Genes

10 pages, 509 KB

Open AccessArticle

Transcriptional Regulation of CYP2E1: Promoter Methylation in In Vitro Models and Human Liver Disease Samples

by Nina Komaniecka, Mateusz Kurzawski, Sylwia Szeląg-Pieniek, Joanna Łapczuk-Romańska, Mariola Post, Urszula Adamiak-Giera and Marek Droździk

Genes 2025, 16(8), 990; https://doi.org/10.3390/genes16080990 - 21 Aug 2025

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Abstract

Background/Objectives: DNA methylation is a critical epigenetic mechanism involved in gene expression regulation. This study examines promoter methylation of CYP2E1 in healthy liver, intestinal mucosa, as well as pathological liver samples, alongside in in vitro cell models. Methods: First, in tissue samples from [...] Read more.

Background/Objectives: DNA methylation is a critical epigenetic mechanism involved in gene expression regulation. This study examines promoter methylation of CYP2E1 in healthy liver, intestinal mucosa, as well as pathological liver samples, alongside in in vitro cell models. Methods: First, in tissue samples from the liver, duodenum, jejunum, and colon of healthy organ donors, CYP2E1 promoter methylation was quantified using the EpiTect Methyl II PCR System, while gene expression was determined by quantitative real-time PCR. Then, in vitro experiments were performed using HepG2 and Caco-2 cell lines. Cells were treated with 5-Aza-2′-deoxycytidine to induce demethylation, with subsequent analysis of CYP2E1 mRNA levels. Subsequently, promoter methylation was assessed via pyrosequencing, while gene expression was quantified using quantitative real-time PCR. Results: The analysis revealed statistically significant differences in the methylation patterns of the CYP2E1 promoter between healthy liver and gastrointestinal tissues. In cell lines, treatment with 5-Aza-2′-deoxycytidine resulted in increased CYP2E1 mRNA levels and demonstrated a strong negative correlation between promoter methylation and gene expression. However, in liver disease samples, differential methylation did not consistently translate into decreased CYP2E1 expression. Conclusions: Although in vitro experiments support a regulatory role of promoter methylation in controlling CYP2E1 expression, the clinical data indicate that additional factors may contribute to gene regulation in liver pathology. Full article

(This article belongs to the Section Epigenomics)

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10 pages, 501 KB

Open AccessCase Report

A Novel Pathogenic Variant of the AVPR2 Gene Leading to Arginine Vasopressin Resistance Since the Neonatal Period

by Agnieszka Szmigielska, Piotr Skrzypczyk, Dorota Czapczak, Marta Dux, Adam Lipka, Beata Pyrżak and Anna Małgorzata Kucharska

Genes 2025, 16(8), 989; https://doi.org/10.3390/genes16080989 - 21 Aug 2025

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Abstract

Background: Diabetes insipidus (DI) in newborns is an extremely rare condition, with the age of presentation strongly suggesting a genetic background of the disease. The differential diagnosis should include arginine vasopressin deficiency (AVD) and arginine vasopressin resistance (AVR). Some novel diagnostic tools [...] Read more.

Background: Diabetes insipidus (DI) in newborns is an extremely rare condition, with the age of presentation strongly suggesting a genetic background of the disease. The differential diagnosis should include arginine vasopressin deficiency (AVD) and arginine vasopressin resistance (AVR). Some novel diagnostic tools such as copeptin evaluation and genetic tests are vital for early diagnosis. Case report: We present the case of a 1-month-old boy with polyuria observed since birth. Laboratory tests showed persistent hypernatremia, elevated plasma and low urine osmolality. An attempt at oral administration of desmopressin had no effect; additionally the copeptin level was increased. A genetic study (NGS of the AVP, AVPR2 and AQP2 genes) was considered and a new pathogenic variant in the AVPR2 gene (hemizygous c.157del) was detected. After the genetic test result was obtained, treatment with hydrochlorothiazide was started. The patient is now 3 months old, developing normally, and the weight and height are normal. Conclusions: Newborns with DI should be subjected to extensive multidisciplinary diagnostics, including endocrine and renal causes. Copeptin evaluation and prompt genetic diagnosis allows for the early diagnosis and implementation of appropriate treatment. Full article

(This article belongs to the Special Issue Genetics and Genomics of Endocrine Diseases in Children and Adolescents)

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12 pages, 2155 KB

Open AccessArticle

Abnormal ERV Expression and Its Clinical Relevance in Colon Cancer

by Aditya Bhagwate, William Taylor, John Kisiel and Zhifu Sun

Genes 2025, 16(8), 988; https://doi.org/10.3390/genes16080988 - 21 Aug 2025

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Abstract

Background/Objectives: Human endogenous retroviruses (ERVs) are genomic sequences integrated into the human genome from ancestral exogenous retroviruses and are epigenetically silenced under normal conditions. Growing evidence has shown that they can be reactivated in human diseases such as cancers and autoimmune diseases. However, [...] Read more.

Background/Objectives: Human endogenous retroviruses (ERVs) are genomic sequences integrated into the human genome from ancestral exogenous retroviruses and are epigenetically silenced under normal conditions. Growing evidence has shown that they can be reactivated in human diseases such as cancers and autoimmune diseases. However, their clinical implications in colon cancer are yet to be explored. Methods: RNA-seq data were downloaded from RNA Atlas and TCGA for cell lines and tissue samples, respectively. After alignment, ERV expression was quantified against comprehensively compiled ERVs (3220). ERV expression profiles were compared between sequencing protocols, cancer and normal cells, and matched tumor and normal tissue pairs. Unsupervised clustering was used to identify ERV-defined tumor subtypes and their associations with clinical and other molecular features. ERV association with disease-specific survival (DSS) was performed using the Cox regression model. Results: PolyA and total RNA protocols were comparable in ERV expression detection. Cancer cells had significantly increased ERV expression and reactivation. Upregulated ERVs were significantly enriched in viral protein interactions with cytokine and cytokine receptors. ERV expression-defined tumor classes were significantly associated with tumor mutation burden and immuno-phenotypes such as antigen processing and presenting machinery and tumor immune infiltration score. Survival analysis identified 152 ERVs to be independently associated with DSS. Conclusions: ERV abnormal expression is common in colon cancer. The ERV-defined subtypes are associated with tumor immunity, and some ERVs are independently associated with patient outcomes. Full article

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

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14 pages, 1495 KB

Open AccessArticle

Genetic and Clinical Spectrum of Limb–Girdle Muscular Dystrophies in Western Sicily

by Nicasio Rini, Antonino Lupica, Paolo Alonge, Grazia Crescimanno, Antonia Pignolo, Christian Messina, Sandro Santa Paola, Marika Giuliano, Eugenia Borgione, Mariangela Lo Giudice, Carmela Scuderi, Vincenzo Di Stefano and Filippo Brighina

Genes 2025, 16(8), 987; https://doi.org/10.3390/genes16080987 - 21 Aug 2025

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Abstract

Background and Objectives: Limb–girdle muscular dystrophies (LGMDs) are a group of muscular dystrophies characterized by predominantly proximal-muscle weakness, with a highly heterogeneous genetic etiology. Despite recent efforts, the epidemiology of LGMDs is still under-evaluated. However, a better understanding of the distribution and genetic [...] Read more.

Background and Objectives: Limb–girdle muscular dystrophies (LGMDs) are a group of muscular dystrophies characterized by predominantly proximal-muscle weakness, with a highly heterogeneous genetic etiology. Despite recent efforts, the epidemiology of LGMDs is still under-evaluated. However, a better understanding of the distribution and genetic characteristics of LGMDs is required to optimize the diagnostic process and to address future research. Therefore, the aim of the present study is to investigate and identify new pathogenic variants, to better characterize LGMDs in Sicily. Methods: We enrolled patients with genetic and clinical diagnosis of LGMD referred to our clinic between the years 2019 and 2025. A targeted next-generation-sequencing (NGS) panel was performed, based on the reported disease frequency. A retrospective analysis of the clinical, laboratory, electrophysiological, and histological features was performed. Results: A total of 28 LGMDs patients aged 56.6 years (47.2–60.5 IQR) were identified (16 males, 57%). A molecular diagnosis was achieved in 24 (85.7%) of patients, most commonly carrying mutations in CAPN3 (14 patients, 50%), followed by DYSF, LAMA2, ANO5, FKTN and TTN genes. Pathogenic variants in CAPN3 and LAMA2 were associated with earlier onset and longer disease duration, whereas ANO5 presented later with a milder course. Cardiac involvement was observed more frequently in patients with LAMA2 and FKTN mutations. Association between heterozygous mutations in the CAPN3 and DYSF, as well as between CAPN3 and DMD variants were reported. Discussion: The findings of this study provide valuable insights into the epidemiology of LGMDs in the Western Sicily, offering important contributions to genotype–phenotype correlations. Our analysis highlights the role of genetic diagnosis in achieving accurate classification of the disease and optimizing clinical management. Full article

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

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24 pages, 1394 KB

Open AccessReview

Intron Retention: A Reemerging Paradigm in RNA Biology and Post-Transcriptional Gene Regulation

by Ana L. Porras-Tobias, Abigail Caldera and Isabel Castro-Piedras

Genes 2025, 16(8), 986; https://doi.org/10.3390/genes16080986 - 21 Aug 2025

Viewed by 609

Abstract

For 40 years, Intron Retention (IR) was dismissed as splicing noise and is now recognized as a dynamic and evolutionarily conserved mechanism of post-transcriptional gene regulation. Unlike canonical splicing, which excises all introns from pre-mRNAs, IR selectively retains intronic sequences, albeit at seemingly [...] Read more.

