Genes

23 pages, 2147 KB

Open AccessArticle

Integrated Transcriptomic Analysis Identifies Novel Candidate Genes Associated with Calcific Aortic Valve Disease

by Jing Chen, Shichao Guo, Junming Zhu, Haiou Hu, Bing Tang, Lingchen Huang, Chenhan Zhang, Suwei Chen, Sanbao Chai, Zhiyu Qiao and Hongfeng Jiang

Genes 2026, 17(2), 246; https://doi.org/10.3390/genes17020246 - 20 Feb 2026

Abstract

Background: Calcified aortic valve disease (CAVD) is a prevalent valvular disorder in the elderly and a major cause of aortic stenosis. Surgical and transcatheter aortic valve replacement remain the primary treatments for advanced CAVD; however, effective pharmacological therapies to prevent or slow disease [...] Read more.

Background: Calcified aortic valve disease (CAVD) is a prevalent valvular disorder in the elderly and a major cause of aortic stenosis. Surgical and transcatheter aortic valve replacement remain the primary treatments for advanced CAVD; however, effective pharmacological therapies to prevent or slow disease progression are lacking. Therefore, there is an urgent need to explore potential novel candidate biomarkers and therapeutic targets. Methods: In this study, transcriptomic data from multiple independent datasets were integrated to comprehensively characterize the transcriptional profile of CAVD. Feature genes were identified using complementary machine learning approaches, followed by functional pathway enrichment and protein–protein interaction (PPI) network analyses to uncover novel candidate genes associated with CAVD. Single-cell RNA sequencing (sc-RNA-Seq) data were further analyzed using pseudotime trajectory analysis to explore transcriptional dynamics during valve interstitial cells’ (VICs) osteogenic progression. Quantitative PCR and Western blot analyses of human calcified aortic valve tissues were used for validation. Results: A total of 119 CAVD-associated genes were identified, primarily involved in ossification, extracellular matrix organization, and cell–substrate adhesion. Among these, the ossification-associated genes BAMBI, HAND2, and MYOC exhibited potential discriminatory power between CAVD and control samples, with notable downregulation in calcified valves. Pseudotime analysis showed that the expression of these genes gradually decreased along the transcriptional trajectory associated with osteogenic differentiation. In addition, the analysis of relative immune signatures revealed negative correlations between these genes and multiple immune signatures. Conclusions: This study identifies novel candidate genes underlying CAVD pathogenesis and highlights BAMBI, HAND2, and MYOC as potential biomarkers and therapeutic targets, providing new insights into disease mechanisms and opportunities for novel interventions. Full article

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

17 pages, 2035 KB

Open AccessArticle

Integrative Computational Analysis of TP53 Exon 5–6 Mutations in Oral Cavity, Prostate, and Breast Cancers in a Senegalese Population

by Mouhamed Mbaye, Fatimata Mbaye and Mbacke Sembene

Genes 2026, 17(2), 245; https://doi.org/10.3390/genes17020245 - 20 Feb 2026

Abstract

Background/Objectives: The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancers, with alterations predominantly affecting its DNA-binding domain (DBD). However, the mutational landscape and functional consequences of TP53 variants remain poorly characterized in African populations. This [...] Read more.

Background/Objectives: The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancers, with alterations predominantly affecting its DNA-binding domain (DBD). However, the mutational landscape and functional consequences of TP53 variants remain poorly characterized in African populations. This study aimed to characterize mutations in exons 5–6 of TP53 in oral cavity cancer (OCC), prostate cancer (PC), and breast cancer (BC) in a Senegalese population, and to assess their structural effects, functional consequences, and impact on protein–protein interactions with BCL-2. Methods: Seventy-eight archived tumor DNA samples from Senegalese patients with OCC, PC, and BC were analyzed. Variants were annotated using COSMIC and dbSNP databases. Functional impact was evaluated with PolyPhen-2. Structural stability changes (

Δ Δ G

) were predicted using FoldX, conformational dynamics (

Δ Δ S_{v i b}

) were assessed with ENCoM, and effects on the p53–BCL-2 interaction were analyzed using DDMut-PPI. Statistical analyses were also performed. Results: BC exhibited the highest TP53 mutation frequency, whereas OCC showed greater mutational diversity. Exon-level analysis revealed a significant enrichment of exon 6 mutations in BC. Structural analyses indicated that exon 5 mutations across all cancers and mutations in OCC were predominantly destabilizing and associated with loss-of-function effects. In contrast, recurrent exon 6 mutations in PC and BC, particularly V217L and V218M, were predicted to stabilize the p53 structure. Conformational dynamics differences between exons were significant only in PC. All analyzed mutations were predicted to stabilize the p53–BCL-2 interaction. Conclusions: This integrative in silico study identified cancer and exon-specific TP53 mutation patterns in a Senegalese population, highlighting exon 6 as a context-dependent hotspot with potential oncogenic implication in PC and BC. Despite its computational nature, the study provides valuable insights that merit further investigation. Full article

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

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17 pages, 2577 KB

Open AccessArticle

Characterization and Phylogenetic Analysis of the Complete Mitochondrial Genome of Celaenorrhinus victor (Lepidoptera: Hesperiidae)

by Yaping Hu, Site Luo, Zhentian Yan, Xiaomin Ge, Le Wang, Xu Zhou, Bin Chen, Hui Ding and Xiao Zheng

Genes 2026, 17(2), 244; https://doi.org/10.3390/genes17020244 - 19 Feb 2026

Abstract

Background: Skipper butterflies (Hesperiidae) are a morphologically distinctive lineage within Papilionoidea, yet relationships among many groups remain difficult to resolve, and mitochondrial genomic resources remain limited for some tribes, including Celaenorrhinini. Methods: We sequenced and characterized the complete mitochondrial genome of [...] Read more.

