Genes

19 pages, 1901 KB

Open AccessArticle

The Regulation of p53 by Ubiquitination and Implications for Therapeutic Targeting in Colorectal Cancer

by Ioannis A. Voutsadakis

Genes 2026, 17(3), 270; https://doi.org/10.3390/genes17030270 - 26 Feb 2026

Background: The turnaround of the tumor suppressor p53 protein, the guardian of the genome, is closely regulated to ensure avoidance of its untimely activation, which could lead to the demise of normal cells. Cancer cells often display mutations in the gene TP53 encoding [...] Read more.

Background: The turnaround of the tumor suppressor p53 protein, the guardian of the genome, is closely regulated to ensure avoidance of its untimely activation, which could lead to the demise of normal cells. Cancer cells often display mutations in the gene TP53 encoding for p53, which interferes with its normal function. Methods: The genomic series of colorectal cancer from the Cancer Genome Atlas (TCGA) was interrogated to discover genomic alterations and determine the mRNA expression of enzymes affecting p53 ubiquitination in colorectal cancers with wild-type and mutant TP53. Results: Genomic alterations of p53-regulating E3 ubiquitin ligases were uncommon in colorectal cancers, the most frequent being mutations in RCHY1. Several p53-regulating E3 ligases were well expressed in subsets of colorectal cancers, two of which, MDM2 and TRIM24, displayed higher mRNA expressions than the normal colorectal epithelia. The former was particularly upregulated in TP53 wild-type colorectal cancers, and the latter was upregulated in both wild-type and mutant TP53 cancers. Upregulation of TRIM24 in TP53 mutant cancers was observed independently of the type of mutations (gain-of-function or other). Among E3 ligases used in proteolysis-targeting chimeras (PROTACs), VHL was upregulated together with its E2-conjugating enzyme UBE2S in colorectal cancers. Conclusions: This survey of p53-targeting ubiquitin ligases provides a roadmap for potential therapeutic strategies working by promoting the destruction of the mutant protein or reactivating its normal function in TP53-mutated colorectal cancers and promoting p53 function by preventing degradation in TP53 wild-type cancers. Full article

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

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13 pages, 1744 KB

Open AccessArticle

Distribution of Sequencing Coverage Gaps in Exomes and Genomes: Potential Implications for Diagnostic Accuracy in Neurodevelopmental Disorder Genes

by Emanuela Iovino, Claudia De Masi, Anna Ballestrazzi, Alessandro Mattiaccio, Federica Isidori, Marco Seri and Tommaso Pippucci

Genes 2026, 17(3), 269; https://doi.org/10.3390/genes17030269 - 26 Feb 2026

Abstract

Background: Exome (ES) and genome sequencing (GS) are powerful tools for diagnosing neurodevelopmental disorders (NDDs), yet sequencing coverage failures can leave clinically relevant variants undetected. Analyzing the distribution of coverage gaps across sequencing approaches and batches is therefore informative for diagnostic accuracy. Methods: [...] Read more.

Background: Exome (ES) and genome sequencing (GS) are powerful tools for diagnosing neurodevelopmental disorders (NDDs), yet sequencing coverage failures can leave clinically relevant variants undetected. Analyzing the distribution of coverage gaps across sequencing approaches and batches is therefore informative for diagnostic accuracy. Methods: We analyzed sequencing data from 43 NDD patients across four ES runs, including 14 individuals sequenced by both ES (Twist Human-Core-Exome-v1.3) and GS. Low-coverage regions (LCRs) were defined as target intervals with mean depth <20 x, and z-scores < −1.96 were used to identify batch-specific systematic LCRs. LCRs were clinically annotated using OMIM and SysNDD databases. Results: LCR patterns were highly consistent within each ES batch but were characterized by extreme variability between batches. Higher global mean coverage increased intra-batch consistency, but batches sequenced at a commonly accepted yield in clinical sequencing (>100 x mean coverage) showed thousands of batch-specific LCRs. LCR patterns substantially diverged between ES and GS, displaying preferential impact on different genes. Although a restricted group of genes accumulates LCRs disproportionately, most LCRs are broadly dispersed throughout the genome. LCRs were not systematically associated with features such as GC content and genomic location (e.g., exon 1). Interestingly, LCRs affected OMIM/SysNDD genes and occasionally overlapped ClinVar pathogenic variants, indicating potential impact on diagnostic sensitivity. Conclusion: The global distribution of coverage gaps appears strongly influenced by batch-specific effects, making the occurrence of LCRs partly unpredictable even within clinically relevant gene sets. These findings support systematic assessment of LCRs as a component of quality evaluation in diagnostic sequencing workflows. Full article

(This article belongs to the Special Issue Next-Generation Sequencing in Rare Genetic Diseases)

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11 pages, 425 KB

Open AccessArticle

Monocyte Titin Gene Expression as a Biomarker of Left Ventricular Dysfunction in Acute Myocarditis

by Spyridon Maragkoudakis, Aleksi Sallo, Ioanna Kontaraki, Emmanouil Marakas Sideras, Gabriela Lilikaki, Onoufrios Malikidis, Konstantinos Fragkiadakis, Eleutherios Kallergis, Nick Kopidakis, Ioannis Kopidakis, Evangelos Zacharis, Vasiliki Katsi, Emmanouil Kampanieris, George Kochiadakis, Emmanouil Simantirakis and Maria Marketou

Genes 2026, 17(3), 268; https://doi.org/10.3390/genes17030268 - 26 Feb 2026

Abstract

Background: Titin (TTN), a giant structural and signaling protein of striated muscle, participates in intracellular signaling networks and cytoskeletal organization, potentially influencing cell activation, trafficking, and interactions with other tissues, including the heart. Methods: In this pilot study, 29 patients with acute myocarditis [...] Read more.