For 40 years, Intron Retention (IR) was dismissed as splicing noise and is now recognized as a dynamic and evolutionarily conserved mechanism of post-transcriptional gene regulation. Unlike canonical splicing, which excises all introns from pre-mRNAs, IR selectively retains intronic sequences, albeit at seemingly random places; however, current research now reveals that this process is strategic in its retention. IR influences mRNA stability, localization, and translational potential. Retained introns can lead to nonsense-mediated decay, promote nuclear retention, or give rise to novel protein isoforms that contribute to expanding proteomic and transcriptomic profiles. IR is finely regulated by splice site strength, splicing regulatory elements, chromatin structure, methylation patterns, RNA polymerase II elongation rates, and the availability of co-transcriptional splicing factors. IR plays critical roles in cell-type and tissue-specific gene expression with observed patterns, particularly during neuronal, cardiac, hematopoietic, and immune development. It also functions as a molecular switch during cellular responses to environmental and physiological stressors such as hypoxia, heat shock, and infection. Dysregulated IR is increasingly associated with cancer, neurodegeneration, aging, and immune dysfunction, where it may alter protein function, suppress tumor suppressor genes, or generate immunogenic neoepitopes. Experimental and computational tools like RNA-seq, RT-PCR, IRFinder, and IntEREst have enabled transcriptome-wide detection and validation of IR events, uncovering their widespread functional roles. This review will examine current knowledge on the function, regulation, and detection of IR, and also summarize recent advances in understanding its role in both normal and pathophysiological settings. Full article

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

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14 pages, 8079 KB

Open AccessArticle

Epilepsy Associated Gene, Pcdh7, Is Dispensable for Brain Development in Mice

by Jennifer Rakotomamonjy, Devin Davies, Xavier Valencia, Olivia Son, Ximena Gomez-Maqueo and Alicia Guemez-Gamboa

Genes 2025, 16(8), 985; https://doi.org/10.3390/genes16080985 - 21 Aug 2025

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Abstract

Background/Objectives: Protocadherin 7 (Pcdh7) belongs to the protocadherin family, the largest subgroup of cell adhesion molecules. Members of this family are highly expressed in the brain, where they serve fundamental roles in many neurodevelopmental processes, including axon guidance, dendrite self-avoidance, [...] Read more.

Background/Objectives: Protocadherin 7 (Pcdh7) belongs to the protocadherin family, the largest subgroup of cell adhesion molecules. Members of this family are highly expressed in the brain, where they serve fundamental roles in many neurodevelopmental processes, including axon guidance, dendrite self-avoidance, and synaptic formation. PCDH7 has been strongly associated with epilepsy in multiple genome-wide association studies (GWAS), as well as with schizophrenia, PTSD, and childhood aggression. Despite these associations, the specific contributions of PCDH7 to epileptogenesis and brain development remain largely unexplored. Most of the existing literature on PCDH7 focuses on its function during cancer progression, with only one study suggesting that PCDH7 regulates dendritic spine morphology and synaptic function via interaction with GluN1. Methods: Here, we generate, validate, and characterize a murine null Pcdh7 allele in which a large deletion was introduced by CRISPR. Results: Analysis of embryonic, postnatal, and adult brain datasets confirmed PCDH7 widespread expression. Pcdh7^+/− and Pcdh7^−/− mice present no gross morphological defects and normal cortical layer formation. However, a seizure susceptibility assay revealed increased latencies in Pcdh7^+/− mice, but not in Pcdh7^+/+ and Pcdh7^−/− mice, potentially explaining the association of PCDH7 with epilepsy. Conclusions: This initial characterization of Pcdh7 null mice suggests that, despite its widespread expression in the CNS and involvement in human epilepsy, PCDH7 is not essential for murine brain development and thus is not a suitable animal model for understanding PCDH7 disruption in humans. However, further detailed analysis of this mouse model may reveal circuit or synaptic abnormalities in Pcdh7 null brains. Full article

(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)

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23 pages, 3996 KB

Open AccessArticle

Unveiling Conserved Molecular Pathways of Intramuscular Fat Deposition and Shared Metabolic Processes in Semitendinosus Muscle of Hereford, Holstein, and Limousine Cattle via RNA-Seq Analysis

by Saideh Eskandri Nasab, Gholam Reza Dashab, Mohammad Rokouei, Zahra Roudbari and Tomasz Sadkowski

Genes 2025, 16(8), 984; https://doi.org/10.3390/genes16080984 - 21 Aug 2025

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Abstract

Background: Intramuscular fat (IMF) enhances marbling, improving meat quality and value. Transcriptome analysis enables the identification of genes and pathways involved in IMF deposition, supporting targeted breeding and nutritional strategies to improve beef quality. Methods: This study used RNA-Seq to compare gene expression [...] Read more.

Background: Intramuscular fat (IMF) enhances marbling, improving meat quality and value. Transcriptome analysis enables the identification of genes and pathways involved in IMF deposition, supporting targeted breeding and nutritional strategies to improve beef quality. Methods: This study used RNA-Seq to compare gene expression in high- (Hereford; Her), moderate- (Holstein Friesian; Hf), and low-marbling (Limousine; Lim) Semitendinosus muscle. Using Illumina’s NovaSeqX Plus, sequencing data underwent quality control with FastQC to remove low-quality reads and adapters, followed by alignment to the bovine genome using HISAT2. Differential expression analysis was performed using DESeq2, and genes were filtered based on a threshold of p-value < 0.05 and |log2FC| > 0.5 to identify significantly regulated genes. Results: A total of 21,881 expressed genes were detected, with 3025 and 7407 significantly differentially expressed in Her and Hf vs. Lim, respectively (|log2FC| > 0.5, p < 0.05). Protein–protein interaction analysis revealed 20 hub genes, including SMAD3, SCD, PLIN2, SHH, SQLE, RXRA, NPPA, NR1H4, PRKCA, and IL10. Gene ontology and KEGG pathway analyses linked these genes to lipid metabolism and IMF-associated pathways, such as PPAR signaling, fatty acid metabolism, and PI3K–Akt signaling. Conclusions: These findings highlight RNA-Seq’s utility in uncovering the genetic basis of marbling and the importance of aligning beef production with consumer demands through genetic improvements. This study aimed to identify breed-independent molecular mechanisms of intramuscular fat deposition and shared metabolic processes in the Semitendinosus muscle to improve beef quality. Full article

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

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28 pages, 3288 KB

Open AccessArticle

Replication of the GWAS-Identified GALNT13 rs10196189 Polymorphism in Relation to Speed–Power Elite Active Athlete Status and Multidimensional Phenotypic Differences in Chinese Han Males: A Pilot Study

by Lun Chen, Mingrui Wang, Longtianjiao Liu, Xiaoyu Jiang, Zihang Cao, Samuhaer Azhati, Hangyu Chen, Kaixin She, Jinyao Zhu, Ming Chen, Jinda Li, Junhao Kong, Jiahao Zhang, Yuang Yan, Yi Dong, Apudumalike Mieryazi, Songyu Liu, Yanyan Zhang, Yixuan Ma and Lijun Shi

Genes 2025, 16(8), 983; https://doi.org/10.3390/genes16080983 - 20 Aug 2025

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Abstract

Background/Objectives: Previous multi-ethnic genome-wide association studies (GWAS) have identified the GALNT13 rs10196189 polymorphism as a potential genetic marker linked to sprint–power performance. However, its relevance in East Asian populations, particularly the Han Chinese, remains untested. This study aimed to replicate the association [...] Read more.