Background: Skipper butterflies (Hesperiidae) are a morphologically distinctive lineage within Papilionoidea, yet relationships among many groups remain difficult to resolve, and mitochondrial genomic resources remain limited for some tribes, including Celaenorrhinini. Methods: We sequenced and characterized the complete mitochondrial genome of Celaenorrhinus victor using Illumina short-read sequencing. Gene content and organization were annotated, codon-usage patterns were assessed across Celaenorrhinus using relative synonymous codon usage and multiple compositional/selection tests (ENC–GC3s, neutrality, and PR2 analyses), selective constraints were evaluated using Ka/Ks for 13 protein-coding genes, and phylogenetic relationships were inferred with a partitioned maximum-likelihood analysis of 66 complete hesperiid mitogenomes. Results: The circular mitogenome of C. victor is 15,180 bp and contains the typical 37 genes (13 protein-coding genes, 22 tRNAs, and two rRNAs) plus an A + T-rich control region, with an overall A + T content of 79.64%. Gene order and orientation match those of other Celaenorrhinus and hesperiid mitogenomes. All protein-coding genes use standard invertebrate mitochondrial start codons (with cox1 initiating with TTG) and terminate with complete TAA stop codons. Codon usage is strongly biased toward A/U-ending codons and is broadly similar among five sampled Celaenorrhinus mitogenomes; ENC–GC3s, neutrality, and PR2 analyses indicate a predominant influence of A + T-directed mutational pressure with additional effects beyond base composition. Ka/Ks values for all 13 protein-coding genes were <1, consistent with pervasive purifying selection; cox genes were the most conserved, whereas several NADH dehydrogenase subunit genes evolved comparatively faster. The phylogeny recovered monophyletic Celaenorrhinini and a well-supported Celaenorrhinus clade, placing C. victor as sister to Celaenorrhinus consanguineus, while deeper nodes among major hesperiid lineages showed only moderate support in parts of the tree. Conclusions: This study provides a new mitogenomic resource for Celaenorrhinini and a comparative reference for codon usage and selective constraints within Celaenorrhinus, supporting the placement of C. victor within Hesperiidae while highlighting remaining uncertainty at deeper hesperiid divergences. Full article

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

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15 pages, 4641 KB

Open AccessArticle

The Mitochondrial Genome of Curcuma longa: A Large and Structurally Complex Genome with Extensive Intracellular DNA Transfer

by Bing Xu, Minlong Jia, Jiali Kong, Liyun Nie, Jie Wang, Luke R. Tembrock, Zhiqiang Wu, Sen Li and Xuezhu Liao

Genes 2026, 17(2), 243; https://doi.org/10.3390/genes17020243 - 19 Feb 2026

Abstract

Background: Plant mitochondrial genomes exhibit extreme variation in size and structure while maintaining a conserved set of core protein-coding genes. This combination of structural diversity and functional conservation provides valuable insights into evolutionary processes such as genome expansion, rearrangement, and intracellular DNA [...] Read more.

Background: Plant mitochondrial genomes exhibit extreme variation in size and structure while maintaining a conserved set of core protein-coding genes. This combination of structural diversity and functional conservation provides valuable insights into evolutionary processes such as genome expansion, rearrangement, and intracellular DNA transfer. Curcuma longa, an economically and medicinally important species in the genus Curcuma (Zingiberaceae), has not yet been studied in terms of the organization and evolution of its mitochondrial genome. Methods: In this study, we assembled and annotated the mitochondrial and plastid genomes of C. longa using third-generation HiFi sequencing data, systematically analyzing their genomic structure, repetitive sequence content, and features of sequence transfer between nuclear and organellar genomes. Results: The mitochondrial genome of C. longa was assembled as a complex, network-like structure consisting of 12 contigs with a total length of approximately 7.7 Mb, making it one of the largest mitochondrial genomes reported in monocots to date. Comparative analysis revealed significant differences in repeat types, abundance, and length distribution between the two organellar genomes. Additionally, extensive intracellular DNA transfer events were identified among the nuclear, mitochondrial, and plastid genomes. Conclusions: Overall, this study provides the first comprehensive report on the giant mitochondrial genome of C. longa, detailing its structural organization, repeat content, and intergenomic transfers. These findings lay a foundation for understanding mitochondrial genome evolution in Curcuma and offer broader insights into the mechanisms driving extreme mitochondrial genome expansion in angiosperms and monocots specifically. Full article

(This article belongs to the Special Issue Genetic and Breeding Improvement of Horticultural Crops)

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29 pages, 13047 KB

Open AccessArticle

Integrated Analysis of Transcriptome and Metabolome Profiles in Astragslus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao Seedlings Under Drought Stress

by Aihuan Ma, Kamila Abudourexiti, Zhen Liu, Saideaihemaiti Wulamu, Danye Zhao and Kuerban Tusong

Genes 2026, 17(2), 242; https://doi.org/10.3390/genes17020242 - 18 Feb 2026

Abstract

Background: Astragalus membranaceus is a traditional Chinese medicinal herb with significant pharmacological value. Drought stress adversely affects its biomass accumulation and medicinal quality. Methods: In this study, we performed physiological profiling, transcriptomics, and metabolomics analyses on A. membranaceus (Fisch.) Bge. var. mongholicus [...] Read more.

