Genes

22 pages, 86801 KB

Open AccessArticle

Transcriptome Sequencing Unveils a Novel Mechanism Underlying Breed Distinctions Between Thin- and Fat-Tailed Sheep

by Lei Gao, Yunyun Zhang, Yiyuan Zhang, Weifeng Peng, Zhenliang Zhang, Yucheng Liu, Jingjing Wang, Pengcheng Wan and Zongsheng Zhao

Genes 2026, 17(2), 162; https://doi.org/10.3390/genes17020162 (registering DOI) - 30 Jan 2026

Abstract

Background: Sheep (Ovis aries) tail fat serves as a crucial energy reserve for adapting to harsh environments. However, excessive deposition can reduce farming efficiency and product quality. Elucidating the regulatory mechanisms of tail fat deposition is of great significance for genetic [...] Read more.

Background: Sheep (Ovis aries) tail fat serves as a crucial energy reserve for adapting to harsh environments. However, excessive deposition can reduce farming efficiency and product quality. Elucidating the regulatory mechanisms of tail fat deposition is of great significance for genetic improvement in sheep. Methods: In this study, transcriptome sequencing was conducted on tail fat tissues from fat-tailed Kazakh sheep (KAZ), thin-tailed Suffolk sheep (SFK), and their F2 hybrid sheep (CSH) (3 individuals per group). Subsequently, qRT-PCR validation, Enrichr, and KEGG database analyses were performed to investigate the molecular pathways involved in tail fat deposition. Results: High-quality clean reads were obtained from sequencing, with a genome alignment rate ranging from 76.15% to 79.43% and good data reproducibility. Differential expression analysis revealed multiple differentially expressed genes (DEGs) between KAZ and CSH groups, KAZ and SFK groups, as well as SFK and CSH groups. Five core candidate genes (BDH1, EPHX1, BCAT2, FASN, ACACA) were identified, all enriched in the fatty acid synthesis pathway and highly expressed in fat-tailed sheep, which was confirmed by qRT-PCR. Additionally, 189 lncRNAs were identified to collectively regulate target genes (e.g., FABP family, AGPAT2), along with three common differentially expressed miRNAs (novel_120, novel_171, novel_440) targeting genes enriched in lipid transport and lipid droplet formation pathways. Conclusions: This study confirms that the lncRNA-mRNA-miRNA regulatory axis is a key pathway in tail fat formation, providing important theoretical support and molecular targets for genetic improvement of ovine tail fat deposition traits. Full article

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

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19 pages, 2417 KB

Open AccessArticle

The Repeatome in the Mega-Genus Epidendrum L. (Epidendroideae, Orchidaceae): An In Silico Comparative Analysis

by Ana Carolina Humberto, Magdalena Vaio and Ana Paula Moraes

Genes 2026, 17(2), 161; https://doi.org/10.3390/genes17020161 - 30 Jan 2026

Abstract

Background/Objectives: Variation in repeatome composition is a major determinant of genome architecture and an important substrate for evolutionary change in plants. Despite the availability of genomic sequence data, repeatome-wide assessments have not been performed for Epidendrum, the largest Neotropical genus of Orchidaceae. [...] Read more.

Background/Objectives: Variation in repeatome composition is a major determinant of genome architecture and an important substrate for evolutionary change in plants. Despite the availability of genomic sequence data, repeatome-wide assessments have not been performed for Epidendrum, the largest Neotropical genus of Orchidaceae. Here, we assessed repeatome profiles across 34 Epidendrum species using publicly available genomic datasets. Methods:Epidendrum repeatomes were characterized with the RepeatExplorer2 pipeline, and patterns of repeat composition were evaluated for phylogenetic structure using a species phylogeny. Results: Repeat composition showed no clear phylogenetic structure, with closely related species often displaying divergent satDNA and TE profiles. satDNA content varied widely among species (15.5–69% of the repeatome fraction). A total of 208 satDNA families were detected, which were used to build a custom database for comparative analyses. We detected 73 satDNA clusters shared among species, whereas only three were species-specific. Regarding TEs, Class I elements were the most abundant repeats, dominated by Ty3-Gypsy LTR retrotransposons. Only two Class II TIR superfamilies were detected (EnSpm/CACTA and hAT). Conclusions: This study provides the first comprehensive characterization of the Epidendrum repeatome and establishes a resource for future work on cytogenomic diversity within this megagenus. The heterogeneous distribution of repeats among closely related species is consistent with lineage-specific amplification and loss, highlighting rapid repeatome turnover in Epidendrum. Potential drivers, as hybridization and ecological differentiation, should be tested explicitly in future analyses integrating broader genome size sampling and trait data. Full article

(This article belongs to the Section Cytogenomics)

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7 pages, 587 KB

Open AccessCase Report

Genotype-Phenotype Delineation of Autoimmune Polyendocrinopathy, Candidiasis, and Ectodermal Dystrophy in a Pediatric Patient: A Case Report

by Rima Hanna-Wakim, Pascale E. Karam, Mazen Kurban and Nadine Yazbeck

Genes 2026, 17(2), 160; https://doi.org/10.3390/genes17020160 - 29 Jan 2026

Abstract

Background/Objectives: Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy is an extremely rare autosomal recessive disorder caused by inborn errors of immunity. It is due to a loss-of-function mutation in the AIRE autoimmune regulator gene. Its manifestations include autoimmunity affecting endocrine glands, in addition [...] Read more.

