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MTHFR Gene Polymorphisms: A Single Gene with Wide-Ranging Clinical Implications—A Review
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Role of MicroRNAs in Acute Myeloid Leukemia
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SYNGAP1 Syndrome and the Brain Gene Registry
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Genetics of Suicide
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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
Journal Description
Genes
Genes
is a peer-reviewed, open access journal of genetics and genomics published monthly online by MDPI. The Spanish Society for Nitrogen Fixation (SEFIN) is affiliated with Genes and their members receive discounts on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
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- Journal Rank: JCR - Q2 (Genetics and Heredity) / CiteScore - Q2 (Genetics (clinical))
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 14.6 days after submission; acceptance to publication is undertaken in 2.5 days (median values for papers published in this journal in the first half of 2025).
- Recognition of Reviewers: Reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Impact Factor:
2.8 (2024);
5-Year Impact Factor:
3.2 (2024)
Latest Articles
Clinician-Based Functional Scoring and Genomic Insights for Prognostic Stratification in Wolf–Hirschhorn Syndrome
Genes 2025, 16(7), 820; https://doi.org/10.3390/genes16070820 (registering DOI) - 12 Jul 2025
Abstract
Background/Objectives: Wolf–Hirschhorn syndrome (WHS; OMIM #194190) is a rare neurodevelopmental disorder, caused by deletions in the distal short arm of chromosome 4. It is characterized by developmental delay, epilepsy, intellectual disability, and distinctive facial dysmorphism. Clinical presentation varies widely, complicating prognosis and
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Background/Objectives: Wolf–Hirschhorn syndrome (WHS; OMIM #194190) is a rare neurodevelopmental disorder, caused by deletions in the distal short arm of chromosome 4. It is characterized by developmental delay, epilepsy, intellectual disability, and distinctive facial dysmorphism. Clinical presentation varies widely, complicating prognosis and individualized care. Methods: We assembled a cohort of 140 individuals with genetically confirmed WHS from Spain and Latin-America, and developed and validated a multidimensional, Clinician-Reported Outcome Assessment (ClinRO) based on the Global Functional Assessment of the Patient (GFAP), derived from standardized clinical questionnaires and weighted by HPO (Human Phenotype Ontology) term frequencies. The GFAP score quantitatively captures key functional domains in WHS, including neurodevelopment, epilepsy, comorbidities, and age-corrected developmental milestones (selected based on clinical experience and disease burden). Results: Higher GFAP scores are associated with worse clinical outcomes. GFAP showed strong correlations with deletion size, presence of additional genomic rearrangements, sex, and epilepsy severity. Ward’s clustering and discriminant analyses confirmed GFAP’s discriminative power, classifying over 90% of patients into clinically meaningful groups with different prognoses. Conclusions: Our findings support GFAP as a robust, WHS-specific ClinRO that may aid in stratification, prognosis, and clinical management. This tool may also serve future interventional studies as a standardized outcome measure. Beyond its clinical utility, GFAP also revealed substantial social implications. This underscores the broader socioeconomic burden of WHS and the potential value of GFAP in identifying high-support families that may benefit from targeted resources and services.
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(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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Open AccessArticle
Uridine Kinase-like Protein (GhUKL4) Positively Regulates Resistance to Verticillium Wilt in Cotton
by
Baimei Cheng, Yanmeng Sun, Xiaohui Sang, Jianhua Lu, Pei Zhao, Wei Chen, Yunlei Zhao and Hongmei Wang
Genes 2025, 16(7), 819; https://doi.org/10.3390/genes16070819 (registering DOI) - 12 Jul 2025
Abstract
Background: Verticillium wilt (VW), caused by the fungal pathogen Verticillium dahliae, is a destructive disease that severely compromises cotton yield and fiber quality. Pyrimidine nucleotides, as essential metabolites and nucleic acid components, play critical roles in plant development and stress responses. However,
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Background: Verticillium wilt (VW), caused by the fungal pathogen Verticillium dahliae, is a destructive disease that severely compromises cotton yield and fiber quality. Pyrimidine nucleotides, as essential metabolites and nucleic acid components, play critical roles in plant development and stress responses. However, genes involved in pyrimidine metabolism, especially their roles in disease resistance, remain largely uncharacterized in plants. Methods: Ghir_D05G039120, a gene encoding uridine kinase, shown to be associated with VW resistance in our previous study, was cloned and named as GhUKL4. The differential expression of GhUKL4 between the resistant and susceptible cultivars at multiple time points post-inoculation with V. dahliae was analyzed by quantitative real-time PCR (qRT-PCR), and the uracil phosphoribosyl transferase (UPRT) and uridine 5′-monophosphate kinase (UMPK) domains were verified by analyzing the amino acid sequences of GhUKL4. The role of GhUKL4 in the defense against VW infection was estimated by silencing GhUKL4 in the resistant and susceptible cultivars using virus-induced gene silencing (VIGS) analysis. Results: There were significant differences in the expression level of Ghir_D05G039120/ GhUKL4 among resistant and susceptible cotton lines. GhUKL4 contains UPRTase and UMPK domains, and there was one SNP between the resistant and susceptible cultivars in its 3‘-UTR region. The silencing of GhUKL4 reduced cotton’s resistance to VW through mediating hormone signaling (JA) and oxidative stress (ROS) pathways. Conclusions: GhUKL4, encoding UMPK and UPRTase domain proteins, is a new regulatory factor associated with VW resistance in Gossypium hirsutum through fine-tuning JA-signalling and ROS bursting.
