively correlated with TRON (R² = 0.98) (see Graphic Abstract). Conclusions: The correlation between ENC rank and GC rank differs among species, shaping codon usage distributions in opposite ways depending on whether a species’ nuclear-encoded genes are AT-rich or GC-rich. Understanding these patterns might provide insights into translation efficiency, epigenetics mediated by CpG DNA methylation, epitranscriptomics of RNA modifications, RNA secondary structures, evolutionary pressures, and potential applications in genetic engineering and biotechnology. Full article

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

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17 pages, 5777 KB

Open AccessEditor’s ChoiceArticle

Identification and Expression Analysis of CCCH Zinc Finger Family Genes in Oryza sativa

by Zhihan Wang, Shunyuan Li, Hongkai Wu, Linzhou Huang, Liangbo Fu, Chengfang Zhan, Xueli Lu, Long Yang, Liping Dai and Dali Zeng

Genes 2025, 16(4), 429; https://doi.org/10.3390/genes16040429 - 3 Apr 2025

Cited by 4 | Viewed by 1585

Abstract

Background: CCCH zinc finger proteins (OsC3Hs) are a class of transcriptional regulators that play important roles in plant development and stress responses. Although their functional significance has been widely studied in model species, comprehensive genome-wide characterization of CCCH proteins in rice (Oryza [...] Read more.

Background: CCCH zinc finger proteins (OsC3Hs) are a class of transcriptional regulators that play important roles in plant development and stress responses. Although their functional significance has been widely studied in model species, comprehensive genome-wide characterization of CCCH proteins in rice (Oryza sativa) remains limited. Methods: Using Arabidopsis CCCH proteins as references, we identified the CCCH gene family in rice and analyzed the physicochemical properties, subcellular localization, conserved structures, phylogeny, cis-regulatory elements, synteny analysis, spatiotemporal expression patterns, and expression patterns under drought, ABA, and MeJA treatments for the identified CCCH family members. Results: The results showed that the rice CCCH family comprises 73 members, which are unevenly distributed across the 12 chromosomes. Phylogenetic analysis classified them into 11 subfamilies. Subcellular localization indicated that most members are localized in the nucleus. The upstream regions of CCCH promoters contain a large number of cis-regulatory elements related to plant hormones and biotic stress responses. Most genes respond to drought, abscisic acid (ABA), and methyl jasmonate (MeJA) treatments. OsC3H36 was highly expressed under drought, ABA, and MeJA treatments. Haplotype analysis of this gene revealed two major allelic variants (H1 and H2), with H1 predominantly found in japonica rice and associated with increased grain width and 1000-grain weight. Functional validation using a chromosome segment substitution line (CSSL1) confirmed these findings. Conclusions: CCCH genes play important roles in rice growth, development, and stress responses. Additionally, we validated that OsC3H36 is associated with rice grain width and 1000-grain weight. Full article

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

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21 pages, 348 KB

Open AccessFeature PaperEditor’s ChoiceReview

Genetics of Suicide

by Mostafa Khalil, Anil Kalyoncu and Alfredo Bellon

Genes 2025, 16(4), 428; https://doi.org/10.3390/genes16040428 - 3 Apr 2025

Cited by 2 | Viewed by 5119

Abstract

Over the past two decades, suicide has consistently ranked among the leading causes of death in the United States. While suicide deaths are closely associated with uicidal ideation and attempts, these are not good predictors of future suicide deaths. Establishing who is at [...] Read more.

Over the past two decades, suicide has consistently ranked among the leading causes of death in the United States. While suicide deaths are closely associated with uicidal ideation and attempts, these are not good predictors of future suicide deaths. Establishing who is at risk of suicide remains a challenge that is mostly hampered by the lack of understanding of its pathophysiology. Nonetheless, evidence continues to accumulate suggesting that suicide is driven by a complex and dynamic interaction between environmental factors and genetics. The identification of genes that place people at risk of suicide remains elusive, but data are rapidly evolving. In this narrative review, we describe how Tryptophan hydroxylase (TPH) genes, particularly TPH1 and TPH2, have been associated with suicide in various publications. There is also replicated evidence linking the brain-derived neurotrophic factor gene to suicide, with its most consistent results originating from epigenetic studies. Not surprisingly, many genes involved in the hypothalamic–pituitary–adrenal axis have been connected with suicide, but these data require replication. Finally, among the inflammatory genes studied in suicide, only specific polymorphisms in TNF-alpha and IL-6 may increase susceptibility to suicidal behavior. In conclusion, significant work remains to be performed as inconsistencies undermine the reliability of genetic results in suicide. Potential avenues for future research are proposed. Full article

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