Background: Astragalus membranaceus is a traditional Chinese medicinal herb with significant pharmacological value. Drought stress adversely affects its biomass accumulation and medicinal quality. Methods: In this study, we performed physiological profiling, transcriptomics, and metabolomics analyses on A. membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao seedlings to elucidate the response mechanisms in both aboveground and root tissues under varying drought stress intensities (Control, CK; Light Drought LD; Moderate Drought MD; Severe Drought SD). Results: Our findings indicate that LD primarily activated antioxidant enzymes, whereas severe stress led to the dominance of osmotic adjustment. Compared with CK, drought treatments resulted in 2987 differentially expressed genes (DEGs; 1674 up-regulated and 1313 down-regulated) and 921 differentially accumulated metabolites (DAMs)—562 in positive ionization mode (224 up, 338 down) and 359 in negative ionization mode (166 up, 193 down). Both gene expression and metabolite accumulation exhibited pronounced stress intensity-dependent patterns, suggesting that A. mongholicus initiates a broad, gene activation-led “active coping” strategy and mobilizes increasingly extensive metabolic pathways as drought intensifies. Conclusions: Integrated transcriptomic and metabolomic analyses revealed a tissue-specific “shoot–root partitioned coordination” mechanism: aboveground tissues activated a glutathione metabolism-centered “antioxidant–osmotic adjustment” defense, while root tissues reconfigured amino acid metabolism to maintain energy supply and signaling. This synergistic coordination represents a core adaptive strategy of A. mongholicus under drought conditions. Our study provides deeper insights into the drought resistance mechanisms of Astragalus and offers valuable references for breeding drought-tolerant varieties of Astragalus and other medicinal plants. Full article

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

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15 pages, 10132 KB

Open AccessArticle

Regulatory Potential of piRNAs Targeting Klotho and Other Genes

by Anna Pyrkova, Kyrmyzy Akhmetova, Murat Zhanuzakov, Makpal Tauassarova, Aizhan Rakhmetulina, Raigul Niyazova, Saltanat Orazova, Piotr Zielenkiewicz and Anatoliy Ivashchenko

Genes 2026, 17(2), 241; https://doi.org/10.3390/genes17020241 - 18 Feb 2026

Abstract

Background/Objectives: piRNAs (PIWI-interacting RNAs) can significantly modify the expression of protein-coding genes by suppressing the translation process. The aim of this work was to computationally evaluate the potential interactions between piRNAs and the mRNA of the Klotho gene, as well as other genes [...] Read more.

Background/Objectives: piRNAs (PIWI-interacting RNAs) can significantly modify the expression of protein-coding genes by suppressing the translation process. The aim of this work was to computationally evaluate the potential interactions between piRNAs and the mRNA of the Klotho gene, as well as other genes involved in key metabolic pathways related to health and lifespan regulation. Methods: Bioinformatic analysis was conducted using the MirTarget program, which determines the quantitative characteristics of predicted nucleotide interactions between piRNAs and mRNA targets. Results: Several piRNAs (piR-44682, piR-1940042, piR-3008660, piR-3215034, piR-6885965, and piR-7980636) were predicted to bind within a single cluster of binding sites on the KL mRNA. In addition, piR-6890096 was predicted to interact with the KL mRNA through full complementarity. The mRNAs of AFF2, BCL2L11, CPT1A, DAZAP1, NDRG3, SKIDA1, WBP4, ZIC5, and ZSWIM6 were predicted to interact with piR-3215034 and piR-6885965, forming clusters of binding sites located in the 5′ untranslated region (5′UTR), coding sequence (CDS), and 3′ untranslated region (3′UTR). Additionally, piR-576442, piR-1501557, piR-1845735, piR-2069834, and piR-3029987 were predicted to bind only within the 3′UTR of FGF23 mRNA. These results suggest that piRNAs are potential regulators of KL and other genes involved in key metabolic processes. Conclusions: The findings provide a basis for further experimental validation of predicted piRNA–mRNA interactions and their possible roles in gene regulation. Full article

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

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16 pages, 3269 KB

Open AccessArticle

Assembly of the Delphinium densiflorum Chloroplast Genome and Comparative Genomics Within Delphinium

by Siqi Chen, Min Wang, Xinhang Lu, Yuying Sun and Min Ma

Genes 2026, 17(2), 240; https://doi.org/10.3390/genes17020240 - 17 Feb 2026

Abstract

Background/Objectives: Chloroplast genomes are essential for understanding the systematics and adaptive evolution of alpine plants, yet genomic data for high-altitude Delphinium species remain scarce. Delphinium densiflorum, a medicinal plant endemic to the Qinghai-Tibet Plateau, exhibits notable high-altitude adaptations, but its plastome [...] Read more.

Background/Objectives: Chloroplast genomes are essential for understanding the systematics and adaptive evolution of alpine plants, yet genomic data for high-altitude Delphinium species remain scarce. Delphinium densiflorum, a medicinal plant endemic to the Qinghai-Tibet Plateau, exhibits notable high-altitude adaptations, but its plastome features and evolutionary position are still unclear. This study aims to assemble and characterize its complete chloroplast genome and clarify its phylogenetic placement within Delphinium. Methods: Using Illumina NovaSeq data, we de novo assembled the D. densiflorum plastome, annotated it with CPGAVAS2, and compared it with 12 published Ranunculaceae plastomes. We analyzed IR-boundary dynamics, genome-wide sequence variation, and codon-usage bias and constructed a maximum-likelihood phylogeny based on 69 shared protein-coding genes. Results: The plastome is 154,161 bp (GC 38.24%) with a canonical quadripartite structure, encoding 131 genes (87 CDS, 8 rRNA, 37 tRNA). An IR expansion into the SSC region yields the shortest SSC reported among the compared Delphinium species and produces unique structural variants. Photosynthetic genes are extremely conserved (nucleotide diversity Pi ≤ 0.01), whereas several loci (e.g., ycf1 and psaC) are highly divergent (Pi ≥ 0.05). Codon usage shows a strong bias toward AU-ending triplets. Phylogenetically, D. densiflorum forms a 100%-bootstrap clade with other high-altitude congeners, supporting the non-monophyly of Delphinium. Conclusions: This study delineates the plastome architecture and putative adaptive signatures of D. densiflorum, identifies robust candidate loci for DNA barcoding, and provides molecular evidence for taxonomic revision and conservation strategies in Delphinium. Full article

