Genes

15 pages, 3291 KB

Open AccessArticle

Investigating the Therapeutic Effects of Naringenin and Oleuropein on Prostate Cancer Cell Mat-LyLu via miR-155-5p: A Bioinformatics and Molecular Docking Analysis of KRAS and CDK2 Networks

by Cigdem Gungormez

Genes 2026, 17(1), 79; https://doi.org/10.3390/genes17010079 - 9 Jan 2026

Abstract

Background: This study systematically investigates the therapeutic effects of naringenin (NAR) and oleuropein (OLE) on prostate cancer through miR-155-5p regulation. Methods: Experimental studies conducted on MAT-LyLu prostate cancer cell lines revealed that the application of NAR (50 μM) and OLE (75 μM) significantly [...] Read more.

Background: This study systematically investigates the therapeutic effects of naringenin (NAR) and oleuropein (OLE) on prostate cancer through miR-155-5p regulation. Methods: Experimental studies conducted on MAT-LyLu prostate cancer cell lines revealed that the application of NAR (50 μM) and OLE (75 μM) significantly increased miR-155-5p expression by 2.89-fold and 1.74-fold, respectively (p < 0.05). Bioinformatics analyses have indicated that miR-155-5p interacts with critical oncogenic pathways such as KRAS, CDK2, NF-κB, and TGF-β/Smad2. Computational analyses have revealed that miR-155-5p interacts with 16 critical oncogenic targets, including KRAS and CDK2. Molecular docking studies showed that NAR binds to the Switch I/II region of KRAS with a binding energy of −8.2 kcal/mol, while OLE binds to the ATP-binding pocket of CDK2 with an affinity of −9.1 kcal/mol. Pharmacokinetic evaluations revealed that NAR indicated high oral bioavailability (93.763% HIA) and full compliance with Lipinski’s rules, while OLE required advanced formulation strategies due to its high polarity. Network pharmacology analyses have shown that NAR affects lysosomal functions and enzyme regulation, while OLE affects G protein-coupled receptors and oxidoreductase activity. Results: Results indicate that NAR and OLE exhibit antitumor effects through multiple mechanisms by increasing miR-155-5p expression and inhibiting critical oncogenic targets in prostate cancer. Conclusion: Findings suggest that the dietary intake of these natural compounds (citrus and olive products) should be considered in prostate cancer prevention strategies, shedding light on the epigenetic mechanisms of polyphenols in cancer treatment and contributing to the development of new therapeutic strategies. Full article

(This article belongs to the Section Bioinformatics)

14 pages, 2159 KB

Open AccessArticle

Interdependent Regulation of Alternative Splicing by Serine/Arginine-Rich and Heterogeneous Nuclear Ribonucleoprotein Splicing Factors

by Megan E. Holmes and Klemens J. Hertel

Genes 2026, 17(1), 78; https://doi.org/10.3390/genes17010078 - 9 Jan 2026

Abstract

Background: Alternative pre-mRNA splicing is a combinatorial process involving serine/arginine-rich (SR) and heterogeneous nuclear ribonucleoprotein (hnRNP) splicing factors. These proteins can silence or enhance splicing based on their expression levels and binding positions. Objectives: To better understand the combinatorial and interdependent regulation between [...] Read more.

Background: Alternative pre-mRNA splicing is a combinatorial process involving serine/arginine-rich (SR) and heterogeneous nuclear ribonucleoprotein (hnRNP) splicing factors. These proteins can silence or enhance splicing based on their expression levels and binding positions. Objectives: To better understand the combinatorial and interdependent regulation between SR and hnRNP splicing factors during alternative splicing. Methods: Computational analyses were performed using cell knockdown and binding datasets from available databases. Results: Analyses of differential splicing data for 9 SR proteins and 21 hnRNP knockdowns revealed statistically significant interdependent regulation among several RNA-binding protein (RBP) combinations, albeit at different levels. Neither SR proteins nor hnRNPs showed strong preferences for collaborating with specific RBP classes in mediating exon inclusion. While SRSF3, hnRNPK, hnRNPC, and hnRNPL stand out as major influencers of alternative splicing, they do so predominantly independent of other RBPs. Minor influencers of alternative splicing, such as hnRNPDL and hnRNPR, predominantly regulate exon inclusion in concert with other RBPs, indicating that exon inclusion can be mediated by both single and multiple RBPs. Interestingly, the higher the number of RBPs that regulate the inclusion of an exon, the more variable exon inclusion preferences become. Interdependently regulated exons are more modular and can be characterized by weaker splice sites compared to their independently regulated counterparts. A comparison of RBP interdependence between HeLa and other cell lines provides a framework that explains cell-type-specific alternative splicing. Conclusions: Our study highlights the importance of the interdependent regulation of alternative exons and identifies characteristics of interdependently regulated exons that differ from independently regulated exons. Full article

(This article belongs to the Special Issue The 15th Anniversary of Genes: Feature Papers in the "RNA" Section)

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14 pages, 6199 KB

Open AccessArticle

Multiplex Gene Editing and Effect Analysis of Yield, Fragrance, and Blast Resistance Genes in Rice

by Shuhui Guan, Yingchun Han, Jingwen Zhang, Yanxiu Du, Zhen Chen, Chunbo Miao and Junzhou Li

Genes 2026, 17(1), 77; https://doi.org/10.3390/genes17010077 - 9 Jan 2026

Abstract

Background: The coordinated improvement of yield, quality and resistance is a primary goal in rice breeding. Gene editing technology is a novel method for precise multiplex gene improvement. Methods: In this study, we constructed a multiplex CRISPR/Cas9 vector targeting yield-related genes (GS3 [...] Read more.

