Genes

21 pages, 4647 KB

Open AccessArticle

Multi-Omics Analysis of the Co-Expression Features of Specific Neighboring Gene Pairs Suggests an Association with Catechin Regulation in Camellia sinensis

by Shuaibin Lian, Feixiang Ren, Shuanghui Cai, Zhong Wang, Youchao Tu, Ke Gong and Wei Zhang

Genes 2026, 17(1), 117; https://doi.org/10.3390/genes17010117 - 22 Jan 2026

Abstract

Background/Objectives: The arrangement and positioning of genes on chromosomes are non-random in plant genomes. Adjacent gene pairs often exhibit similar co-expression patterns and regulatory mechanisms. However, the genomic and epigenetic features influencing such co-expression, particularly in perennial crops like tea (Camellia sinensis [...] Read more.

Background/Objectives: The arrangement and positioning of genes on chromosomes are non-random in plant genomes. Adjacent gene pairs often exhibit similar co-expression patterns and regulatory mechanisms. However, the genomic and epigenetic features influencing such co-expression, particularly in perennial crops like tea (Camellia sinensis), remain largely uncharacterized. Methods: Firstly, we identified 771 specific neighboring gene pairs (SNGs) in C. sinensis (YK10) and investigated the contributions of intergenic distance and gene length to SNGs’ co-expression. Secondly, we integrated multi-omics data including transcriptome, ATAC-seq, Hi-C and histone modification data to explore the factors influencing their co-expression. Thirdly, we employed logistic regression models to individually assess the contributions of nine factors—ATAC-seq, H3K27ac, Hi-C, GO, distance, length, promoter, enhancer, and expression level—to the co-expression of SNGs. Finally, by integrating co-expression networks with metabolic profiles, several transcription factors potentially involved in the regulation of catechin metabolic pathways were identified. Results: Intergenic distance was significantly negatively correlated with co-expression strength, while gene length showed a positive correlation. Furthermore, these two features exerted synergistic effects with threshold characteristics and functional significance. SNGs marked by either ATAC-seq or H3K27ac peaks displayed significantly higher expression levels, suggesting that epigenetic regulation promotes co-expression. In addition, correlation analysis revealed that the expression of certain SNGs was closely associated with catechin accumulation, particularly epicatechin gallate (EGC) and epigallocatechin gallate (EGCG), highlighting their potential role in modulating tissue-specific catechin levels. Conclusions: Collectively, this study reveals a multilayered regulatory framework governing SNG co-expression and provides theoretical insights and candidate regulators for understanding metabolic regulation in tea plants. Full article

(This article belongs to the Special Issue Genetics and Breeding of Tea Tree and Tea Plant)

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18 pages, 1229 KB

Open AccessReview

Composition and Function of Gut Microbiome: From Basic Omics to Precision Medicine

by Yan Ma, Lamei Wang, Haitao Hu, Audrey Ruei-En Shieh, Edward Li, Dongdong He, Lin He, Zhong Liu, Thant Mon Paing, Xinhua Chen and Yangchun Cao

Genes 2026, 17(1), 116; https://doi.org/10.3390/genes17010116 - 22 Jan 2026

Abstract

The gut microbiome is defined as the collective assembly of microbial communities inhabiting the gut, along with their genes and metabolic products. The gut microbiome systematically regulates host metabolism, immunity, and neuroendocrine homeostasis via interspecies interaction networks and inter-organ axes. Given the importance [...] Read more.

The gut microbiome is defined as the collective assembly of microbial communities inhabiting the gut, along with their genes and metabolic products. The gut microbiome systematically regulates host metabolism, immunity, and neuroendocrine homeostasis via interspecies interaction networks and inter-organ axes. Given the importance of the gut microbiome to the host, this review integrates the composition, function, and genetic basis of the gut microbiome with host genomics to provide a systematic overview of recent advances in microbiome–host interactions. This encompasses a complete technological pipeline spanning from in vitro to in vivo models to translational medicine. This technological pipeline spans from single-bacterium CRISPR editing, organoid–microbiome co-culture, and sterile/humanized animal models to multi-omics integrated algorithms, machine learning causal inference, and individualized probiotic design. It aims to transform microbiome associations into precision intervention strategies that can be targeted and predicted for clinical application through interdisciplinary research, thereby providing the cornerstone of a new generation of precision treatment strategies for cancer, metabolic, and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Unveiling Human Microbiome Composition and Functions to Improve Health and Disease Research)

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15 pages, 5525 KB

Open AccessArticle

Multi-Omics Analysis Identifies the Key Defence Pathways in Chinese Cabbage Responding to Black Spot Disease

by Wenyuan Yan, Hong Zhang, Weiqiang Fan, Xiaohui Liu, Zhiyin Huang, Yong Wang, Yerong Zhu, Chaonan Wang and Bin Zhang

Genes 2026, 17(1), 115; https://doi.org/10.3390/genes17010115 - 21 Jan 2026

Abstract

Background: Black spot disease severely constrains Chinese cabbage production. Methods: To elucidate the defence mechanisms underlying this response, transcriptomic and metabolomic profiles were analysed in leaves of the Chinese cabbage line 904B at 24 h post-inoculation (hpi) with Alternaria brassicicola. In parallel, [...] Read more.