Background/Objectives: Previous multi-ethnic genome-wide association studies (GWAS) have identified the GALNT13 rs10196189 polymorphism as a potential genetic marker linked to sprint–power performance. However, its relevance in East Asian populations, particularly the Han Chinese, remains untested. This study aimed to replicate the association of rs10196189 with elite sprint–power athlete status in Han Chinese males and examine its potential influence on physical performance traits and tissue-specific gene regulation. Methods: A total of 188 healthy Han Chinese males (49 elite sprint–power athletes and 139 non-athletic controls) were genotyped using the TaqMan assay. Assessments included strength, sprint, jump, anaerobic power, DXA-derived body composition, and muscle ultrasound. Logistic regression and ROC analyses evaluated the predictive value of rs10196189. Linear regression models adjusted for age and BMI tested genotype–phenotype associations. Tissue expression and functional networks were analyzed using GTEx and HumanBase databases. Results: The G allele frequency was significantly higher in athletes (12.2%) than in controls (5.4%, p = 0.042). Dominant and additive models effectively predicted athlete status (OR = 2.53–2.58, p < 0.05). Although most traits showed no significant associations post-correction, medial gastrocnemius thickness showed a nominal association (β = 0.371, p = 0.011). Functional analyses revealed high GALNT13 expression in brain tissue and co-expression networks enriched in synaptic signaling and glycosylation pathways. Conclusions: This is the first study to validate the association of GALNT13 rs10196189 with elite athletic status in Han Chinese males. Findings provide novel population-specific evidence and propose tissue-specific glycosylation and neural mechanisms as pathways linking this variant to sprint–power phenotypes. Full article

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

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13 pages, 2959 KB

Open AccessArticle

A Pathogenic L2HGDH Variant Impairs Mitochondrial Targeting and Enzyme Function in L-2-Hydroxyglutaric Aciduria: Clinical and Functional Evidence from Two Affected Siblings

by Qiang Guo, Thilo Löhr, Patrick Giavalisco, Vera Riehmer and Hans Zempel

Genes 2025, 16(8), 982; https://doi.org/10.3390/genes16080982 - 20 Aug 2025

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Abstract

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder caused by biallelic loss-of-function variants in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene, leading to accumulation of L-2-hydroxyglutarate in the brain and other tissues. While various variants have been reported, the pathogenic [...] Read more.

Background: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder caused by biallelic loss-of-function variants in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene, leading to accumulation of L-2-hydroxyglutarate in the brain and other tissues. While various variants have been reported, the pathogenic mechanism of specific variants remains unclear. In this study, we aimed to investigate the molecular consequences of the c.905C>T p.(Pro302Leu) variant, identified in two siblings with typical symptoms of L2HGA, by analyzing its effects on protein localization and enzymatic activity in a cell model. Methods: HA-tagged wild-type and p.(Pro302Leu) mutant L2HGDH constructs were overexpressed in HEK293T cells. We assessed protein expression, subcellular localization, and enzymatic activity using Western blot analysis, immunofluorescence microscopy, and a specific enzyme assay measuring 2,6-dichloroindophenol (DCIP) reduction to assess L2HGDH enzymatic activity. Results: Western blotting showed that wild-type L2HGDH exists primarily in the processed, mature mitochondrial form, whereas the p.(Pro302Leu) mutant remained largely in the unprocessed precursor form. Immunofluorescence and differential centrifugation revealed that wild-type protein localized to mitochondria, while the mutant protein accumulated in the cytoplasm in a diffuse or punctate pattern. Enzyme activity assays demonstrated that the mutant retained <30% of wild-type activity. Conclusions: These findings indicate that the p.(Pro302Leu) variant leads to aggregation of mislocalized protein, thereby impairing L2HGDH function rather than decreasing enzymatic function. This study provides clinical and molecular evidence supporting the pathogenicity of this previously reported mutation and highlights the importance of mitochondrial import for enzyme functionality in L2HGA. Full article

(This article belongs to the Special Issue Genetics and Treatment in Neurodegenerative Diseases)

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9 pages, 469 KB

Open AccessReview

Deep Learning Models: Their Relationship with Embryonic Euploidies and Reproductive Outcomes

by Aikaterini Selntigia, Lucia Maresca, Diletta Montanino Oliva, Camilla Coianiz and Daniela Galliano

Genes 2025, 16(8), 981; https://doi.org/10.3390/genes16080981 - 20 Aug 2025

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Abstract

Background: Embryo selection in in vitro fertilization (IVF) aims to prioritize embryos with the highest reproductive potential. While preimplantation genetic testing for aneuploidy (PGT-A) remains the gold standard for identifying euploid embryos, it is invasive and not universally applicable. Deep learning (DL)-based models, [...] Read more.

Background: Embryo selection in in vitro fertilization (IVF) aims to prioritize embryos with the highest reproductive potential. While preimplantation genetic testing for aneuploidy (PGT-A) remains the gold standard for identifying euploid embryos, it is invasive and not universally applicable. Deep learning (DL)-based models, such as the intelligent data analysis (iDA) score, have emerged as non-invasive alternatives for embryo assessment. This review critically evaluates the relationship between iDAScore (versions 1.0 and 2.0), embryo euploidy, and clinical outcomes, including live birth and miscarriage rates. Methods: A narrative review was performed using PubMed and Google Scholar, covering studies published from January 2020 to May 2025. The search included terms such as “iDAScore,” “deep learning,” “euploidy,” and “live birth.” Only English-language full-text studies assessing the predictive performance of iDAScore relative to chromosomal status or reproductive outcomes were included. Results: Six retrospective studies met the inclusion criteria. All reported a statistically significant association between higher iDAScore values and embryo euploidy. AUC values for euploidy prediction ranged from 0.60 to 0.68. In several studies, iDAScore was also positively associated with live birth rates and negatively with miscarriage rates. However, the predictive accuracy was moderate when restricted to euploid embryo cohorts, indicating that iDAScore may be more effective in broader populations where chromosomal status is unknown. Conclusions: iDAScore represents a promising adjunct to traditional embryo assessment. Although it cannot replace PGT-A, it may aid in embryo prioritization when genetic testing is not feasible. Larger prospective studies are warranted to further validate its clinical utility. Full article

(This article belongs to the Section Bioinformatics)

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13 pages, 1706 KB

Open AccessArticle

Genetic and Sonographic Insights into First-Trimester Fetal Cystic Hygroma: A Retrospective 30-Year Analysis Using 3D/4D Ultrasound and Cytogenetic Evaluation in Croatia (1993–2023)

by Petra Podobnik, Tomislav Meštrović, Mario Podobnik, Igor Lončar, Ivan Bertović-Žunec, Kristian Kurdija, Dženis Jelčić, Zlata Srebreniković and Slava Podobnik-Šarkanji

Genes 2025, 16(8), 980; https://doi.org/10.3390/genes16080980 - 20 Aug 2025

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Abstract

Background/Objectives: Cystic hygroma is a congenital lymphatic malformation often identified during early pregnancy and frequently associated with chromosomal abnormalities and adverse outcomes. We aimed to appraise the genetic and clinical characteristics of fetuses diagnosed with cystic hygroma in the first/early second trimester, assess [...] Read more.

Background/Objectives: Cystic hygroma is a congenital lymphatic malformation often identified during early pregnancy and frequently associated with chromosomal abnormalities and adverse outcomes. We aimed to appraise the genetic and clinical characteristics of fetuses diagnosed with cystic hygroma in the first/early second trimester, assess the resolution patterns in chromosomally normal cases, and provide insights into prognosis—based on data collected over a 30-year period. Methods: A retrospective cohort study was conducted on 405 consecutive fetuses diagnosed with nuchal cystic hygroma between 8.0 and 14.0 weeks of gestation from 1993 to 2023 at two tertiary care centers. Diagnoses were established using high-resolution transabdominal and transvaginal 3D/4D ultrasonography. All cases underwent prenatal cytogenetic analysis, including karyotyping. Fetuses with a normal karyotype were observed through serial ultrasounds through the remainder of the pregnancy to verify the eventual resolution of hygromas. Both descriptive and inferential statistical methods were used, with p < 0.05 as a cut-off (two-tailed). Results: Of the 405 fetuses, 210 (51.9%) had chromosomal abnormalities, most commonly trisomy 21, while 195 (48.1%) had a normal karyotype. A significantly higher frequency of trisomy 21 was observed compared to other identified chromosomal abnormalities (p < 0.001). In the chromosomally normal group, 85 (43.6%) showed spontaneous resolution of the hygroma within four weeks, and these pregnancies resulted in phenotypically normal live births. Septated hygromas were significantly more frequent in the abnormal karyotype group (71.4%). Conclusions: The finding and diagnosis of cystic hygroma in first trimester and early second-trimester pregnancy represent a strong predictor of chromosomal aneuploidy and warrant comprehensive prenatal genetic testing and close follow-up. However, in the absence of genetic abnormalities and additional malformations, spontaneous resolution is common, and neonatal outcomes are generally favorable. Health systems should provide equitable access to genetic testing and fetal imaging to support accurate diagnosis and informed decisions. Full article

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

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11 pages, 2943 KB

Open AccessArticle

The Complete Mitochondrial Genome of Aspidophorodon (Eoessigia) indicum (Hemiptera: Aphididae: Aphidinae) and Insights into Its Phylogenetic Position

by Jiayu Ding, Xiaolu Zhang, Liyun Jiang, Gexia Qiao and Jing Chen

Genes 2025, 16(8), 979; https://doi.org/10.3390/genes16080979 - 20 Aug 2025

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Abstract

Background: Aspidophorodon Verma, 1967 (Macrosiphini: Aphidinae), is a genus within Aphididae (aphids) with ecological importance and a unique distribution, but there is a lack of mitogenomic data on the evolutionary relationships within this genus, hindering a comprehensive understanding of its evolutionary history. Methods: [...] Read more.