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

21 pages, 13963 KB

Open AccessArticle

Identification of a Tertiary Lymphoid Structure Signature for Predicting Tumor Outcomes Through Transcriptomics Analysis

by Mengdi Zhou, Fangliangzi Meng, Fan Wu and Chi Zhou

Genes 2026, 17(2), 239; https://doi.org/10.3390/genes17020239 - 16 Feb 2026

Abstract

Background: Tertiary lymphoid structures (TLSs) play a crucial role in regulating tumor invasion and metastasis and serve as a promising prognostic biomarker in immunotherapy, influencing survival and immune response in multiple cancers. However, existing studies rely on limited gene signatures to assess TLSs, [...] Read more.

Background: Tertiary lymphoid structures (TLSs) play a crucial role in regulating tumor invasion and metastasis and serve as a promising prognostic biomarker in immunotherapy, influencing survival and immune response in multiple cancers. However, existing studies rely on limited gene signatures to assess TLSs, and there remains a lack of comprehensive TLS-related features for pan-cancer prognosis or immunotherapy response prediction. Methods: Based on published TLS gene signatures, mutation data, and expression profiles from 33 tumor types in TCGA, along with data from 15 immune checkpoint blockade (ICB) cohorts, we first systematically evaluated six TLS gene signatures in relation to immune-related indicators and assessed their predictive and prognostic performance across tumors and immunotherapy. Subsequently, using meta-analysis, we constructed a de novo TLS-related gene feature set, termed predictTLS, designed to predict ICB efficacy and prognosis. The rationality and effectiveness of predictTLS were validated using internal validation sets, single-cell transcriptomic, and spatial transcriptomic data. Results: The evaluation revealed associations between TLS gene signatures and key immune-related indicators. The newly constructed predictTLS feature set demonstrated effectiveness in predicting both ICB therapy outcomes and patient prognosis across the analyzed cohorts. Validation across internal datasets, single-cell profiles, and spatial transcriptomics supported the robustness and biological relevance of predictTLS. Conclusions: This study provides a systematically validated, de novo TLS-related gene signature that can serve as a clinical biomarker for predicting immunotherapy response and prognosis in pan-cancer settings. These findings offer new tools for risk stratification and potential therapeutic targeting in tumor immunotherapy. Full article

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

14 pages, 1511 KB

Open AccessCase Report

Xp22.33 Duplication Encompassing PAR1 in a Male with Syndromic Neurodevelopmental Disorder and Tall Stature

by Dibyendu Dutta, Xi Luo and Ria Garg

Genes 2026, 17(2), 238; https://doi.org/10.3390/genes17020238 - 15 Feb 2026

Abstract

Background: Duplications involving Xp22.33, particularly within the pseudoautosomal region 1 (PAR1), are rare. While copy number variants (CNVs) involving SHOX, a dosage-sensitive gene in PAR1, are known to cause growth disorders, large duplications encompassing the entire PAR1 region and beyond show variable [...] Read more.

Background: Duplications involving Xp22.33, particularly within the pseudoautosomal region 1 (PAR1), are rare. While copy number variants (CNVs) involving SHOX, a dosage-sensitive gene in PAR1, are known to cause growth disorders, large duplications encompassing the entire PAR1 region and beyond show variable associations with skeletal and neurodevelopmental abnormalities. Duplication of the near-complete, isolated PAR1 with a comprehensive clinical description has not been reported. Case Presentation: We report a male patient with a 2.49 Mb duplication encompassing nearly the entire PAR1 region (chrX:200854–2692897, GRCh37). Clinical features included global developmental delay (GDD), autism spectrum disorder (ASD), recurrent seizures, hypotonia with joint hypermobility, dysmorphic features, and proportionate tall stature. The duplicated segment contains 30 genes, including 15 protein-coding genes that escape X-inactivation. Among these, SHOX, DHRSX, ASMT, and CSF2RA are notable candidates contributing to the observed phenotype. Conclusions: This report presents a detailed clinical characterization of a rare, near-complete, isolated PAR1 duplication in a male individual. The co-occurrence of tall stature, GDD, ASD, and seizures raises the possibility of a dosage-related phenotypic effect involving one or more genes within the duplicated interval. While causality cannot be definitively established, these observations contribute to the emerging understanding of the functional consequences of Xp22.33 duplications and suggest that increased copy number within this region may be associated with a clinically significant neurodevelopmental phenotype. Full article

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

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20 pages, 1913 KB

Open AccessArticle

Transcriptome-Based Selection and Validation of Reference Genes for Gene Expression Analysis in Roegneria ciliaris ‘Liao Sheng’ Across Various Tissues and Under Drought Stress

by Qianyun Luo, Yue Liu, Yifan Wang, Guanghao Zhang, Jiafen Liu, Hongxin Li, Zhen Liang, Ying Liu, Long Bai and Sijia Liu

Genes 2026, 17(2), 237; https://doi.org/10.3390/genes17020237 - 14 Feb 2026

Abstract

Backgrounds: Roegneria ciliaris is a perennial tetraploid wild relative of wheat that is widely distributed in China. It can be used both as a forage crop and ecological grass (the grasses specifically bred for ecological restoration) due to its strong stress tolerance, early [...] Read more.

