Genes

13 pages, 649 KiB

Open AccessArticle

Cross-Population Analysis of Sjögren’s Syndrome Polygenic Risk Scores and Disease Prevalence: A Pilot Study

by Elisabetta Ferrara, Alessandro D’Albenzio, Biagio Rapone, Giuseppe Balice and Giovanna Murmura

Genes 2025, 16(8), 901; https://doi.org/10.3390/genes16080901 - 28 Jul 2025

Background: Polygenic risk scores (PRS) have emerged as promising tools for disease risk stratification. However, their validity across different populations remains unclear, particularly for autoimmune diseases, where environmental factors may play crucial roles. Methods: We calculated the population-level PRS for Sjögren’s syndrome using [...] Read more.

Background: Polygenic risk scores (PRS) have emerged as promising tools for disease risk stratification. However, their validity across different populations remains unclear, particularly for autoimmune diseases, where environmental factors may play crucial roles. Methods: We calculated the population-level PRS for Sjögren’s syndrome using seven validated genetic variants (PGS001308) and allele frequency data from the 1000 Genomes Project Phase 3 for five European populations (CEU, TSI, FIN, GBR, and IBS). PRS values were correlated with published prevalence estimates from a systematic literature review. Statistical analyses included Pearson’s correlation and sensitivity analyses. Results: PRS values varied across European populations, ranging from 0.317 in the Spanish population to 0.370 in the Northern European population. A non-significant negative trend was observed between population PRS and Sjögren’s syndrome prevalence (r = −0.407, R² = 0.166). Italy showed the lowest genetic risk score (TSI: 0.349) but the highest disease prevalence (58.2 per 100,000), while Northern European populations demonstrated a higher PRS but lower prevalence. Conclusions: No significant correlation was found between genetic risk scores and disease prevalence in this limited sample of five European populations. Larger studies are needed to clarify the relationship between polygenic risk and disease prevalence. Full article

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

17 pages, 1268 KiB

Open AccessArticle

Community Composition and Diversity of β-Glucosidase Genes in Soils by Amplicon Sequence Variant Analysis

by Luis Jimenez

Genes 2025, 16(8), 900; https://doi.org/10.3390/genes16080900 (registering DOI) - 28 Jul 2025

Abstract

Cellulose, the most abundant organic polymer in soil, is degraded by the action of microbial communities. Cellulolytic taxa are widespread in soils, enhancing the biodegradation of cellulose by the synergistic action of different cellulase enzymes. β-glucosidases are the last enzymes responsible for the [...] Read more.

Cellulose, the most abundant organic polymer in soil, is degraded by the action of microbial communities. Cellulolytic taxa are widespread in soils, enhancing the biodegradation of cellulose by the synergistic action of different cellulase enzymes. β-glucosidases are the last enzymes responsible for the degradation of cellulose by producing glucose from the conversion of the disaccharide cellobiose. Different soils from the states of Delaware, Maryland, New Jersey, and New York were analyzed by direct DNA extraction, PCR analysis, and next generation sequencing of amplicon sequences coding for β-glucosidase genes. To determine the community structure and diversity of microorganisms carrying β-glucosidase genes, amplicon sequence variant analysis was performed. Results showed that the majority of β-glucosidase genes did not match any known phylum or genera with an average of 84% of sequences identified as unclassified. The forest soil sample from New York showed the highest value with 95.62%. When identification was possible, the bacterial phyla Pseudomonadota, Actinomycetota, and Chloroflexota were found to be dominant microorganisms with β-glucosidase genes in soils. The Delaware soil showed the highest diversity with phyla and genera showing the presence of β-glucosidase gene sequences in bacteria, fungi, and plants. However, the Chloroflexota genus Kallotanue was detected in 3 out of the 4 soil locations. When phylogenetic analysis of unclassified β-glucosidase genes was completed, most sequences aligned with the Chloroflexota genus Kallotenue and the Pseudomonadota species Sphingomonas paucimobilis. Since most sequences did not match known phyla, there is tremendous potential to discover new enzymes for possible biotechnological and pharmaceutical applications. Full article