Background: The coordinated improvement of yield, quality and resistance is a primary goal in rice breeding. Gene editing technology is a novel method for precise multiplex gene improvement. Methods: In this study, we constructed a multiplex CRISPR/Cas9 vector targeting yield-related genes (GS3, OsPIL15, Gn1a), fragrance gene (OsBADH2) and rice blast resistance gene (Pi21) to pyramid traits for enhanced yield, quality, and disease resistance in rice. A tRNA-assisted CRISPR/Cas9 multiplex gene editing vector, M601-OsPIL15/GS3/Gn1a/OsBADH2/Pi21-gRNA, was constructed. Genetic transformation was performed using the Agrobacterium-mediated method with the japonica rice variety Xin Dao 53 as the recipient. Mutation editing efficiency was detected in T₀ transgenic plants. Grain length, grain number per panicle, thousand-grain weight, 2-acetyl-1-pyrroline (2-AP) content, and rice blast resistance of homozygous lines were measured in the T₃ generations. Results: Effectively edited plants were obtained in the T₀ generation. The simultaneous editing efficiency for all five genes reached 9.38%. The individual gene editing efficiencies for Pi21, GS3, OsBADH2, Gn1a, and OsPIL15 were 78%, 63%, 56%, 54%, and 13%, respectively. Five five-gene homozygous edited lines with two genotypes were selected in the T₂ generation. In the T₃ generation, compared with the wild-type (WT), the edited homozygous lines showed increased grain number per panicle (14.60–25.61%), increased grain length (7.39–11.16%), increased grain length–width ratio (8.37–13.02%), increased thousand-grain weight (3.79–9.15%), a 42–64 folds increase in the fragrant substance 2-AP content, and significantly enhanced rice blast resistance. Meanwhile, there were no significant changes in other agronomic traits. Conclusions: CRISPR/Cas9-mediated multiplex gene editing technology enabled the simultaneous editing of genes related to rice yield, quality, and disease resistance. This provides an effective approach for obtaining new japonica rice germplasm with blast resistance, long grains, and fragrance. Full article

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

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13 pages, 2502 KB

Open AccessArticle

Comparative Transcriptome Analysis Reveals the Seawater Adaptation Mechanism in Pseudaspius hakonensis

by Ziyue Xu, Wen Zheng, Wenjun Chen, Min Zhou, Dongdong Zhai, Ming Xia, Hongyan Liu, Fei Xiong and Ying Wang

Genes 2026, 17(1), 76; https://doi.org/10.3390/genes17010076 - 9 Jan 2026

Abstract

Background: The family Cyprinidae is predominantly restricted to freshwater habitats, making the evolution of diadromy and seawater adaptation exceptionally rare within this group. Pseudaspius hakonensis, a rare anadromous cyprinid, and its strictly freshwater congener P. leptocephalus, provide an ideal comparative model [...] Read more.

Background: The family Cyprinidae is predominantly restricted to freshwater habitats, making the evolution of diadromy and seawater adaptation exceptionally rare within this group. Pseudaspius hakonensis, a rare anadromous cyprinid, and its strictly freshwater congener P. leptocephalus, provide an ideal comparative model to investigate the molecular mechanisms underlying salinity adaptation. This study aimed to elucidate the tissue-specific transcriptional reprogramming, identify candidate genes and key pathways, and explore their association with seawater acclimation in P. hakonensis. Methods: We performed comparative transcriptomic analyses of gill, liver, and kidney tissues from both species using RNA-Seq. Sequencing reads were aligned to a high-quality reference genome of P. hakonensis. Differential expression analysis was conducted using DESeq2, followed by functional enrichment analyses (GO and KEGG) to identify significant biological processes and pathways. Results: A total of 8784, 5965, and 5719 differentially expressed genes (DEGs) were identified in gill, kidney, and liver tissues, respectively, with the gill showing the highest differences. Functional enrichment revealed tissue-specific roles: gill DEGs were associated with protein synthesis and energy metabolism; kidney DEGs with transport and detoxification; and liver DEGs with metabolic regulation and stress signaling. Cross-tissue analysis highlighted three core pathways consistently enriched: MAPK signaling, ABC transporters, and glutathione metabolism. Key candidate genes, including DUSP10, SLC38A2, ATP8B1, GSTA4, and MGST1, were significantly upregulated in P. hakonensis. Conclusions: This first multi-tissue transcriptomic comparison of an anadromous and a freshwater cyprinid reveals pervasive, tissue-specific molecular reprogramming underlying seawater adaptation in P. hakonensis. The coordinated activation of MAPK signaling, glutathione metabolism, and transporter pathways suggests an integrated regulatory network for osmoregulation and stress resistance. These findings provide novel insights into the genetic basis of salinity adaptation in cyprinids and identify candidate genes for future functional validation. Full article

(This article belongs to the Special Issue Innovations in Aquaculture Breeding via Genetic Technologies)

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25 pages, 3767 KB

Open AccessSystematic Review

The Genetic Diversity of African Common Bean Germplasm: A Systematic Review of Reported Molecular Studies

by Tatenda Ephraim Chikasha, Rogerio Marcos Chiulele, Wilson Nkhata and Bernado Lazaro Muatinte

Genes 2026, 17(1), 75; https://doi.org/10.3390/genes17010075 - 9 Jan 2026

Abstract

Background: Common bean (Phaseolus vulgaris L.) is an important grain legume crop of nutritional and economic value across Africa. Genetic improvements of the crop to enhance productivity and resilience depend on understanding the diversity within the African germplasm. Methods: Following [...] Read more.