Backgrounds: Roegneria ciliaris is a perennial tetraploid wild relative of wheat that is widely distributed in China. It can be used both as a forage crop and ecological grass (the grasses specifically bred for ecological restoration) due to its strong stress tolerance, early green-up, vigorous seedling growth in spring, and great palatability. Methods: It is necessary to select and validate appropriate reference genes (RGs) for gene expression normalization by qRT-PCR in order to decipher the stress tolerance mechanism of this grass species. Therefore, eight candidate RGs were identified from transcriptome data of R. ciliaris ‘Liao sheng’ in response to drought stress. The expression stability of these RGs was evaluated by five algorithms (∆Ct, geNorm, NormFinder, Bestkeeper and ReFinder) using samples from different tissues and drought stress. Results: The results showed that MDH and RPL19 were the most stable RGs among all samples, while GAPDH and TUBA presented the lowest expression stability. These representative RGs were further used to normalize the expression level of the pyrroline-5-carboxylate synthase (P5CS) and protein phosphatase 2C (PP2C) genes in different tissues and under drought stress. The results of P5CS and PP2C expression were consistent with transcriptome data. Conclusion: Our study provided the first systematic evaluation of the most stable RG selection for qRT-PCR normalization in R. ciliaris, which will promote further research on its tissue-specific gene expression and mechanism of drought tolerance. Full article

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

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27 pages, 2051 KB

Open AccessReview

Environmental Substances Associated with Neurodegeneration: An Overview of Parkinson’s Disease and Related Genotoxic Endpoints

by Mohammad Shoeb, Breanna Alman, Harpriya Kaur, Moon Han, Fahim Atif, William Wu Kim, Siddhi Desai, Patricia Ruiz and Gregory M. Zarus

Genes 2026, 17(2), 236; https://doi.org/10.3390/genes17020236 - 13 Feb 2026

Abstract

Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by age, genetic predispositions, and environmental exposures, with a growing global incidence. This review aims to summarize findings from ATSDR Toxicological Profiles, EPA Risk Assessments, and other sources of peer-reviewed literature to examine the [...] Read more.

Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by age, genetic predispositions, and environmental exposures, with a growing global incidence. This review aims to summarize findings from ATSDR Toxicological Profiles, EPA Risk Assessments, and other sources of peer-reviewed literature to examine the potential associations between PD and select metals, pesticides, and chlorinated organic compounds. Additionally, it explores using computational toxicology methods to elucidate the interactions between specific chemicals, associated genes, and their possible roles in PD. A total of 29 substances were identified to be neurotoxic with direct or probable association with PD. Risk of disease onset or symptom exacerbation of PD has been linked to exposures to neurodegenerative metals, pesticides, chlorinated organic compounds, and other environmental toxicants, alongside intrinsic factors such as genetic predisposition and aging. Supporting evidence from neurotoxicological studies directly or possibly associated with PD are summarized in referenced toxicological profiles and EPA risk assessments. Genotoxic endpoints evaluated in exposure-induced neurodegeneration including oxidative stress, DNA strand breaks, mitochondrial dysfunction, impaired DNA repair, and telomere alterations may play a critical role in linking environmental exposures to PD pathogenesis. Although these endpoints represent imperative data gaps between environmental and genetic risk factors for PD, isolating individual substances may not be necessary for prevention, as many co-occur at contaminated sites or within certain occupations. Further research is needed to clarify causal relationships between environmental exposure and genotoxic endpoints seen in neurodegenerative processes that can also be seen in PD for consideration in the development of preventive and therapeutic strategies. Full article

(This article belongs to the Section Neurogenomics)

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18 pages, 1613 KB

Open AccessArticle

Antibiotic-Driven Evolutionary Engineering in Salmonella Heidelberg Reveals Genomic Signatures of Attenuation

by Ruy D. Chacón, Manuel Ramírez, Claudete S. Astolfi-Ferreira and Antonio J. Piantino Ferreira

Genes 2026, 17(2), 235; https://doi.org/10.3390/genes17020235 - 12 Feb 2026

Abstract

Background/Objectives: Salmonella Heidelberg (SH) is a globally distributed pathogen associated with gastrointestinal disease in humans and animals and frequently affects poultry. Among the classic strategies used in vaccine development, evolutionary engineering enables the generation of attenuated bacterial strains through exposure to selective [...] Read more.

Background/Objectives: Salmonella Heidelberg (SH) is a globally distributed pathogen associated with gastrointestinal disease in humans and animals and frequently affects poultry. Among the classic strategies used in vaccine development, evolutionary engineering enables the generation of attenuated bacterial strains through exposure to selective pressures such as antibiotics. In this study, spontaneous antibiotic-resistant mutant strains of SH were generated by exposure to high concentrations of streptomycin and rifampicin, after which their phenotypic and genotypic characteristics were evaluated. Methods: The wild-type strain SA628 wt was subjected to continuous and discontinuous selection under antibiotic pressure. Phenotypic characterization included biochemical profiling and antibiotic susceptibility testing. Whole-genome sequencing was performed to identify genetic changes affecting virulence- and resistance-associated genes, plasmid content, and point mutations using variant calling approaches. The potential functional relationships of the mutated genes were further analyzed through genetic network analysis. Results: The mutant strains SA628 mut1 and SA628 mut3 were obtained through discontinuous selection, whereas strain SA628 mut2 was generated under continuous selection. Phenotypically, all the mutant strains exhibited resistance to streptomycin, whereas SA628 mut2 and SA628 mut3 also exhibited resistance to rifampicin. Genomic analyses revealed mutations in rpoS, ascD, ynfE, rpoB, and cyaA associated with discontinuous selection and in iscU, ybiO, rpoB, and rsmG associated with continuous selection. Network analysis indicated that these genes are functionally connected within regulatory and metabolic interaction networks, including global transcriptional regulation, anaerobic metabolism, cAMP-mediated signaling, translation, and iron–sulfur cluster biogenesis. Conclusions: Collectively, these findings suggest that antibiotic-driven selection promotes coordinated genetic changes affecting stress responses and metabolism, which may contribute to reduced virulence. This work provides insights into bacterial adaptation under antibiotic stress and supports the potential use of evolutionary engineering for the development of attenuated strains. Full article