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

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28 pages, 5315 KiB

Open AccessArticle

Integrated Transcriptome and Metabolome Analysis Provides Insights into the Low-Temperature Response in Sweet Potato (Ipomoea batatas L.)

by Zhenlei Liu, Jiaquan Pan, Sitong Liu, Zitong Yang, Huan Zhang, Tao Yu and Shaozhen He

Genes 2025, 16(8), 899; https://doi.org/10.3390/genes16080899 - 28 Jul 2025

Abstract

Background/Objectives: Sweet potato is a tropical and subtropical crop and its growth and yield are susceptible to low-temperature stress. However, the molecular mechanisms underlying the low temperature stress of sweetpotato are unknown. Methods: In this work, combined transcriptome and metabolism analysis was employed [...] Read more.

Background/Objectives: Sweet potato is a tropical and subtropical crop and its growth and yield are susceptible to low-temperature stress. However, the molecular mechanisms underlying the low temperature stress of sweetpotato are unknown. Methods: In this work, combined transcriptome and metabolism analysis was employed to investigate the low-temperature responses of two sweet potato cultivars, namely, the low-temperature-resistant cultivar “X33” and the low-temperature-sensitive cultivar “W7”. Results: The differentially expressed metabolites (DEMs) of X33 at different time stages clustered in five profiles, while they clustered in four profiles of W7 with significant differences. Differentially expressed genes (DEGs) in X33 and W7 at different time points clustered in five profiles. More DEGs exhibited continuous or persistent positive responses to low-temperature stress in X33 than in W7. There were 1918 continuously upregulated genes and 6410 persistent upregulated genes in X33, whereas 1781 and 5804 were found in W7, respectively. Core genes involved in Ca²⁺ signaling, MAPK cascades, the reactive oxygen species (ROS) signaling pathway, and transcription factor families (including bHLH, NAC, and WRKY) may play significant roles in response to low temperature in sweet potato. Thirty-one common differentially expressed metabolites (DEMs) were identified in the two cultivars in response to low temperature. The KEGG analysis of these common DEMs mainly belonged to isoquinoline alkaloid biosynthesis, phosphonate and phosphinate metabolism, flavonoid biosynthesis, cysteine and methionine metabolism, glycine, serine, and threonine metabolism, ABC transporters, and glycerophospholipid metabolism. Five DEMs with identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were selected for correlation analysis. KEGG enrichment analysis showed that the carbohydrate metabolism, phenylpropanoid metabolism, and glutathione metabolism pathways were significantly enriched and played vital roles in low-temperature resistance in sweet potato. Conclusions: These findings contribute to a deeper understanding of the molecular mechanisms underlying plant cold tolerance and offer targets for molecular breeding efforts to enhance low-temperature resistance. Full article

(This article belongs to the Special Issue Genetic and Functional Genomics Insights into the Genetic Improvement of Stress Resistance in Economic Crops)

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24 pages, 6890 KiB

Open AccessArticle

Multi-Level Transcriptomic and Physiological Responses of Aconitum kusnezoffii to Different Light Intensities Reveal a Moderate-Light Adaptation Strategy

by Kefan Cao, Yingtong Mu and Xiaoming Zhang

Genes 2025, 16(8), 898; https://doi.org/10.3390/genes16080898 - 28 Jul 2025

Abstract

Objectives: Light intensity is a critical environmental factor regulating plant growth, development, and stress adaptation. However, the physiological and molecular mechanisms underlying light responses in Aconitum kusnezoffii, a valuable alpine medicinal plant, remain poorly understood. This study aimed to elucidate the adaptive [...] Read more.