Background/Objectives: Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy is an extremely rare autosomal recessive disorder caused by inborn errors of immunity. It is due to a loss-of-function mutation in the AIRE autoimmune regulator gene. Its manifestations include autoimmunity affecting endocrine glands, in addition to non-endocrine manifestations including dental enamel hypoplasia, alopecia areata, hepatitis, and chronic mucocutaneous candidiasis. Globally, 10 cases per million are affected by this condition, with higher incidence in highly consanguineous populations. Here, we describe a novel AIRE gene mutation in a pediatric patient from Lebanon, along with the observed phenotype. Method: A nine-year-old boy with history of craniosynostosis presented with jaundice. His past medical history was significant for recurrent oral thrush, keratoconjunctivitis, nail dystrophy, and alopecia. Upon presentation, he had jaundice, isolated splenomegaly, and severe failure to thrive. Laboratory tests showed transaminitis, cholestasis, and hypergammaglobulinemia. Abdominal ultrasound findings were suggestive of cirrhosis with compensated portal hypertension. The differential diagnosis included viral infection, inborn errors of metabolism, and autoimmune hepatitis. Results: Exome sequencing identified a novel homozygous pathogenic variant in the AIRE gene, NM_000383.4: c.1066dup p.(Arg356Profs*16), confirming the diagnosis. Conclusions: This study expands the genotypic and phenotypic spectrum of a rare inborn error of immunity in a child with chronic mucocutaneous candidiasis, enamel hypoplasia, and hepatitis. Full article

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

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20 pages, 1315 KB

Open AccessArticle

CELF1 Downregulation Promotes Cardiomyocyte Hypertrophy via Regulating Alternative Splicing of Tead1

by Lingjie Hu, Kaili Zhu, Siying Zeng, Yiqiao Liu, Shengqi Zhang and Le Ni

Genes 2026, 17(2), 159; https://doi.org/10.3390/genes17020159 - 29 Jan 2026

Abstract

Background/Objectives: The RNA-binding protein CELF1 is crucial for cardiac development, but its role in cardiomyocyte hypertrophy is unclear. This study investigates the effects of acute CELF1 knockdown on alternative splicing and hypertrophic growth in cardiomyocytes. Methods: Neonatal rat cardiomyocytes (NRCMs) were transfected with [...] Read more.

Background/Objectives: The RNA-binding protein CELF1 is crucial for cardiac development, but its role in cardiomyocyte hypertrophy is unclear. This study investigates the effects of acute CELF1 knockdown on alternative splicing and hypertrophic growth in cardiomyocytes. Methods: Neonatal rat cardiomyocytes (NRCMs) were transfected with two siRNAs targeting CELF1. Hypertrophy was assessed by cell size and expression of hypertrophic markers via qPCR and Western blot. RNA sequencing was performed in NRCMs to identify alternative splicing events. Tead1 function was tested by knockdown in NRCMs. Selected mechanistic assays were performed primarily in HeLa cells. Results: CELF1 knockdown in NRCMs increased cardiomyocyte size and upregulated hypertrophic markers, while its overexpression restored the phenotype. RNA-seq revealed that CELF1 knockdown alters the alternative splicing pattern. Specifically, the splicing of the transcription factor Tead1 shifted from the full-length long Tead1 isoform (Tead1-L) to the exon 4-skipped short isoform (Tead1-S). In HeLa cells, CELF1 interacted with hnRNPC, an m⁶A reader and splicing factor, and CELF1 perturbation correlated with changes in global m⁶A abundance. Conclusions: These findings suggest that CELF1 regulates hypertrophic phenotypes in cardiomyocytes and is associated with alternative splicing of Tead1. Full article

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

17 pages, 2364 KB

Open AccessArticle

Genome-Wide Identification and Expression Analysis of Tubby-like Proteins (TLPs) in Fragaria × ananassa Reveals Their Role in Abiotic Stress Responses

by Pedro Fernández-Roldán, M. Dolores Moreno-Recio, Facundo Spadoni-Revol, Francisco J. Molina-Hidalgo, José L. Caballero, Juan Muñoz-Blanco, Rosario Blanco-Portales and Enriqueta Moyano

Genes 2026, 17(2), 158; https://doi.org/10.3390/genes17020158 - 29 Jan 2026

Abstract

Background: Cultivated strawberry (Fragaria × ananassa) is one of the most valuable horticultural crops worldwide. Nevertheless, its productivity is increasingly constrained by high susceptibility to adverse environmental conditions, which are intensified by climate change. Drought represents a major limitation, often accompanied [...] Read more.

Background: Cultivated strawberry (Fragaria × ananassa) is one of the most valuable horticultural crops worldwide. Nevertheless, its productivity is increasingly constrained by high susceptibility to adverse environmental conditions, which are intensified by climate change. Drought represents a major limitation, often accompanied by water deficiency and elevated soil salinity. Plants counteract such abiotic stresses through complex molecular defense mechanisms involving transcription factors that regulate stress-responsive gene expression. Methods: In this study, we conducted a systematic bioinformatic analysis of the Tubby-like protein (TLP) transcription factor family in Fragaria × ananassa. RT-qPCR was used to analyze the expression patterns of FaTLP genes under different conditions to elucidate their potential roles in stress adaptation. Results: Eight FaTLP genes were identified in each of the four subgenomes, most of which retained the characteristic TUBBY and F-box domains. Gene expression profiling revealed that several FaTLP genes were differentially expressed in leaves under drought and salt stress, with FaTLP2 and FaTLP7 exhibiting strong induction. In addition, the expression of FaTLP2 and FaTLP7 under various oxidative and signaling-related treatments, as well as in different tissues of strawberry plants were analyzed. Promoter analysis identified multiple cis-regulatory elements associated with phytohormone signaling and abiotic stress responses, such as ABRE, MYB, and MYC motifs. Phylogenetic analysis showed that FaTLP2 and FaTLP7 share high sequence similarity with orthologous TLPs from other plant species known for enhanced stress tolerance, suggesting that these proteins may play conserved roles in the molecular mechanisms underlying drought and salinity resilience. Conclusions: This study provides valuable insights into the potential roles of FaTLPs in regulating environmental signal transduction and transcriptional control, contributing to abiotic stress tolerance in Fragaria × ananassa. Full article