(This article belongs to the Special Issue Unraveling Genomic Mechanisms of Stress Tolerance and Antimicrobial Resistance in Foodborne Pathogens)

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17 pages, 514 KB

Open AccessArticle

Diagnostic Value of Karyotype, Microarray, RASopathy Gene Testing and Ultrasound in Fetuses with Nuchal Translucency 3.0–3.4 mm: A Single-Center Cohort Retrospective Study

by Silvia Andrietti, Giuseppe Gullo, Diliana Beleva, Alessia Maccarrone, Lina De Paola, Chiara Roberta Gaggero, Chiara Calcagno, Maria Lucia Furnari and Pierangela De Biasio

Genes 2026, 17(2), 234; https://doi.org/10.3390/genes17020234 - 12 Feb 2026

Abstract

Background: Increased nuchal translucency (NT) is associated with an elevated risk of genetic abnormalities and structural malformations. The clinical utility of invasive testing and the optimal diagnostic approach in mildly increased NT (3.0–3.4 mm) is debated. This study aimed to evaluate genetic [...] Read more.

Background: Increased nuchal translucency (NT) is associated with an elevated risk of genetic abnormalities and structural malformations. The clinical utility of invasive testing and the optimal diagnostic approach in mildly increased NT (3.0–3.4 mm) is debated. This study aimed to evaluate genetic and ultrasound findings in this subgroup and to assess the diagnostic yield of advanced genetic testing. Methods: We retrospectively included a total of 107 fetuses with NT between 3.0 and 3.4 mm from a single fetal medicine unit. Complete outcome data were available for 97 pregnancies. Invasive prenatal testing with standard karyotype, chromosomal microarray analysis (CMA) and RASopathy panel testing were offered. All patients underwent detailed ultrasound examination to detect structural abnormalities at 16 and 20 weeks, regardless of whether invasive testing was performed. Results: Invasive prenatal testing, amniocentesis or chorionic villus sampling, (CVS), was performed in 77/97 cases (79.4%). Genetic abnormalities were detected in 28/97 (28.9%). Overall, five rare genetic anomalies were identified; none would have been detected by quantitative fluorescent polymerase chain reaction (QF-PCR) or non-invasive prenatal testing (NIPT). Two anomalies were detectable by standard karyotype, two exclusively by CMA and one exclusively by RASopathy panel. When considering all cases undergoing advanced genetic testing (CMA or RASopathy panel, n = 35) the overall diagnostic yield was 8.5% (3/35). When calculated across the entire cohort with complete follow-up, the additional diagnostic yield was 3.1% (3/97). Major structural malformations were identified in 17/97 cases (17.5%), of which 10 (58.8%) were associated with genetic abnormalities. Conclusions: Fetuses with NT measurements between 3.0 and 3.4 mm show a substantially increased risk of genetic abnormalities and structural malformations. These findings support a comprehensive prenatal evaluation, including invasive testing with advanced genetic analysis and detailed ultrasound assessment, to optimize diagnosis and counseling. Full article

(This article belongs to the Section Genetic Diagnosis)

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26 pages, 506 KB

Open AccessReview

Alzheimer’s 2030: From Precision Genomics to Artificial Intelligence

by Valeria D’Argenio, Rossella Tomaiuolo, Silvia Bargeri and Giulia Sancesario

Genes 2026, 17(2), 233; https://doi.org/10.3390/genes17020233 - 12 Feb 2026

Abstract

Alzheimer’s disease (AD) represents a critical global health challenge, with its prevalence and associated costs expected to double significantly by 2030 and 2050. While lifestyle interventions are crucial, sporadic late-onset AD has a substantial genetic component (40–80% heritability), though known variants limit the [...] Read more.

Alzheimer’s disease (AD) represents a critical global health challenge, with its prevalence and associated costs expected to double significantly by 2030 and 2050. While lifestyle interventions are crucial, sporadic late-onset AD has a substantial genetic component (40–80% heritability), though known variants limit the scope of traditional precision medicine. Crucially, sex and gender are significant risk determinants, with women accounting for two-thirds of cases due to a complex interplay of biological and sociocultural factors. This review focuses on the influence of genetic and gender-related factors, examining large-scale genome-wide association studies (GWASs) and their role in developing advanced genetic risk scores (GRS) for precision genomics. We also explore the potential of Artificial Intelligence (AI) for multimodal big data analysis and digital health tools to promote personalized prevention and emerging concerns about ethics, privacy and data treatment. The convergence of these findings underscores the urgent need for a genetic-, sex- and gender-informed precision-medicine approach to AD. Full article

(This article belongs to the Special Issue 15th Anniversary of Genes: Feature Papers in “Neurogenetics and Neurogenomics”)

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21 pages, 446 KB

Open AccessPerspective

Conversation with Future Clinical Cytogeneticists: The New Frontiers

by Jing Christine Ye, Rishi Chowdhury and Henry H. Heng

Genes 2026, 17(2), 232; https://doi.org/10.3390/genes17020232 - 12 Feb 2026

Abstract

The post-genomic era has transformed medical genetics, raising renewed debate over the role of medical cytogenetics in clinical practice. High-throughput sequencing and chromosomal microarray technologies now dominate cancer diagnostics, prenatal testing, and rare disease evaluation by enabling rapid detection of gene-level variation, often [...] Read more.