Full article
(This article belongs to the Section Plant Genetics and Genomics)
Open AccessArticle
Brain and CSF Alzheimer’s Biomarkers Are Associated with SERPINE1 Gene Expression
by
Cynthia Picard, Henrik Zetterberg, Kaj Blennow, Sylvia Villeneuve, Judes Poirier and on behalf of the PREVENT-AD Research Group
Genes 2025, 16(7), 818; https://doi.org/10.3390/genes16070818 (registering DOI) - 12 Jul 2025
Abstract
Background: SERPINE1, also known as plasminogen activator inhibitor (PAI), has been proposed as a potential blood biomarker for the early detection and diagnosis of Alzheimer’s disease (AD). Expanding on previous studies, this research contrasted SERPINE1 levels in CSF and brain tissue of AD
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Background: SERPINE1, also known as plasminogen activator inhibitor (PAI), has been proposed as a potential blood biomarker for the early detection and diagnosis of Alzheimer’s disease (AD). Expanding on previous studies, this research contrasted SERPINE1 levels in CSF and brain tissue of AD patients and those at risk for AD with established AD biomarkers. Methods: Utilizing OLINK and immunoassay methods, CSF SERPINE1 protein levels were quantified across two separate cohorts: PREVENT-AD and ADNI. Microarray and RNAseq were used to measure tissue SERPINE1 mRNA levels in two separate cohorts: the Douglas-Bell Canada Brain Bank and the Mayo Clinic Brain Bank. Results: At the pre-clinical stage, elevated CSF levels of pTau, tTau and synaptic markers, alongside reduced hippocampal volume, correlate with CSF SERPINE1 levels. Elevated cortical SERPINE1 mRNA levels in autopsy-confirmed AD show weak correlation with regional plaques and tangles densities, but strong correlation with Braak staging. Conclusions: CSF SERPINE1 levels can be used as an early biomarker for the detection of pathological changes associated with AD. Higher SERPINE1 levels correlate more strongly with tau pathology than with amyloid formation or deposition.
Full article
(This article belongs to the Special Issue Genetics and Treatment in Neurodegenerative Diseases)
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Open AccessArticle
Integrated Single-Cell Analysis Dissects Regulatory Mechanisms Underlying Tumor-Associated Macrophage Plasticity in Hepatocellular Carcinoma
by
Yu Gu, Wenyong Zhu, Zhihui Zhang, Huiling Shu, Hao Huang and Xiao Sun
Genes 2025, 16(7), 817; https://doi.org/10.3390/genes16070817 (registering DOI) - 12 Jul 2025
Abstract
Background: Tumor-associated macrophages (TAMs) are critical regulators of the hepatocellular carcinoma (HCC) microenvironment, yet their epigenetic heterogeneity and regulatory programs remain poorly defined. Methods: We performed integrative analysis on single-cell RNA-seq and ATAC-seq profiling of HCC patients to dissect TAM subtypes
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Background: Tumor-associated macrophages (TAMs) are critical regulators of the hepatocellular carcinoma (HCC) microenvironment, yet their epigenetic heterogeneity and regulatory programs remain poorly defined. Methods: We performed integrative analysis on single-cell RNA-seq and ATAC-seq profiling of HCC patients to dissect TAM subtypes at high resolution. By correlating chromatin accessibility with gene expression, we identified cell-type-specific candidate cis-regulatory elements (CREs). TAM subsets with prognostic significance were determined through integration with HCC clinical cohorts. Pseudotime and multi-regional analyses were used to uncover regulatory trajectories underlying macrophage phenotypic transitions. The identification framework of a super-enhancer (SE) was constructed, and potential therapeutic targets were prioritized using drug–gene interaction data. Results: We delineated the regulatory landscape of TAMs in HCC, revealing cell-type-specific chromatin accessibility patterns underlying TAM heterogeneity. The 65,342 CREs linked to gene expression were identified, with distal CREs contributing most to cell-type-specific regulation. Notably, SPP1+ TAMs were found to be enriched in tumor cores and associated with poor prognosis in HCC. Liver-resident Kupffer cells showed progressive loss of the core transcription factors SPIC and MAFB, suggesting a potential transition into SPP1+ TAMs under tumor pressure. We identified 133 SPP1+ TAM-specific SEs and constructed a TF–SE–target gene regulatory network. Notably, 13 target genes showed higher drug–gene interaction effects, highlighting their therapeutic potential. Conclusions: This study provides the chromatin accessibility map of TAMs in HCC and reveals how distal CRE-driven transcriptional programs shape TAM states. Our findings lay the foundation for understanding the epigenetic regulation of TAM heterogeneity and nominate potential targets for TAM-directed immunotherapy in HCC.
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(This article belongs to the Special Issue Single-Cell and Spatial Multi-Omics in Human Diseases)
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Open AccessArticle
Tracing the Evolutionary Expansion of a Hyperdiverse Antimicrobial Peptide Gene Family in Mytilus spp.: The MyticalinDB Resource
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Dona Kireta, Pietro Decarli, Damiano Riommi, Nicolò Gualandi, Samuele Greco, Alberto Pallavicini and Marco Gerdol
Genes 2025, 16(7), 816; https://doi.org/10.3390/genes16070816 (registering DOI) - 12 Jul 2025
Abstract
Background: The overwhelming majority of the antimicrobial peptides (AMPs) studied in mussels (Mytilus spp.) so far are specifically expressed by hemocytes and display compact disulfide-stabilized structures. However, gill-specific myticalins play a role in mucosal immunity and are one of the very
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Background: The overwhelming majority of the antimicrobial peptides (AMPs) studied in mussels (Mytilus spp.) so far are specifically expressed by hemocytes and display compact disulfide-stabilized structures. However, gill-specific myticalins play a role in mucosal immunity and are one of the very few examples of known molluscan AMPs lacking cysteine residues. Methods: We investigate the molecular evolution of myticalins, compiling a collection of sequences obtained by carefully annotating 169 genome assemblies of different Mytilus species. We determine the gene presence/absence patterns and gene expression profiles for the five myticalin subfamilies, including the newly reported myticalin E. Results: All sequences are deposited in MyticalinDB, a novel database that includes a total of 100 unique mature myticalin peptides encoded by 215 protein precursors, greatly enriching the compendium of these molecules from previous reports. Among the five subfamilies, myticalin A and C are the most widespread and highly expressed across all Mytilus species. Interestingly, structural prediction reveals a previously unreported strong amphipathic nature for some myticalins, which may be highly relevant for their biological activity. Conclusions: The results reported in this work support the role of myticalins in gill-associated mucosal immunity and highlight the importance of inter-individual molecular diversity in establishing an efficient response to microbial infections. The newly established MyticalinDB provides a valuable resource for investigating the evolution and extraordinary molecular diversity of this AMP family.