Background: Black spot disease severely constrains Chinese cabbage production. Methods: To elucidate the defence mechanisms underlying this response, transcriptomic and metabolomic profiles were analysed in leaves of the Chinese cabbage line 904B at 24 h post-inoculation (hpi) with Alternaria brassicicola. In parallel, gene silencing and overexpression were conducted for BraPBL, an RLCK family member in Chinese cabbage. Results: The Chinese cabbage line 904B exhibited marked suppression of cytokinin and auxin signalling, coupled with enhanced expression of genes involved in ethylene and jasmonic acid signalling. Multiple secondary metabolites exhibited differential changes, specifically the sterol compound 4,4-dimethyl-5alpha-cholest-7-en-3beta-ol was significantly upregulated in the treatment group. These metabolites were primarily enriched in the indole alkaloid metabolism and glycerolipid metabolism pathways. Concurrently, BraPBL exhibits increasing expression with prolonged infection. BraPBL overexpression enhances resistance to black spot disease, whereas silencing reduces resistance. Subcellular localization confirmed BraPBL at the plasma membrane. Overexpression of BraPBL upregulates the reactive oxygen species-related gene RBOH and the signal transduction-related gene MEKK1, whilst simultaneously activating the JA pathway. Conclusions: Overall, 904B activates defence-related hormones while suppressing growth and development-related hormones during early infection. Secondary metabolites, particularly the sterol compound 4,4-dimethyl-5alpha-cholest-7-en-3beta-ol, play key roles in defence, and BraPBL functions as a black spot disease–related defence gene in Chinese cabbage. Full article

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

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13 pages, 6367 KB

Open AccessArticle

Gene Expression-Based Colorectal Cancer Prediction Using Machine Learning and SHAP Analysis

by Yulai Yin, Zhen Yang, Xueqing Li, Shuo Gong and Chen Xu

Genes 2026, 17(1), 114; https://doi.org/10.3390/genes17010114 - 20 Jan 2026

Abstract

Objective: To develop and validate a genetic diagnostic model for colorectal cancer (CRC). Methods: First, differential expression genes (DEGs) between colorectal cancer and normal groups were screened using the TCGA database. Subsequently, a two-sample Mendelian randomization analysis was performed using the eQTL genomic [...] Read more.

Objective: To develop and validate a genetic diagnostic model for colorectal cancer (CRC). Methods: First, differential expression genes (DEGs) between colorectal cancer and normal groups were screened using the TCGA database. Subsequently, a two-sample Mendelian randomization analysis was performed using the eQTL genomic data from the IEU OpenGWAS database and colorectal cancer outcomes from the R12 Finnish database to identify associated genes. The intersecting genes from both methods were selected for the development and validation of the CRC genetic diagnostic model using nine machine learning algorithms: Lasso Regression, XGBoost, Gradient Boosting Machine (GBM), Generalized Linear Model (GLM), Neural Network (NN), Support Vector Machine (SVM), k-Nearest Neighbors (KNN), Random Forest (RF), and Decision Tree (DT). Results: A total of 3716 DEGs were identified from the TCGA database, while 121 genes were associated with CRC based on the eQTL Mendelian randomization analysis. The intersection of these two methods yielded 27 genes. Among the nine machine learning methods, XGBoost achieved the highest AUC value of 0.990. The top five genes predicted by the XGBoost method—RIF1, GDPD5, DBNDD1, RCCD1, and CLDN5—along with the five most significantly differentially expressed genes (ASCL2, IFITM3, IFITM1, SMPDL3A, and SUCLG2) in the GSE87211 dataset, were selected for the construction of the final colorectal cancer (CRC) genetic diagnostic model. The ROC curve analysis revealed an AUC (95% CI) of 0.9875 (0.9737–0.9875) for the training set, and 0.9601 (0.9145–0.9601) for the validation set, indicating strong predictive performance of the model. SHAP model interpretation further identified IFITM1 and DBNDD1 as the most influential genes in the XGBoost model, with both making positive contributions to the model’s predictions. Conclusions: The gene expression profile in colorectal cancer is characterized by enhanced cell proliferation, elevated metabolic activity, and immune evasion. A genetic diagnostic model constructed based on ten genes (RIF1, GDPD5, DBNDD1, RCCD1, CLDN5, ASCL2, IFITM3, IFITM1, SMPDL3A, and SUCLG2) demonstrates strong predictive performance. This model holds significant potential for the early diagnosis and intervention of colorectal cancer, contributing to the implementation of third-tier prevention strategies. Full article

(This article belongs to the Section Bioinformatics)

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15 pages, 634 KB

Open AccessReview

Advances in Nondestructive DNA Extraction from Teeth for Human Identification

by Irena Zupanič Pajnič

Genes 2026, 17(1), 113; https://doi.org/10.3390/genes17010113 - 20 Jan 2026

Abstract

This review synthesizes advances in nondestructive DNA extraction from teeth, emphasizing their importance in forensics and archaeogenetics. Because of their mineralized structure and resistance to diagenesis, teeth remain vital for human identification when other tissues are unavailable or degraded. Modern protocols targeting dental [...] Read more.

This review synthesizes advances in nondestructive DNA extraction from teeth, emphasizing their importance in forensics and archaeogenetics. Because of their mineralized structure and resistance to diagenesis, teeth remain vital for human identification when other tissues are unavailable or degraded. Modern protocols targeting dental cementum have shown high success rates in retrieving nuclear DNA while maintaining specimen integrity, supporting ethical standards, and enabling additional morphological and isotopic analyses. Nondestructive extraction methods produce DNA yields comparable to—or in some archaeological cases, greater than—those of traditional destructive approaches, while ensuring strict contamination control and minimal physical impact. Cementum is a reliable source of DNA in aged and degraded teeth, although the petrous part of the temporal bone still represents the best option under extreme preservation conditions. These results highlight the need for context-specific sampling strategies that balance analytical goals with the preservation of museum collections. Future efforts include testing nondestructive protocols across various forensic scenarios and creating predictive models for DNA preservation. Overall, these developments promote ethical, effective, and sustainable practices in human genomic analysis. Full article

(This article belongs to the Special Issue Research Updates in Forensic Genetics)