Background: Titin (TTN), a giant structural and signaling protein of striated muscle, participates in intracellular signaling networks and cytoskeletal organization, potentially influencing cell activation, trafficking, and interactions with other tissues, including the heart. Methods: In this pilot study, 29 patients with acute myocarditis and 10 healthy individuals were prospectively enrolled. Peripheral blood was obtained on the first day of hospital admission, total RNA was isolated from peripheral blood mononuclear cells (PBMCs), and TTN mRNA expression was quantified. Results: TTN expression in PBMCs was significantly higher in patients with acute myocarditis compared with healthy controls (p = 0.015), corresponding to a 2.8-fold median increase. Moreover, TTN expression showed a strong positive correlation with global longitudinal strain impairment (Spearman’s r = 0.576, p < 0.001), a moderate positive correlation with peak hs-cTnI levels (r = 0.435, p = 0.021; and a moderate inverse correlation with baseline LVEF (r = −0.421, p = 0.025). Conclusions: These findings support a pathophysiological link between TTN-related pathways in peripheral immune cells and myocardial injury in acute myocarditis and raise the hypothesis that TTN expression in PBMCs may serve as a novel biomarker of disease severity and long-term ventricular remodeling. Further studies in larger cohorts are warranted to validate these results and to elucidate the mechanistic role of titin in immune–cardiac cross-talk. Full article

(This article belongs to the Special Issue Chromatin Modifications and RNA-Based Regulation of Gene Expression)

14 pages, 450 KB

Open AccessArticle

Diagnosis of Familial Hypercholesterolemia in Children: From Clinical Features Through Gene Variants to Polygenic Score

by Raffaele Buganza, Cecilia Nobili, Giulia Massini, Giovanna Cardiero, Maria Donata Di Taranto, Luisa de Sanctis and Ornella Guardamagna

Genes 2026, 17(3), 267; https://doi.org/10.3390/genes17030267 - 26 Feb 2026

Abstract

Background: Early diagnosis of familial hypercholesterolemia (FH) is crucial to improve long-term outcomes. FH diagnosis relies on elevated low-density lipoprotein cholesterol (LDL-C) levels, familial clinical characteristics, and identification of pathogenic variants in FH-related genes. Secondary factors, such as overweight and obesity, are known [...] Read more.

Background: Early diagnosis of familial hypercholesterolemia (FH) is crucial to improve long-term outcomes. FH diagnosis relies on elevated low-density lipoprotein cholesterol (LDL-C) levels, familial clinical characteristics, and identification of pathogenic variants in FH-related genes. Secondary factors, such as overweight and obesity, are known to influence lipid profiles in the general population. More recently, polygenic risk scores based on single-nucleotide polymorphisms (SNPs) have been proposed as additional determinants of LDL-C levels. Methods: We enrolled 214 pediatric subjects with LDL-C levels ≥95th percentile (after 6 months of dietary intervention) and with at least one parent with LDL-C levels ≥ 95th percentile. All participants underwent biochemical and auxological assessment and genetic testing for FH. In a subgroup of 60 subjects, LDL-C polygenic scores based on 6- and 12-SNPs were calculated. Results: Pathogenic variants confirming heterozygous FH were identified in 190 subjects (variant-positive, V+); 17 were variant-negative (V−), yielding a mutation detection rate of 91.8%. An additional seven patients carrying variants of uncertain significance were excluded from the primary analysis. LDL-C was modestly higher in V+ than V− subjects using both Friedewald (212 vs. 188 mg/dL; p = 0.035) and Martin–Hopkins formulas (208 vs. 187 mg/dL; p = 0.041), while the other main clinical and laboratory parameters were similar. In V+, LDL-C was higher in subjects with null variants, compared to those with defective variants. Body mass index (BMI SDS) was inversely correlated with HDL-C (p < 0.001), and obesity (BMI z-score > 2 SDS) was associated with lower HDL-C and higher LDL-C, non-HDL-C, and ApoB. With regard to the polygenic scores, 12- and 6-SNP scores showed overlap between V+ and V−, and published cut-offs did not discriminate lipid severity in our population; however, in V+ subjects, the 12-SNP score acted as a phenotype modifier, being independently associated with higher LDL-C and non-HDL-C levels after adjustment for age, sex, and BMI SDS. Conclusions: In children selected by LDL-C ≥ 95th percentile, together with autosomal dominant familial hypercholesterolemia, genetic confirmation of FH is achieved in the vast majority of cases. Variant type (null vs. defective), BMI, and polygenic background contribute to phenotypic heterogeneity, supporting the need to address other factors alongside genetic diagnosis. Further validation is needed before polygenic scores can be implemented in routine clinical practice. Full article

(This article belongs to the Section Genetic Diagnosis)

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12 pages, 971 KB

Open AccessArticle

The Expression of Kisspeptin Receptor, Catsper 3 and Acrosome Integrity in Oligozoospermic and Normozoospermic Individuals

by Nejat Ünlükal, Seda Aniç, Duygu Dursunoğlu, Seda Şimşek, Muslu Kazım Körez and Abdullah Şentürk

Genes 2026, 17(3), 266; https://doi.org/10.3390/genes17030266 - 26 Feb 2026

Abstract

Background: Male infertility remains a significant clinical challenge. The KISS1R-CATSPER3 signaling axis and acrosomal integrity are vital for fertilization, yet their regional expression patterns in subfertile men are not fully characterized. Objectives: This study investigated regional expression patterns of KISS1R and [...] Read more.