Background: Aspidophorodon Verma, 1967 (Macrosiphini: Aphidinae), is a genus within Aphididae (aphids) with ecological importance and a unique distribution, but there is a lack of mitogenomic data on the evolutionary relationships within this genus, hindering a comprehensive understanding of its evolutionary history. Methods: In this study, we present the complete mitochondrial genome sequence and features of Aspidophorodon indicum (David, Rajasingh & Narayanan, 1972) (Hemiptera: Aphididae) and further infer its phylogenetic position based on the complete mitochondrial genome sequence. Results: The complete mitochondrial genome of A. indicum is 17,161 bp in length, including 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, a control region, and a repeat region between trnE and trnF. Phylogenetic analyses based on complete mitochondrial genomes of Aphidinae indicated that the two constituent tribes, Macrosiphini and Aphidini, are monophyletic. Aspidophorodon was robustly clustered with the members of Pterocomma and Cavariella. Together, these three genera form the most basal clade within Macrosiphini. Conclusions: The complete mitogenome of A. indicum contains multiple conserved features relative to other aphids, including gene order, nucleotide composition, codon bias, and repeat region. The phylogenetic relationships within Macrosiphini reported here are consistent with previous studies. Our results provide new insights into the phylogenetic position of the genus Aspidophorodon. Full article

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

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13 pages, 2462 KB

Open AccessArticle

Population Genetics of Sillago japonica Among Five Populations Based on Mitochondrial Genome Sequences

by Beiyan Zhu, Tianxiang Gao, Yinquan Qu and Xiumei Zhang

Genes 2025, 16(8), 978; https://doi.org/10.3390/genes16080978 - 20 Aug 2025

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Abstract

Objectives: Sillago japonica is a commercially important marine fish species in the Northwestern Pacific, and understanding its genetic diversity and population structure is crucial for germplasm resource conservation and elucidating population evolution mechanisms. This study specifically aimed to systematically explore the genetic diversity [...] Read more.

Objectives: Sillago japonica is a commercially important marine fish species in the Northwestern Pacific, and understanding its genetic diversity and population structure is crucial for germplasm resource conservation and elucidating population evolution mechanisms. This study specifically aimed to systematically explore the genetic diversity and population structure of S. japonica across five geographic regions (DJW, YSW, ST, ZS, and RS) in its distribution range. Methods: A total of 50 S. japonica individuals from the five geographic regions were analyzed using high-throughput mitochondrial genome sequencing data. We identified single nucleotide polymorphisms (SNPs) and insertion-deletion (InDel) loci, followed by comprehensive population genetic analyses including phylogenetic tree construction, principal component analysis (PCA), ADMIXTURE analysis, and calculation of genetic differentiation indices (Fst) and genetic diversity parameters. Results: A total of 2966 SNPs and 414 insertion-deletion loci were identified. Phylogenetic tree topology, PCA, and ADMIXTURE 1.3.0 analysis consistently showed low genetic differentiation among the five populations, a pattern supported by low pairwise Fst values ranging from 0.00047 to 0.05589, indicating extensive gene flow across regions. Genetic diversity parameters varied slightly among populations: observed heterozygosity (0.00001–0.00528), expected heterozygosity (0.04552–0.07311), percentages of polymorphic loci (19.41–30.36%), and nucleotide diversity (0.04792–0.07697). Conclusions: The low genetic differentiation and diversity observed in S. japonica populations may result from the combined effects of historical bottleneck-induced gene pool reduction and extensive gene flow. These findings provide essential theoretical support for formulating targeted conservation strategies for S. japonica germplasm resources and further studies on its population evolution mechanisms. Full article

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

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17 pages, 2431 KB

Open AccessArticle

The Complete Mitochondrial Genome of Liobagrus huaiheensis (Teleostei: Siluriformes: Amblycipitidae): Characterization, Phylogenetic Placement, and Insights into Genetic Diversity

by Chaoqun Su, Chenxi Tan, Liangjie Zhao, Jiahui Liu, Xusheng Guo, Gaoyou Yao, Weizhao Zhang and Tiezhu Yang

Genes 2025, 16(8), 977; https://doi.org/10.3390/genes16080977 - 19 Aug 2025

Viewed by 445

Abstract

Background/Objectives: Liobagrus huaiheensis, an endemic fish in the Huaihe River basin, is a newly described species with limited molecular genetic research, hindering understanding of its evolutionary status, population structure, and genetic diversity. This study aimed to characterize its complete mitochondrial genome, [...] Read more.

Background/Objectives: Liobagrus huaiheensis, an endemic fish in the Huaihe River basin, is a newly described species with limited molecular genetic research, hindering understanding of its evolutionary status, population structure, and genetic diversity. This study aimed to characterize its complete mitochondrial genome, clarify its phylogenetic position within Liobagrus, and assess its population genetic diversity. Methods: We obtained the complete mitogenome of L. huaiheensis (sourced from the Zhugan River) through sequencing, followed by detailed annotation of this genomic sequence. We analyzed its genomic structure, nucleotide composition, codon usage, and base asymmetry. Selection pressure on 13 protein-coding genes (PCGs) was evaluated using Ka/Ks ratios. Phylogenetic trees were generated by means of Bayesian inference (BI) and maximum likelihood (ML), using a dataset composed of 13 protein-coding genes (PCGs) from 37 species. Population genetic diversity was assessed using the cox1 gene. Results: The mitogenome is a 16,512 bp circular molecule encoding 37 genes and one control region, with a conserved structure typical of Liobagrus. It has high A + T content (55.74%) with A-preference and C-enrichment. All PCGs undergo purifying selection (Ka/Ks < 1). Phylogenetic analyses revealed L. huaiheensis is closest to L. obesus (100% support), with Liobagrus divided into three clades. The cox1 gene analysis showed low diversity (Hd = 0.656, π = 0.00171) and neutral evolution. Conclusions: This study fills the mitogenome data gap for L. huaiheensis, clarifies its evolutionary characteristics and phylogenetic position, and provides a basis for conservation genetics of Huaihe endemic fishes and molecular evolution research on Amblycipitidae. Full article

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

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18 pages, 3414 KB

Open AccessArticle

Identification of Key Genes and Pathways Associated with Frailty and Exercise Effects Using a Network and Evolutionary Approach

by Kyoko Naito, Hiromichi Akahori, Yoshinori Muto and Tomoyoshi Terada

Genes 2025, 16(8), 976; https://doi.org/10.3390/genes16080976 - 19 Aug 2025

Viewed by 507

Abstract

Background: Frailty is an aging-associated syndrome involving a loss of physiological reserve and function, with decreased ability to recover from physical and psychosocial stress. However, the etiology and pathogenesis of frailty remain largely unknown. Aim: This study aimed to investigate key genes involved [...] Read more.

Background: Frailty is an aging-associated syndrome involving a loss of physiological reserve and function, with decreased ability to recover from physical and psychosocial stress. However, the etiology and pathogenesis of frailty remain largely unknown. Aim: This study aimed to investigate key genes involved in frailty pathogenesis, exercise effects, and their contributions. Methods: We performed a weighted gene co-expression network analysis using a microarray dataset. By using the positive selection (PS), human accelerated region (HAR), and aging gene sets, we identified key genes for frailty and exercise-related genes. Results: We identified magenta and pink modules that have the most significant enrichments for the evolutionally elaborated genes. A functional enrichment analysis (FEA) revealed that genes related to redox-process regulation and extracellular-matrix organization were enriched in magenta and pink modules, respectively. We observed that six of the evolutionarily imprinted genes in the modules (MEOX2, PLCB4, LPAR6, SH3KBP1, APP and SPON1) were highly connected and showed signs of hub properties, which might play crucial roles in frailty- and exercise-related mechanisms. Conclusions: Further investigation into the functions of the identified modules and their member genes could aid in identifying diagnostic biomarkers and therapeutic targets for frailty. Full article

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

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10 pages, 1172 KB

Open AccessArticle

Identification of a Pathogenic Mutation for Glycogen Storage Disease Type II (Pompe Disease) in Japanese Quails (Coturnix japonica)

by Abdullah Al Faruq, Takane Matsui, Shinichiro Maki, Nanami Arakawa, Kenichi Watanabe, Yoshiyasu Kobayashi, Tofazzal Md Rakib, Md Shafiqul Islam, Akira Yabuki and Osamu Yamato

Genes 2025, 16(8), 975; https://doi.org/10.3390/genes16080975 - 19 Aug 2025

Viewed by 426

Abstract

Background/Objectives: Pompe disease (PD) is a rare autosomal recessive disorder caused by a deficiency of the lysosomal acid α-1,4-glucosidase (GAA) encoded by the GAA gene, leading to muscular dysfunctions due to pathological accumulation of glycogen in skeletal and cardiac muscles. PD has [...] Read more.