Objectives: Light intensity is a critical environmental factor regulating plant growth, development, and stress adaptation. However, the physiological and molecular mechanisms underlying light responses in Aconitum kusnezoffii, a valuable alpine medicinal plant, remain poorly understood. This study aimed to elucidate the adaptive strategies of A. kusnezoffii under different light intensities through integrated physiological and transcriptomic analyses. Methods: Two-year-old A. kusnezoffii plants were exposed to three controlled light regimes (790, 620, and 450 lx). Leaf anatomical traits were assessed via histological sectioning and microscopic imaging. Antioxidant enzyme activities (CAT, POD, and SOD), membrane lipid peroxidation (MDA content), osmoregulatory substances, and carbon metabolites were quantified using standard biochemical assays. Transcriptomic profiling was conducted using Illumina RNA-seq, with differentially expressed genes (DEGs) identified through DESeq2 and functionally annotated via GO and KEGG enrichment analyses. Results: Moderate light (620 lx) promoted optimal leaf structure by enhancing palisade tissue development and epidermal thickening, while reducing membrane lipid peroxidation. Antioxidant defense capacity was elevated through higher CAT, POD, and SOD activities, alongside increased accumulation of soluble proteins, sugars, and starch. Transcriptomic analysis revealed DEGs enriched in photosynthesis, monoterpenoid biosynthesis, hormone signaling, and glutathione metabolism pathways. Key positive regulators (PHY and HY5) were upregulated, whereas negative regulators (COP1 and PIFs) were suppressed, collectively facilitating chloroplast development and photomorphogenesis. Trend analysis indicated a “down–up” gene expression pattern, with early suppression of stress-responsive genes followed by activation of photosynthetic and metabolic processes. Conclusions: A. kusnezoffii employs a coordinated, multi-level adaptation strategy under moderate light (620 lx), integrating leaf structural optimization, enhanced antioxidant defense, and dynamic transcriptomic reprogramming to maintain energy balance, redox homeostasis, and photomorphogenic flexibility. These findings provide a theoretical foundation for optimizing artificial cultivation and light management of alpine medicinal plants. Full article

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

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13 pages, 1650 KiB

Open AccessArticle

A Fast TaqMan^® Real-Time PCR Assay for the Detection of Mitochondrial DNA Haplotypes in a Wolf Population

by Rita Lorenzini, Lorenzo Attili, Martina De Crescenzo and Antonella Pizzarelli

Genes 2025, 16(8), 897; https://doi.org/10.3390/genes16080897 - 28 Jul 2025

Abstract

Background/Objectives: The gene pool of the Apennine wolf is affected by admixture with domestic variants due to anthropogenic hybridisation with dogs. Genetic monitoring at the population level involves assessing the extent of admixture in single individuals, ranging from pure wolves to recent [...] Read more.

Background/Objectives: The gene pool of the Apennine wolf is affected by admixture with domestic variants due to anthropogenic hybridisation with dogs. Genetic monitoring at the population level involves assessing the extent of admixture in single individuals, ranging from pure wolves to recent hybrids or wolf backcrosses, through the analysis of nuclear and mitochondrial DNA (mtDNA) markers. Although individually non-diagnostic, mtDNA is nevertheless essential for completing the final diagnosis of genetic admixture. Typically, the identification of wolf mtDNA haplotypes is carried out via sequencing of coding genes and non-coding DNA stretches. Our objective was to develop a fast real-time PCR assay to detect the mtDNA haplotypes that occur exclusively in the Apennine wolf population, as a valuable alternative to the demanding sequence-based typing. Methods: We validated a qualitative duplex real-time PCR that exploits the combined presence of diagnostic point mutations in two mtDNA segments, the NDH-4 gene and the control region, and is performed in a single-tube step through TaqMan-MGB chemistry. The aim was to detect mtDNA multi-fragment haplotypes that are exclusive to the Apennine wolf, bypassing sequencing. Results: Basic validation of 149 field samples, consisting of pure Apennine wolves, dogs, wolf × dog hybrids, and Dinaric wolves, showed that the assay is highly specific and sensitive, with genomic DNA amounts as low as 10⁻⁵ ng still producing positive results. It also proved high repeatability and reproducibility, thereby enabling reliable high-throughput testing. Conclusions: The results indicate that the assay presented here provides a valuable alternative method to the time- and cost-consuming sequencing procedure to reliably diagnose the maternal lineage of the still-threatened Apennine wolf, and it covers a wide range of applications, from scientific research to conservation, diagnostics, and forensics. Full article