Full article
(This article belongs to the Section Animal Genetics and Genomics)
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Open AccessArticle
Dark Rearing Does Not Alter Developmental Retinoschisis Cavity Formation in Rs1 Gene Knockout Rat Model of X-Linked Retinoschisis
by
Zeljka Smit-McBride, In Hwan Cho, Ning Sun, Serafina Thomas and Paul A. Sieving
Genes 2025, 16(7), 815; https://doi.org/10.3390/genes16070815 - 11 Jul 2025
Abstract
Background/Objective: The Rs1 exon-1-del rat (Rs1KO) XLRS model shows normal retinal development until postnatal day 12 (P12) when small cystic spaces start to form in the inner nuclear layer. These enlarge rapidly, peak at P15, and then collapse by P19. These events overlap
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Background/Objective: The Rs1 exon-1-del rat (Rs1KO) XLRS model shows normal retinal development until postnatal day 12 (P12) when small cystic spaces start to form in the inner nuclear layer. These enlarge rapidly, peak at P15, and then collapse by P19. These events overlap with eye opening at P12–P15. We investigated whether new light-driven retinal activity could contribute to the appearance and progression of schisis cavities in this rat model of XLRS disease. Methods: For dark rearing (D/D), mating pairs of Rs1KO strain were raised in total darkness in a special vivarium at UC Davis. When pups were born, they were maintained in total darkness, and eyes were collected at P12, P15, and P30 (n = 3/group) for each of the D/D and cyclic light-reared 12 h light–12 h dark (L/D) Rs1KO and wild-type (WT) littermates. Eyes were fixed, paraffin-embedded, and sectioned. Tissue morphology was examined by H&E and marker expression of retinoschisin1 (Rs1), rhodopsin (Rho), and postsynaptic protein 95 (Psd95) by fluorescent immunohistochemistry. H&E-stained images were analyzed with ImageJ version 1.54h to quantify cavity size using the “Analyze Particles” function. Results: Small intra-retinal schisis cavities begin to form by P12 in the inner retina of both D/D and L/D animals. Cavity formation was equivalent or more pronounced in D/D animals than in L/D animals. We compared Iba1 (activation marker of immune cells) distribution and found that by P12, when schisis appeared, Iba1+ cells had accumulated in regions of schisis. Iba1+cells were more abundant in Rs1KO animals than WT animals and appeared slightly more prevalent in D/D- than L/D-reared Rs1KO animals. We compared photoreceptor development using Rho, Rs1, and Psd95 expression, and these were similar; however, the outer segments (OSs) of D/D animals with Rho labeling at P12 were longer than L/D animals. Conclusions: The results showed that cavities formed at the same time in D/D and L/D XLRS rat pups, indicating that the timing of schisis formation is not light stimulus-driven but rather appears to be a result of developmental events. Cavity size tended to be larger under dark-rearing conditions in D/D animals, which could be due to the decreased rate of phagocytosis by the RPE in the dark, allowing for continued growth of the OSs without the usual shedding of the distal tip, a key mechanism behind dark adaptation in the retina. These results highlight the complexity of XLRS pathology; however, we found no evidence that light-driven metabolic activity accounted for schisis cavity formation.
Full article
(This article belongs to the Special Issue Current Advances in Inherited Retinal Disease)
Open AccessArticle
Molecular Network Analysis and Effector Gene Prioritization of Endurance-Training-Influenced Modulation of Cardiac Aging
by
Mingrui Wang, Samuhaer Azhati, Hangyu Chen, Yanyan Zhang and Lijun Shi
Genes 2025, 16(7), 814; https://doi.org/10.3390/genes16070814 - 11 Jul 2025
Abstract
Background/Objectives: Cardiac aging involves the progressive structural and functional decline of the myocardium. Endurance training is a well-recognized non-pharmacological intervention that counteracts this decline, yet the molecular mechanisms driving exercise-induced cardiac rejuvenation remain inadequately elucidated. This study aimed to identify key effector genes
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Background/Objectives: Cardiac aging involves the progressive structural and functional decline of the myocardium. Endurance training is a well-recognized non-pharmacological intervention that counteracts this decline, yet the molecular mechanisms driving exercise-induced cardiac rejuvenation remain inadequately elucidated. This study aimed to identify key effector genes and regulatory pathways by integrating human cardiac aging transcriptomic data with multi-omic exercise response datasets. Methods: A systems biology framework was developed to integrate age-downregulated genes (n = 243) from the GTEx human heart dataset and endurance-exercise-responsive genes (n = 634) from the MoTrPAC mouse dataset. Thirty-seven overlapping genes were identified and subjected to Enrichr for pathway enrichment, KEA3 for kinase analysis, and ChEA3 for transcription factor prediction. Candidate effector genes were ranked using ToppGene and ToppNet, with integrated prioritization via the FLAMES linear scoring algorithm. Results: Pathway enrichment revealed complementary patterns: aging-associated genes were enriched in mitochondrial dysfunction and sarcomere disassembly, while exercise-responsive genes were linked to protein synthesis and lipid metabolism. TTN, PDK family kinases, and EGFR emerged as major upstream regulators. NKX2-5, MYOG, and YBX3 were identified as shared transcription factors. SMPX ranked highest in integrated scoring, showing both functional relevance and network centrality, implying a pivotal role in mechano-metabolic coupling and cardiac stress adaptation. Conclusions: By integrating cardiac aging and exercise-responsive transcriptomes, 37 effector genes were identified as molecular bridges between aging decline and exercise-induced rejuvenation. Aging involved mitochondrial and sarcomeric deterioration, while exercise promoted metabolic and structural remodeling. SMPX ranked highest for its roles in mechano-metabolic coupling and redox balance, with X-inactivation escape suggesting sex-specific relevance. Other top genes (e.g., KLHL31, MYPN, RYR2) form a regulatory network supporting exercise-mediated cardiac protection, offering targets for future validation and therapy.