Background/Objectives: Pompe disease (PD) is a rare autosomal recessive disorder caused by a deficiency of the lysosomal acid α-1,4-glucosidase (GAA) encoded by the GAA gene, leading to muscular dysfunctions due to pathological accumulation of glycogen in skeletal and cardiac muscles. PD has been reported in several animals and Japanese quails (JQ; Coturnix japonica), but a causative mutation has yet to be found in JQs with PD. Here, we aimed to identify a pathogenic mutation in JQs associated with PD. Methods: Paraffin-embedded skeletal muscle blocks from four JQs stored since the 1970s were used in this study. After confirming the histopathological phenotypes of PD, Sanger sequencing was performed to identify a pathological mutation in the GAA I gene of JQs. A genotyping survey was conducted using a real-time polymerase chain reaction assay targeting a candidate mutation using DNA samples extracted from 70 new-hatched JQs and 10 eggs from commercial farms. Results: Microscopic analysis confirmed the presence of the PD phenotype in three affected JQs based on abnormal histopathological changes and accumulated glycogen in the affected muscles, while one JQ was unaffected and served as a control. Sanger sequencing revealed that the three affected JQs were homozygous for the deletion of guanine at position 1096 in the open reading frame (c.1096delG). A genotyping survey of 70 JQs and 10 eggs from commercial farms showed that none carried this deletion mutation. Conclusions: This study identified c.1096delG as the pathogenic mutation for PD in JQs. This mutation induces a frameshift and substitution of amino acids at position 366 (alanine to histidine), resulting in premature termination at the 23rd codon (p.A366Hfs*23). This suggests that this mutation causes the deficient activity of GAA in JQs with PD. The identification of the c.1096delG mutation enabled the systematic maintenance of the flock colony in the PD model. Furthermore, this PD model can be used to clarify unknown aspects of PD pathogenesis and develop therapeutic strategies. Full article

(This article belongs to the Special Issue Genetic Breeding of Poultry)

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15 pages, 1451 KB

Open AccessArticle

CaSR Gene Polymorphisms and PHPT Phenotypes: What Else Can We Learn? A Single-Center Experience on a Cohort of Italian Patients

by Michele Cannito, Giacomo Voltan, Giulia Carraro, Michela Ferrarese, Giacomo Contini, Carlo Mogno, Loris Bertazza, Susi Barollo, Francesca Torresan, Maurizio Iacobone, Caterina Mian and Valentina Camozzi

Genes 2025, 16(8), 974; https://doi.org/10.3390/genes16080974 - 19 Aug 2025

Viewed by 411

Abstract

Purpose: This study investigates the role of CASR gene polymorphisms (A986S, R990G, Q1011E) in PHPT genetic susceptibility and its clinical variability. The aim is to evaluate the prevalence of these polymorphisms in patients with sporadic PHPT and their impact on clinical course, biochemistry, [...] Read more.

Purpose: This study investigates the role of CASR gene polymorphisms (A986S, R990G, Q1011E) in PHPT genetic susceptibility and its clinical variability. The aim is to evaluate the prevalence of these polymorphisms in patients with sporadic PHPT and their impact on clinical course, biochemistry, and histological features. Methods: 106 patients underwent clinical and anamnestic evaluations, focusing on major PHPT complications, as well as biochemical analyses of blood and urine. Genetic testing was conducted for CASR gene polymorphisms. Histological data were available for 68 patients who underwent parathyroidectomy. Results: The sample included 83 women and 23 men; mean age at diagnosis was 54.5 years. 55 patients carried CASR gene polymorphisms, while 51 were wild-type. Prevalence rates of polymorphisms were consistent with data for the Caucasian population, with A986S being the most common (31%). No significant associations were found between polymorphisms and increased levels of ionized calcium or other blood phospho-calcium metabolism parameters. However, 24-h urinary calcium levels were higher in patients with polymorphisms (p = 0.0185), particularly in those older than 50 years (p = 0.030) and with the A986S variant. Hypercalciuria was predictive of CASR polymorphism presence (OR = 2.76, p = 0.003). No significant association with PHPT complications, such as renal calculi or bone involvement, was confirmed. Histological data revealed no clear links between polymorphisms and more aggressive variants. Conclusions: CASR gene polymorphisms are associated with hypercalciuria but do not significantly influence age of onset or clinical phenotype in PHPT. Genetic analysis may be useful in selected cases to better understand individual clinical profiles. Full article

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

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19 pages, 7021 KB

Open AccessArticle

Genome-Wide Identification of the Dirigent Gene Family and Expression Pattern Analysis Under Drought and Salt Stresses of Sorghum bicolor (L.)

by Shipeng Liu, Tingrui Jing, Shuang Liang, Hairuo Wang, Xinyi Guo, Quan Ma, Junshen Wang, Kai Wang, Xiaolong He, Haibin Zhao, Wenting Jiang and Xiangqian Zhang

Genes 2025, 16(8), 973; https://doi.org/10.3390/genes16080973 - 19 Aug 2025

Viewed by 493

Abstract

Background: The Dirigent (DIR) gene family is pivotal for lignin polymerization and stress adaptation in plants, yet its systematic characterization in Sorghum bicolor (S. bicolor), a critical bioenergy crop, remains underexplored. Methods: Leveraging the S. bicolor genome database, we [...] Read more.

Background: The Dirigent (DIR) gene family is pivotal for lignin polymerization and stress adaptation in plants, yet its systematic characterization in Sorghum bicolor (S. bicolor), a critical bioenergy crop, remains underexplored. Methods: Leveraging the S. bicolor genome database, we conducted a genome-wide identification, phylogenetic classification, and expression profiling of the DIR gene family. Evolutionary dynamics, gene structure variations, promoter cis-regulatory elements, and spatiotemporal transcriptome patterns were analyzed using bioinformatics and experimental validation (RT-qPCR). Results: A total of 53 SbDIR genes were systematically identified, exhibiting uneven chromosomal distribution. Phylogenetic analysis clustered them into five clades (DIR-a, DIR-b/d, DIR-c, DIR-e, DIR-f), with subfamily-specific exon number variations suggesting functional divergence. Evolutionary studies revealed tandem duplication (TD) as the primary driver of family expansion, accompanied by strong purifying selection. Promoter analysis highlighted abundant hormone- and stress-responsive cis-elements. Tissue-specific RNA-seq data revealed root-enriched expression of SbDIR2/4/18/39/44/53, implicating their roles in root development. Notably, SbDIR39 and SbDIR53 were significantly upregulated (2.8- and 5-fold, respectively) under 150 mM NaCl stress, underscoring their stress-responsive functions. Conclusions: This study provides the first comprehensive atlas of the DIR gene family in S. bicolor, elucidating its evolutionary mechanisms and tissue-specific/stress-induced expression profiles. Key candidates (SbDIR39/53) were identified as promising targets for molecular breeding or CRISPR-based editing to enhance stress resilience in S. bicolor. These findings lay a foundation for translating genomic insights into agronomic improvements. Full article

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

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7 pages, 906 KB

Open AccessArticle

CRELD1-Associated Neurodevelopmental Disorder: Three New Individuals from Unrelated Families

by Jessica Archer, Shuxiang Goh, Christina Miteff, Sheridan O’Donnell, Kristen Park and Himanshu Goel

Genes 2025, 16(8), 972; https://doi.org/10.3390/genes16080972 - 18 Aug 2025

Viewed by 509

Abstract

Background: CRELD1 encodes a cell adhesion molecule initially implicated in atrioventricular septal defects (AVSDs). More recently, biallelic CRELD1 variants have been associated with syndromic and non-syndromic neurodevelopmental disorders (NDDs). Methods: We describe three individuals from unrelated families with compound heterozygous CRELD1 variants, [...] Read more.