Background: Male infertility remains a significant clinical challenge. The KISS1R-CATSPER3 signaling axis and acrosomal integrity are vital for fertilization, yet their regional expression patterns in subfertile men are not fully characterized. Objectives: This study investigated regional expression patterns of KISS1R and CATSPER3 and evaluated acrosomal integrity in oligozoospermic and normozoospermic individuals, accounting for demographic confounders. Methods: A total of 52 participants were selected from 568 candidates and divided into normozoospermic (n = 26) and oligozoospermic (n = 26) groups. Analysis included qPCR and immunofluorescence for KISS1R and CATSPER3. Regional expression was independently scored by blinded researchers. Statistical models were adjusted for age and body mass index (BMI). Results: Acrosomal integrity was significantly lower in the oligozoospermic group (p < 0.001). After adjusting for age and BMI, overall protein expression of CATSPER3 and KISS1R remained significantly lower in oligozoospermic men (p < 0.05). Regional analysis showed that CATSPER3 head staining differences disappeared after adjustment, whereas lower tail expression persisted. Higher KISS1R head expression in oligozoospermic men remained significant. qPCR showed no differences in KISS1R or CATSPER3 mRNA levels (p > 0.05), indicating post-translational regulation. Conclusions: KISS1R-CATSPER3 axis downregulation is a hallmark of oligozoospermia that persists independently of age and BMI. Regional protein instability, despite stable mRNA levels, suggests that post-translational regulation is critical for fertility. These markers may serve as potential diagnostic or therapeutic indicators for male infertility. Full article

(This article belongs to the Special Issue The Genetics of Male Infertility and Clinical Implications)

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16 pages, 996 KB

Open AccessReview

Genetic Aspects of Dental Impaction: A Scoping Review

by Elena Oliva-Ferrusola, María Baus-Domínguez, Daniel Torres-Lagares and Maria-Angeles Serrera-Figallo

Genes 2026, 17(3), 265; https://doi.org/10.3390/genes17030265 - 26 Feb 2026

Abstract

Background/Objectives: There is a lack of cohesion in integrating current knowledge on the genetic and environmental etiology of dental impaction. The primary aim of this article is to review the current literature to identify candidate genes involved in the pathogenesis of dental impaction. [...] Read more.

Background/Objectives: There is a lack of cohesion in integrating current knowledge on the genetic and environmental etiology of dental impaction. The primary aim of this article is to review the current literature to identify candidate genes involved in the pathogenesis of dental impaction. Methods: A scoping review was conducted following PRISMA-ScR guidelines to identify and organize the available body of evidence. Relevant literature was searched in MEDLINE (via PubMed), Scopus, and Web of Science, with the final search conducted on 03 January 2026. Eligibility criteria included case–control, cohort, cross-sectional observational, and case report studies in humans. Selected studies focused on syndromic and non-syndromic variants, inheritance patterns, and genetic analyses. Risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists and AMSTAR 2. Results: Only 18 studies met the eligibility criteria. Most articles were case reports and retrospective observational studies, revealing a multifaceted genetic landscape underlying dental impaction, with mutations affecting transcription factors and signaling pathways critical for odontogenesis, particularly RUNX2, FGFR1, MSX1, PAX9, and AXIN2. Overall, the included studies showed moderate methodological quality. Conclusions: Current evidence does not clearly support specific genes as causal factors in dental impaction, but instead suggests a complex, likely polygenic susceptibility that modulates the anatomical threshold for tooth eruption. This review highlights RUNX2, FGFR1, MSX1, PAX9, and AXIN2, as well as emerging candidates involved in eruption and bone remodeling pathways. Future progress depends on standardized phenotyping, large replicated cohorts, and functional studies linking genetic variation to dental follicle-mediated eruptive remodeling. Full article

(This article belongs to the Special Issue Genetic, Epigenetic and Environmental Factors in Dental Development and Pathologies: Genes, Interactions and Dental Development)

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21 pages, 4481 KB

Open AccessArticle

Genome-Wide Identification and Expression Analysis of NHX Gene Family in Ziziphus jujuba var. spinosa Under Salt and Drought Stress

by Lulu Li, Xiaojun Ma, Xinhong Wang, Congcong Liu, Xiaohan Tang, Dali Geng, Xuexiang Li, Aiqin Ding and Jing Shu

Genes 2026, 17(3), 264; https://doi.org/10.3390/genes17030264 - 26 Feb 2026

Abstract

Background/Objectives: Ziziphus jujuba var. spinosa (sour jujube) is a traditional medicinal plant with remarkable tolerance to abiotic stresses, particularly salinity. However, the regulatory mechanisms underlying its salt stress tolerance remain unclear. NHX genes play a crucial role in plant adaptation to salt stress [...] Read more.

Background/Objectives: Ziziphus jujuba var. spinosa (sour jujube) is a traditional medicinal plant with remarkable tolerance to abiotic stresses, particularly salinity. However, the regulatory mechanisms underlying its salt stress tolerance remain unclear. NHX genes play a crucial role in plant adaptation to salt stress by mediating Na⁺/K⁺ transport to maintain intracellular ion homeostasis and pH balance. Although the NHX gene family has been characterized in many plant species, its functional characteristics in sour jujube have not yet been systematically investigated. Methods: In this study, using Arabidopsis thaliana as a reference, we identified NHX genes in sour jujube through genome-wide analysis and molecular approaches, and systematically analyzed their phylogenetic relationships, chromosomal locations, conserved motifs, gene structures, cis-regulatory elements in promoter regions, and expression patterns under abiotic stresses, particularly salt stress. Results: The results revealed the presence of eight NHX genes distributed across six chromosomes in sour jujube, which were classified into three subfamilies: Vac-class, Endo-class, and PM-class. Members within the same evolutionary clade exhibited high structural conservation in motif composition and gene architecture. Except for the PM-class, all other clades contained amiloride-binding sites (FF(I/L)(Y/F)LFLLPPI). Analysis of cis-regulatory elements indicated that the promoter regions of these genes were enriched with elements related to defense responses, stress adaptation, and phytohormone signaling, further supporting their role in plant environmental adaptation. Additionally, the qRT-PCR analysis showed that most of the ZjNHX genes in both roots and leaves are up-regulated by salt. Notably, ZjNHX1 expression in roots increased approximately 40-fold within 3 h, whereas ZjNHX2 and ZjNHX3 were strongly induced in leaves under prolonged salt exposure. Conclusions: Taken together, this work gives a detailed overview of the ZjNHX genes and their important roles in response to salt stress in sour jujube. Our findings also provide a foundation for further functional characterization of this gene family. Full article

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

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16 pages, 3605 KB

Open AccessArticle

High-Resolution Microbial Fingerprinting for Forensic Individual Identification: A Proof-of-Concept Study Integrating 2bRAD-M and Hierarchical Attention Network

by Haoran Li, Zhiyao Yu, Zhijing Wu, Yuxin Lin, Tao Liu, Yuli Liu, Juan An, Jing Zhao, Yan Liu, Xueman Ma and Haiyan Wang

Genes 2026, 17(3), 263; https://doi.org/10.3390/genes17030263 - 26 Feb 2026

Abstract

Background: Human skin and saliva microbial communities have emerged as promising forensic biomarkers due to their individual specificity. However, existing studies are limited by small sample sizes and methodological inconsistencies. This proof-of-concept study aims to develop a novel framework integrating 2bRAD-M sequencing [...] Read more.