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

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11 pages, 709 KB

Open AccessArticle

Complexity of Inheritance of Pathogenic Mutations Associated with Epilepsy in Consanguine Families from Pakistan

by Khajista Tahira, Anwar Ullah, Fazl Ullah, Jeena Aziz, Muhammad Ishaq Javed, Aasma Kiyani, Azra Khanum, Kerstin Hallmann, Tobias Baumgartner, Rainer Surges, Pakeeza Arzoo Shaiq and Wolfram S. Kunz

Genes 2026, 17(2), 157; https://doi.org/10.3390/genes17020157 - 29 Jan 2026

Abstract

Background/Objectives: Consanguine families are helpful to identify recessive candidate genes for inherited diseases, but can also show an unusual inheritance pattern of pathogenic mutations. In this case series, we demonstrate this in five consanguine families with epilepsy from Pakistan. Methods: We [...] Read more.

Background/Objectives: Consanguine families are helpful to identify recessive candidate genes for inherited diseases, but can also show an unusual inheritance pattern of pathogenic mutations. In this case series, we demonstrate this in five consanguine families with epilepsy from Pakistan. Methods: We performed whole exome sequencing of respective index patients, analyzed the data using two different models for inheritance of mutations and determined the segregation pattern of relevant mutations in the families by bi-directional Sanger sequencing. Results: Apart from mutations in classical dominant epilepsy genes (TSC2, DEPDC5, and CACNA1I), pathogenic mutations in rare recessive epilepsy-related genes (PGAP2, NOVA2, and CCDC88C) were also identified. Interestingly, we were able to provide evidence that GALR2 is potentially an additional gene associated with a recessive form of epilepsy. In one family, a homozygous ‘pathogenic’ TRAF3IP1 p. Gly387* nonsense mutation was identified, which, most probably due to stop-codon read-through, did not contribute to the phenotype. Conclusions: Our case series of consanguine families with epilepsy exemplifies the inheritance pattern of mutations in rare recessive epilepsy genes, and shows that mutations in classical epilepsy genes showing dominant or sporadic inheritance can also be relevant. That requires the analysis of whole exome data on the basis of different inheritance models. Full article

(This article belongs to the Special Issue Molecular Genetics of Neurodevelopmental Disorders: 2nd Edition)

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18 pages, 2001 KB

Open AccessArticle

RNAi-Induced Expression of Paternal UBE3A

by Hye Ri Kang, Violeta Zaric, Volodymyr Rybalchenko, Steven J. Gray and Ryan K. Butler

Genes 2026, 17(2), 156; https://doi.org/10.3390/genes17020156 - 29 Jan 2026

Abstract

Background/Objectives: Angelman syndrome is a neurodevelopmental disorder resulting from a deficiency of the maternally inherited UBE3A gene. In mature neurons, UBE3A expression is restricted to the maternal allele due to tissue-specific genomic imprinting, while the paternal allele is silenced in cis by the [...] Read more.

Background/Objectives: Angelman syndrome is a neurodevelopmental disorder resulting from a deficiency of the maternally inherited UBE3A gene. In mature neurons, UBE3A expression is restricted to the maternal allele due to tissue-specific genomic imprinting, while the paternal allele is silenced in cis by the UBE3A antisense transcript (UBE3A-ATS). To date, numerous strategies have been employed to activate paternal UBE3A expression. In this study, we utilized RNA interference (RNAi) to investigate the downregulation of UBE3A-ATS in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons. Methods: To induce paternal UBE3A expression, we employed small interfering RNA (siRNA) oligonucleotides (20 mouse candidates and 47 human candidates) and lentiviral short hairpin RNA (LV-shRNA) targeting SNORD115 to suppress UBE3A-ATS expression in both mouse primary neurons and iPSCs. Subsequently, we assessed the expression levels of Angelman syndrome-related neighboring and target genes at the transcript and, where applicable, protein levels. Results: Following treatment with siSnord115 or LV-shSnord115, we observed a reduction in Ube3a-ATS and a corresponding activation of paternal Ube3a RNA and protein expression in both Ube3a^P-YFP/m+ and Ube3a^p+/m− mouse primary neurons. A similar effect was observed upon treatment with LV-shSNORD115s in human iPSC-derived neurons. Conclusions: shRNA-mediated inhibition of Ube3a-ATS by targeting Snord115 effectively restores Ube3a/UBE3A expression in both mouse neurons and human iPSCs. While promising, the mild reduction in Snord116 raises concerns about potential off-target effects. AAV-based delivery of shRNA shows potential, but its translational applicability remains to be evaluated in vivo. Full article

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

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13 pages, 694 KB

Open AccessArticle

Assessing Genetic Risk for Physical Activity and Its Interaction with Diet in Predicting Activity Levels and Weight Loss in the iMPROVE Study

by Maria Kafyra, Panagiotis Symianakis, Ioanna Panagiota Kalafati, Panagiotis Moulos and George V. Dedoussis

Genes 2026, 17(2), 155; https://doi.org/10.3390/genes17020155 - 29 Jan 2026

Abstract

Background: Physical activity (PA) and weight regulation are influenced by both genetic and lifestyle factors. This study aimed to evaluate the predictive value of Polygenic Risk Scores (PRSs) for PA and weight outcomes, and their interaction with dietary habits. Methods: Baseline phenotypic data [...] Read more.