Background: CRELD1 encodes a cell adhesion molecule initially implicated in atrioventricular septal defects (AVSDs). More recently, biallelic CRELD1 variants have been associated with syndromic and non-syndromic neurodevelopmental disorders (NDDs). Methods: We describe three individuals from unrelated families with compound heterozygous CRELD1 variants, identified through exome sequencing. Clinical and genetic data were reviewed to delineate shared and divergent features. Results: All three patients presented with developmental delay, intellectual disability, seizures, hypotonia, and dysmorphic facial features. Patient 1 and patient 2 carried a recurrent variant combination previously reported in five individuals, while Patient 3 harboured the recurrent frameshift p.(Gln320Argfs*25) variant in trans with a novel missense variant. The milder clinical course of patient 3 highlights phenotypic heterogeneity. Notably, none of the patients had cardiac anomalies or immunological abnormalities, further expanding the clinical spectrum associated with CRELD1. Conclusion: Our findings reinforce genotype–phenotype correlations and provide additional evidence that biallelic CRELD1 variants underlie a distinct autosomal recessive neurodevelopmental disorder, broadening both the phenotypic and genetic spectrum of this emerging syndrome. Full article

(This article belongs to the Special Issue Pediatric Rare Diseases: Genetics and Diagnosis)

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12 pages, 599 KB

Open AccessArticle

Association Between UGT1A1 mRNA Expression and Cis-Acting Genetic Variants and Trans-Acting Transcriptional Regulators in Human Liver Samples

by Matthew J. Taylor, Joseph M. Collins, Abelardo D. Montalvo and Danxin Wang

Genes 2025, 16(8), 971; https://doi.org/10.3390/genes16080971 - 18 Aug 2025

Viewed by 399

Abstract

Background: UDP-glucuronosyltransferase 1A1 (UGT1A1) metabolizes endogenous substances and pharmaceuticals. Genetic polymorphisms, particularly TA repeats in the UGT1A1 promoter TATA region (UGT1A1*28/*36/*37) and a nearby single-nucleotide polymorphism (SNP) rs887829, are associated with UGT1A1-related phenotypes and used as biomarkers for guiding drug therapy. However, these [...] Read more.

Background: UDP-glucuronosyltransferase 1A1 (UGT1A1) metabolizes endogenous substances and pharmaceuticals. Genetic polymorphisms, particularly TA repeats in the UGT1A1 promoter TATA region (UGT1A1*28/*36/*37) and a nearby single-nucleotide polymorphism (SNP) rs887829, are associated with UGT1A1-related phenotypes and used as biomarkers for guiding drug therapy. However, these associations are inconsistent, especially in individuals of African ancestry. The objectives of this study are to investigate the association between UGT1A1 expression and its genetic variants in liver samples obtained from European American (EA, n = 119) and African American (AA, n = 138) donors and to clarify the function of genetic variants. Methods: The associations between UGT1A1 expression and genetic variants were tested using multiple linear regression analysis, and the transcriptional activities of genetic variants were tested using reporter gene assays. Results: Both rs887829 and UGT1A1*28/*37 showed similar associations with UGT1A1 expression in AA and EA samples. Reporter gene assays confirmed that UGT1A1*36 (5TA) had significantly higher activity than reference UGT1A1*1 (6TA), while UGT1A1*28 (7TA) and *37 (8TA) had lower activity. In contrast, rs887829 showed no direct effect on promoter activity, indicating that its association is likely caused by high LD with UGT1A1*28/*37. Additionally, we found that ancestral differences in associations with trans-acting regulators and combined genetic variants and TFs account for substantially higher total variability in UGT1A1 expression in EAs than in AAs (53% vs. 39%). Conclusions: Our findings reveal differences in UGT1A1 regulation between AA and EA populations and suggest that additional cis- and/or trans-acting factors regulating UGT1A1 expression remain to be discovered in individuals of African ancestry. Full article

(This article belongs to the Section Pharmacogenetics)

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11 pages, 4923 KB

Open AccessArticle

Expanding the Phenotypic Spectrum of SPG4: Autism Spectrum Disorder in Early-Onset and Complex SPAST-HSP and Case Study

by Carlo Alberto Quaranta, Alice Gardani, Giulia Andorno, Anna Pichiecchio, Simone Gana, Renato Borgatti and Simona Orcesi

Genes 2025, 16(8), 970; https://doi.org/10.3390/genes16080970 - 18 Aug 2025

Viewed by 489

Abstract

Background/Objectives: Hereditary spastic paraplegias (HSPs) comprise a heterogenous spectrum of rare neurogenetic disorders predominantly characterized by progressive spasticity and weakness of the lower extremities. Among autosomal-dominant forms of HSP, molecular defects in the SPAST gene—particularly those associated with the SPG4 subtype—represent the most [...] Read more.

Background/Objectives: Hereditary spastic paraplegias (HSPs) comprise a heterogenous spectrum of rare neurogenetic disorders predominantly characterized by progressive spasticity and weakness of the lower extremities. Among autosomal-dominant forms of HSP, molecular defects in the SPAST gene—particularly those associated with the SPG4 subtype—represent the most frequent genetic cause. SPAST encodes spastin, a microtubule-severing ATPase, crucial for cytoskeletal remodeling, neuronal connectivity, and intracellular trafficking. Disruption of spastin function can impair neurite outgrowth and synaptic formation, processes increasingly implicated in neurodevelopmental disorders (NDDs). Methods: We conducted a comprehensive clinical, neurological, and dysmorphological evaluation of a 4-year-old male. Standardized neuropsychological assessments were administered. Whole-exome sequencing (WES) was performed to identify underlying genetic causes. EEG and 3T-brain MRI were also acquired. Results: The proband harbored two novel de novo heterozygous missense variants in cis of the SPAST gene, displaying the typical features of early-onset and complex HSP, in addition to global developmental delay and severe autism spectrum disorder (ASD), an underexplored manifestation in this rare genetic disorder. Conclusions: These findings broaden the clinical and mutational spectrum of SPG4, underscoring the importance of considering SPAST gene analysis in patients with ASD in the early years of life and early motor delay, even in the presence of only subtle pyramidal signs. We advocate for comprehensive neuropsychiatric assessment in the diagnostic pathway of early-onset complex HSP presentations and support further investigation into the role of spastin in neuronal connectivity. Full article

(This article belongs to the Section Neurogenomics)

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18 pages, 3463 KB

Open AccessArticle

Expression of miRNA in the Semitendinosus Muscle of Cattle Breeds with Varying Intramuscular Fat Deposition

by Anna Ciecierska, Abdolvahab Ebrahimpour Gorji, Alicja Majewska and Tomasz Sadkowski

Genes 2025, 16(8), 969; https://doi.org/10.3390/genes16080969 - 18 Aug 2025

Viewed by 462

Abstract

Background: This study investigates the expression of microRNAs (miRNAs) in the semitendinosus muscle of cattle breeds with varying intramuscular fat (IMF) deposition to identify key miRNA regulators of beef marbling, utilizing Hereford (HER; higher IMF) and Holstein-Friesian (HF; moderate IMF) bulls, and [...] Read more.

Background: This study investigates the expression of microRNAs (miRNAs) in the semitendinosus muscle of cattle breeds with varying intramuscular fat (IMF) deposition to identify key miRNA regulators of beef marbling, utilizing Hereford (HER; higher IMF) and Holstein-Friesian (HF; moderate IMF) bulls, and Limousin (LIM; low IMF) bulls with lower IMF in the semitendinosus muscle. Methods: MicroRNA profiling used custom bovine microarrays and the Agilent software. The selected miRNAs, miR-34a, miR-149-5p, miR-208b, miR-499, miR-660, and miR-1343-5p, were chosen for validation using real-time PCR, confirming their differential expression. Target prediction utilized miRWalk, while functional and pathway analyses were conducted using the DAVID database to interpret biological relevance. Results: Microarray analysis identified 51 differentially expressed miRNAs. Among these, 24 exhibited consistent expression patterns in high-marbling breeds compared to the low-marbling LIM breed. Bioinformatic analysis of the 4941 predicted target genes of these 24 miRNAs revealed significant enrichment in pathways crucial for marbling, including the adipocytokine, AMPK, MAPK, and PI3K-Akt signaling pathways, as well as biological processes such as cell differentiation and lipid homeostasis. Notably, miR-34a and miR-149-5p emerged as significant regulators, with miR-34a targeting genes like SIRT1, HMGA2, PTPN11, VEGFA, FGF1, FGF2, and BRAF, and miR-149-5p influencing adipogenesis and lipid metabolism through its association with crucial KEGG pathways such as PI3K–Akt, MAPK, PPAR, TGF-β, cAMP, and Wnt signaling, all of which collectively influence adipocyte differentiation, lipid metabolism, cell cycle control, and angiogenesis. Conclusions: The findings underscore identified miRNAs’ possible coordinated regulatory role, particularly miR-34a and miR-149-5p, in the complex molecular mechanisms governing IMF deposition in cattle, providing potential targets for improving beef quality. Full article

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

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15 pages, 1898 KB

Open AccessFeature PaperReview

Mechano-Signal Transduction Pathways of the Diaphragmatic Muscle and Role of Cytoskeleton

by Junaith S. Mohamed, Patricia S. Pardo and Aladin M. Boriek

Genes 2025, 16(8), 968; https://doi.org/10.3390/genes16080968 - 18 Aug 2025

Viewed by 421

Abstract

Mechanotransduction, also referred to as mechano-signal transduction, is a biophysical process wherein cells perceive and respond to mechanical stimuli by converting them into biochemical signals that initiate specific cellular responses. This mechanism is fundamental to the development and growth, and proper functioning of [...] Read more.