Background: Human skin and saliva microbial communities have emerged as promising forensic biomarkers due to their individual specificity. However, existing studies are limited by small sample sizes and methodological inconsistencies. This proof-of-concept study aims to develop a novel framework integrating 2bRAD-M sequencing with a hierarchical attention network (HAN) for forensic individual identification, addressing these limitations through large-scale public data integration and controlled validation. Methods: We utilized 2263 skin and saliva samples from public databases (Qiita, HMP, NCBI SRA) for model development. These public data included longitudinal samples collected over periods up to 180 days. A contemporary validation cohort of 6 volunteers, providing 26 forensic-relevant samples (including simulated touch evidence), was sequenced using 2bRAD-M for validation. Data integration involved batch effect correction (ComBat), normalization (CSS), and cross-database harmonization using GTDB for taxonomic assignment. The HAN model was optimized with triplet margin loss for metric learning. Results: The HAN model achieved 98.7% Rank-1 accuracy for pristine samples, outperforming random forest (70.2%) and CNN (75.8%). Microbial signatures showed high temporal stability (ICC = 0.86 over 180 days) and robustness in mixed samples (87.4% accuracy). Discriminatory biomarkers included Cutibacterium (skin) and Prevotella (saliva). Particulate matter exposure significantly influenced microbial composition (PERMANOVA R² = 0.32, p < 0.001). Conclusions: This study establishes a proof-of-concept pipeline for microbial forensics, demonstrating high accuracy under controlled conditions. Future work must address antibiotic exposure, sample diversity, and cross-laboratory validation before forensic implementation. Full article

(This article belongs to the Special Issue Advances in Forensic Genetics and DNA)

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13 pages, 1120 KB

Open AccessArticle

Genomic Profiling of Antibody Repertoire in Rongchang Pigs Uncovers Conserved V(D)J Gene Usage and Breed-Specific Diversification

by Qiao Li, Meng Wu, Xueqin Liu, Xingping Wu, Chuanxiang Ding, Liangpeng Ge, Hailin Zhang and Jing Sun

Genes 2026, 17(3), 262; https://doi.org/10.3390/genes17030262 - 26 Feb 2026

Abstract

Background: Pigs are economically critical livestock andan optimal model for investigating the development and diversification of antibody repertoires. The Rongchang (RC) pig, a nationally protected indigenous breed in China, possesses unique genetic characteristics, yet genomic-level research on its antibody repertoire remains limited, as [...] Read more.

Background: Pigs are economically critical livestock andan optimal model for investigating the development and diversification of antibody repertoires. The Rongchang (RC) pig, a nationally protected indigenous breed in China, possesses unique genetic characteristics, yet genomic-level research on its antibody repertoire remains limited, as most porcine antibody studies have focused on Landrace pigs. Methods: To decipher the genetic features of the antibody library in RC pigs, we used immunogenomic high-throughput sequencing to systematically analyze the antibody repertoires of five healthy purebred pig breeds, including two indigenous breeds (RC and BM) and three commercial breeds (Yorkshire, Duroc, and Landrace), with a focus on comparing conserved patterns and breed-specific differences in V(D)J gene utilization between Rongchang pigs and the other four breeds. Results: All five breeds exhibited a strong preference for a conserved subset of core IGHV genes. Notably, this study detected functional IGHJ3 expression (0.40.8%) in all examined breeds, contradicting the conventional view that only IGHJ5 is functional in porcine antibody repertoires. Among them, RC pigs showed the lowest IGHJ3 frequency. Furthermore, RC pigs ranked second in antibody repertoire diversity among the five breeds, implying abundant antigen-binding specificity, and exhibited the lowest CDR3 proportion, indicating breed-specific V(D)J recombination preferences. Conclusions: These results clarify the conserved and breed-specific characteristics of RC pig antibody repertoires, establishing a basis for exploring the genetic regulation of V(D)J-mediated antibody repertoire changes under varied immune conditions. This work also provides genomic support for the rational utilization of RC pig genetic resources. Full article

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

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20 pages, 2093 KB

Open AccessArticle

SSR-Based Analysis of Genetic Diversity and Resistance to Barley Scald and Net Blotch in a Collection of Barley from Kazakhstan

by Yuliya Genievskaya, Akerke Maulenbay, Alibek Zatybekov, Saule Abugalieva and Yerlan Turuspekov

Genes 2026, 17(3), 261; https://doi.org/10.3390/genes17030261 - 25 Feb 2026

Abstract

Background/Objectives: Barley (Hordeum vulgare L.) is a major cereal crop in Kazakhstan; however, its productivity is frequently constrained by foliar diseases, particularly barley scald (BS) and net blotch (NB). Understanding the genetic diversity of barley germplasm and identifying resistance-associated alleles are [...] Read more.