Background: Physical activity (PA) and weight regulation are influenced by both genetic and lifestyle factors. This study aimed to evaluate the predictive value of Polygenic Risk Scores (PRSs) for PA and weight outcomes, and their interaction with dietary habits. Methods: Baseline phenotypic data from 202 participants enrolled in the iMPROVE study were analyzed. The sample included 59 men and 143 women, aged 19–65 years. Based on baseline Body Mass Index (BMI), 75 participants were classified as having overweight and 126 as having obesity. Polygenic risk scores (PRSs) were calculated for 197 participants with available genetic data. PA was operationalized as metabolic equivalent of task minutes per week (MET-mins/week), derived from self-reported activity questionnaires. Weight-related outcomes included log-transformed weight loss from baseline to month 3 and change in BMI post-intervention. Interactions with diet were examined using both the randomized intervention dietary groups and previously extracted dietary patterns from the iMPROVE cohort. Correlation analyses and linear regression models were used to assess the main effects of PRSs and dietary patterns, as well as gene–diet interactions. Results: The measured PA PGS002254 presented a nominal significant interaction with diet group for weight loss post-intervention (B = 7.57, SE = 3.57 × 10⁰, p = 0.04; R² = 0.06). Similarly, the sedentary behavior PGS001923 presented a significant interaction with the “High in unsaturated fats and fruit juice consumption” pattern for baseline MET-mins/week (B = 1.51 × 10³, SE = 4.135 × 10², p = 0.001; R² = 0.091). Conclusions: Genetic predisposition influences short-term activity and weight outcomes, with dietary patterns moderating these effects. However, the multifactorial nature of lifestyle behaviors is being underscored by the modest variance explained. Full article

(This article belongs to the Special Issue Application of Genome-Wide Association Studies in Rare Diseases Research)

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16 pages, 2948 KB

Open AccessArticle

The Clinical Details of MYH9-Related Disease and DFNA17 in a Large Japanese Hearing Loss Cohort

by Shinichi Goto, Akira Sasaki, Shin-ya Nishio, Chikako Shinkawa, Kiyoshi Oda, Tetsuro Wada, Kotaro Ishikawa, Tetsuo Ikezono, Shin-ichiro Oka, Nobuhiro Nishiyama, Taku Ito, Marina Kobayshi, Kozo Kumakawa, Naoko Sakuma, Hiroshi Nakanishi, Chihiro Morimoto, Natsumi Uehara, Testuya Okazaki, Kazuma Sugahara, Takeshi Nakamura and Shin-ichi Usami Show full author list Hide full author list

Genes 2026, 17(2), 154; https://doi.org/10.3390/genes17020154 - 29 Jan 2026

Abstract

Background/Objectives: MYH9 gene variants cause MYH9-related disease (MYH9-RD), which is also known as Epstein syndrome, Fechtner syndrome, May–Hegglin anomaly, and Sebastian syndrome. MYH9-RD is characterized by sensorineural hearing loss, macrothrombocytopenia, thrombocytopenia, hematuria/proteinuria, glomerulonephritis, cataracts purpura, and mucosal bleeding. [...] Read more.

Background/Objectives: MYH9 gene variants cause MYH9-related disease (MYH9-RD), which is also known as Epstein syndrome, Fechtner syndrome, May–Hegglin anomaly, and Sebastian syndrome. MYH9-RD is characterized by sensorineural hearing loss, macrothrombocytopenia, thrombocytopenia, hematuria/proteinuria, glomerulonephritis, cataracts purpura, and mucosal bleeding. In addition, the MYH9 gene is also known to be causative of autosomal dominant non-syndromic hearing loss (DFNA17). MYH9-RD is a relatively rare disorder, and the detailed clinical features and mutational spectra remain unclear. Methods: In this study, we performed next-generation sequencing analysis for 15,684 hearing loss patients and identified MYH9-associated hearing loss patients. Detailed clinical information was collected for these patients and summarized. Results: In this study, we identified 24 patients from 18 families with MYH9-associated hearing loss. We clarified the details of hearing deterioration observed in patients based on collected serial audiogram data. Some cases showed rapid hearing deterioration that worsened by about 50 dB within 5 years. Hearing loss is more likely to progress in patients with myosin head domain variants than in patients with myosin tail domain variants, but hearing loss in each set of patients finally deteriorates to bilateral profound hearing loss. Conclusions: In this study, we were able to clarify the detailed characteristics of MYH9-RD- and DFNA17-related hearing loss in a relatively large number of patients, particularly in some cases that showed rapid and asymmetrical hearing deterioration progressing to bilateral profound hearing loss. Our data will be useful for providing more appropriate treatment and follow-up for MYH9-associated hearing loss. Full article

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

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14 pages, 823 KB

Open AccessReview

Genomic Subtypes and Computational Biomarkers in Non-Muscle-Invasive Bladder Cancer Guiding Optimal Timing of Radical Cystectomy and BCG Response Prediction

by Vlad-Horia Schițcu, Vlad Cristian Munteanu, Mihnea Bogdan Borz, Ion Cojocaru, Octavia Morari, Mircea Gîrbovan and Andrei-Ionuț Tișe

Genes 2026, 17(2), 153; https://doi.org/10.3390/genes17020153 - 29 Jan 2026

Abstract

Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 70% of newly diagnosed bladder cancer cases but exhibits significant clinical heterogeneity in treatment response and progression risk. While intravesical bacillus Calmette–GuérinCa (BCG) therapy remains the gold standard for high-risk disease, approximately 30–50% of patients experience [...] Read more.

Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 70% of newly diagnosed bladder cancer cases but exhibits significant clinical heterogeneity in treatment response and progression risk. While intravesical bacillus Calmette–GuérinCa (BCG) therapy remains the gold standard for high-risk disease, approximately 30–50% of patients experience BCG failure, creating a critical decision point between additional bladder-sparing therapy (BST) and early radical cystectomy (RC). Recent clinical data from the CISTO study suggest that, in appropriately selected patients, RC may be associated with higher 12-month recurrence-free survival while maintaining comparable cancer-specific survival and physical functioning. In this narrative review, we synthesize contemporary evidence on NMIBC genomic and transcriptomic subtypes, immune contexture, and clinicopathologic features associated with BCG response and progression risk, with emphasis on clinically oriented classification systems such as BCG Response Subtypes (BRS1–3) and UROMOL21. We highlight how tumor-intrinsic biology (e.g., EMT-associated programs), immune phenotypes (inflamed vs. immune-cold microenvironments), and genomic alterations may help refine risk stratification beyond traditional clinicopathologic models. To facilitate clinical integration, we propose a conceptual decisional framework that combines molecular subtype assignment, immune profiling, key pathologic risk factors, and patient considerations to generate probabilistic risk tiers that support selection among early RC, BST, and clinical trial strategies. Standardized multicenter cohorts and prospective evaluation are needed to validate integrated models and define their clinical utility for the precision timing of cystectomy in BCG-unresponsive NMIBC. Full article

(This article belongs to the Special Issue Computational Genomics and Bioinformatics of Cancer)

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17 pages, 1922 KB

Open AccessArticle

Foundations of an Ovine Model of Fragile X Syndrome

by Victoria Hawkins, Skye R. Rudiger, Clive J. McLaughlan, Jennifer M. Kelly, Klaus Lehnert, Jessie C. Jacobsen, Renee R. Handley, Kimiora Henare, Paul J. Verma and Russell G. Snell

Genes 2026, 17(2), 152; https://doi.org/10.3390/genes17020152 - 28 Jan 2026

Abstract

Background: Fragile X Syndrome (FXS) is an X-linked neurodevelopmental disorder characterised by intellectual disability, developmental delays, anxiety, and social and behavioural challenges. Currently, no effective treatments exist to address the root cause of FXS. Mouse models are the most widely used for studying [...] Read more.

Background: Fragile X Syndrome (FXS) is an X-linked neurodevelopmental disorder characterised by intellectual disability, developmental delays, anxiety, and social and behavioural challenges. Currently, no effective treatments exist to address the root cause of FXS. Mouse models are the most widely used for studying molecular pathogenesis and conducting preclinical treatment testing. However, therapeutic interventions that show promise in rodent models have yet to succeed in clinical trials. After evaluating the current models, we have developed an ovine model to address this clinical translation gap. We expect this model to more accurately reflect the human condition in brain size, structure, and neurodevelopmental trajectory. We aim to establish this model as a valuable preclinical platform for testing therapies for FXS. Methods: To generate the sheep model, we used CRISPR-Cas9 dual-guide editing to knock out the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene in ovine embryos. Results: Two founder animals were created, one ram (male) and one ewe (female), both of which carried FMR1 gene knockouts. The ewe carries inactivating mutations on both alleles, with the edits in both animals resulting in no detectable Fragile X Messenger Ribonucleoprotein (FMRP) as expected. Both founders have undergone molecular characterisation and basic health checks, with the female founder showing increased joint flexibility, a characteristic of FXS. The ram has been used for breeding, with the successful transmission of the edited allele to his offspring. Importantly, specific lamb cohorts for postnatal treatment testing can be produced efficiently utilising accelerated breeding methods and preimplantation selection. Full article

(This article belongs to the Special Issue Fragile X Syndrome and Fragile X Premutation Associated Conditions)

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26 pages, 1925 KB

Open AccessReview

Nuclear and Mitochondrial Epigenetic Mechanisms Underlying Neurodegeneration and Gut–Brain Axis Dysregulation Induced by Micro- and Nanoplastics

by Dragica Pavlovic, Dragana Papic, Vladimir Janjic, Marina Mitrovic, Milica Dimitrijevic Stojanovic and Marina Gazdic Jankovic

Genes 2026, 17(2), 151; https://doi.org/10.3390/genes17020151 - 28 Jan 2026

Abstract

The increasing and global distribution of microplastics and nanoplastics (MPs/NPs) in the environment has led to concern about their potential influence on human health, especially on the gastrointestinal tract, as well as the brain. MPs/NPs could traverse epithelial and endothelial barriers, disrupt the [...] Read more.