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15 pages, 1533 KB

Open AccessArticle

Comparative Chromosomal Analysis of the Z Chromosome in South American Bird Species Shows a High Rate of Intrachromosomal Rearrangements

by Marie Rosellynn C. Enguito, Analía Del Valle Garnero, Ricardo José Gunski, Marcelo Santos de Souza, Rebecca E. O’Connor, Kornsorn Srikulnath, Worapong Singchat, Edivaldo Herculano Correa de Oliveira, Michael N. Romanov, Darren Karl Griffin and Rafael Kretschmer

Genes 2026, 17(1), 112; https://doi.org/10.3390/genes17010112 - 20 Jan 2026

Abstract

Background: Intrachromosomal rearrangements in birds play a subtle but important role in shaping genomic evolution, phenotypic diversity and speciation. However, the avian sex chromosome system (homogametic ZZ males; heterogametic ZW females) remains relatively understudied, and evolutionary rearrangements of the Z chromosome have not [...] Read more.

Background: Intrachromosomal rearrangements in birds play a subtle but important role in shaping genomic evolution, phenotypic diversity and speciation. However, the avian sex chromosome system (homogametic ZZ males; heterogametic ZW females) remains relatively understudied, and evolutionary rearrangements of the Z chromosome have not been mapped in most species. To address this, we employed universally hybridizing avian Z chromosome probes to metaphases of 11 avian species from South America. Methods: Chromosome preparations were obtained from fibroblast cell cultures of 11 birds representing nine different orders; four bacterial artificial chromosome (BAC) probes were used in our interspecies fluorescence in situ hybridization (FISH) experiments. We identified chromosomal rearrangements in the species investigated, tracing the evolution of the Z chromosome in these species through comparison with reptiles from Southeast Asia (three snake species used as an outgroup), along with two reference species: chicken (Galliformes) and zebra finch (Passeriformes). Results: We observed high rates of intrachromosomal rearrangements in the avian Z chromosome, with most species showing different patterns from chicken and zebra finch. Nannopterum brasilianum (Suliformes) and Jacana jacana (Charadriiformes) showed the same BAC order as chicken, but centromere repositioning was evident. Apart from Piciformes, all other species exhibited a conserved Z chromosome size. The corresponding Z chromosome sequences were homologous to regions of the long arms of Chromosome 2 and W in snakes but not on the Z chromosomes. Conclusions: Comparative analysis of the Z chromosome across avian orders provides important insights into the dynamics of avian sex chromosomes and the evolution of sex chromosome systems in general. Full article

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

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22 pages, 837 KB

Open AccessArticle

Mitochondrial DNA Variation of the Striped Hyena (Hyaena hyaena) in Algeria and Further Insights into the Species’ Evolutionary History

by Louiza Derouiche, Mónica Rodrigues, Hafida Benameur-Hasnaoui, Ridah Hadj Aissa, Yasaman Hassan-Beigi, Seyed Massoud Madjdzadeh, Zuhair Amr, Aimee Cokayne, Paul Vercammen and Carlos Rodríguez Fernandes

Genes 2026, 17(1), 111; https://doi.org/10.3390/genes17010111 - 20 Jan 2026

Abstract

Background: The striped hyena (Hyaena hyaena) occurs in a wide range from north and east Africa, through southwest Asia to India, but its distribution is increasingly patchy and many of its populations are in decline due to intense human pressure. [...] Read more.

Background: The striped hyena (Hyaena hyaena) occurs in a wide range from north and east Africa, through southwest Asia to India, but its distribution is increasingly patchy and many of its populations are in decline due to intense human pressure. Its genetic diversity and structure, phylogeography, and evolutionary history, remain poorly understood. Methods: In this study, we investigated mitochondrial DNA variation in Algerian striped hyenas. Moreover, with the aim of contributing to our understanding of the evolutionary history of the species, we also examined samples from other geographic regions and compared our results with those of the only previous study in which individuals from across the range of the species were analyzed. In particular, we performed a wide range of analyses of demographic history and estimation of the age of the extant mitochondrial DNA variation. Results and Conclusions: The Algerian population sample was monomorphic. Overall, the global patterns of genetic diversity and the results of some demographic history analyses support a scenario of population growth in the species, estimated to have occurred in the Late Pleistocene, but many of the analyses did not detect a significant signal of growth, most likely a result of the limited power provided by a small number of segregating sites. The estimates, from three different methods, for the time to the most recent common ancestor (TMRCA) of the mitochondrial DNA variation hovered around 400 ka, coinciding with one of the longest and warmest interglacials of the last 800,000 years, with environmental conditions similar to the Holocene. Full article

(This article belongs to the Section Population and Evolutionary Genetics and Genomics)

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15 pages, 719 KB

Open AccessArticle

Bioinformatic Analysis of Differentially Expressed Long Non-Coding RNAs in Skeletal Muscle Following Aerobic and Resistance Exercise

by Kassia Régnier, Lucas P. R. Beaupre, Ian F. Coccimiglio, Taylor J. McColl, David C. Clarke and Brendon J. Gurd

Genes 2026, 17(1), 110; https://doi.org/10.3390/genes17010110 - 20 Jan 2026

Abstract

Background/Objectives: Emerging evidence suggests that long non-coding RNA (lncRNA) molecules influence the adaptive response to exercise, but how lncRNA responses differ between endurance and resistance exercise (RE) modalities is poorly understood. The purpose of this study was to bioinformatically infer the expression [...] Read more.