The post-genomic era has transformed medical genetics, raising renewed debate over the role of medical cytogenetics in clinical practice. High-throughput sequencing and chromosomal microarray technologies now dominate cancer diagnostics, prenatal testing, and rare disease evaluation by enabling rapid detection of gene-level variation, often leading to the perception that cytogenetics is obsolete. However, this view overlooks the unique and complementary strengths of cytogenetic analysis. Although the relationship between cytogenetics and current NGS technologies can be compared to that between forests and trees versus leaves—both of which are necessary for clinical diagnosis—cytogenetic methods uniquely enable direct in situ visualization of chromosomes, allowing detection of large-scale structural and numerical genome alterations at the level of individual cells and cell populations. These system-level features that are frequently invisible or difficult to interpret using sequencing-based approaches alone yet are critical in disease contexts where genome architecture itself carries biological and clinical significance beyond individual genes. This article, therefore, advances a new perspective based on Genome Architecture Theory: that karyotype-level information organizes gene-level function and that many previous gene-centric genetic concepts require reexamination within a unified framework of clinical genomics. Rather than being replaced, cytogenetics is increasingly integrated with sequencing within a unified framework of clinical genomics that combines high-resolution molecular detail with system-level insight into genome organization. Reassessing the role of cytogenetics, therefore, has important implications for medical education, diagnostic strategy, and healthcare policy, as cytogenetics provides the appropriate platform for understanding system-level inheritance through karyotype coding and for advancing molecular medicine from a genome systems perspective. Full article

(This article belongs to the Special Issue Cytogenetics and Cytogenomics in Clinical Diagnostics: Innovations and Applications)

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18 pages, 2894 KB

Open AccessArticle

Reassessing Benign ASXL1 Variants in Bohring–Opitz Syndrome: The Role of Population Databases in Variant Reinterpretation

by Liliana Fernández-Hernández, Sergio Enríquez-Flores, Nancy L. Hernández-Martínez, Melania Abreu-González, Esther Lieberman-Hernández, Gerardo Rodríguez-González, Sinuhé Reyes-Ruvalcaba and Miriam E. Reyna-Fabián

Genes 2026, 17(2), 231; https://doi.org/10.3390/genes17020231 - 12 Feb 2026

Abstract

Background/Objectives: ASXL1 is a chromatin-associated gene implicated in both hematologic malignancies and neurodevelopmental disorders, including Bohring–Opitz syndrome (BOS). Although many ASXL1 variants are well classified, a substantial proportion remain variants of uncertain significance (VUS), complicating molecular diagnosis and genetic counseling. The objective [...] Read more.

Background/Objectives: ASXL1 is a chromatin-associated gene implicated in both hematologic malignancies and neurodevelopmental disorders, including Bohring–Opitz syndrome (BOS). Although many ASXL1 variants are well classified, a substantial proportion remain variants of uncertain significance (VUS), complicating molecular diagnosis and genetic counseling. The objective of this study was to evaluate whether structural context can inform the interpretation of selected ASXL1 missense variants in a clinical setting. Methods: We describe a 17-year-old female with clinical features consistent with BOS carrying the heterozygous ASXL1 variant p.Q1448R, currently classified as benign under ACMG/AMP guidelines. Three-dimensional in silico structural modeling was performed using AlphaFold3 and available crystallographic data. Three additional ASXL1 missense variants classified as VUS in ClinVar (p.R265H, p.T297M, and p.Y358C) were also analyzed. Evolutionary conservation, domain localization, and residue-level interactions were assessed. Results: Structural modeling indicated that the p.Q1448R substitution alters polar interactions and introduces a steric constraint near a conserved PHD-type zinc finger domain. Variants p.R265H and p.T297M affected stabilizing interactions within the DEUBAD, which is involved in BAP1 activation, while p.Y358C altered a polar microenvironment adjacent to a chromatin-interacting region. All analyzed variants, except p.T297M, localized to evolutionarily conserved regions. Conclusions: This study demonstrates that in silico structural analysis can provide complementary, domain-level insights for the interpretation of ASXL1 missense variants that remain classified as benign, likely benign or VUS under current frameworks. Such approaches may assist in prioritizing variants for further functional evaluation and refining molecular interpretation when experimental data are limited. Full article

(This article belongs to the Collection Genetics and Genomics of Rare Disorders)

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28 pages, 1118 KB

Open AccessReview

CRISPR-Mediated Silkworm: The Oncoming Agricultural Revolutions and a Rising Model Organism

by Qiaoling Sun, Yongkang Guo, Liting Wang, Ling Jia, Peng Wei and Sanyuan Ma

Genes 2026, 17(2), 230; https://doi.org/10.3390/genes17020230 - 12 Feb 2026

Abstract

The silkworm (Bombyx mori) is essential to sericulture and is also becoming a key model organism in genomics and agriculture. For decades, genetic studies of the silkworm were limited by inefficient and inflexible genome tools. CRISPR genome editing allows precise and [...] Read more.