The increasing and global distribution of microplastics and nanoplastics (MPs/NPs) in the environment has led to concern about their potential influence on human health, especially on the gastrointestinal tract, as well as the brain. MPs/NPs could traverse epithelial and endothelial barriers, disrupt the gut microbiota, and perturb the microbiota–gut–brain axis, leading to systemic inflammation and possibly extending neurodegenerative processes. Experimental models now demonstrate that MPs/NPs reprogram nuclear and mitochondrial epigenetics—DNA methylation, histone modifications, non-coding RNAs, and mitochondrial DNA regulation—in gut, immune, and neural cells with downstream effects on synaptic function, neuronal survival, and protein aggregation. This mechanistic narrative review integrates preclinical and emerging human evidence of how MPs/NPs compromise intestinal barrier integrity, modulate gut microbiota composition, affect the blood–brain barrier, and converge on oxidative stress, neuroinflammatory signaling, and cell death pathways within the central nervous system across key neurodegenerative diseases. Overall, the review offers an integrated model in which environmental exposure to chronic MPs/NPs disrupts the microbiota–gut–brain axis and drives concurrent nuclear and mitochondrial epigenetic remodeling, lowering the threshold for neurodegeneration in susceptible individuals, while outlining candidate mechanistic readouts that require exposure-specific validation in human-relevant models and longitudinal cohorts. Full article

(This article belongs to the Special Issue The Development of Genetic Assessment for Neurotoxicity)

22 pages, 2376 KB

Open AccessArticle

Genetically Shared Signatures Between COVID-19 and Cancer Identified Through In Silico Case–Control Analysis

by Ammar Yasir Ahmed Ahmed and Sevinç Akçay

Genes 2026, 17(2), 150; https://doi.org/10.3390/genes17020150 - 28 Jan 2026

Abstract

Background/Objectives: Cancer patients are highly susceptible to infectious diseases due to malignancy- and treatment-induced immunosuppression. The coronavirus disease 2019 (COVID-19) pandemic highlighted this vulnerability, particularly in aggressive tumors such as triple-negative breast cancer (TNBC) and clear cell renal cell carcinoma (ccRCC). However, the [...] Read more.

Background/Objectives: Cancer patients are highly susceptible to infectious diseases due to malignancy- and treatment-induced immunosuppression. The coronavirus disease 2019 (COVID-19) pandemic highlighted this vulnerability, particularly in aggressive tumors such as triple-negative breast cancer (TNBC) and clear cell renal cell carcinoma (ccRCC). However, the molecular mechanisms linking cancer progression with COVID-19 severity remain poorly defined. This study aimed to identify shared molecular signatures between COVID-19 and TNBC, breast cancer, and ccRCC using integrative bioinformatics approaches. Methods: A comprehensive in silico case–control analysis was conducted using publicly available GEO transcriptomic datasets (GSE164805, GSE139038, GSE45498, and GSE105261). Differentially expressed genes (DEGs) were identified by comparing mild and severe COVID-19 cases with each cancer type. Protein–protein interaction (PPI) networks were constructed to identify hub genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Regulatory networks involving microRNAs (miRNAs) and transcription factors (TFs) were also examined. Results: Shared hub genes were identified across COVID-19 and cancer datasets, including IGF1, MMP9, and NOTCH1 in TNBC; TOP2A, PXN, and CCNB1 in breast cancer; and ASPM and TTK in ccRCC. These genes are linked to immune regulation, inflammation, cell cycle control, and tumor progression. Enrichment analyses revealed convergent pathways such as MAPK signaling, cytokine–cytokine receptor interaction, Ras signaling, and proteoglycans in cancer. Key regulatory molecules, including miR-145-5p, miR-192-5p, miR-335-5p, and transcription factors NFKB1, BRCA1, and TP53, modulated both viral and oncogenic processes. Severe COVID-19 was associated with enhanced inflammatory and proliferation-related signaling across all cancer types. Conclusions: This integrative, severity-stratified analysis identifies shared molecular and regulatory features linking severe COVID-19 with aggressive cancers, highlighting persistent immune activation and altered immune communication as common underlying themes without implying causality or clinical outcome effects. These findings provide a systems-level, hypothesis-generating framework for understanding virus–cancer interactions and may inform future biomarker discovery and immune-focused therapeutic strategies in vulnerable cancer populations. Full article

(This article belongs to the Section Bioinformatics)

15 pages, 17617 KB

Open AccessArticle

Comparative Chloroplast Genome Analyses Reveal a Fine-Scale Phylogenetic Framework and Cryptic Diversity in the Fagopyrum dibotrys Complex (Polygonaceae)

by Yi-Ming Wei, Xiao-Ting Xie, Shu-Qing Lei and Bo Li

Genes 2026, 17(2), 149; https://doi.org/10.3390/genes17020149 - 28 Jan 2026

Abstract

Background/Objectives: The Fagopyrum dibotrys complex is a specialized high-altitude lineage in southwestern China with medicinal and breeding potential, but species delimitation remains unresolved. Methods: We sequenced 26 complete chloroplast genomes from the Hengduan Mountains to the Yunnan–Guizhou Plateau, analyzing genomic structures, variation patterns, [...] Read more.

Background/Objectives: The Fagopyrum dibotrys complex is a specialized high-altitude lineage in southwestern China with medicinal and breeding potential, but species delimitation remains unresolved. Methods: We sequenced 26 complete chloroplast genomes from the Hengduan Mountains to the Yunnan–Guizhou Plateau, analyzing genomic structures, variation patterns, and phylogenetic relationships. Results: All genomes exhibited typical quadripartite structures (152,213–160,302 bp), containing 133 genes (88 protein-coding, 8 rRNA, and 37 tRNA) with GC content of 37.9%. Collinearity analysis revealed highly conserved structures without structural rearrangements. Variations were concentrated in the large single-copy(LSC)/small single-copy(SSC) non-coding regions, with hotspots at ycf4–cemA and ndhF–rpl32. Codon usage showed an A/U bias, with leucine being most abundant and cysteine the least. Simple sequence repeats (SSRs) were predominantly mononucleotide repeats enriched in the LSC, while long repeats were mainly palindromic/forward. Maximum likelihood and Bayesian phylogenies consistently resolved three clades: Tibetan high-altitude specialists, limestone specialists, and a widespread Hengduan–Yunnan–Guizhou clade, with geographic clustering indicating isolation as the primary differentiation driver. Conclusions: This study refines the phylogenetic resolution of the F. dibotrys complex and identifies informative chloroplast markers, providing a genomic foundation for reliable species delimitation, evolutionary inference, and conservation management of this medicinal lineage. Full article