Background: Common bean (Phaseolus vulgaris L.) is an important grain legume crop of nutritional and economic value across Africa. Genetic improvements of the crop to enhance productivity and resilience depend on understanding the diversity within the African germplasm. Methods: Following PRISMA guidelines, the genetic diversity and population structure of common bean in Africa were reviewed systematically based on existing research. A protocol for conducting the systematic review was developed registered in OSF. Twenty-nine studies met the inclusion criteria after a comprehensive search in ScienceDirect, PubMed, Google Scholar, PubMed, AGRICOLA, Taylor & Francis, and SpringerLink. Data on molecular markers and diversity metrics, thus PIC, He, and AMOVA, were extracted and synthesized qualitatively. Results: Despite substantial heterogeneity in panel sizes, reporting completeness, and marker systems (SSR, SNP, POX, ISSR), consistent patterns emerged. Studies revealed moderate to high levels of genetic diversity. Population-structure analyses recovered the canonical Andean and Mesoamerican gene pools with extensive admixture and high gene flow. AMOVA results indicated that a substantial proportion of total genetic variation was attributed to within-population components. Conclusions: The results are consistent with previous studies, but the sample size and types of markers make direct comparisons impossible. More future studies should use standardized genotyping approaches to increase data consistency. These insights are useful for yield improvement under both non-stress and stress conditions and for developing Africa’s diverse environments. Full article

(This article belongs to the Special Issue Genetic and Morphological Diversity in Plants)

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15 pages, 1558 KB

Open AccessArticle

TMPRSS6 Non-Coding Variants in the Expression of Iron Refractory Iron Deficiency Anemia in Monoallelic Subjects

by Vera Hoving, Albertine E. Donker, Roel J. P. Smeets, Bert P. W. J. van den Heuvel, Saskia E. M. Schols and Dorine W. Swinkels

Genes 2026, 17(1), 74; https://doi.org/10.3390/genes17010074 - 8 Jan 2026

Abstract

Background: Iron-refractory iron deficiency anemia (IRIDA) is a rare hereditary disorder caused by pathogenic variants in TMPRSS6, characterized by microcytic anemia, low circulating iron levels, and inappropriately high hepcidin levels. Although IRIDA is typically an autosomal recessive disorder, some individuals with a [...] Read more.

Background: Iron-refractory iron deficiency anemia (IRIDA) is a rare hereditary disorder caused by pathogenic variants in TMPRSS6, characterized by microcytic anemia, low circulating iron levels, and inappropriately high hepcidin levels. Although IRIDA is typically an autosomal recessive disorder, some individuals with a monoallelic pathogenic exonic TMPRSS6 variant exhibit the phenotype, suggesting additional contributing factors. The mechanisms underlying monoallelic IRIDA remain unclear, complicating diagnosis. This study aimed to investigate the potential role of non-coding TMPRSS6 variants and polygenic inheritance in monoallelic IRIDA. Methods: We performed full-gene sequencing of TMPRSS6 in a cohort of 27 subjects, including 6 families (7 symptomatic monoallelic, 7 asymptomatic monoallelic, and 4 wild-type subjects) and 9 isolated symptomatic monoallelic subjects. Whole-exome sequencing of other iron-regulating genes was conducted to evaluate polygenic inheritance. Non-coding variants were assessed for inheritance patterns using family segregation analysis, when available, and for pathogenic potential using in silico prediction tools. Results: Sequencing identified 219 non-coding variants, of which 31 (14 trans-inherited and 17 with unknown inheritance) were exclusive to symptomatic subjects. Two trans-inherited variants (rs80140288 (c.229+945C>T) and rs146953827 (c.230-938_230-937del)) were predicted to affect splicing, while two additional variants (rs78987624 (c.-7001G>A) and rs117575523 (c.*503C>G)) were located in regulatory regions (with unknown inheritance). Whole-exome sequencing did not support polygenic involving other iron-regulating genes. Conclusions: This study highlights four candidate non-coding variants that may contribute to IRIDA expression in monoallelic subjects, offering new insights into its genetic basis. Functional validation is required to confirm their role in disease pathogenesis, refine genotype-phenotype correlations, and improve diagnostic accuracy in monoallelic IRIDA. Full article

(This article belongs to the Section Genetic Diagnosis)

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16 pages, 3769 KB

Open AccessArticle

Sex-Specific Downregulation of CDK5RAP3 Exacerbates ER Stress-Mediated Inflammation and Apoptosis in CCl₄-Induced Acute Liver Injury

by Jian Ruan, Qianyi Dong, Fangling Xu, Yufan Jin, Yuhong Yang, Jun Li and Yafei Cai

Genes 2026, 17(1), 73; https://doi.org/10.3390/genes17010073 - 8 Jan 2026

Abstract

Background/Objectives: Sex-specific differences in the mechanisms of acute liver injury remain poorly understood. CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) is crucial for liver development and endoplasmic reticulum (ER) homeostasis. This study aimed to investigate sex-dependent changes in CDK5RAP3 expression in a carbon tetrachloride [...] Read more.

Background/Objectives: Sex-specific differences in the mechanisms of acute liver injury remain poorly understood. CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) is crucial for liver development and endoplasmic reticulum (ER) homeostasis. This study aimed to investigate sex-dependent changes in CDK5RAP3 expression in a carbon tetrachloride (CCl₄)-induced acute liver injury model and to explore the mechanisms underlying differential susceptibility between males and females. Methods: Acute liver injury was induced in male and female mice by CCl₄ administration. Liver injury was evaluated by serum biochemical parameters and histopathological analysis. CDK5RAP3 expression, inflammatory cytokines, and ER stress-related apoptotic markers were assessed. Hepatocyte apoptosis was examined by TUNEL staining. In addition, CDK5RAP3 was conditionally deleted in mouse embryonic fibroblasts (MEFs) using 4-hydroxytamoxifen to assess its direct role in regulating inflammatory and apoptotic responses in vitro. Results: CCl₄ exposure caused liver injury in both sexes, with male mice showing more severe biochemical and histological damage. CDK5RAP3 expression was significantly reduced after CCl₄ treatment, particularly in males. Inflammatory mediators and ER stress-associated apoptotic markers were upregulated, accompanied by increased hepatocyte apoptosis. A similar enhancement of inflammatory and apoptotic signaling was observed in CDK5RAP3-deficient MEFs. Conclusions: Downregulation of CDK5RAP3 is associated with ER stress, inflammation, and apoptosis, contributing to increased susceptibility of male mice to acute liver injury. These findings provide insight into sex-specific mechanisms of hepatic injury and highlight CDK5RAP3 as a potential therapeutic target. Full article