Background/Objectives: Emerging evidence suggests that long non-coding RNA (lncRNA) molecules influence the adaptive response to exercise, but how lncRNA responses differ between endurance and resistance exercise (RE) modalities is poorly understood. The purpose of this study was to bioinformatically infer the expression of lncRNA in skeletal muscle following acute aerobic exercise (AE) and RE. Methods: We downloaded publicly available RNA-seq data, performed a differential expression (DE) analysis, and compared lncRNA expression profiles between different exercise types (AE vs. RE) at three timepoints: baseline, 1 h post-exercise, and 4 h post-exercise. Results: We observed distinct lncRNA profiles between acute AE and RE at different timepoints, suggesting that lncRNA perform distinct roles in controlling the response to different exercise modalities in skeletal muscle. Conclusions: Future studies should investigate the specific roles of these lncRNAs in the response to acute exercise in skeletal muscle. Full article

(This article belongs to the Section RNA)

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23 pages, 1644 KB

Open AccessReview

Joint Acidosis and GPR68 Signaling in Osteoarthritis: Implications for Cartilage Gene Regulation

by Colette Hyde, Adam Yung, Ryan Taffe, Bhakti Patel and Nazir M. Khan

Genes 2026, 17(1), 109; https://doi.org/10.3390/genes17010109 - 20 Jan 2026

Abstract

Joint acidosis is increasingly recognized as an important determinant of cellular behavior in osteoarthritis (OA). Declines in extracellular pH (pHe) occur across cartilage, meniscus, synovium, and subchondral bone, where they influence inflammation, matrix turnover, and pain. Among proton-sensing G protein-coupled receptors, GPR68 responds [...] Read more.

Joint acidosis is increasingly recognized as an important determinant of cellular behavior in osteoarthritis (OA). Declines in extracellular pH (pHe) occur across cartilage, meniscus, synovium, and subchondral bone, where they influence inflammation, matrix turnover, and pain. Among proton-sensing G protein-coupled receptors, GPR68 responds to the acidic pH range characteristic of human OA joints. The receptor is activated between pH 6.8 and 7.0, couples to Gq/PLC-MAPK, cAMP-CREB, G12/13-RhoA-ROCK signaling pathways, and is expressed most prominently in articular cartilage, with additional expression reported in synovium, bone, vasculature, and some neuronal populations. These pathways regulate transcriptional programs relevant to cartilage stress responses, inflammation, and matrix turnover. GPR68 expression is increased in human OA cartilage and aligns with regions of active matrix turnover. We previously reported that pharmacologic activation of GPR68 suppresses IL1β-induced MMP13 expression in human chondrocytes under acidic conditions, indicating that increased GPR68 expression may represent a microenvironment-responsive, potentially adaptive signaling response rather than a driver of cartilage degeneration. Evidence from intestinal, stromal, and vascular models demonstrates that GPR68 integrates pH changes with inflammatory and mechanical cues, providing mechanistic context, although these effects have not been directly established in most joint tissues. Small-molecule modulators, including the positive allosteric agonist Ogerin and the inhibitor Ogremorphin, illustrate the tractability of GPR68 as a drug target, although no GPR68-directed therapies have yet been evaluated in preclinical models of OA. Collectively, current data support GPR68 as a functionally relevant proton sensor within the acidic OA joint microenvironment. Full article

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

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20 pages, 1552 KB

Open AccessReview

Engineered Mesenchymal Stromal Cells in Oncology: Navigating Between Therapeutic Delivery and Tumor Promotion

by Marta Warzycha, Agnieszka Oleksiuk, Olga Suska, Tomasz Jan Kolanowski and Natalia Rozwadowska

Genes 2026, 17(1), 108; https://doi.org/10.3390/genes17010108 - 20 Jan 2026

Abstract

Mesenchymal stromal cells (MSCs) are intensively investigated in oncology owing to their intrinsic tumor-homing ability and capacity to deliver therapeutic agents directly into the tumor microenvironment (TME). Recent advances in genetic engineering have enabled precise modification of MSCs, allowing controlled expression of therapeutic [...] Read more.

Mesenchymal stromal cells (MSCs) are intensively investigated in oncology owing to their intrinsic tumor-homing ability and capacity to deliver therapeutic agents directly into the tumor microenvironment (TME). Recent advances in genetic engineering have enabled precise modification of MSCs, allowing controlled expression of therapeutic genes and other cargo delivery, thus improving targeting efficiency. As cellular carriers, MSCs have been engineered to transport oncolytic viruses, suicide genes in gene-directed enzyme prodrug therapy (GDEPT), multifunctional nanoparticles, and therapeutic factors such as IFN-β or TRAIL, while engineered MSC-derived extracellular vesicles (MSC-EVs) offer a promising cell-free alternative. These strategies increase intratumoral drug concentration, amplify bystander effects, and synergize with standard therapies while reducing systemic toxicity. Conversely, accumulating evidence highlights the tumor-promoting properties of MSCs: once recruited by inflammatory and hypoxic cues, they remodel the tumor microenvironment by stimulating angiogenesis, suppressing immune responses, differentiating into cancer-associated fibroblasts, and promoting epithelial-to-mesenchymal transition (EMT), ultimately enhancing invasion, metastasis, and therapy resistance. This duality has sparked both enthusiasm and concern in the oncology field. The present review outlines the paradoxical role of MSCs in oncology—ranging from their potential to promote tumor growth to their emerging utility as vehicles for targeted drug delivery. By highlighting both therapeutic opportunities and biological risks, we aim to provide a balanced perspective on how MSC-based strategies might be refined, optimized, and safely integrated into future cancer therapies. Full article

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

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19 pages, 6983 KB

Open AccessArticle

Assembly, Characterization and Comparative Analysis of the Complete Mitogenome of Small-Leaved Eriobotrya seguinii (Maleae, Rosaceae)

by Muhammad Idrees, Fardous Mohammad Safiul Azam, Meng Li, Zhiyong Zhang, Hui Wang and Yunyun Lv

Genes 2026, 17(1), 107; https://doi.org/10.3390/genes17010107 - 20 Jan 2026

Abstract

Background. Eriobotrya seguinii (Lév.) Cardot ex Guillaumin (Rosaceae, Maleae) is native to China and inhabits various altitudes within the subtropical biome of the Yunnan-Guizhou Plateau. The complexity of the plant mitogenome has impeded a systematic description of this species, leading to a limited [...] Read more.