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

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13 pages, 248 KB

Open AccessArticle

Heritability Estimates of Traits Assessed in Field Performance Tests of Polish Warmblood Mares

by Dorota Lewczuk, Alicja Borowska, Małgorzata Maśko and Emilia Bagnicka

Genes 2026, 17(2), 148; https://doi.org/10.3390/genes17020148 - 28 Jan 2026

Abstract

Background/objectives: Knowledge of the genetic background of evaluated traits has been the basis for genetic progress in every horse-breeding population and is essential for precise breeding and up-to-date decision-making. The study aimed to estimate the heritability coefficients for field performance traits in [...] Read more.

Background/objectives: Knowledge of the genetic background of evaluated traits has been the basis for genetic progress in every horse-breeding population and is essential for precise breeding and up-to-date decision-making. The study aimed to estimate the heritability coefficients for field performance traits in mares. Methods: The research was based on 1408 evaluations of mares conducted during the years 2002–2021 in 51 training centers in Poland. The preliminary analyses of the effects, significant for the investigated traits, were obtained using analysis of variance, and these additional data are also presented (SAS program, GLM and Mixed procedures). The final statistical model for the AI-REML procedure of the DMU program included a fixed effect of the training center-season-year of evaluation, a random effect of the animal, and a regression on age in years. Results: The heritability coefficients of the performance traits were moderate to high (0.32–0.60) with the SE within the range of 0.06–0.08. The highest heritability was estimated for the free jumping, trot, and overall results. The lowest heritability was achieved for the rideability. Conclusions: The level of heritability estimations allowed for the population progress in the evaluated traits. Full article

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

31 pages, 25746 KB

Open AccessArticle

Integrated Physiological and Multi-Omics Analyses Reveal the Coordinated Regulation of Carbon and Nitrogen Metabolism in Rapeseed (Brassica napus L.) Tolerance to Saline-Alkaline Stress

by Li He, Weichao Wang, Chenhao Zhang and Fenghua Zhang

Genes 2026, 17(2), 147; https://doi.org/10.3390/genes17020147 - 28 Jan 2026

Abstract

Background/Objectives: Soil salinization and alkalization critically limit global agricultural production. This study aimed to investigate the differential response mechanisms of rapeseed (Brassica napus L.) varieties to saline and alkaline stresses at the seedling stage. Methods: Seedlings of a salt-tolerant variety, Huayouza 62 [...] Read more.

Background/Objectives: Soil salinization and alkalization critically limit global agricultural production. This study aimed to investigate the differential response mechanisms of rapeseed (Brassica napus L.) varieties to saline and alkaline stresses at the seedling stage. Methods: Seedlings of a salt-tolerant variety, Huayouza 62 (H62), and a non-salt-tolerant variety, Xiangyou 15 (X15), were exposed to saline (NaCl:Na₂SO₄ = 1:1) and alkaline (Na₂CO₃:NaHCO₃ = 1:1) stresses. An integrated analysis combining physiology, biochemistry, transcriptomics, and metabolomics was conducted to systematically elucidate their differential stress responses. Results: (1) H62 maintained favorable photosynthetic and carbon–nitrogen homeostasis. Notably, under saline and alkaline stresses, the activity of glutamate dehydrogenase (GDH) in H62 showed a significant increasing trend, whereas it was inhibited in X15. (2) Alkaline stress triggered more differential genes than saline stress, with H62 exhibiting broader transcriptional up-regulation in carbon–nitrogen metabolism. (3) Metabolomic profiling showed that H62 accumulated more beneficial metabolites than X15 under both stresses, such as phenolic acids, amino acids, and their derivatives. (4) In multi-omics analysis, key genes in starch–sucrose and amino acid metabolism in H62 were up-regulated to accumulate osmolytes, enabling an efficient defense network. However, X15’s responses were disordered. Conclusions: H62 leverages robust transcriptional reprogramming to coordinate carbon–nitrogen metabolism, constituting a multidimensional defense network. This study provides potential physiological indicators, candidate genes, and metabolite markers associated with short-term saline–alkaline stress responses, laying a foundation for further exploration of stress response mechanisms. Full article

(This article belongs to the Special Issue 5Gs in Crop Genetic and Genomic Improvement: 2025–2026)

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30 pages, 964 KB

Open AccessReview

The Mystery of the Hidden Trace: Emerging Genetic Approaches to Improve Body Fluid Identification

by Dana Macfarlane, Gabriela Roca, Christian Stadler and Sara C. Zapico

Genes 2026, 17(2), 146; https://doi.org/10.3390/genes17020146 - 28 Jan 2026

Abstract

Body fluid identification at crime scenes is the first step in the forensic biology workflow, leading to the identification of the perpetrator and/or, in some cases, the victim. Current methods that are regularly used in forensic criminal evidence analysis utilize well-studied properties of [...] Read more.