(This article belongs to the Section Toxicogenomics)

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14 pages, 1404 KB

Open AccessArticle

In Silico Functional and Structural Analysis of STAT4 Variants of Uncertain Significance

by Karla Mayela Bravo-Villagra, Eric Jonathan Maciel-Cruz, Rosa Michel Martínez-Contreras, Itzae Adonai Gutiérrez-Hurtado, Alexis Missael Vizcaíno-Quirarte, José Francisco Muñoz-Valle and Andres López-Quintero

Genes 2026, 17(1), 72; https://doi.org/10.3390/genes17010072 - 7 Jan 2026

Abstract

Background: The STAT4 gene plays a key role in immune regulation and is associated with susceptibility to autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Objectives: The objective of this study is to analyze variants of uncertain significance (VUSs) [...] Read more.

Background: The STAT4 gene plays a key role in immune regulation and is associated with susceptibility to autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Objectives: The objective of this study is to analyze variants of uncertain significance (VUSs) in STAT4 using bioinformatics tools to predict their functional and structural impact. Methods: A total of 48,295 variants of the STAT4 gene (ENSG00000138378) were retrieved from the Ensembl database. A tiered filtering approach was used to assess VUS pathogenicity, integrating in silico prediction tools such as SIFT, PolyPhen, MutPred2, and Align-GVGD, as well as structural modeling platforms including Chimera, ModRefiner, Missense3D, HOPE, and DynaMut2. Results: Eighty missense VUSs were identified; of these, 13 were prioritized based on concordant signals across multiple computational predictors. These variants showed significant alterations in the physicochemical properties of the protein, including changes in hydrophobicity and disruption of hydrogen bonding. Notably, the rs140675301 (Glu128Val) variant lies within a conserved loop, and in silico analyses suggest that this mutation may alter kinase specificity regarding the phosphorylation of serine 130. Conclusions: The integrative use of the bioinformatic tools employed represents a valuable preliminary step prior to undertaking more complex and resource-intensive functional studies. This complementary strategy strengthens the interpretative framework for VUS, guiding subsequent experimental validation and supporting a structured assessment of variant relevance, particularly in the context of immune-related genes such as STAT4. Full article

(This article belongs to the Special Issue Advances in Bioinformatics of Human Diseases)

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22 pages, 321 KB

Open AccessReview

Molecular and Genetic Biomarkers in Prostate Cancer Active Surveillance: Recent Developments and Future Perspectives

by Stephanie F. Smith, Robert D. Mills, Colin S. Cooper and Daniel S. Brewer

Genes 2026, 17(1), 71; https://doi.org/10.3390/genes17010071 - 6 Jan 2026

Abstract

Background/Objectives: Active surveillance (AS) has become the standard of care for many men with localised prostate cancer, aiming to avoid the overtreatment of indolent disease while maintaining oncological safety. Despite improvements in diagnostic techniques, misclassification at diagnosis and the limited ability to predict [...] Read more.

Background/Objectives: Active surveillance (AS) has become the standard of care for many men with localised prostate cancer, aiming to avoid the overtreatment of indolent disease while maintaining oncological safety. Despite improvements in diagnostic techniques, misclassification at diagnosis and the limited ability to predict disease progression remain major challenges in AS. Novel molecular and genetic biomarkers, assessed through liquid biopsy approaches, offer the potential to refine patient selection and support risk-adapted monitoring in AS. Methods: We conducted a narrative review of biomarkers in the context of AS for prostate cancer, framing the discussion in terms of the challenges in AS and how biomarkers may address these. PubMed and Embase were searched for English-language peer-reviewed studies published between 2000 and 2025. International guidelines (AUA, EAU, NCCN, NICE) and reference lists were reviewed manually. Priority was given to large prospective cohorts, meta-analyses, and high-impact publications. Results: Blood-based assays such as PHI and the 4K score, urinary tests including ExoDx and SelectMDx, and the Prostate Urine Risk (PUR) signatures have all shown associations with disease progression or decisions to undergo earlier treatment. However, studies are often small, use surrogate endpoints, and lack validation in MRI-integrated cohorts. Biomarkers appear most informative in men with Gleason Grade 1 (GG1) disease, while evidence in GG2 cohorts is limited. Cost-effectiveness, heterogeneity of endpoints, and uncertainty in managing discordant biomarker and MRI results remain barriers to clinical adoption. Conclusions: Molecular and genetic biomarkers show promise for improving AS by reducing diagnostic misclassification and enhancing prediction of progression. Future research should define clinically relevant cut-offs, clarify integration with MRI, and evaluate longitudinal use. Demonstrating utility in contemporary cohorts could enable the development of biomarker-guided, personalised AS that maintains safety while minimising harm. Full article

(This article belongs to the Special Issue Application of Molecular or Genetic Markers in Liquid Biopsy for Urogenital Cancers)

15 pages, 752 KB

Open AccessArticle

Methylation Biomarker of Chronic Heavy Alcohol Consumption (HAC), but Not Acute HAC, Predicts All-Cause Mortality in Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

by Steven R. H. Beach, James A. Mills, Jeffrey D. Long and Robert A. Philibert

Genes 2026, 17(1), 70; https://doi.org/10.3390/genes17010070 - 6 Jan 2026

Abstract

Background: Due to variability in patterns of consumption as well as well-known difficulties in obtaining valid self-report from heavy drinkers, quantifying the effects of heavy alcohol consumption on mortality is challenging. Using a DNA methylation biomarker of chronic heavy alcohol consumption (HAC) named [...] Read more.