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(This article belongs to the Section Human Genomics and Genetic Diseases)
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Open AccessArticle
Cotton STARD Gene Family: Characterization, Evolution, and Expression Profiles During Salt Stress
by
Ruifeng Cui, Jiuguang Sun, Shuyan Li, Yupeng Cui, Cun Rui, Minshan Sun and Wuwei Ye
Genes 2025, 16(7), 813; https://doi.org/10.3390/genes16070813 - 11 Jul 2025
Abstract
Background: Cotton, a key global economic crop, suffers yield and quality losses due to salt stress. This study aims to analyze the cotton STARD gene family and its role in salt stress responses. Methods: We conducted a genome-wide analysis of the
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Background: Cotton, a key global economic crop, suffers yield and quality losses due to salt stress. This study aims to analyze the cotton STARD gene family and its role in salt stress responses. Methods: We conducted a genome-wide analysis of the STARD gene family in four cotton species, using phylogenetic trees, chromosomal mapping, and collinearity analyses to explore their evolutionary relationships and expansion mechanisms. We also examined gene structures, conserved motifs, and promoter cis-elements. Results: STARD genes are evenly distributed across the four cotton species. Segmental duplication was found to be the main driver of gene expansion, with most pairs undergoing purifying selection. Distinct structural features and potential roles in plant growth and stress responses were identified. Notably, 11 GhSTARD genes showed significant expression changes under salt stress, especially GhSTARD45 in root tissues. Conclusions: This study provides new insights into the function and salt stress response mechanisms of the cotton STARD gene family, suggesting GhSTARD45 plays a key role in root-mediated salt tolerance and highlighting the potential of STARD genes in enhancing cotton’s salt tolerance.
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(This article belongs to the Special Issue 15th Anniversary of Genes: Feature Papers in the “Plant Genetics and Genomics” Section)
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Open AccessArticle
Intelligent Multi-Modeling Reveals Biological Mechanisms and Adaptive Phenotypes in Hair Sheep Lambs from a Semi-Arid Region
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Robson Mateus Freitas Silveira, Fábio Augusto Ribeiro, João Pedro dos Santos, Luiz Paulo Fávero, Luis Orlindo Tedeschi, Anderson Antonio Carvalho Alves, Danilo Augusto Sarti, Anaclaudia Alves Primo, Hélio Henrique Araújo Costa, Neila Lidiany Ribeiro, Amanda Felipe Reitenbach, Fabianno Cavalcante de Carvalho and Aline Vieira Landim
Genes 2025, 16(7), 812; https://doi.org/10.3390/genes16070812 - 11 Jul 2025
Abstract
Background: Heat stress challenges small ruminants in semi-arid regions, requiring integrative multi-modeling approaches to identify adaptive thermotolerance traits. This study aimed to identify phenotypic biomarkers and explore the relationships between thermoregulatory responses and hematological, behavioral, morphometric, carcass, and meat traits in lambs. Methods:
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Background: Heat stress challenges small ruminants in semi-arid regions, requiring integrative multi-modeling approaches to identify adaptive thermotolerance traits. This study aimed to identify phenotypic biomarkers and explore the relationships between thermoregulatory responses and hematological, behavioral, morphometric, carcass, and meat traits in lambs. Methods: Twenty 4-month-old non-castrated male lambs, with an average body weight of 19.0 ± 5.11 kg, were evaluated under natural heat stress. Results: Thermoregulatory variables were significantly associated with non-carcass components (p = 0.002), carcass performance (p = 0.027), commercial meat cuts (p = 0.032), and morphometric measures (p = 0.029), with a trend for behavioral responses (p = 0.078). The main phenotypic traits related to thermoregulation included idleness duration, cold carcass weight, blood, liver, spleen, shank, chest circumference, and body length. Exploratory factor analysis reduced the significant indicators to seven latent domains: carcass traits, commercial meat cuts, non-carcass components, idleness and feeding behavior, and morphometric and thermoregulatory responses. Bayesian network modeling revealed interdependencies, showing carcass traits influenced by morphometric and thermoregulatory responses and non-carcass traits linked to ingestive behavior. Thermoregulatory variables were not associated with meat quality or hematological traits. Conclusions: These findings highlight the complex biological relationships underlying heat adaptation and emphasize the potential of combining phenomic data with computational tools to support genomic selection for climate-resilient and welfare-oriented breeding programs.