Mechanotransduction, also referred to as mechano-signal transduction, is a biophysical process wherein cells perceive and respond to mechanical stimuli by converting them into biochemical signals that initiate specific cellular responses. This mechanism is fundamental to the development and growth, and proper functioning of mechanically active tissues, such as the diaphragm—a respiratory muscle vital for breathing in mammals. In vivo, the diaphragm is subjected to transdiaphragmatic pressure, and therefore, its muscle fibers are subjected to mechanical forces not only in the direction of the muscle fibers but also in the direction transverse to the fibers. Previous research conducted in our laboratory uncovered that stretching the diaphragm in either the longitudinal or transverse direction activates distinct mechanotransduction pathways. This indicates that signaling pathways in the diaphragm muscle are regulated in an anisotropic manner. In this review paper, we discussed the underlying mechanisms that regulate the anisotropic signaling pathways in the diaphragmatic muscle, emphasizing the mechanical role of cytoskeletal proteins in this context. Furthermore, we explored the regulatory mechanisms governing mechanosensitive gene transcription, including microRNAs (mechanomiRs), within the diaphragm muscle. Finally, we examined potential links between anisotropic signaling in the diaphragm muscle and various skeletal muscle disorders. Full article

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

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14 pages, 569 KB

Open AccessArticle

Interaction Between Vitamin D Metabolism Genetic Variants: Association with Hypovitaminosis D, Rheumatoid Arthritis, and Its Clinical Disease Activity

by Bertha Campos-López, Melissa Rivera-Escoto, Adolfo I. Ruiz-Ballesteros, Karen Pesqueda-Cendejas, Paulina E. Mora-García, Mónica R. Meza-Meza, Isela Parra-Rojas, José M. Moreno-Ortíz, Eneida Turiján-Espinoza, Juan M. Vargas-Morales, Sergio Cerpa-Cruz and Ulises De la Cruz-Mosso

Genes 2025, 16(8), 967; https://doi.org/10.3390/genes16080967 - 18 Aug 2025

Viewed by 439

Abstract

Background: Hypovitaminosis D has been associated with worse rheumatoid arthritis (RA) manifestations. Notably, different genetic studies have reported that approximately 65% of hypovitaminosis D can be partially explained using the presence of single-nucleotide variants (SNVs) in key genes involved in its metabolism. This [...] Read more.

Background: Hypovitaminosis D has been associated with worse rheumatoid arthritis (RA) manifestations. Notably, different genetic studies have reported that approximately 65% of hypovitaminosis D can be partially explained using the presence of single-nucleotide variants (SNVs) in key genes involved in its metabolism. This study aimed to investigate the association and gene–gene interactions of four SNVs in vitamin D metabolism genes, rs10741657 (CYP2R1), rs10877012 (CYP27B1), rs4809959 (CYP24A1), and rs731236 TaqI (VDR), with hypovitaminosis D, RA, and its clinical disease activity in a Mexican mestizo population. Methods: This study was conducted among females: 204 RA patients and 204 control subjects (CS). Vitamin D serum levels (calcidiol) were analyzed using ELISA, SNVs through allelic discrimination with TaqMan^® probes, and were analyzed using a multifactor dimensionality reduction (MDR) method. Results: MDR analysis suggested that GG and TT genotypes of rs10877012 (CYP27B1) were linked to lower calcidiol levels, while the CT and CC genotypes of rs731236 TaqI (VDR) were associated with increased RA susceptibility and higher disease activity. Logistic regression confirmed that the GG genotype of rs10877012 (CYP27B1) was associated with hypovitaminosis D (OR = 1.8; CI: 1.1–3.0; p = 0.01), and the CT genotype of rs731236 TaqI (VDR) with RA (OR = 1.9; CI: 1.2–2.9; p < 0.01) and high DAS28-ESR (OR = 3.6; CI: 1.3–10.7; p < 0.01). Conclusions: The GG genotype of rs10877012 CYP27B1 was associated with susceptibility to hypovitaminosis D, whereas the CT genotype of rs731236 TaqI VDR confers susceptibility to RA and high clinical disease activity in the Mexican mestizo population. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Factors for Autoimmune Diseases)

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13 pages, 280 KB

Open AccessArticle

Genotype-by-Environment Interaction in Red Tilapia (Oreochromis spp.): Implications for Genetic Parameters and Trait Performance

by Tran Huu Phuc, Pham Dang Khoa, Nguyen Thi Dang, Tran Thi Mai Huong, Huynh Thi Bich Lien, Vo Thi Hong Tham, Nguyen Huynh Duy and Nguyen Hong Nguyen

Genes 2025, 16(8), 966; https://doi.org/10.3390/genes16080966 - 18 Aug 2025

Viewed by 615

Abstract

The intensive farming of aquaculture species such as red tilapia (Oreochromis spp.) across diverse production systems can lead to changes in genetic parameters and responses of economically important traits in this species. This study represents the first attempt to understand these changes [...] Read more.

The intensive farming of aquaculture species such as red tilapia (Oreochromis spp.) across diverse production systems can lead to changes in genetic parameters and responses of economically important traits in this species. This study represents the first attempt to understand these changes in growth traits (body weight, total length), quality attributes (body colour), and survival rate in red tilapia. Data for these traits were collected from 75,950 individual fish, progeny of 970 full-sib families (comprising 970 dams and 486 sires); they were selected for high body weight and evaluated in two distinct culture environments: fresh- and saltwater ponds. A multi-trait mixed model was employed to estimate genetic parameters and selection responses. Genetic variance estimates for the quality and survival traits varied across the two environments. However, genetic correlations among the traits studied were similar between fresh and saline water. Furthermore, significant G × E interactions, particularly for the quality and survival traits, were evidenced by divergent genetic correlations (r_g = 0.57–0.83) between homologous traits across different environments. The findings emphasise the importance of incorporating G × E interactions into the selection program for red tilapia, particularly when the breeding objectives extend to include quality and survival traits. Selection strategies should consider the prevailing culture system—for instance, favouring genotypes suited to the freshwater pond environment over those adapted to the saltwater environment. Continual assessment of full-sib groups across these environments is recommended to refine our understanding of G × E interactions and optimise future breeding programs for red tilapia. This may involve selecting genotypes capable of consistent performance across environments or developing environment-specific breeding programs. Full article

(This article belongs to the Special Issue Molecular Genetics Applied to Aquaculture: From Breeding Stock Selection to Biotechnological Innovations)

21 pages, 992 KB

Open AccessReview

Prime Editing for Crop Improvement: A Systematic Review of Optimization Strategies and Advanced Applications

by Shuangrui Tian, Lan Yao, Yuhong Zhang, Xiaoyu Rao and Hongliang Zhu

Genes 2025, 16(8), 965; https://doi.org/10.3390/genes16080965 - 16 Aug 2025

Viewed by 970

Abstract

Prime editing (PE), a novel “search-and-replace” genome editing technology, demonstrates significant potential for crop genetic improvement due to its precision and versatility. However, since its initial application in plants, PE technology has consistently faced challenges of low and variable editing efficiency, [...] Read more.

Prime editing (PE), a novel “search-and-replace” genome editing technology, demonstrates significant potential for crop genetic improvement due to its precision and versatility. However, since its initial application in plants, PE technology has consistently faced challenges of low and variable editing efficiency, representing a major bottleneck hindering its broader application. Therefore, this study conducted a systematic review following the PRISMA 2020 guidelines. We systematically searched databases—Web of Science, PubMed, and Google Scholar—for studies published up to June 2025 focusing on enhancing PE performance in crops. After a rigorous screening process, 38 eligible primary research articles were ultimately included for comprehensive analysis. Our analysis revealed that early PE systems such as PE2 could perform diverse edits, including all 12 base substitutions and small insertions or deletions (indels), but their efficiency was highly variable across species, targets, and edit types. To overcome this bottleneck, researchers developed four major optimization strategies: (1) engineering core components such as Cas9, reverse transcriptase (RT), and editor architecture; (2) enhancing expression and delivery via optimized promoters and vectors; (3) improving reaction processes by modulating DNA repair pathways or external conditions; and (4) enriching edited events through selectable or visual markers. These advancements broadened PE’s targeting scope with novel Cas9 variants and enabled complex, kilobase-scale DNA insertions and rearrangements. The application of PE technology in plants has evolved from basic functional validation, through systematic optimization for enhanced efficiency, to advanced stages of functional expansion. This review charts this trajectory and clarifies the key strategies driving these advancements. We posit that future breakthroughs will increasingly depend on synergistically integrating these strategies to enable the efficient, precise, and predictable application of PE technology across diverse crops and complex breeding objectives. This study provides an important theoretical framework and practical guidance for subsequent research and application in this field. Full article

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

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22 pages, 1031 KB

Open AccessReview

Endogenous Retroviruses in Host-Virus Coevolution: From Genomic Domestication to Functional Innovation

by Ruqi Jiang, Jingjun Zhou, Yue Liu, Guanjin Zhou, Dongdong Fan, Lixin Xiang, Ye Chen and Jianzhong Shao

Genes 2025, 16(8), 964; https://doi.org/10.3390/genes16080964 - 15 Aug 2025

Viewed by 626

Abstract

Endogenous retroviruses (ERVs) are remnants of retroviral infections that have become stably integrated into host germline genomes. Far beyond passive genomic elements, ERVs actively shape host evolution through complex mechanisms involving genetic innovation, immune modulation, and species adaptation. This review provides a comprehensive [...] Read more.