Background: Due to variability in patterns of consumption as well as well-known difficulties in obtaining valid self-report from heavy drinkers, quantifying the effects of heavy alcohol consumption on mortality is challenging. Using a DNA methylation biomarker of chronic heavy alcohol consumption (HAC) named the alcohol T-score (ATS), we previously showed that chronic HAC was a strong predictor of mortality. However, whether there is a similar effect when measures of shorter-term heavy alcohol use, i.e., recent “binge” drinking, were used to predict mortality was not examined. This is a critical issue because most biomarkers of HAC assess only short-term HAC. Methods: Therefore, we examined the prediction of all-cause mortality from a DNA methylation biomarker of smoking (cg05575921), the ATS and a short-term biomarker of recent heavy alcohol use (cg07375256) in 708 subjects from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial using Cox Proportional Hazards Regression Modeling. Models were compared using Akaike’s Information Criterion. Results: The ATS was the best single predictor among three-variable models that included controls for sex and age. Of the possible four variable models, the model consisting of age, sex, cg05575921 methylation and ATS best predicted mortality. The addition of cg07375256 methylation did not improve model performance. In sensitivity analyses using only participants who provided alcohol SR (n = 639), the importance of the ATS and cg05575921 was replicated. We also found that ATS values were higher among those who declined to provide self-report alcohol use, indicating that missing self-report data about alcohol intake are not missing at random, and sometimes reflects elevated alcohol consumption. Finally, cg05575921 methylation was strongly associated with ATS values but only weakly with alcohol SR and not at all with cg07375256 methylation. Conclusions: Accordingly, this study indicates a strong effect of chronic HAC, but not short-term HAC, on mortality, further highlights the limitations of self-reported alcohol use in the prediction of all-cause mortality and indicates the value of assessing HAC in addition to smoking. Full article

(This article belongs to the Section Genetic Diagnosis)

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21 pages, 346 KB

Open AccessReview

Clinical Utility of GBA Genotyping Prior to Deep Brain Stimulation: A Narrative Review

by Valentino Rački, Slaven Lasić, Filip Ðerke, Andrej Belančić and Matija Sošić

Genes 2026, 17(1), 69; https://doi.org/10.3390/genes17010069 - 6 Jan 2026

Abstract

Background: Variants in the GBA gene represent the most common genetic risk factor for Parkinson’s disease and are associated with a more aggressive disease course. Deep brain stimulation is an established therapy for advanced Parkinson’s disease, yet the influence of GBA status [...] Read more.

Background: Variants in the GBA gene represent the most common genetic risk factor for Parkinson’s disease and are associated with a more aggressive disease course. Deep brain stimulation is an established therapy for advanced Parkinson’s disease, yet the influence of GBA status on postoperative outcomes remains incompletely defined. This review aims to summarize the clinical relevance of GBA genotyping prior to DBS and to evaluate its potential contribution to decision-making, risk stratification, and long-term management. Methods: A structured narrative review was conducted. The literature on sequencing methodology, variant interpretation, and postoperative outcomes in GBA-positive and GBA-negative patients was examined. Particular focus was placed on motor, cognitive, and neuropsychiatric outcomes, and on studies comparing trajectories across variant classes. Results: Across all study designs, patients with GBA-associated Parkinson’s disease demonstrated robust motor improvement after DBS, with outcomes comparable to those in non-carriers. Cognitive and neuropsychiatric decline occurred more rapidly in GBA carriers. Recent evidence indicates that cognitive and neuropsychiatric decline is influenced more by the genetic profile than the stimulation procedure. Variant severity appears to influence postoperative trajectories. Long-read sequencing improves detection of recombinant alleles and may refine genotype–phenotype associations. Genotyping provides additional value in counseling, expectation management, and postoperative planning. Conclusions: DBS remains an effective motor therapy for patients with GBA-associated Parkinson’s disease. Current findings indicate GBA genotyping should inform, and not limit, candidate selection. Integration of clinical, cognitive and genetic data supports more individualized management. Methodological advances in sequencing and the development of prediction models may further enhance personalized DBS planning. Full article

(This article belongs to the Section Neurogenomics)

12 pages, 1357 KB

Open AccessArticle

22q11.2 Deletion Syndrome in Offspring Conceived via Assisted Reproductive Technology Versus Spontaneously

by Jennifer Borowka, Terrence Blaine Crowley, Ashika Mani, Victoria Guinta, Daniel E. McGinn, Bekah Wang, Audrey Green, Lydia Rockart, Oanh Tran, Beverly S. Emanuel, Elaine H. Zackai, Lorraine Dugoff, Kathleen Valverde and Donna M. McDonald-McGinn

Genes 2026, 17(1), 68; https://doi.org/10.3390/genes17010068 - 6 Jan 2026

Abstract

Background/Objectives: The majority of chromosome 22q11.2 deletions are de novo, resulting from meiotic non-allelic homologous recombination (NAHR). While 22q11.2 deletion syndrome (22q11.2DS)-associated phenotypes are well characterized, risk factors leading to NAHR are poorly understood, including the possible relationship with assisted reproductive technology [...] Read more.