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(This article belongs to the Section Animal Genetics and Genomics)
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Open AccessArticle
Research on Key Genes for Flowering of Bambusaoldhamii Under Introduced Cultivation Conditions
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Shanwen Ye, Xuhui Wei, Jiamei Chen, Suzhen Luo, Tingguo Jiang, Jie Yang, Rong Zheng and Shuanglin Chen
Genes 2025, 16(7), 811; https://doi.org/10.3390/genes16070811 - 11 Jul 2025
Abstract
Background: Bambusaoldhamii is an important economic bamboo species. However, flowering occurred after its introduction and cultivation, resulting in damage to the economy of bamboo forests. Currently, the molecular mechanism of flowering induced by introduction stress is still unclear. This study systematically explored the
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Background: Bambusaoldhamii is an important economic bamboo species. However, flowering occurred after its introduction and cultivation, resulting in damage to the economy of bamboo forests. Currently, the molecular mechanism of flowering induced by introduction stress is still unclear. This study systematically explored the key genes and regulatory pathways of flowering in Bambusaoldhamii under introduction stress through field experiments combined with transcriptome sequencing and weighted gene co-expression network analysis (WGCNA), with the aim of providing a basis for flower-resistant cultivation and molecular breeding of bamboo. Results: The study conducted transcriptome sequencing on flowering and non-flowering Bambusaoldhamii bamboo introduced from Youxi, Fujian Province for 2 years, constructed a reference transcriptome containing 213,747 Unigenes, and screened out 36,800–42,980 significantly differentially expressed genes (FDR < 0.05). The results indicated that the photosensitive gene CRY and the temperature response gene COR413-PM were significantly upregulated in the flowering group; the expression level of the heavy metal detoxification gene MT3 increased by 27.77 times, combined with the upregulation of the symbiotic signaling gene NIN. WGCNA analysis showed that the expression level of the flower meristem determination gene AP1/CAL/FUL in the flowering group was 90.38 times that of the control group. Moreover, its expression is regulated by the cascade synergy of CRY-HRE/RAP2-12-COR413-PM signals. Conclusions: This study clarifies for the first time that the stress of introducing Bambusaoldhamii species activates the triad pathways of photo-temperature signal perception (CRY/COR413-PM), heavy metal detoxification (MT3), and symbiotic regulation (NIN), collaboratively driving the AP1/CAL/FUL gene expression network and ultimately triggering the flowering process.
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(This article belongs to the Section Genes & Environments)
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Open AccessArticle
FST Polymorphisms Associate with Musculoskeletal Traits and Modulate Exercise Response Differentially by Sex and Modality in Northern Han Chinese Adults
by
Wei Cao, Zhuangzhuang Gu, Ronghua Fu, Yiru Chen, Yong He, Rui Yang, Xiaolin Yang and Zihong He
Genes 2025, 16(7), 810; https://doi.org/10.3390/genes16070810 - 10 Jul 2025
Abstract
Background/Objectives: To investigate associations between Follistatin (FST) gene polymorphisms (SNPs) and baseline musculoskeletal traits, and their interactions with 16-week exercise interventions. Methods: A cohort of 470 untrained Northern Han Chinese adults (208 males, 262 females), sourced from the “Research
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Background/Objectives: To investigate associations between Follistatin (FST) gene polymorphisms (SNPs) and baseline musculoskeletal traits, and their interactions with 16-week exercise interventions. Methods: A cohort of 470 untrained Northern Han Chinese adults (208 males, 262 females), sourced from the “Research on Key Technologies for an Exercise and Fitness Expert Guidance System” project, was analyzed. These participants were previously randomly assigned to one of four exercise groups (Hill, Running, Cycling, Combined) or a non-exercising Control group, and completed their respective 16-week protocols. Body composition, bone mineral content (BMC), bone mineral density (BMD), and serum follistatin levels were all assessed pre- and post-intervention. Dual-energy X-ray absorptiometry (DXA) was utilized for the body composition, BMC, and BMD measurements. FST SNPs (rs3797296, rs3797297) were genotyped using matrix assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) or microarrays. To elucidate the biological mechanisms, we performed in silico functional analyses for rs3797296 and rs3797297. Results: Baseline: In females only, the rs3797297 T allele was associated with higher muscle mass (β = 1.159, 95% confidence interval (CI): 0.202–2.116, P_adj = 0.034) and BMC (β = 0.127, 95% CI: 0.039–0.215, P_adj = 0.009), with the BMC effect significantly mediated by muscle mass. Exercise Response: Interventions improved body composition, particularly in females. Gene-Exercise Interaction: A significant interaction occurred exclusively in women undertaking hill climbing: the rs3797296 G allele was associated with attenuated muscle mass gains (β = −1.126 kg, 95% CI: −1.767 to −0.485, P_adj = 0.034). Baseline follistatin correlated with body composition (stronger in males) and increased post-exercise (primarily in males, Hill/Running groups) but did not mediate SNP effects on exercise adaptation. Functional annotation revealed that rs3797297 is a likely causal variant, acting as a skeletal muscle eQTL for the mitochondrial gene NDUFS4, suggesting a mechanism involving muscle bioenergetics. Conclusions: Findings indicate that FST polymorphisms associate with musculoskeletal traits in Northern Han Chinese. Mechanistic insights from functional annotation reveal potential pathways for these associations, highlighting the potential utility of these genetic markers for optimizing training program design.
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(This article belongs to the Section Human Genomics and Genetic Diseases)
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Open AccessReview
Harnessing Multi-Omics and Predictive Modeling for Climate-Resilient Crop Breeding: From Genomes to Fields
by
Adnan Amin, Wajid Zaman and SeonJoo Park
Genes 2025, 16(7), 809; https://doi.org/10.3390/genes16070809 - 10 Jul 2025
Abstract
The escalating impacts of climate change pose significant threats to global agriculture, necessitating a rapid development of climate-resilient crop varieties. The integration of multi-omics technologies—such as genomics, transcriptomics, proteomics, metabolomics, and phenomics—has revolutionized our understanding of the intricate molecular networks that govern plant
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The escalating impacts of climate change pose significant threats to global agriculture, necessitating a rapid development of climate-resilient crop varieties. The integration of multi-omics technologies—such as genomics, transcriptomics, proteomics, metabolomics, and phenomics—has revolutionized our understanding of the intricate molecular networks that govern plant stress responses. Coupled with advanced predictive modeling approaches such as machine learning, deep learning, and multi-omics-assisted genomic selection, these integrated frameworks enable accurate genotype-to-phenotype predictions that accelerate breeding for augmented stress tolerance. This review comprehensively synthesizes the current strategies for multi-omics data integration, highlighting computational tools, conceptual frameworks, and challenges in harmonizing heterogeneous datasets. We examine the contribution of digital phenotyping platforms and environmental data in dissecting genotype-by-environment interactions critical for climate adaptation resilience. Further, we discuss technical, biological, and ethical challenges, encompassing computational bottlenecks, trait complexity, data standardization, and equitable data sharing. Finally, we outline future directions that prioritize scalable infrastructures, interpretability, and collaborative platforms to facilitate the deployment of multi-omics-guided breeding in diverse agroecological contexts. This integrative approach possesses transformative potential for the development of resilient crops, ensuring agricultural sustainability amidst increasing environmental volatility.