Background/Objectives: Barley (Hordeum vulgare L.) is a major cereal crop in Kazakhstan; however, its productivity is frequently constrained by foliar diseases, particularly barley scald (BS) and net blotch (NB). Understanding the genetic diversity of barley germplasm and identifying resistance-associated alleles are essential for improving disease resistance in breeding programs. The objective of this study was to assess the genetic diversity and population structure in a collection of two-rowed spring barley accessions and to identify SSR alleles associated with resistance to BS and NB. Methods: A total of 86 two-rowed spring barley accessions were genotyped using 14 SSR markers. Phenotypic evaluation for BS and NB resistance was conducted under natural infection conditions across two environments in southeastern and southern Kazakhstan. Genetic diversity and population structure were analyzed using Neighbor-Joining (NJ) clustering, Principal Coordinate Analysis (PCoA), and STRUCTURE. Marker–trait associations were evaluated using MLM method. Results: Phenotypic assessments revealed significant environment-dependent variation in disease severity for both BS and NB. Population structure analyses consistently identified distinct genetic clusters within the collection. Seven significant (p < 0.05) allele–trait associations were detected. The Bmac209 176 bp allele exhibited the strongest association with NB severity at KRIAPG. Among the identified markers, Bmag206 246 bp was uniquely associated with reduced NB infection, whereas Bmag206 252 bp, Bmag613 176 bp, and HvLEU 186 bp were linked with higher susceptibility to NB and BS. Conclusions: The identified resistance- and susceptibility-associated SSR alleles provide useful diagnostic markers for marker-assisted selection and support the potential of allele pyramiding for developing barley cultivars with combined resistance to BS and NB. This study establishes a genetic framework to enhance barley disease resistance in Central Asian breeding programs. Full article

(This article belongs to the Special Issue Genetic Mechanisms of Plant Resistance to Biotic Stress)

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11 pages, 491 KB

Open AccessArticle

Gene Polymorphisms of TLR2 Subfamily and Bacterial Meningitis in Angolan Children

by Johanna Teräsjärvi, Elina Tenhu, Manuel Leite Cruzeiro, Okko Savonius, Emilie Rugemalira, Qiushui He and Tuula Pelkonen

Genes 2026, 17(3), 260; https://doi.org/10.3390/genes17030260 - 25 Feb 2026

Abstract

Background/Objectives: Bacterial meningitis is a severe disease with a fatality rate of 5–50%. It is mainly caused by Streptococcus pneumoniae or Neisseria meningitidis, which can also cause simultaneous infections outside the central nervous system. Toll-like receptors (TLRs) have an important role in [...] Read more.

Background/Objectives: Bacterial meningitis is a severe disease with a fatality rate of 5–50%. It is mainly caused by Streptococcus pneumoniae or Neisseria meningitidis, which can also cause simultaneous infections outside the central nervous system. Toll-like receptors (TLRs) have an important role in the innate immune system. The TLR2 subfamily comprises the four highly homologous members TLR1, TLR2, TLR6, and TLR10, which also have an important immunomodulatory role in infectious diseases. Methods: The study cohort consists of 190 bacterial meningitis patients aged 1 to 147 months from randomized clinical trials and 268 controls from Luanda, Angola. Polymorphisms of TLR2 (rs111200466) and TLR10 (rs10856837 and rs11096956) were determined using PCR-based methods and Sanger sequencing. The genotyping results were analyzed together with clinical data to determine whether gene polymorphisms of TLR2 and TLR10 are associated with susceptibility and outcome of bacterial meningitis in Angolan children. Results: At admission and during hospitalization, patients with pneumococcal meningitis carrying a variant (ins/del or del/del) of TLR2 rs111200466 had a significantly lower risk of coexisting infections (OR 0.27; 95% CI 0.11–0.65; p = 0.004), particularly pneumonia (OR 0.18; 95% CI 0.06–0.49; p = 0.001). In addition, haplotype analysis demonstrated that a variant genotype of TLR2 rs111200466 together with a wildtype of TLR10 SNPs (rs10856837 and rs11096956) may protect against coexisting pneumonia (OR 0.2; 95% CI 0.06–0.6; p = 0.007). Conclusions: This study suggests an association between coexisting infection and genetic variation in TLR2 and TLR10 of bacterial meningitis in Angolan children. Full article

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

19 pages, 909 KB

Open AccessReview

Miscarriage and the Microbiome: Host Genetics, Immunity, and the Reproductive Tract Ecosystem

by Nektaria Zagorianakou, Stylianos Makrydimas, Efthalia Moustakli, Ioannis Mitrogiannis and George Makrydimas

Genes 2026, 17(3), 259; https://doi.org/10.3390/genes17030259 - 25 Feb 2026

Abstract

Background/Objectives: Pregnancy loss is a common and multifactorial complication of human reproduction, traditionally attributed to fetal chromosomal abnormalities, maternal anatomical and endocrine disorders, and immune dysfunction. Growing evidence now indicates that the maternal microbiome, particularly within the reproductive tract, plays a critical role [...] Read more.

Background/Objectives: Pregnancy loss is a common and multifactorial complication of human reproduction, traditionally attributed to fetal chromosomal abnormalities, maternal anatomical and endocrine disorders, and immune dysfunction. Growing evidence now indicates that the maternal microbiome, particularly within the reproductive tract, plays a critical role in implantation, placental development, and the maintenance of immune tolerance during early pregnancy. Importantly, the influence of the microbiome on miscarriage appears to be strongly modulated by host genetic background and immune regulation. Methods: This narrative review summarizes current evidence linking alterations in the vaginal, endometrial, placental, and gut microbiomes to miscarriage, with a specific focus on host genetics and immune–microbial interactions. Results: We discuss how genetic variation in innate and adaptive immune pathways, inflammatory signaling, and mucosal barrier function may shape host responses to microbial communities, thereby influencing susceptibility to PL. In addition, we highlight emerging data on microbiome-driven regulation of gene expression and epigenetic modifications in the endometrium and decidua, emphasizing the role of microbial metabolites in immune tolerance and placental function. Conclusions: By integrating findings from microbiome research, host genomics, immunology, and epigenetics, this review proposes a framework in which miscarriage is viewed as a consequence of disrupted host–microbe crosstalk rather than isolated pathology. Finally, we address key methodological challenges and outline future research directions aimed at advancing mechanistic understanding and translational applications. Full article

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

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21 pages, 345 KB

Open AccessReview

Integrative Forensic Genetics, Biochemical, and Histological Methods for Reconstructing Biological Profiles from Aged Human Skeletal Remains

by Irena Zupanič Pajnič and Tamara Leskovar

Genes 2026, 17(3), 258; https://doi.org/10.3390/genes17030258 - 25 Feb 2026

Abstract

The reconstruction of biological profiles from aged or degraded human skeletal remains represents a major challenge in both forensic and bioarcheological contexts, particularly when conventional identification approaches fail. Recent advances in molecular genetics, biochemical and histological analyses, and biomolecular anthropology have substantially expanded [...] Read more.