Background/Objectives: The majority of chromosome 22q11.2 deletions are de novo, resulting from meiotic non-allelic homologous recombination (NAHR). While 22q11.2 deletion syndrome (22q11.2DS)-associated phenotypes are well characterized, risk factors leading to NAHR are poorly understood, including the possible relationship with assisted reproductive technology (ART). Here we examined the prevalence of ART conceptions and medical comorbidities in patients with 22q11.2DS vs. spontaneously conceived (SC) patients with 22q11.2DS. Methods: Retrospective analysis, under IRB approval, of medical records on 1184 patients with laboratory-confirmed de novo chromosome 22q11.2 deletions was performed. ART conceptions included IVF with and without ICSI. Deletion size and obstetric, family, and medical histories were examined. Results: We identified 30 pregnancies conceived using ART (2.57%) compared with the U.S. general population rate of 2.3% (p-value = 0.6603). ART and SC sub-cohorts demonstrated no significant differences in deletion size or perinatal outcomes, including preterm birth, multiples, polyhydramnios, or congenital heart disease. Controlling for these factors, neonates conceived via ART were more likely to be admitted to the ICU (aOR = 6.3). Conclusions: Pregnancies conceived via ART, and later found to have 22q11.2DS, demonstrated no significant differences in prevalence or perinatal outcomes compared with the U.S. general population. Moreover, NAHR is unrelated to ART in this population. Likewise, associated phenotypic features are unrelated. These data will be reassuring to those families where ART was employed to conceive children who were later found to have 22q11.2DS. Full article

(This article belongs to the Special Issue From Genetic Mechanisms Discovery to Patient-Centered Care: The Expanse of Genomics Research)

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25 pages, 868 KB

Open AccessReview

Factors Involved in Host Resilience to Enteric Infections in Pigs: Current Knowledge in Genetic, Immune, and Microbiota Determinants of Infection Resistance

by Alejandro Ucero-Carretón, Héctor Puente, Marie Ithurbide, Jordi Estellé, Ana Carvajal and Héctor Argüello

Genes 2026, 17(1), 67; https://doi.org/10.3390/genes17010067 - 6 Jan 2026

Abstract

Enteric infections remain a major health and economic challenge in swine production, with outcomes determined not only by pathogen virulence but also by the complex interplay between host genetics, immune competence, and the intestinal microbiota. This review synthesises current knowledge on host–pathogen genomic [...] Read more.

Enteric infections remain a major health and economic challenge in swine production, with outcomes determined not only by pathogen virulence but also by the complex interplay between host genetics, immune competence, and the intestinal microbiota. This review synthesises current knowledge on host–pathogen genomic interactions in pigs, with a focus on resilience mechanisms against enteric diseases in swine. For this purpose, 103 articles were used as information sources, retrieved through structured keyword searches in PubMed. The review first addresses host genetic factors, highlighting genomic variants and quantitative trait loci associated with resistance or resilience to viral and bacterial pathogens such as porcine epidemic diarrhoea virus (PEDV) or Escherichia coli. Next, the key factors of the immune system to confer protection are also reviewed, emphasising the role of innate and adaptive responses in controlling each pathogen and disclosing the contribution of regulatory networks that balance pathogen clearance. Finally, the last section of the review is devoted to exploring current knowledge in the involvement of the microbiota in resilience against enteric pathogens, mostly, but not exclusively, enteric bacteria. In this sense, competitive exclusion is a concept which has gained attention in recent years. The review pinpoints and discusses the state of the art about how the microbial community provides colonisation resistance, shapes immune development, and influences pathogen fitness within the intestinal niche. As final perspectives, the review explores future drivers in the genetic immune and microbiota resistance. By bridging host genomic data with functional insights into immunity and microbial ecology, this review underscores the potential of multi-omics approaches to enhance resilience against enteric infections in pigs and advance sustainable swine health management. Full article

(This article belongs to the Special Issue Genetics of Host–Pathogen Interactions)

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22 pages, 858 KB

Open AccessReview

The Genetic and Epigenetic Architecture of Keratoconus: Emerging Pathways and Clinical Implications

by Francesco Cappellani, Matteo Capobianco, Federico Visalli, Cosimo Mazzotta, Fabiana D’Esposito, Daniele Tognetto, Caterina Gagliano and Marco Zeppieri

Genes 2026, 17(1), 66; https://doi.org/10.3390/genes17010066 - 6 Jan 2026

Abstract

Background: Keratoconus (KC) is a progressive corneal ectasia and a leading cause of corneal transplantation in young adults. Once regarded as a biomechanical disorder, KC is now recognized as a complex disease driven by genetic predisposition, epigenetic modulation, and environmental triggers. Advances in [...] Read more.

Background: Keratoconus (KC) is a progressive corneal ectasia and a leading cause of corneal transplantation in young adults. Once regarded as a biomechanical disorder, KC is now recognized as a complex disease driven by genetic predisposition, epigenetic modulation, and environmental triggers. Advances in genomics and transcriptomics have begun to elucidate the molecular mechanisms underlying corneal thinning and ectasia. Objectives: This review synthesizes two decades of evidence on the genetic and epigenetic architecture of keratoconus, highlights key molecular pathways implicated by these findings, and discusses translational implications for early diagnosis, risk prediction, and novel therapeutic strategies. Methods: A narrative review was conducted of peer-reviewed human, animal, and in vitro studies published from 2000 to 2025, with emphasis on genome-wide association studies (GWAS), sequencing data, methylation profiling, and non-coding RNA analyses. Findings were integrated with functional studies linking genetic variation to molecular and biomechanical phenotypes. Results: Genetic studies consistently implicate loci such as ZNF469, COL5A1, LOX, HGF, FOXO1, and WNT10A, alongside rare variants in Mendelian syndromes (e.g., brittle cornea syndrome, Ehlers–Danlos spectrum). Epigenetic research demonstrates altered DNA methylation, dysregulated microRNAs (e.g., MIR184, miR-143, miR-182), and aberrant lncRNA networks influencing extracellular matrix remodeling, collagen cross-linking, oxidative stress, and inflammatory signaling. Gene–environment interactions, particularly with eye rubbing and atopy, further shape disease expression. Translational progress includes polygenic risk scores, tear-based biomarkers, and early preclinical studies using RNA-based approaches (including siRNA and antisense oligonucleotides targeting matrix-degrading and profibrotic pathways) and proof-of-concept gene-editing strategies demonstrated in corneal cell and ex vivo models. Conclusions: Keratoconus arises from the convergence of inherited genomic risk, epigenetic dysregulation, and environmental stressors. Integrating multi-omic insights into clinical practice holds promise for earlier detection, precision risk stratification, and development of targeted therapies that move beyond biomechanical stabilization to disease modification. Full article