Endogenous retroviruses (ERVs) are remnants of retroviral infections that have become stably integrated into host germline genomes. Far beyond passive genomic elements, ERVs actively shape host evolution through complex mechanisms involving genetic innovation, immune modulation, and species adaptation. This review provides a comprehensive synthesis of ERV biology, highlighting recent advances in their classification, amplification mechanisms, and epigenetic silencing. Particular emphasis is placed on the cross-talk between ERVs and exogenous retroviruses (XRVs), demonstrating how receptor competition, recombination, and immune evasion contribute to virus-host co-evolution. We explore ERVs as molecular markers for phylogenetic reconstruction, with case studies such as Koala retrovirus (KoRV) and HERV-K illustrating regional transmission dynamics and co-opted immune functions. Additionally, we discuss the functional domestication of ERVs into regulatory elements, non-coding RNAs, and envelope-derived fusion proteins that influence gene expression, antiviral defense, and placental development. Full article

(This article belongs to the Section Viral Genomics)

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16 pages, 1339 KB

Open AccessArticle

Can Cis-Regulatory Elements Explain Differences in Petunia Pollination Syndromes?

by Aléxia G. Pereira, João Pedro C. Filgueiras and Loreta B. Freitas

Genes 2025, 16(8), 963; https://doi.org/10.3390/genes16080963 - 15 Aug 2025

Viewed by 388

Abstract

Background: Transcription factors have been linked to changes in various physiological processes, such as attractive and rewarding phenotypes during plant–pollinator interactions. In the genus Petunia, most species are pollinated by bees, but hawkmoth- and bird pollination are also observed. Here, we [...] Read more.

Background: Transcription factors have been linked to changes in various physiological processes, such as attractive and rewarding phenotypes during plant–pollinator interactions. In the genus Petunia, most species are pollinated by bees, but hawkmoth- and bird pollination are also observed. Here, we aimed to test the hypothesis that species with the same pollination syndrome evolved through convergence, while differences in pollinators indicate divergence. We selected six genes (MYB-FL, DFR, EOBII, ODO1, BPBT, and NEC1) involved in establishing pollination syndromes to explore the potential role of cis-regulatory elements in shifts among pollination syndromes, attracting and rewarding pollinators. Methods: We retrieved the genomic sequences of genes from the genomes of four Petunia species, which exhibit distinct pollination syndromes. We analyzed the cis-regulatory elements, focusing on the structure and composition of motifs, and inferred the functions of these transcription factors using Gene Ontology analysis. Results: All sequences were highly conserved among species, with variations in promoter motif structure and TF binding sites. The evolutionary relationships among the genes closely reflected the species’ phylogeny. Likewise, regulatory elements and gene structure mostly followed the species’ evolutionary history. However, different pollination syndromes are present, and there is an unexpected lack of convergence between the two bee-pollinated species. Conclusions: Our findings showed that the most recent common ancestor of these species better predicts relationships among gene regulatory elements than does the pollination syndrome. To fully understand the evolution of pollination syndromes in Petunia, additional studies are needed to analyze entire pathways and compare genomes and transcriptomes. Full article

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

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16 pages, 901 KB

Open AccessReview

Genomics in Lung Cancer: A Scoping Review of the Role of ctDNA in Non-Advanced Non-Small-Cell Lung Cancer in the Prediction of Prognosis After Multimodality Therapeutic Approaches

by Carolina Sassorossi, Jessica Evangelista, Alessio Stefani, Marco Chiappetta, Antonella Martino, Annalisa Campanella, Elisa De Paolis, Dania Nachira, Marzia Del Re, Francesco Guerrera, Luca Boldrini, Andrea Urbani, Stefano Margaritora, Angelo Minucci, Emilio Bria and Filippo Lococo

Genes 2025, 16(8), 962; https://doi.org/10.3390/genes16080962 - 15 Aug 2025

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Abstract

Background: Circulating tumor DNA (ctDNA), shed into bodily fluids by cancer cells through apoptosis, necrosis, or active secretion, is currently used in the field of genomic investigation in clinical settings, primarily for advanced stages of non-small-cell lung cancer (NSCLC). However, its potential [...] Read more.

Background: Circulating tumor DNA (ctDNA), shed into bodily fluids by cancer cells through apoptosis, necrosis, or active secretion, is currently used in the field of genomic investigation in clinical settings, primarily for advanced stages of non-small-cell lung cancer (NSCLC). However, its potential role in guiding the multi-omic approach to early-stage NSCLC is emerging as a promising area of investigation. Efforts are being made to integrate the genomics not only in surgery, but also in the definition of long-term prognosis after surgical or radiotherapy and for the prediction of recurrence. Methods: An extensive literature search was conducted on PubMed, covering publications from 2000 to 2024. Using the advanced search tool, titles and abstracts were filtered based on the following keywords: ctDNA, early stage, NSCLC. From this search, 20 studies that fulfilled all inclusion criteria were selected for analysis in this review. Results: This review highlights the growing body of evidence supporting the potential clinical use of ctDNA as a genomic biomarker in managing early-stage NSCLC. Baseline ctDNA levels offer valuable information about tumor molecular biology and histological characteristics. Beyond its prognostic value before treatment, liquid biopsy has proven useful for tracking minimal residual disease and forecasting recurrence following curative interventions such as surgery or radiotherapy. Future adjuvant treatment decisions may increasingly rely on predictive models that incorporate liquid biopsy findings alongside other clinical factors. Conclusions: The potential use of this analyte introduces new opportunities for the integration of genomic data in treatment, as well as relapse monitoring with more accurate and innovative than traditional methods, particularly in patients with early-stage NSCLC Full article

(This article belongs to the Special Issue Clinical Diagnosis and Analysis of Cancers)

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19 pages, 14487 KB

Open AccessArticle

Genome-Wide Identification Analysis of the Rab11 Gene Family in Gossypium hirsutum and Its Expression Analysis in Verticillium dahliae

by Mengyuan Ma, Meng Zhao, Jiaxing Wang, Jianhang Zhang, Shuwei Qin, Ji Ke, Lvbing Fan, Wanting Yang, Wenjie Shen, Yaqian Lu, Mingqiang Bao, Aiping Cao, Hongbin Li and Asigul Ismayil

Genes 2025, 16(8), 961; https://doi.org/10.3390/genes16080961 - 14 Aug 2025

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Abstract

Background/Objectives: RAB11 (RABA) is a type of RAB GTPase. RAB GTPases are key components of membrane trafficking mechanisms, Rab11 is implicated in a variety of biological developmental processes and responses to biotic and abiotic stresses. Nevertheless, the role of Rab11 in the [...] Read more.

Background/Objectives: RAB11 (RABA) is a type of RAB GTPase. RAB GTPases are key components of membrane trafficking mechanisms, Rab11 is implicated in a variety of biological developmental processes and responses to biotic and abiotic stresses. Nevertheless, the role of Rab11 in the defense mechanisms of cotton against Verticillium dahliae (V. dahliae) remains to be elucidated. Methods: In the present study, by analyzing the transcriptome data of Gossypium hirsutum (G. hirsutum) infected with V. dahliae, in combination with gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the research focused on endocytosis. Further, through bioinformatics approaches, the endocytosis-related gene Rab11 was identified. We conducted a genome-wide identification and analysis of Rab11 in G. hirsutum. In addition, by integrating transcription factor (TF) prediction, prediction of protein–protein interactions (PPI) and quantitative real-time polymerase chain reaction (qRT-PCR), the gene expression of Rab11 at different infection periods of V. dahliae (0, 24 and 72 hpi) were analyzed and validated. Results: The analysis of transcriptome data revealed that the endocytosis pathway is implicated in the stress response of cotton to V. dahliae. Additionally, three Rab11 genes were identified as being involved in this stress response. Phylogenetic analysis revealed that the 65 genes in the Rab11 family could be divided into four subgroups, each with similar gene structures and conserved motif patterns. Conclusions: The downregulation of Rab11 in G. hirsutum is closely linked to its defense against V. dahliae. TF prediction coupled with PPI offers a roadmap for dissecting the signaling pathways, functional validation, and network construction of the three GhRab11 genes. Full article

(This article belongs to the Special Issue Physiological and Molecular Mechanisms of Plant Stress Response)

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Genes, Volume 16, Issue 8 (August 2025) – 142 articles

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