The reconstruction of biological profiles from aged or degraded human skeletal remains represents a major challenge in both forensic and bioarcheological contexts, particularly when conventional identification approaches fail. Recent advances in molecular genetics, biochemical and histological analyses, and biomolecular anthropology have substantially expanded the range of information that can be recovered from compromised remains. This review synthesizes current integrative approaches combining genomic analyses, stable isotope investigations, epigenetic age estimation, proteomic sex determination, and complementary histological techniques to infer sex, ancestry, kinship, age, diet, mobility, and geographic origin. Genetic methods, including next-generation sequencing (NGS), enable increasingly robust inference even from highly degraded samples. Stable isotope analyses provide insights into dietary patterns and mobility, while DNA methylation markers improve age estimation accuracy. Tooth cementum annulation (TCA), although a histological rather than molecular method, contributes an additional chronological indicator within an integrative analytical framework. Rather than treating these approaches independently, this review proposes a multidisciplinary perspective in which complementary datasets collectively support biological profile reconstruction. Integrative interpretation enhances identification potential and provides more nuanced life-history reconstructions, demonstrating the value of combining molecular, biochemical, and histological evidence in forensic and archaeological investigations. Full article

(This article belongs to the Special Issue Advances and Challenges in Forensic Genetics)

25 pages, 2001 KB

Open AccessArticle

Transcriptomic Responses of Zebrafish Embryos to Environmentally Relevant, Low-Dose (2-Ethylhexyl) Phthalate Exposure at 96–120 hpf

by Mariagiovanna Pais, Kate McCafferty, Guillermo Lopez Campos and Gary Hardiman

Genes 2026, 17(3), 257; https://doi.org/10.3390/genes17030257 - 25 Feb 2026

Abstract

Background: Di(2-ethylhexyl) phthalate (DEHP) is a high-production-volume plasticizer and ubiquitous environ-mental contaminant with established endocrine-disrupting potential. While zebrafish transcriptomic studies have typically used high concentrations and long exposure windows, less is known about genome-wide responses during late embryogenesis/early larval maturation under environmentally relevant [...] Read more.

Background: Di(2-ethylhexyl) phthalate (DEHP) is a high-production-volume plasticizer and ubiquitous environ-mental contaminant with established endocrine-disrupting potential. While zebrafish transcriptomic studies have typically used high concentrations and long exposure windows, less is known about genome-wide responses during late embryogenesis/early larval maturation under environmentally relevant exposures. Here we profiled whole-organism transcriptomic responses to a short DEHP exposure during a developmentally sensitive transition (96–120) hours post-fertilization, hpf) and interpreted responses using differential expression, enrichment analyses, and endocrine-focused protein–protein interaction (PPI) network modeling. Methods: Wild-type AB zebrafish lar-vae (96 hpf) were exposed to DEHP at [10⁻⁹ M] or solvent control for 24 h. Larvae were pooled per replicate (25 lar-vae/pool) and processed for poly(A)-selected RNA-seq. Reads were quality-controlled, aligned to the Danio rerio reference genome, and quantified at gene- level. Differential expression was performed using DESeq2. Functional enrichment used KEGG over-representation analysis (ORA) and gene set enrichment analysis (GSEA). Zebrafish genes were mapped to human orthologs for GO/KEGG and STRING-based endocrine subnetworks, which were visualized and interrogated using STRINGdb and visNetwork. Results: Low-dose, short-term exposure does not produce large gene-level effects but induces coordinated, pathway-level transcriptional remodeling. KEGG ORA showed significant enrichment of MAPK signaling and regulation of actin cytoskeleton with additional enrichment of axon guidance and neuroactive ligand–receptor interaction. GSEA detected coordinated downregulation of KEGG neurodegeneration collections with negative normalized enrichment scores reflecting shared gene sets re-lated to mitochondrial function, proteostasis, cytoskeletal organization, and stress-response pathways. Endo-crine-focused STRING subnetworks indicated consistent downregulation of CYP19A1 within estrogen metabo-lism/biosynthesis modules and downregulation of upstream androgen biosynthetic enzymes HSD3B2 and CYP17A1, alongside upregulation of HSD17B3 and proteostasis-associated factors including DNAJA1. Endocrine network to-pology highlighted regulatory and cofactor nodes affecting receptor-linked transcription, consistent with indirect endocrine modulation rather than large receptor-transcript changes. Conclusions: In summary, this study demon-strates that exposure to low-dose DEHP during a critical period of zebrafish embryonic development is associated with modest but coordinated transcriptomic changes across multiple biological pathways. Pathway enrichment and network-based analyses highlight estrogen- and androgen-associated processes, along with broader signaling, met-abolic, and structural pathways, as transcriptionally responsive during this window. Importantly, these findings reflect molecular-level associations rather than direct evidence of functional or physiological endocrine disruption. Instead, they identify candidate pathways and regulatory networks that may be sensitive to low-level environmen-tal exposure and warrant further investigation. Collectively, this work underscores the value of systems-level tran-scriptomic approaches for detecting subtle, pathway-wide responses to environmentally relevant exposures during development. Full article

(This article belongs to the Section Toxicogenomics)