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(This article belongs to the Section Genes & Environments)
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Open AccessArticle
The Distribution and Survival Association of Genetic Polymorphisms in Thai Patients with Hepatocellular Carcinoma According to Underlying Liver Disease
by
Theint Cho Zin Aung, Bootsakorn Boonkaew, Maneerat Chayanupatkul, Kittiyod Poovorawan, Natthaya Chuaypen and Pisit Tangkijvanich
Genes 2025, 16(7), 808; https://doi.org/10.3390/genes16070808 - 9 Jul 2025
Abstract
Background/Objectives: The influence of single-nucleotide polymorphisms (SNPs) on hepatocellular carcinoma (HCC) in terms of etiological factors remains to be explored. This study evaluated the distribution of PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314 and overall survival of HCC patients with metabolic dysfunction-associated steatotic
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Background/Objectives: The influence of single-nucleotide polymorphisms (SNPs) on hepatocellular carcinoma (HCC) in terms of etiological factors remains to be explored. This study evaluated the distribution of PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314 and overall survival of HCC patients with metabolic dysfunction-associated steatotic liver disease (MASLD-HCC) and viral-related HCC (VIRAL-HCC). Methods: This study included 564 patients with HCC: 254 with MASLD-HCC and 310 with VIRAL-HCC. The SNPs were determined by real-time PCR using TaqMan assays. Results: The mean ages of patients with MASLD-HCC and VIRAL-HCC were 68.4 vs. 60.9 years (p < 0.001), with a significant difference between groups. The prevalence of PNPLA3 GG genotype in MASLD-HCC was significantly higher in MASLD-HCC than in VIRAL-HCC (24.0% vs. 15.5%, OR = 1.86, 95% CI = 1.14–3.05, p = 0.009). Similarly, the prevalence of TM6SF2 TT genotype in MASLD-HCC and VIRAL-HCC was 7.1% vs. 2.6% (OR = 3.39, 95% CI = 1.36–9.21, p = 0.003), while HSD17B13 GG genotype in the corresponding groups was 7.1% vs. 12.6% (OR = 0.53, 95% CI = 0.27–1.01, p = 0.039). The overall median survival of MASLD-HCC was significantly shorter than that of the VIRAL-HCC group (42 vs. 66 months, p = 0.035). In Cox regression hazard analysis, HSD17B13 GG genotype was significantly associated with a lower mortality rate in MASLD-HCC (HR = 0.38, 95% CI = 0.18–0.81, p = 0.011). In contrast, PNPLA3 and TM6SF2 were not associated with overall survival in patients with MASLD-HCC or VIRAL-HCC. Conclusions: Our data demonstrated that the prevalence of the SNPs significantly differed between MASLD-HCC and VIRAL-HCC. The HSD176B13 GG genotype was also associated with a survival benefit in Thai patients with MASLD-HCC. Thus, assessing the HSD176B13 genotype might be beneficial in risk stratification and potential therapeutic inhibition of HSD17B13 among patients with MASLD-HCC.
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(This article belongs to the Section Molecular Genetics and Genomics)
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Open AccessArticle
Gene-Based Burden Testing of Rare Variants in Hemiplegic Migraine: A Computational Approach to Uncover the Genetic Architecture of a Rare Brain Disorder
by
Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rodney A. Lea and Lyn R. Griffiths
Genes 2025, 16(7), 807; https://doi.org/10.3390/genes16070807 - 9 Jul 2025
Abstract
Background: HM is a rare, severe form of migraine with aura, characterised by motor weakness and strongly influenced by genetic factors affecting the brain. While pathogenic variants in CACNA1A, ATP1A2, and SCN1A genes have been implicated in familial HM, approximately 75%
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Background: HM is a rare, severe form of migraine with aura, characterised by motor weakness and strongly influenced by genetic factors affecting the brain. While pathogenic variants in CACNA1A, ATP1A2, and SCN1A genes have been implicated in familial HM, approximately 75% of cases lack known pathogenic variants in these genes, suggesting a more complex genetic basis. Methods: To advance our understanding of HM, we applied a variant prioritisation approach using whole-exome sequencing (WES) data from patients referred for HM diagnosis (n = 184) and utilised PathVar, a bioinformatics pipeline designed to identify pathogenic variants. Our analysis incorporated two strategies for association testing: (1) PathVar-identified single nucleotide variants (SNVs) and (2) PathVar SNVs combined with missense and rare variants. Principal component analysis (PCA) was performed to adjust for ancestral and other unknown differences between cases and controls. Results: Our results reveal a sequential reduction in the number of genes significantly associated with HM, from 20 in the first strategy to 11 in the second, which highlights the unique contribution of PathVar SNVs to the genetic architecture of HM. PathVar SNVs were more distinctive in the case cohort, suggesting a closer link to the functional changes underlying HM compared to controls. Notably, novel genes, such as SLC38A10, GCOM1, and NXPH2, which were previously not implicated in HM, are now associated with the disorder, advancing our understanding of its genetic basis. Conclusions: By prioritising PathVar SNVs, we identified a broader set of genes potentially contributing to HM. Given that HM is a rare condition, our findings, utilising a sample size of 184, represent a unique contribution to the field. This iterative analysis demonstrates that integrating diverse variant schemes provides a more comprehensive view of the genetic factors driving HM.