Background. Eriobotrya seguinii (Lév.) Cardot ex Guillaumin (Rosaceae, Maleae) is native to China and inhabits various altitudes within the subtropical biome of the Yunnan-Guizhou Plateau. The complexity of the plant mitogenome has impeded a systematic description of this species, leading to a limited understanding of its evolutionary position. Methods. In this study, we constructed, annotated, characterized, and compared the complete E. seguinii mitogenome with previously reported Eriobotrya japonica. Results. The E. seguinii mitogenome exhibited a typical circular architecture, spanning 372,899 bp in length, with a GC content of 46%, making it the smallest and highest GC content of any known Eriobotrya species. It encodes 71 unique genes, comprising 47 protein-coding genes, 20 transfer RNA (tRNA) genes, and 4 ribosomal RNA (rRNA) genes. The genome contains rich repetitive sequences, with mononucleotides, A/T bias, and forward and palindromic repeats being the most prevalent. The predominant codons were GCU (Ala) and UAU (Tyr), with frequencies of 1.54 and 1.53, respectively. Thirteen genes (atp9, atp6, atp1, rps14, sdh4, sdh3, rps12, rnaseH, nad1, nad6, nad7, rpl16, and mttB) demonstrated high Pi values, ranging from 0.84 to 1. The evolutionary lineage of E. seguinii was explored using mitogenome data from 19 genera within the Rosaceae family, revealing that Eriobotrya species are monophyletic and closely related to E. japonica (MN481990). Conclusions. Understanding the mitogenome characteristics of E. seguinii enhances our understanding of its genesis and classification based on mitochondrial genome data. This study provides additional evidence for future research on the evolutionary relationships among species in the Rosaceae family. Full article

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

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17 pages, 1796 KB

Open AccessArticle

Optical Genome Mapping Enhances Structural Variant Detection and Refines Risk Stratification in Chronic Lymphocytic Leukemia

by Soma Roy Chakraborty, Michelle A. Bickford, Narcisa A. Smuliac, Kyle A. Tonseth, Jing Bao, Farzana Murad, Irma G. Domínguez Vigil, Heather B. Steinmetz, Lauren M. Wainman, Parth Shah, Elizabeth M. Bengtson, Swaroopa PonnamReddy, Gabriella A. Harmon, Liam L. Donnelly, Laura J. Tafe, Jeremiah X. Karrs, Prabhjot Kaur and Wahab A. Khan

Genes 2026, 17(1), 106; https://doi.org/10.3390/genes17010106 - 19 Jan 2026

Abstract

Background: Optical genome mapping (OGM) detects genome-wide structural variants (SVs), including balanced rearrangements and complex copy-number alterations beyond standard-of-care cytogenomic assays. In chronic lymphocytic leukemia (CLL), cytogenetic and genomic risk stratification is traditionally based on fluorescence in situ hybridization (FISH), karyotyping, targeted next-generation [...] Read more.

Background: Optical genome mapping (OGM) detects genome-wide structural variants (SVs), including balanced rearrangements and complex copy-number alterations beyond standard-of-care cytogenomic assays. In chronic lymphocytic leukemia (CLL), cytogenetic and genomic risk stratification is traditionally based on fluorescence in situ hybridization (FISH), karyotyping, targeted next-generation sequencing (NGS), and immunogenetic assessment of immunoglobulin heavy chain variable region (IGHV) somatic hypermutation status, each of which interrogates only a limited aspect of disease biology. Methods: We retrospectively evaluated fifty patients with CLL using OGM and integrated these findings with cytogenomics, targeted NGS, IGHV mutational status, and clinical time-to-first-treatment (TTFT) data. Structural variants were detected using OGM and pathogenic NGS variants were derived from a clinical heme malignancy panel. Clinical outcomes were extracted from the electronic medical record. Results: OGM identified reportable structural variants in 82% (41/50) of cases. The most frequent abnormality was del(13q), observed in 29/50 (58%) and comprising 73% (29/40) of all OGM-detected deletions with pathologic significance. Among these, 12/29 (42%) represented large RB1-spanning deletions, while 17/29 (58%) were focal deletions restricted to the miR15a/miR16-1 minimal region, mapping to the non-coding host gene DLEU2. Co-occurrence of adverse lesions, including deletion 11q/ATM, BIRC3 loss, trisomy 12, and deletion 17p/TP53, were recurrent and strongly associated with shorter TTFT. OGM also uncovered multiple cryptic rearrangements involving chromosomal loci that are not represented in the canonical CLL FISH probe panel, including IGL::CCND1, IGH::BCL2, IGH::BCL11A, IGH::BCL3, and multi-chromosomal copy-number complexity. IGHV data were available in 37/50 (74%) of patients; IGHV-unmutated status frequently co-segregated with OGM-defined high-risk profiles (del(11q), del(17p), trisomy 12 with secondary hits, and complex genomes whereas mutated IGHV predominated in OGM-negative or structurally simple del(13q) cases and aligned with indolent TTFT. Integration of OGM with NGS further improved genomic risk classification, particularly in cases with discordant or inconclusive routine testing. Conclusions: OGM provides a comprehensive, genome-wide view of structural variation in CLL, resolving deletion architecture, identifying cryptic translocations, and defining complex multi-hit genomic profiles that tracked closely with clinical behavior. Combining OGM and NGS analysis refined risk stratification beyond standard FISH panels and supports more precise, individualized management strategies in CLL. Prospective studies are warranted to evaluate the clinical utility of OGM-guided genomic profiling in contemporary treatment paradigms. Full article