The silkworm (Bombyx mori) is essential to sericulture and is also becoming a key model organism in genomics and agriculture. For decades, genetic studies of the silkworm were limited by inefficient and inflexible genome tools. CRISPR genome editing allows precise and scalable alterations to genes regulating development, physiology, and industrial traits. This review summarizes silkworm genome-editing breakthroughs, highlighting CRISPR’s evolution from simple gene knockouts to large-scale genome-wide screening. We highlight how these advancements contribute to disease resistance, higher yields, and the development of new silk-based materials, as well as how they influence the development and growth rate of the sericulture. The creation of high-quality reference genomes, pangenomes, and genome-wide screening systems has made the silkworm a major model for integrating multiple biological datasets and approaches, such as genomic, transcriptomic, and proteomic. By considering the unique biological characteristics of the silkworm, this provides new insights for research on silk biology, piRNA synthetic biology, and hormonal signaling regulation. Finally, we examine new areas at the intersection of CRISPR, pangenomics, and artificial intelligence (AI) and suggest future paths for molecular breeding, pest control, and synthetic biology. Moreover, AI-assisted prediction of CRISPR outcomes is utilized to inform the design of targeted trait modifications, representing an approach to enhancing biomanufacturing efficiency and eco-friendly silk production. Together, these advances have made the silkworm a flexible genetic platform and an important part of sustainable agriculture and biomanufacturing. Full article

(This article belongs to the Special Issue Application of CRISPR/Cas9 Technology in Insects)

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23 pages, 2413 KB

Open AccessArticle

Next-Generation Sequencing Defines a Molecularly Confirmed ARPKD Core Within the Broader PKHD1-Associated Disease Spectrum

by Paloma Lapunzina-Soler, Amir Shabaka, Ramón Peces, Ángel Alonso, Emilio Cuesta, Rocío Mena, Laura Espinosa-Román, Marta Melgosa, Gema Fernández, Yolanda Muñoz-GᵃPorrero, Jair Tenorio-Castaño, Pablo Lapunzina and Julián Nevado

Genes 2026, 17(2), 229; https://doi.org/10.3390/genes17020229 - 11 Feb 2026

Abstract

Background/Objectives: Autosomal recessive polycystic kidney disease (ARPKD) is a severe ciliopathy caused by biallelic pathogenic variants in PKHD1, characterized by variable renal and hepatobiliary involvement. The widespread use of next-generation sequencing (NGS) has revealed a large number of rare PKHD1 variants, [...] Read more.

Background/Objectives: Autosomal recessive polycystic kidney disease (ARPKD) is a severe ciliopathy caused by biallelic pathogenic variants in PKHD1, characterized by variable renal and hepatobiliary involvement. The widespread use of next-generation sequencing (NGS) has revealed a large number of rare PKHD1 variants, creating major challenges in distinguishing molecularly confirmed ARPKD from a broader spectrum of PKHD1-associated disease. Methods: We performed an integrated clinical and molecular analysis of 68 individuals referred for suspected ARPKD. Using phase-aware and family-informed ACMG classification, patients were stratified into three genetically defined groups: 40 with molecularly confirmed ARPKD (biallelic pathogenic, likely pathogenic or segregation-supported VUS-LP variants in trans), 10 with biallelic PKHD1 variants of uncertain pathogenicity, and 18 monoallelic carriers. Genotype–phenotype correlations were restricted to the molecularly confirmed ARPKD group. Results: Among the 40 molecularly confirmed ARPKD patients, 17 (42.5%) carried two loss-of-function (LoF) alleles, 16 (40%) carried one LoF allele, and 7 (17.5%) carried only non-LoF alleles. A strong allele-dose effect was observed. Neonatal or infantile onset occurred in 88% of LoF/LoF patients, compared with 56% of LoF/non-LoF and 29% of non-LoF/non-LoF individuals (p < 0.001). Progression to renal replacement therapy occurred in 65%, 31%, and 0% of patients (p = 0.002). In contrast, hepatobiliary disease was highly prevalent across all genotype classes and showed no significant association with LoF burden. Conclusions: Phase-aware and family-informed interpretation of PKHD1 variants distinguishes a molecularly confirmed ARPKD core from a broader PKHD1 variant spectrum. Within confirmed ARPKD, loss-of-function allele burden is the primary determinant of renal and perinatal severity, whereas hepatic disease is largely independent of truncating allele burden. These findings refine diagnosis, prognosis, and genetic counseling in the genomic era. Full article

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

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16 pages, 1054 KB

Open AccessReview

DNA Methylation in the Ovary and Uterus of Mammalian Animal Models: Implications for Reproductive Function

by Oliwia Serej, Magdalena K. Kowalik and Robert Rekawiecki

Genes 2026, 17(2), 228; https://doi.org/10.3390/genes17020228 - 11 Feb 2026

Abstract

DNA methylation is a key epigenetic modification that regulates gene expression and maintains genome stability, particularly in mammalian reproductive tissues. This review summarizes the current knowledge of DNA methylation and demethylation fluctuations with a specific focus on the regulation of ovarian development and [...] Read more.

DNA methylation is a key epigenetic modification that regulates gene expression and maintains genome stability, particularly in mammalian reproductive tissues. This review summarizes the current knowledge of DNA methylation and demethylation fluctuations with a specific focus on the regulation of ovarian development and uterine function during pregnancy. This modification primarily occurs at CpG-rich regions and is catalyzed by DNA methyltransferases (DNMTs): DNMT1 maintains existing patterns during replication, while DNMT3A and DNMT3B establish de novo methylation. Demethylation is mediated by ten-eleven translocation enzymes (TET1, TET2, and TET3), which oxidize 5-methylcytosine, ultimately replacing it with unmethylated cytosine. These processes play essential roles in folliculogenesis, oocyte maturation, steroidogenesis, and tissue-specific gene regulation. Understanding these epigenetic mechanisms provides important insights into veterinary medicine and offers potential applications in fertility preservation across diverse mammalian species. Consequently, further research is essential to elucidate the clinical implications of these epigenetic processes for improving reproductive health outcomes in animals. Full article

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

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