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13 pages, 233 KB

Open AccessArticle

Epilepsy as a Component of the Dysmorphic–Neurodevelopmental Phenotype in Pediatric Patients with Recurrent Copy Number Variants

by Marlena Młynek, Dorota Wicher, Agata Cieślikowska, Katarzyna Urbańska, Kamila Przywoźna-Zduńczyk, Urszula Zawadzka-Więch, Klaudia Markowska-Krawczyk, Aneta Bal, Sylwia Purwin, Danuta Sielska-Rotblum, Paulina Halat-Wolska, Piotr Iwanowski, Katarzyna Iwanicka-Pronicka, Maria Jędrzejowska, Monika Kowalczyk-Rusak, Justyna Pietrasik, Krystyna Chrzanowska, Dorota Domańska-Pakieła, Katarzyna Kotulska-Jóźwiak, Małgorzata Krajewska-Walasek and Agnieszka Madej-Pilarczyk Show full author list Hide full author list

Genes 2026, 17(3), 256; https://doi.org/10.3390/genes17030256 - 25 Feb 2026

Abstract

Objective: Copy number variants (CNVs) overlapping genes associated with neurodevelopmental disorders in patients with epilepsy are particularly concentrated in epilepsy hotspot loci. The aim of this study was to evaluate epilepsy as a component of the dysmorphic–neurodevelopmental phenotype in patients with recurrent CNVs. [...] Read more.

Objective: Copy number variants (CNVs) overlapping genes associated with neurodevelopmental disorders in patients with epilepsy are particularly concentrated in epilepsy hotspot loci. The aim of this study was to evaluate epilepsy as a component of the dysmorphic–neurodevelopmental phenotype in patients with recurrent CNVs. Methods: The study included genetic and clinical data from 177 pediatric patients carrying 17 recurrent CNVs showing well-documented enrichment in epilepsy or associated with genetic OMIM syndromes. Results: Epilepsy was diagnosed in 50 of 177 children (28.2%), developmental delay in 147 (83.0%), dysmorphic features in 104 (58.8%), behavioral problems in 62 (35.0%), and congenital anomalies in 55 (31.1%). Among recurrent CNV hotspots, the del16p11.2 BP4–BP5 deletion was the most frequent, occurring in 39 of 177 patients. Ten children (25.6%) with del16p11.2 presented with epilepsy as part of the phenotype. Other frequently represented CNVs included del15q11.2 BP1–BP2 (OMIM #615656; 19/177 patients, 4/19 with epilepsy), del1q21.1 (OMIM #612474; 15/177, 6/15 with epilepsy), del15q13.3 (OMIM #612001; 13/177, 4/13 with epilepsy), and dup16p11.2 (OMIM #614671; 12/177, 1/12 with epilepsy). The highest proportion of epilepsy as a phenotypic component was observed in patients with del1p36 (OMIM #607872; 6/9 patients) and del1q21.1 (OMIM #612474; 6/15 patients). Conclusions: Our data support the clinical utility of CNV testing in patients with epilepsy accompanied by additional neurodevelopmental or dysmorphic features, in line with current diagnostic guidelines. The epilepsy-plus phenotype may help clinicians identify patients who are most likely to benefit from CNV analysis. Full article

(This article belongs to the Section Cytogenomics)

8 pages, 865 KB

Open AccessBrief Report

Vav-iCre-Mediated Deletion of TFAM Is Not Recoverable and Is Consistent with Embryonic Lethality

by Rituparna Ghosh, Elina Shakur and Matthew J. Yousefzadeh

Genes 2026, 17(3), 255; https://doi.org/10.3390/genes17030255 - 25 Feb 2026

Abstract

Genome stability is the cornerstone of cellular health, and imbalances can cause a number of outcomes, including aging, cancer, and other pathologies. DNA damage is a strong driver of both cellular senescence and mitochondrial dysfunction, two other key hallmarks of aging. Both nuclear [...] Read more.

Genome stability is the cornerstone of cellular health, and imbalances can cause a number of outcomes, including aging, cancer, and other pathologies. DNA damage is a strong driver of both cellular senescence and mitochondrial dysfunction, two other key hallmarks of aging. Both nuclear and mitochondrial genome instability have been shown to drive aging in the hematopoietic system, which then propagates to non-lymphoid tissues, enhancing morbidity and mortality. The loss of TFAM, a key regulator of mitochondrial DNA replication and nucleoid stability, in T cells has been shown to cause mitochondrial dysfunction, leading to premature immune aging and eventual systemic aging. We sought to investigate whether the loss of TFAM in all immune cells would have a comparable or stronger effect on both the immune system and parenchyma. To address this, we attempted to generate Vav-iCre^+/−; Tfam^fl/fl mice, which are deficient in TFAM in all immune cells. However, this genotype was unrecoverable as no mutant pups were born, suggesting embryonic lethality. Conversely, we generated mice lacking SIRT6, a nuclear DNA repair enzyme that also regulates mitochondrial homeostasis, in all immune cells and found them to be viable and born at expected Mendelian frequencies. Our findings demonstrate the necessity of mitochondrial genome maintenance and homeostasis repair in immunity. Full article

(This article belongs to the Special Issue DNA Repair, Genomic Instability and Cancer)

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14 pages, 432 KB

Open AccessArticle

Analysis of the rs3807135, rs3757385 and rs3778754 Variants of the IRF5 Gene and mRNA Expression in Patients with Melanoma Cancer from Western Mexico

by Claudia A. Tapia-Leyva, Fernando Valdez-Salazar, Luis A. Jiménez-Del Río, Jorge R. Padilla-Gutiérrez, José F. Muñoz-Valle and Emmanuel Valdés-Alvarado

Genes 2026, 17(3), 254; https://doi.org/10.3390/genes17030254 - 24 Feb 2026

Abstract

Objective: To analyze the association between the IRF5 gene variants rs3807135, rs3757385, and rs3778754 and mRNA expression levels in patients from western Mexico diagnosed with melanoma. Methods: An analytical cross-sectional study was conducted including 374 individuals (153 patients with newly diagnosed melanoma and [...] Read more.