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

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12 pages, 847 KB

Open AccessArticle

Improving CNV Detection Performance Except for Software-Specific Problematic Regions

by Jinha Hwang, Jung Hye Byeon, Baik-Lin Eun, Myung-Hyun Nam, Yunjung Cho and Seung Gyu Yun

Genes 2026, 17(1), 105; https://doi.org/10.3390/genes17010105 - 19 Jan 2026

Abstract

Background/Objectives: Whole exome sequencing (WES) is an effective method for detecting disease-causing variants. However, copy number variation (CNV) detection using WES data often has limited sensitivity and high false-positive rates. Methods: In this study, we constructed a reference CNV set using [...] Read more.

Background/Objectives: Whole exome sequencing (WES) is an effective method for detecting disease-causing variants. However, copy number variation (CNV) detection using WES data often has limited sensitivity and high false-positive rates. Methods: In this study, we constructed a reference CNV set using chromosomal microarray analysis (CMA) data from 44 of 180 individuals who underwent WES and CMA and evaluated four WES-based CNV callers (CNVkit, CoNIFER, ExomeDepth, and cn.MOPS) against this benchmark. For each tool, we first defined software-specific problematic genomic regions across the full WES cohort and filtered out the CNVs that overlapped these regions. Results: The four algorithms showed low mutual concordance and distinct distributions in the problematic regions. On average, 2210 sequencing target baits (1.23%) were classified as problematic; these baits had lower mappability scores and higher coefficients of variation in RPKM than the remaining probes. After the supplementary filtration step, all tools demonstrated improved performance. Notably, ExomeDepth achieved gains of 14.4% in sensitivity and 7.9% in positive predictive value. Conclusions: We delineated software-specific problematic regions and demonstrated that targeted filtration markedly reduced false positives in WES-based CNV detection. Full article

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

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17 pages, 3278 KB

Open AccessArticle

Interstitial 12p Deletion Syndrome: Revised Minimal Critical Region and Review of the Literature

by Flavia Privitera, Stefano Pagano, Lorenzo Cipriano, Giulia Nutile, Annarita Milone and Filippo Maria Santorelli

Genes 2026, 17(1), 104; https://doi.org/10.3390/genes17010104 - 19 Jan 2026

Abstract

Background: Interstitial deletions of the short arm of chromosome 12 are rare, and very little is known about the potential genetic basis of the most common phenotypic presentations to date described in the literature. Methods: In the present study, we present a new [...] Read more.

Background: Interstitial deletions of the short arm of chromosome 12 are rare, and very little is known about the potential genetic basis of the most common phenotypic presentations to date described in the literature. Methods: In the present study, we present a new patient carrying a heterozygous de novo 12p deletion, identified by a-CGH. Results: Comparison between the new case with phenotypically similar 12p-deleted patients drawn from the literature and from the DECIPHER (the DatabasE of Chromosomal Imbalances and Phenotypes using Ensembl Resources) database allowed us to analyze 22 cases and to define a revised minimal critical region not previously considered. Discussion: Within the new minimal critical region, we identified genes intolerant to haploinsufficiency, highlighting the involvement of PTHLH and CCDC91 in the onset of skeletal abnormalities and proposing the involvement of PPFIBP1 in neurodevelopmental disorders (although it has previously been associated only with autosomal recessive conditions). Conclusions: We suggest that clinical severity in cases with 12p deletions varies depending on the cytobands involved, being more moderate when they occur at 12p11—where the gene DENND5B (12p11.23) has recently been associated with a dominant neurodevelopmental disorder—than at 12p12. Full article

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

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17 pages, 580 KB

Open AccessArticle

Early Detection of Pacing-Induced Cardiomyopathy Using MicroRNA-208b-3p and MicroRNA-9: A Prospective Cohort Analysis

by Onoufrios Malikides, Aleksi Sallo, Andria Papazachariou, Ioannis Kopidakis, Angeliki Alifragki, Joanna Kontaraki, Konstantinos Fragkiadakis, Gregory Chlouverakis, Eleftherios Kallergis, Emmanuel Simantirakis and Maria Marketou

Genes 2026, 17(1), 103; https://doi.org/10.3390/genes17010103 - 19 Jan 2026

Abstract

Background/Objectives: Pacing-induced cardiomyopathy (PiCM) is a recognized complication of chronic right ventricular pacing (RVP), characterized by left ventricular (LV) dysfunction, adverse remodeling, and progression to heart failure. MicroRNAs (miRs) regulate gene expression and play an important role in ventricular remodeling. This study aimed [...] Read more.