Body fluid identification at crime scenes is the first step in the forensic biology workflow, leading to the identification of the perpetrator and/or, in some cases, the victim. Current methods that are regularly used in forensic criminal evidence analysis utilize well-studied properties of each fluid as the foundation of the protocol. Among these approaches, alternative light sources, chemical reactions, lateral flow immunochromatographic tests, and microscopic detection stand out to identify the main body fluids encountered at crime scenes: blood, semen, and saliva. However, these often come with limits for specificity and sensitivity. There is also difficulty with fluid mixtures, environmental degradation, and destruction of the sample by the method used. Other fluids, like vaginal fluid and fecal matter, lack standardized protocols and require innovative ideas for accurate analysis without compromising the sample. Emerging technologies based on molecular methods have been the focus of body fluid research, with emphasis on topics such as mRNA, microRNA, epigenetics, and microbial analysis. Additional information alongside the determination of fluid origin could be an advantage from new molecular techniques, such as the identification of donors from SNP analysis, if regular STR analysis is not possible. Validation studies and the integration of such research have the potential to expand and enhance the laboratory practices of forensic science. This article will provide an overview of the current methods applied in the crime lab for body fluid identification before exploring active research in this field, pointing out the potential of these techniques for application in forensic cases to overcome present issues and expand the variety of body fluids identified. Full article

(This article belongs to the Section Genetic Diagnosis)

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15 pages, 1262 KB

Open AccessArticle

Structural Insights into HLA-DQ–Associated Susceptibility to Celiac Disease Through an Integrated Genetic and In Silico Approach in a Sardinian Population

by Faustina Barbara Cannea, Daniela Diana, Rossano Rossino and Alessandra Padiglia

Genes 2026, 17(2), 145; https://doi.org/10.3390/genes17020145 - 28 Jan 2026

Abstract

Background: Celiac disease (CD) is a multifactorial autoimmune disorder strongly associated with specific HLA class II molecules, particularly HLA-DQ–encoding haplotypes. Although the genetic contribution of these loci is well established, the structural features accompanying allele-specific disease susceptibility remain incompletely explored. Methods: In this [...] Read more.

Background: Celiac disease (CD) is a multifactorial autoimmune disorder strongly associated with specific HLA class II molecules, particularly HLA-DQ–encoding haplotypes. Although the genetic contribution of these loci is well established, the structural features accompanying allele-specific disease susceptibility remain incompletely explored. Methods: In this study, molecular HLA typing was integrated with in silico secondary structure analysis to examine the relationship between genetic predisposition and structural organization of HLA class II molecules in a Sardinian population. A total of 100 patients with CD and 100 healthy controls were genotyped for HLA-DR and HLA-DQ alleles, and allelic and haplotypic distributions were compared between groups. Secondary structure predictions were performed using PSIPRED on selected HLA class II alleles, focusing on groove-forming domains of HLA-DRB1 and HLA-DQA1. Results: CD patients showed a marked enrichment of the DR3–DQ2.5 haplotype, together with a population-specific predominance of DQ2.5 and a reduced contribution of DQ8. Secondary structure analysis of the HLA-DRB1 β1 domain revealed a largely conserved organization, with only modest allele-dependent variations. In contrast, comparative analysis of HLA-DQA1 identified localized differences within the α1 domain, with the DQ2.5 molecule displaying a more coherent secondary structure organization compared with the lower-risk DQ2.2 variant. Conclusions: By integrating genetic and in silico structural analyses, this study highlights that HLA-associated susceptibility to celiac disease reflects not only allele and haplotype distribution but also subtle, allele-specific features in the structural organization of peptide-binding regions. These findings provide a refined framework for interpreting HLA-DQ–mediated genetic risk and support the relevance of structural coherence as a complementary dimension in the assessment of disease susceptibility. Full article

(This article belongs to the Section Bioinformatics)

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25 pages, 1070 KB

Open AccessReview

Driven by Dopamine: Genetic Insights into Motivation and Performance in Sports and Esports

by Natalia Majchrzak, Kinga Humińska-Lisowska and Agata Leońska-Duniec

Genes 2026, 17(2), 144; https://doi.org/10.3390/genes17020144 - 28 Jan 2026

Abstract

Background/Objectives: The dopaminergic system regulates motivation, executive functions, motor learning, and emotional responses—processes that are key in both sport and esports. Although many studies analyse dopaminergic gene polymorphisms, their impact on psychophysical predispositions remains unclear. This narrative review aims to summarise current [...] Read more.

Background/Objectives: The dopaminergic system regulates motivation, executive functions, motor learning, and emotional responses—processes that are key in both sport and esports. Although many studies analyse dopaminergic gene polymorphisms, their impact on psychophysical predispositions remains unclear. This narrative review aims to summarise current knowledge about the mechanisms of dopamine action and genetic determinants that may influence athletic and cognitive performance. Methods: The PubMed, Scopus, and Web of Science databases (publications from January 2010 to December 2025) were searched using keywords related to the DRD1–DRD5, COMT, SLC6A3/DAT1, and TH genes, as well as the terms ‘sport’ and ‘esport.’ Studies of athletes were included in which the relationship between dopaminergic polymorphisms and motivational and personality traits was assessed, and the results of neuroimaging and epigenetic studies were also considered. Results: Dopaminergic polymorphisms are associated with differences in reward processing, cognitive flexibility, motivation, and stress resilience. The most essential critical effects concern the DRD2 and DRD4 variants, which are associated with novelty seeking, reward dependence, and coping with stress. The COMT Val158Met polymorphism affects dopamine levels in the prefrontal cortex, modulating executive functions. The effects of individual polymorphisms are moderate, and conclusions regarding esports remain speculative due to limited research in this area. Conclusions: Dopaminergic predispositions involve interactions among genetics, neural activity, and the environment. However, current evidence is limited by small sample sizes, a predominance of European populations, scarce data on esports players, and difficulties in separating genetic effects from training-related adaptations. Full article

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

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