(This article belongs to the Section Epigenomics)

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25 pages, 392 KB

Open AccessReview

Genes and Genetic Pathways Regarding the Etiology and Pathogenesis of Ameloblastoma

by Vasileios Zisis, Petros Papadopoulos, Stylianos Papadopoulos, Konstantinos Poulopoulos, Christina Charisi, Dimitrios Parlitsis and Athanasios Poulopoulos

Genes 2026, 17(1), 65; https://doi.org/10.3390/genes17010065 - 6 Jan 2026

Abstract

Background/Objectives: Ameloblastoma is a benign odontogenic neoplasm characterized by locally aggressive behavior and frequent recurrences despite surgical treatment. It originates from odontogenic epithelium, including the cell rests of the dental lamina, remnants of the enamel organ, epithelial cell rests of Malassez, or the [...] Read more.

Background/Objectives: Ameloblastoma is a benign odontogenic neoplasm characterized by locally aggressive behavior and frequent recurrences despite surgical treatment. It originates from odontogenic epithelium, including the cell rests of the dental lamina, remnants of the enamel organ, epithelial cell rests of Malassez, or the basal cell layer of the oral mucosa. Investigation of the etiopathogenesis of ameloblastoma has gained critical relevance due to the need for extensive surgical procedures, high recurrence rates, and its malignant potential. Accordingly, the aim of the present narrative review is to summarize current evidence regarding key aspects of ameloblastoma etiopathogenesis, with emphasis on signaling pathways, mutations, epigenetics, and epithelial–stromal interactions. Methods: An extensive literature search was conducted using the PubMed, Scopus, and Google Scholar databases, employing the keywords: “etiology”, “pathogenesis”, “molecular”, “biomarkers”, “cellular”, “epigenetic”, “mutation”, “pathway”, and “ameloblastoma”. In vitro studies, clinical studies, case reports, and narrative and systematic reviews published in English were included, without restriction on publication year. Results: Current evidence indicates that ameloblastoma pathogenesis is driven by dysregulation of multiple signaling pathways, particularly the MAPK and Sonic Hedgehog pathways, through recurrent activating BRAF and SMO mutations. In addition, alterations affecting the WNT/β-Catenin and PI3K/AKT signaling cascades, epigenetic modifications, and epithelial–stromal interactions, contribute to tumor behavior. Conclusions: Despite significant advances, genotype–phenotype correlations, mutation frequencies and coexistence, clonality, and other associations remain incompletely understood. Larger tumor cohorts and robust meta-analyses are required to clarify these associations and to leverage the development of personalized therapeutic strategies. Full article

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

13 pages, 3995 KB

Open AccessArticle

Genomic Identification and Characterization of the Cotton YABBY Gene Family

by Guoqiang Zhang, Zhen Liu, Mingli Xia, Sainan Zhang, Zhixian Li and Quanwei Lu

Genes 2026, 17(1), 64; https://doi.org/10.3390/genes17010064 - 6 Jan 2026

Abstract

Background: YABBY transcription factors play important roles in plant growth and development. Although this gene family has been characterized in many plant species, a comprehensive analysis in cotton remains unavailable. Methods: In this study, we investigated the YABBY gene family in [...] Read more.

Background: YABBY transcription factors play important roles in plant growth and development. Although this gene family has been characterized in many plant species, a comprehensive analysis in cotton remains unavailable. Methods: In this study, we investigated the YABBY gene family in cotton by integrating multiple bioinformatics methods. Results: YABBY genes were identified in the genomes of four cotton species (Gossypium hirsutum, Gossypium barbadense, Gossypium arboretum and Gossypium raimondii) and these identified genes were further classified into six groups. Following this classification, the expansion of the cotton YABBY gene family was examined, and we found that the family exhibits diverse expansion patterns during evolution, with segmental duplication acting as the primary driving force. In contrast, the notably larger repertoire of YABBY genes in G. raimondii is likely attributable to transposon activity. Regarding their evolutionary trajectory, Ka/Ks analysis showed that the YABBY gene family has undergone purifying selection. Beyond evolution, expression and cis-element analyses further demonstrated that YABBY genes possess diverse functions. In addition, we identified YABBY genes involved in different developmental stages of cotton fibers. Conclusions: We clarify the function and evolution of the cotton YABBY gene family in this work, and these results will provide a critical resource for further research on YABBY genes. Full article

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

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13 pages, 1310 KB

Open AccessArticle

FLOURY ENDOSPERM 2 Coordinates Starch Biosynthesis to Maintain Endosperm Structural Integrity in Rice

by Hye-Mi Lee, Jin-Young Kim, Hak-Dong Kim, Hak-Soo Kim, Jong-Geun Park, Yu-Jin Jung and Kwon-Kyoo Kang

Genes 2026, 17(1), 63; https://doi.org/10.3390/genes17010063 - 5 Jan 2026

Abstract

Background/Objectives: FLOURY ENDOSPERM 2 (FLO2) is known to affect rice endosperm development and starch quality, yet its role in determining flour physicochemical behavior and endosperm structural integrity has not been quantitatively defined. This study aimed to elucidate how loss of FLO2 function alters [...] Read more.