Background/Objectives: Pacing-induced cardiomyopathy (PiCM) is a recognized complication of chronic right ventricular pacing (RVP), characterized by left ventricular (LV) dysfunction, adverse remodeling, and progression to heart failure. MicroRNAs (miRs) regulate gene expression and play an important role in ventricular remodeling. This study aimed to observe whether dynamic changes in miRs according to a novel peripheral blood mononuclear cell (PBMC)-based approach could serve as early predictive biomarkers of PiCM. Methods: A prospective, single-center cohort study was conducted in adult patients undergoing pacemaker implantation. Clinical characteristics, echocardiographic parameters and expression levels of miR-208b-3p and miR-9 were assessed immediately and 3 months post-pacemaker implantation. PiCM was defined as a ≥10% reduction in LVEF at one year, with no alternative cause. Statistical analyses included correlation testing, ROC curve analysis, and multivariate regression to identify factors associated with PiCM. Results: Among 126 patients, 11.1% developed PiCM. Compared with the non-PiCM group, those who developed PiCM exhibited more pronounced 3-month changes in miR-208b-3p (median Δ₃log miR: +1.3 vs. −0.4, p = 0.013) and miR-9 (median Δ₃log miR: −1.7 vs. +0.21, p = 0.011). In multivariate analyses, Δ₃LV-GLS, Δ₃logmiR-208b-3p, and Δ₃logmiR-9 were associated with a higher likelihood of PiCM. Among PiCM patients, Δ₃logmiR-208b-3p correlated inversely with Δ₃LV-GLS (r = −0.73, p = 0.016), while Δ₃logmiR-9 correlated positively (r = 0.88, p < 0.001). ROC analyses demonstrated good predictive ability for Δ₃LV-GLS (AUC = 0.924), Δ₃log miR-208b-3p (AUC = 0.783), and Δ₃log miR-9 (AUC = 0.835), with no significant differences between curves. Conclusions: Early LV-GLS deterioration and dynamic changes in expression of miR-208b-3p and miR-9 in PBMCs precede overt LV systolic dysfunction. These miRs may serve as early predictive biomarkers for PiCM. Full article

(This article belongs to the Special Issue Genomic and Molecular Landscapes of Cardiac Remodeling and Heart Failure)

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14 pages, 1788 KB

Open AccessArticle

CDHR1-Associated Retinal Dystrophies: Expanding the Clinical and Genetic Spectrum with a Hungarian Cohort

by Ágnes Takács, Balázs Varsányi, Mirella Barboni, Rita Vámos, Balázs Lesch, Dominik Dobos, Emília Clapp, András Végh, Ditta Zobor, Krisztina Knézy, Zoltán Zsolt Nagy and Viktória Szabó

Genes 2026, 17(1), 102; https://doi.org/10.3390/genes17010102 - 19 Jan 2026

Abstract

Aim: To report on the clinical and genetic spectrum of retinopathy associated with CDHR1 variants in a Hungarian cohort. Methods: A retrospective cohort study was conducted at a single tertiary care referral center. The study enrolled nine patients harboring biallelic variants [...] Read more.

Aim: To report on the clinical and genetic spectrum of retinopathy associated with CDHR1 variants in a Hungarian cohort. Methods: A retrospective cohort study was conducted at a single tertiary care referral center. The study enrolled nine patients harboring biallelic variants in the CDHR1 gene. Detailed clinical history, multimodal imaging, electroretinography, and molecular genetics are presented. Results: We identified four CDHR1 variants predicted to cause loss-of-function and five phenotypes (cone dystrophy, central areolar choroidal dystrophy, cone-rod dystrophy, rod-cone dystrophy, and late-onset macular dystrophy). The most frequent variant was the synonymous CDHR1 c.783G>A (p.Pro261=) variant (10/18 alleles, 55.6%). A novel splice acceptor site variant, CDHR1 c.349-1G>A, and a novel intronic variant, CDHR1 c.1168-10A>G, were also detected. Fundus examination revealed macular atrophy with or without peripheral retinal changes. Full-field electroretinography, available in seven patients, demonstrated decreased light-adapted and extinguished dark-adapted responses in both the rod-cone dystrophy group and patients with macular involvement. OCT imaging indicated ellipsoid zone disruption with foveal sparing in two out of nine patients and severe retinal damage in rod-cone dystrophy cases. Conclusions: The predominant clinical manifestations of cone dystrophy, cone-rod dystrophy, and macular dystrophy in the Hungarian patient cohort showed heterogeneity, with a rod-cone dystrophy phenotype observed in five of nine cases (55.6%). The natural history of CDHR1-associated retinopathy typically follows a slow progression, providing a therapeutic window, which makes the disease a candidate for gene therapy. Full article

(This article belongs to the Special Issue Current Advances in Inherited Retinal Disease)

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12 pages, 724 KB

Open AccessArticle

Population of Northern Portugal: Study of Genetic Diversity and Forensic Parameters of 26 Y-STR Markers

by Bárbara Maia, Jennifer Fadoni, Laura Cainé, Luís Souto and António Amorim

Genes 2026, 17(1), 101; https://doi.org/10.3390/genes17010101 - 19 Jan 2026

Abstract

Background: Short tandem repeats (STRs) are highly variable sequences present along the human genome, including the Y-chromosome. Y-STRs are exclusive to males, and the haplotypes they define are informative. Objectives: Twenty-six Y-STR loci were genotyped in 252 males from Northern Portugal [...] Read more.

Background: Short tandem repeats (STRs) are highly variable sequences present along the human genome, including the Y-chromosome. Y-STRs are exclusive to males, and the haplotypes they define are informative. Objectives: Twenty-six Y-STR loci were genotyped in 252 males from Northern Portugal to characterise Y-chromosome genetic variation using the Investigator Argus Y28 QS Kit. Methods: The kit mentioned was used to amplify male DNA samples, and capillary electrophoresis was used to analyze the fragments. Forensic parameters and haplotype diversity were computed, and samples’ haplogroups were predicted. A multidimensional scaling (MDS) plot was used to graphically represent the R_ST genetic distances, including reference populations. Results: A total of 250 different haplotypes were observed, including 248 unique ones, yielding a very high haplotype diversity (HD = 0.999) and discriminatory power (DP = 0.992). Haplogroup analysis indicated a predominance of R1b (58.7%), followed by E1b1b, I and J, pointing to a population history shaped by Mediterranean and North African gene flow. Comparative analysis between Portugal and 5 other populations showed greater genetic affinity with Spain and Italy, while revealing marked differentiation from Greece, Morocco, and former Portuguese colonies. Conclusions: The results confirm that the Northern Portuguese Population exhibits high Y-STR variability and robust forensic resolution. The dataset was submitted to the YHRD database, enhancing the representation of the Portuguese population and underscoring the value of the 26 locus panel for applications in forensic science, genealogy, and population genetics. Full article