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(This article belongs to the Special Issue AI and Neurogenomics: Innovations in Precision Medicine for Brain Disorders)
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Open AccessArticle
Compositional and Functional Disparities in the Breast Oncobiome Between Patients Living in Urban or Rural Areas
by
Fazia Ait Zenati, Simone Baldi, Leandro Di Gloria, Ferhat Djoudi, Sara Bertorello, Matteo Ramazzotti, Elena Niccolai and Amedeo Amedei
Genes 2025, 16(7), 806; https://doi.org/10.3390/genes16070806 - 9 Jul 2025
Abstract
Background/Objectives: Breast cancer (BC) is the leading cause of cancer incidence and mortality among women and the recent identification of a resident mammary microbiota has highlighted its potential role in breast carcinogenesis. Given that environmental and socioeconomic factors influence both BC prevalence
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Background/Objectives: Breast cancer (BC) is the leading cause of cancer incidence and mortality among women and the recent identification of a resident mammary microbiota has highlighted its potential role in breast carcinogenesis. Given that environmental and socioeconomic factors influence both BC prevalence and tumor-associated bacterial composition, this study aimed to evaluate the compositional and functional features of the mammary microbiota in cancerous (oncobiome) and adjacent healthy BC tissues from patients living in urban and rural areas. Methods: Microbiota composition in both the oncobiome and adjacent healthy BC tissues was analyzed using 16S rRNA sequencing. Results: Significant variations in breast oncobiome composition were observed among BC patients from urban and rural areas. A statistically significant β dispersion among breast oncobiome of patients from urban or rural areas was highlighted. Specifically, the genera Selenomonas, Centipeda, Leptotrichia, Neisseria and Porphyromonas were found exclusively in BC tissues of patients from rural areas. Additionally, bacteria from the Neisseriaceae, Porphyromonadaceae, and Selenomonadaceae families, as well as the Selenomonas genus, were significantly enriched in the oncobiome of rural BC patients. Furthermore, the results of the PICRUSt2 (phylogenetic investigation of communities by reconstruction of unobserved states) revealed a significant increase in phospholipid biosynthesis pathways in breast oncobiome of patients from rural areas compared to those from urban areas. Conclusions: This study provides evidence of distinct compositional and functional differences in the breast oncobiome between BC patients from rural and urban areas. These findings suggest that environmental factors influence local microbiome composition, potentially contributing to BC development and/or progression.
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(This article belongs to the Special Issue Feature Papers in Microbial Genetics and Genomics)
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Open AccessArticle
The Problem of the Presence of DNA in Cosmetic and Medicinal Products Obtained from Animals on the CITES List
by
Aleksandra Figura, Magdalena Gryzinska and Andrzej Jakubczak
Genes 2025, 16(7), 805; https://doi.org/10.3390/genes16070805 - 8 Jul 2025
Abstract
Background: The illegal trade in wildlife remains a critical threat to biodiversity, prompting the development of international regulatory frameworks such as the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). One of the key challenges in enforcement is
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Background: The illegal trade in wildlife remains a critical threat to biodiversity, prompting the development of international regulatory frameworks such as the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). One of the key challenges in enforcement is the detection of CITES-listed species in highly processed consumer goods. Methods: This study investigates the use of molecular techniques to detect animal DNA in two selected commercially available medicinal products—a balm and a gel—marketed with ingredients suggestive of protected species such as the brown bear (Ursus arctos) and the medicinal leech (Hirudo medicinalis). Results: Although DNA from these target species was not detected, the analysis revealed the presence of genetic material from the American mink (Neovison vison) and domestic pig (Sus scrofa), indicating the undeclared use of animal-derived substances. While limited in scope, these findings suggest potential ethical and transparency concerns, particularly for consumers adhering to vegetarian, vegan, or religious dietary practices. Conclusions: The study illustrates the feasibility of applying DNA-based screening methods in complex, degraded matrices and their potential as supportive tools in consumer product assessment. However, broader studies are necessary before drawing general regulatory or conservation conclusions.
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(This article belongs to the Section Molecular Genetics and Genomics)
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Open AccessArticle
Aquaporin mRNA in Human Saliva
by
Katharina Rump, Daria Pakosch-Nowak, Andrea Witowski, Bjoern Koos, Dominik Ziehe, Jennifer Orlowski, Michael Adamzik, Martin Kunkel and Markus Baumann
Genes 2025, 16(7), 804; https://doi.org/10.3390/genes16070804 - 8 Jul 2025
Abstract
Background: Aquaporins (AQPs) are integral membrane proteins that facilitate water transport across biological membranes. While their role is well-characterized in various tissues, their function in the oral cavity remains poorly understood. Saliva is an easily accessible, non-invasive biofluid that contains stable extracellular RNA
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Background: Aquaporins (AQPs) are integral membrane proteins that facilitate water transport across biological membranes. While their role is well-characterized in various tissues, their function in the oral cavity remains poorly understood. Saliva is an easily accessible, non-invasive biofluid that contains stable extracellular RNA and can reflect both systemic and local physiological or pathological processes, making it a promising source for RNA analyses. This study investigates AQP mRNA levels in human saliva. Methods: Saliva samples were collected from patients of a dental practice and analyzed using quantitative PCR to detect AQP levels. An in silico analysis of AQPs in cells of the oral cavity were performed. Baseline data of the patients were recorded. Results: Our findings demonstrate the presence of multiple AQP subtypes in human saliva. AQP5 was the most abundant, followed by AQP9 and AQP1. The levels of several AQPs showed intercorrelation, whereas AQP3 appeared to be independently regulated and did not correlate with the other AQPs. Conclusions: This study demonstrates that differential AQP mRNA levels can be detected in human saliva. These findings suggest that salivary AQP mRNA may serve as surrogate markers for altered AQP levels in cells of the oral cavity. In the future, such patterns of AQP levels could potentially be used to identify or monitor pathological conditions affecting the oral mucosa or salivary glands. Further studies are required to validate this approach and to understand its diagnostic relevance.