Background/Objectives: FLOURY ENDOSPERM 2 (FLO2) is known to affect rice endosperm development and starch quality, yet its role in determining flour physicochemical behavior and endosperm structural integrity has not been quantitatively defined. This study aimed to elucidate how loss of FLO2 function alters starch organization and functional properties of rice flour. Methods: Two independent homozygous, T-DNA-free OsFLO2 knockout lines were generated in the japonica cultivar Dongjin using CRISPR/Cas9. Grain appearance was evaluated in mature seeds. Flour physicochemical properties were analyzed by Rapid Visco Analyzer (RVA) and differential scanning calorimetry (DSC). Amylopectin chain-length distribution was determined by isoamylase debranching followed by HPAEC-PAD, and endosperm microstructure was examined by scanning electron microscopy. Results: OsFLO2 mutants exhibited floury, opaque endosperms, with chalkiness increasing from 4.8% in the WT to 27–29%. RVA analysis showed a marked reduction in peak viscosity (1193 cP to 263–293 cP) and a decrease in pasting temperature (77.2 °C to 68.9–70.5 °C). DSC indicated a tendency toward reduced gelatinization enthalpy in the mutants. These changes were associated with a reduced proportion of short amylopectin chains (DP 6–12), decreased long chains (DP ≥ 37), and a relative increase in intermediate-long chains (DP 25–36), along with disrupted granule packing and a 1.33–1.36-fold increase in endosperm porosity. Conclusions: These results demonstrate that FLO2 plays an important role in maintaining the structural integrity of rice endosperm by harmonizing the microstructure of amylopectin with the thermal and gelatinization properties of starch. Full article

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

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17 pages, 555 KB

Open AccessArticle

New Candidate Genes for a Chicken Pectoralis Muscle Weight QTL Identified by a Hypothesis-Free Integrative Genetic Approach

by Akihiro Furuta and Akira Ishikawa

Genes 2026, 17(1), 62; https://doi.org/10.3390/genes17010062 - 5 Jan 2026

Cited by 1

Abstract

Background/Objectives: Identifying candidate genes underlying quantitative trait loci (QTL) in poultry has traditionally required labor-intensive positional cloning. Previous studies using an F₂ population derived from native Japanese Nagoya (NAG) and White Plymouth Rock (WPR) breeds revealed a major QTL on chromosome [...] Read more.

Background/Objectives: Identifying candidate genes underlying quantitative trait loci (QTL) in poultry has traditionally required labor-intensive positional cloning. Previous studies using an F₂ population derived from native Japanese Nagoya (NAG) and White Plymouth Rock (WPR) breeds revealed a major QTL on chromosome 2 affecting 3-week body weight and 4-week pectoralis muscle weight. This study aimed to identify candidate genes for this QTL using a hypothesis-free integrative genetic approach. Methods: We employed a multi-step analytical framework combining QTL remapping, transcriptome analysis, gene enrichment analysis, haplotype frequency comparison, and correlation analysis. QTL remapping was performed using individual traits and their first principal component (PC1) in 239 F₂ chickens. RNA-sequencing (RNA-seq) of liver tissue was conducted for F₂ individuals with extreme PC1 scores, followed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) validation. Results: QTL remapping refined the 95% confidence interval to a chromosome 2 region containing 329 genes. RNA-seq analysis identified 23 differentially expressed genes (DEGs) within this interval. Although gene enrichment analysis initially highlighted GATA binding protein 6 (GATA6) as a potential candidate, RT-qPCR in NAG, WPR, and F₁ chickens showed no significant expression differences, excluding GATA6. Haplotype frequency and correlation analyses prioritized cadherin-17 (CDH17) as the strongest candidate gene and ring finger protein 151 (RNF151) as a secondary candidate. Conclusions: Our hypothesis-free integrative approach effectively refined candidate genes for a chromosome 2 QTL influencing early growth and pectoralis muscle weight. CDH17 and RNF151 represent promising targets for functional validation and may support marker-assisted selection to improve muscle-related traits in chickens. Full article

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

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10 pages, 788 KB

Open AccessArticle

The Role of Genetic Testing in Pediatric Expressive Language Delay: Evidence from the National Brain Gene Registry

by Shivani Waghmare, Alexa M. Taylor, Cecilia Bouska, Ana Moreno Chaza and Andrea Gropman

Genes 2026, 17(1), 61; https://doi.org/10.3390/genes17010061 - 5 Jan 2026

Abstract

Background/Objectives: Speech and language delay (SLD) is one of the most prevalent developmental conditions in childhood, with post-pandemic data indicating a notable increase in identified cases. Within this group, expressive language disorder (ELD) frequently appears alongside neurodevelopmental disorders such as autism spectrum disorder [...] Read more.

Background/Objectives: Speech and language delay (SLD) is one of the most prevalent developmental conditions in childhood, with post-pandemic data indicating a notable increase in identified cases. Within this group, expressive language disorder (ELD) frequently appears alongside neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability. Although awareness of ELD has grown, the role of genetic testing in its evaluation remains unclear, as such testing is not routinely pursued for isolated expressive language concerns. This gap highlights the need to better define the diagnostic value of genetic analysis and to examine the interval between an ELD diagnosis and the return of genetic testing results. Methods: This study investigated genetic contributions to ELD using the National Brain Gene Registry (BGR), a multisite database of rare neurodevelopmental disorders. Participants with ICD-10 code F80.1 were identified through electronic health records; demographic data, comorbidities, genetic variants, inheritance patterns, age at diagnosis, and timing of interventions were analyzed. Results: Of 687 BGR participants, 32 (4.7%) had documented ELD. The cohort, aged 3–19 years, presented with common comorbidities like developmental delays, ASD, epilepsy, and hypotonia. Across 42 genes, 49 unique variants were identified: 26 pathogenic or likely pathogenic, 22 variants of uncertain significance, and one benign variant. Seventeen variants were de novo, and 10 participants carried multiple variants. Most children (80%) received an expressive language diagnosis prior to genetic testing, with reports returned an average of 1.5 years following the diagnosis. Conclusions: Overall, children with ELD commonly carry genetic variants and neurodevelopmental comorbidities, yet genetic testing is typically pursued well after diagnosis and does not currently alter early management. These findings underscore the need for clearer, evidence-based guidelines to define when genetic testing adds diagnostic or prognostic value in the evaluation of ELD. Full article

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

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