(This article belongs to the Section Population and Evolutionary Genetics and Genomics)

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23 pages, 3693 KB

Open AccessArticle

Platy-1 SINEs from Thirteen Diverse Genomes Reveal Callithrichidae Unique Amplification, Recent Alouatta Mobilization and Insights into Platyrrhine Phylogenetics

by Jessica M. Storer, Jerilyn A. Walker, Sarah O. Massey, Thomas O. Beckstrom and Mark A. Batzer

Genes 2026, 17(1), 100; https://doi.org/10.3390/genes17010100 - 19 Jan 2026

Abstract

Background/Objectives: In 2023, we reported that the tamarins (genus Saguinus) Saguinus imperator and Saguinus midas have had an extensive independent expansion of Platy-1 SINEs compared to previously characterized platyrrhine genomes among traditional cebids. This study investigates the amplification dynamics of Platy-1 insertions [...] Read more.

Background/Objectives: In 2023, we reported that the tamarins (genus Saguinus) Saguinus imperator and Saguinus midas have had an extensive independent expansion of Platy-1 SINEs compared to previously characterized platyrrhine genomes among traditional cebids. This study investigates the amplification dynamics of Platy-1 insertions across thirteen diverse genomes representing each Platyrrhini family, including two from Pitheciidae and three from Atelidae. Methods: By comparing the distribution of Platy-1 subfamily content, total interspersed repeat content and the proximity of Platy-1 insertions to, or within, other repeats across evolutionary taxa, this study begins to identify genomic landscape features that are unique to family Callithrichidae that correlate with LINE (L1). Results: Platy-1 radiation in non-callithrichid taxa derives primarily from older subfamilies 1-4, 1-4a (as reported here for genus Alouatta) and 1-5, whereas callithrichids proliferate higher numbers of Platy-1 copies via independent bursts from much younger sources. Linage-specific Platy-1 activity was notable in two of the new genomes studied, Bolivian titi and mantled howler monkey, both with a relatively low copy number. Variable presence/absence patterns across evolutionary taxa support the traditional platyrrhine branching order Pitheciidae–Atelidae–Cebidae. Only one Platy-1-4a insertion polymorphism placed Aotidae between Atelidae and Cebidae, as opposed to between Cebidae and Callithrichidae. Conclusions: This study shows that callithrichids, and Saguinus tamarins in particular, are unique among platyrrhines with regard to their extensive rate of Platy-1 mobilization, a dynamic that appears to be correlated with LINE (L1) genomic content. Alouatta has two young lineage-specific Platy-1 subfamilies. With strong evidence of incomplete lineage sorting (ILS) and rapid radiation, the accurate placement of Aotus remains elusive. Full article

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

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12 pages, 416 KB

Open AccessArticle

Molecular Analysis Based on Fine-Needle Aspiration Washout Samples in Thyroid Nodules

by Sevgül Fakı, Cevdet Aydın, Şefika Burçak Polat, Gülsüm Karahmetli, Ahmet Cevdet Ceylan, Mustafa Altan, Ayşegül Aksoy Altınboğa, Bülent Çomçalı, Oya Topaloğlu, Reyhan Ersoy and Bekir Çakır

Genes 2026, 17(1), 99; https://doi.org/10.3390/genes17010099 - 19 Jan 2026

Abstract

Background: Molecular testing is recommended to refine risk stratification in indeterminate thyroid nodules (Bethesda III–IV), but data on dual-gene (BRAF and RAS) testing using fresh FNA washout specimens are limited. We aimed to evaluate the performance of BRAF and RAS mutation analysis from [...] Read more.

Background: Molecular testing is recommended to refine risk stratification in indeterminate thyroid nodules (Bethesda III–IV), but data on dual-gene (BRAF and RAS) testing using fresh FNA washout specimens are limited. We aimed to evaluate the performance of BRAF and RAS mutation analysis from fresh thyroid FNA washout material, with a focus on indeterminate cytology. Methods: We retrospectively analyzed 1139 patients who underwent washout-based molecular testing between May 2022 and October 2024 at a tertiary endocrine center. Of these, 307 had available histopathologic results after surgery. Primary outcomes were sample adequacy, mutation spectrum, and diagnostic metrics (sensitivity, specificity, PPV, NPV, and accuracy). Analyses were repeated under two assumptions that classified borderline/low-risk neoplasms as benign vs. malignant, and within the Bethesda III–IV subset. Results: Adequate material for molecular analysis was obtained in 1037/1139 samples (90.9%). In the operated cohort (n = 307), malignant lesions comprised 31.9% and low-risk neoplasms 8.5%. When borderline lesions were considered benign, mutation positivity yielded a sensitivity of 48.0%, a specificity of 89.6%, a PPV of 75.9%, an NPV of 71.9%, and an accuracy of 72.9%. In Bethesda III–IV nodules (n = 153), sensitivity, specificity, and accuracy were 41.0%, 85.2%, and 66.0% (malignant assumption). Isolated BRAF positivity showed high specificity (~96.7%) with modest sensitivity. Conclusions: Our findings extend current diagnostic approaches by showing that dual-gene (BRAF and RAS) testing from fresh FNA washouts is technically feasible (≥90% adequacy) and provides high specificity with modest sensitivity for malignancy in indeterminate nodules. In settings lacking comprehensive commercial panels, this low-complexity approach offers a practical adjunct to cytology and imaging for preoperative decision-making. Full article

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

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