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(This article belongs to the Section Molecular Genetics and Genomics)
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Transcriptome Profiling Reveals Differences Between Rainbow Trout Eggs with High and Low Potential for Gynogenesis
by
Konrad Ocalewicz, Artur Gurgul, Stefan Dobosz, Igor Jasielczuk, Tomasz Szmatoła, Ewelina Semik-Gurgul, Mirosław Kucharski and Rafał Rożyński
Genes 2025, 16(7), 803; https://doi.org/10.3390/genes16070803 - 8 Jul 2025
Abstract
Background/Objectives: Fish eggs activated with UV-irradiated spermatozoa and exposed to the High Hydrostatic Pressure (HHP) shock to inhibit first cell cleavage develop as gynogenetic Doubled Haploids (DHs) that are fully homozygous individuals. Due to the expression of the recessive genes and side effects
[...] Read more.
Background/Objectives: Fish eggs activated with UV-irradiated spermatozoa and exposed to the High Hydrostatic Pressure (HHP) shock to inhibit first cell cleavage develop as gynogenetic Doubled Haploids (DHs) that are fully homozygous individuals. Due to the expression of the recessive genes and side effects of the gamete treatment, survival of fish DHs is rather low, and most of the mitotic gynogenotes die before hatching. Nevertheless, as maternal gene products provided during oogenesis control the initial steps of embryonic development in fish, a maternal effect on the survival of gynogenotes needs to be also considered to affect efficiency of gynogenesis. Thus, the objective of this research was to apply an RNA-seq approach to discriminate transcriptional differences between rainbow trout (Oncorhynchus mykiss) eggs with varied abilities to develop after gynogenetic activation. Methods: Gynogenetic development of rainbow trout was induced in eggs originated from eight females. Maternal RNA was isolated and sequenced using RNA-Seq approach. Survival rates of gynogenotes and transcriptome profiles of eggs from different females were compared. Results: RNA-seq analysis revealed substantial transcriptional differences between eggs originated from different females, and a significant correlation between the ability of the eggs for gynogenesis and their transcriptomic profiles was observed. Genes whose expression was altered in eggs with the increased survival of DHs were mostly associated (GO BP) with the following biological processes: development, cell differentiation, cell migration and protein transport. Some of the genes are involved in the oocyte maturation (RASL11b), apoptosis (CASPASE 6, PGAM5) and early embryogenesis, including maternal to zygotic transition (GATA2). Conclusions: Inter-individual variation of the transcription of maternal genes correlated with the competence of eggs for gynogenesis suggest that at least part of the mortality of the rainbow trout DHs appear before activation of zygotic genome and expression of the lethal recessive traits.
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(This article belongs to the Special Issue Molecular Genetics Applied to Aquaculture: From Breeding Stock Selection to Biotechnological Innovations)
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A Study on the Diagnostic and Prognostic Value of Extrachromosomal Circular DNA in Breast Cancer
by
Fuyu Li, Wenxiang Lu, Lingsong Yao and Yunfei Bai
Genes 2025, 16(7), 802; https://doi.org/10.3390/genes16070802 - 6 Jul 2025
Abstract
Objectives: To investigate the clinical diagnostic and prognostic value of extrachromosomal circular DNA (eccDNA) in breast cancer, eccDNA profiles were constructed for 81 breast cancer tumor tissues and 33 adjacent non-tumor tissues. Methods: The distribution characteristics of eccDNA across functional genomic elements and
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Objectives: To investigate the clinical diagnostic and prognostic value of extrachromosomal circular DNA (eccDNA) in breast cancer, eccDNA profiles were constructed for 81 breast cancer tumor tissues and 33 adjacent non-tumor tissues. Methods: The distribution characteristics of eccDNA across functional genomic elements and repetitive sequences were systematically analyzed. Furthermore, a diagnostic model for differentiating malignant and normal breast tissues, as well as a prognostic prediction model, was developed using a random forest algorithm. Results: EccDNA in breast cancer tissues harbor a higher proportion of functional elements and repetitive sequences, with their annotated genes significantly enriched in tumor- and immune-related pathways. However, no significant differences in eccDNA features were observed across breast cancer subtypes or pathological stages. In the validation cohort, the eccDNA-based diagnostic model achieved an AUC of 0.83, with repetitive elements and enhancer-associated features contributing the most to diagnostic performance. The prognostic model achieved an AUC of 0.78, with repetitive element annotations also showing strong prognostic relevance. Conclusions: These findings highlight the promising potential of eccDNA in the development of precision diagnostics and prognostic systems for breast cancer.
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(This article belongs to the Section Molecular Genetics and Genomics)
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Open AccessReview
Exploring the Role of Genetic and Genomic Factors in Therapeutic Response to Heart Failure: A Comprehensive Analytical Review
by
Aurora Ferro, Andrea Segreti, Simone Pasquale Crispino, Riccardo Cricco, Anna Di Cristo, Martina Ciancio, Fiorella Gurrieri, Gian Paolo Ussia and Francesco Grigioni
Genes 2025, 16(7), 801; https://doi.org/10.3390/genes16070801 - 4 Jul 2025
Abstract
Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Despite significant advances in pharmacological therapies, responses to treatment vary widely among patients. Growing evidence suggests that genetic factors play a crucial role in influencing individual responses to HF therapies. Genetic
[...] Read more.
Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. Despite significant advances in pharmacological therapies, responses to treatment vary widely among patients. Growing evidence suggests that genetic factors play a crucial role in influencing individual responses to HF therapies. Genetic variations, including single-nucleotide polymorphisms (SNPs), gene expression profiles, and epigenetic modifications, have been shown to affect drug metabolism, receptor sensitivity, and the molecular pathways involved in HF progression. These genetic determinants may not only predict the efficacy of common therapeutic agents such as angiotensin-converting enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors, but also help identify patients at risk of adverse drug reactions. As personalized medicine continues to advance, a deeper understanding of the genetic basis of drug response in HF could enable more tailored treatment strategies, improving clinical outcomes and minimizing adverse effects. This review explores the current evidence on the genetic underpinnings of response to HF treatment and discusses its potential implications in clinical practice, highlighting current knowledge gaps.
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(This article belongs to the Section Human Genomics and Genetic Diseases)
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