Objective: To analyze the association between the IRF5 gene variants rs3807135, rs3757385, and rs3778754 and mRNA expression levels in patients from western Mexico diagnosed with melanoma. Methods: An analytical cross-sectional study was conducted including 374 individuals (153 patients with newly diagnosed melanoma and no previous treatment, and 221 controls). The melanoma group was matched to the reference group. Genotyping of the rs3807135 (T>C), rs3757385 (T>G), and rs3778754 (C>G) variants was performed using the allelic discrimination method with TaqMan^® probes. Relative mRNA expression was quantified by qPCR using the 2^–ΔΔCT method, comparing IRF5 expression levels with those of the housekeeping gene GAPDH. Statistical analyses were performed in R, and allelic and genotypic frequencies were compared between patients and controls using the Chi-square test. Results: No statistically significant associations were identified between IRF5 SNVs rs3807135, rs3757385, and rs3778754 and melanoma risk. The haplotypic pattern comprised TTC, CGG, and CGC, with CGG showing a non-significant protective tendency. The mean relative expression of IRF5 was lower in melanoma patients compared with controls (≈0.39 vs. 1.0; Δ = 0.61), although this difference did not reach statistical significance (U = 1725; p = 0.841). These findings suggest a modest modulatory effect of IRF5 at the haplotypic level, likely driven by combined variant effects. Conclusions: In conclusion, the present study did not identify statistically significant associations between the IRF5 single-nucleotide variants rs3807135, rs3757385, and rs3778754 and melanoma risk in the analyzed population from western Mexico. Likewise, no significant differences in allele or genotype distributions were observed between melanoma patients and control individuals. These findings suggest that the evaluated IRF5 genetic variants do not constitute major susceptibility factors for melanoma in this cohort. Full article

(This article belongs to the Special Issue Genetics and Genomics in Cancer)

16 pages, 566 KB

Open AccessReview

Plant Adaptation to Salinity: Physiological Pathways and Prospects for Crop Improvement—A Review

by Himabindhu Badavath and Christopher A. Saski

Genes 2026, 17(3), 253; https://doi.org/10.3390/genes17030253 - 24 Feb 2026

Abstract

Soil salinity is a major abiotic constraint on crop growth, yield, and quality. Advancing salt-tolerant agriculture requires an integrated understanding of salinity-induced osmotic stress, ionic toxicity, and oxidative damage, and how physiological and molecular networks regulate these processes. This review synthesizes key responses [...] Read more.

Soil salinity is a major abiotic constraint on crop growth, yield, and quality. Advancing salt-tolerant agriculture requires an integrated understanding of salinity-induced osmotic stress, ionic toxicity, and oxidative damage, and how physiological and molecular networks regulate these processes. This review synthesizes key responses to salt stress, including osmotic adjustment, ion transport and compartmentalization, photosynthetic acclimation, reactive oxygen species detoxification, and phytohormone-mediated regulation by integrating mechanistic trial-level and deployment-focused insights while providing a fundamental translational insight into durable crop salt tolerance. We further summarize transcriptional and post-transcriptional control mechanisms involving stress-responsive genes, transcription factor families, and microRNA/non-coding RNA regulation. Finally, we compare progress and constraints in conventional breeding, transgenic approaches, genome editing, and epigenetic strategies for improving salinity tolerance and highlight priorities for translating these mechanistic insights into durable field performance. Full article

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

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15 pages, 406 KB

Open AccessArticle

SULT and UGT Genetic Variants Modulate Side Effect Profiles in South African Breast Cancer Patients Treated with Tamoxifen

by Bianca Kruger, Emile Chimusa, Aron Abera, Jesmika Singh, Delva Shamley and Collet Dandara

Genes 2026, 17(3), 252; https://doi.org/10.3390/genes17030252 - 24 Feb 2026

Abstract

Background: Tamoxifen remains the cornerstone of endocrine therapy for hormone receptor-positive breast cancer across Africa. Understanding the factors that influence tamoxifen tolerability is critical, as treatment-related side effects can reduce adherence and compromise therapeutic outcomes. Yet, the contribution of pharmacogenetic variation to [...] Read more.

Background: Tamoxifen remains the cornerstone of endocrine therapy for hormone receptor-positive breast cancer across Africa. Understanding the factors that influence tamoxifen tolerability is critical, as treatment-related side effects can reduce adherence and compromise therapeutic outcomes. Yet, the contribution of pharmacogenetic variation to tamoxifen-related toxicity remains poorly characterized in African populations. This study, therefore, investigated whether genetic variation in key pharmacogenes influences the risk of treatment-related side effects in a South African breast cancer cohort. Methods: A total of 166 women of Mixed and African Ancestry treated with 20 mg/day tamoxifen at Groote Schuur Hospital, South Africa, were included in the study. Genetic variation across 28 variants in nine pharmacogenes, including CYP2D6, CYP3A4/5, UGT1A4, UGT2B7/15, SULT1A1/2, and SULT1E1, was assessed using various genotyping methods. Associations between genetic and non-genetic factors and tamoxifen side effects were evaluated with logistic regression. Results: Over 70% of participants reported at least one treatment-related side effect. Overall side-effect burden was associated with SULT1A1 copy number variation (p = 0.030) and SULT1E1 rs3736599 (p = 0.042). Musculoskeletal complaints were the most common (40%) and were associated with UGT2B7 rs7439366 (p = 0.040) and CYP3A4 rs2242480 (p = 0.051). Gynecological symptoms affected more than 20% of participants and were linked to SULT1A2*2 (p = 0.050), SULT1E1 rs3736599 (p = 0.016), and UGT2B15 rs4148269 (p = 0.039). Hot flashes were frequent, affecting 33% of patients, but showed no clear pharmacogenetic associations. Conclusions: This study demonstrates that pharmacogenetic variation is associated with interindividual differences in treatment-related side effects, underscoring the need to expand research in African populations to better inform precision endocrine therapy. Full article

(This article belongs to the Section Pharmacogenetics)

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