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

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16 pages, 336 KiB

Open AccessReview

TIGR-Tas and the Expanding Universe of RNA-Guided Genome Editing Systems: A New Era Beyond CRISPR-Cas

by Douglas M. Ruden

Genes 2025, 16(8), 896; https://doi.org/10.3390/genes16080896 - 28 Jul 2025

Abstract

The recent discovery of TIGR-Tas (Tandem Interspaced Guide RNA–Targeting Systems) marks a major advance in the field of genome editing, introducing a new class of compact, programmable DNA-targeting systems that function independently of traditional CRISPR-Cas pathways. TIGR-Tas effectors use a novel dual-spacer guide [...] Read more.

The recent discovery of TIGR-Tas (Tandem Interspaced Guide RNA–Targeting Systems) marks a major advance in the field of genome editing, introducing a new class of compact, programmable DNA-targeting systems that function independently of traditional CRISPR-Cas pathways. TIGR-Tas effectors use a novel dual-spacer guide RNA (tigRNA) to recognize both strands of target DNA without requiring a protospacer adjacent motif (PAM). These Tas proteins introduce double-stranded DNA cuts with characteristic 8-nucleotide 3′ overhangs and are significantly smaller than Cas9, offering delivery advantages for in vivo editing. Structural analyses reveal homology to box C/D snoRNP proteins, suggesting a previously unrecognized evolutionary lineage of RNA-guided nucleases. This review positions TIGR-Tas at the forefront of a new wave of RNA-programmable genome-editing technologies. In parallel, I provide comparative insight into the diverse and increasingly modular CRISPR-Cas systems, including Cas9, Cas12, Cas13, and emerging effectors like Cas3, Cas10, CasΦ, and Cas14. While the CRISPR-Cas universe has revolutionized molecular biology, TIGR-Tas systems open a complementary and potentially more versatile path for programmable genome manipulation. I discuss mechanistic distinctions, evolutionary implications, and potential applications in human cells, synthetic biology, and therapeutic genome engineering. Full article

(This article belongs to the Special Issue Advances in Developing Genomics and Computational Approaches)

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11 pages, 242 KiB

Open AccessArticle

Genetic Insights into Hemiplegic Migraine: Whole Exome Sequencing Highlights Vascular Pathway Involvement via Association Analysis

by Zizi Molaee, Robert A. Smith, Neven Maksemous and Lyn R. Griffiths

Genes 2025, 16(8), 895; https://doi.org/10.3390/genes16080895 - 28 Jul 2025

Abstract

Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points [...] Read more.

Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points to an overlap between migraine and cerebral small vessel disease (SVD), implicating vascular dysfunction in HM pathophysiology. Objective: This study aimed to identify rare or novel variants in genes associated with SVD in a cohort of patients clinically diagnosed with HM who tested negative for known familial hemiplegic migraine (FHM) pathogenic variants. Methods: We conducted a case-control association analysis of whole exome sequencing (WES) data from 184 unrelated HM patients. A targeted panel of 34 SVD-related genes was assessed. Variants were prioritised based on rarity (MAF ≤ 0.05), location (exonic/splice site), and predicted pathogenicity using in silico tools. Statistical comparisons to gnomAD’s Non-Finnish European population were made using chi-square tests. Results: Significant variants were identified in several SVD-related genes, including LRP1 (p.Thr4077Arg), COL4A1 (p.Pro54Leu), COL4A2 (p.Glu1123Gly), and TGFBR2 (p.Met148Leu and p.Ala51Pro). The LRP1 variant showed the strongest association (p < 0.001). All key variants demonstrated pathogenicity predictions in multiple computational models, implicating them in vascular dysfunction relevant to migraine mechanisms. Conclusions: This study provides new insights into the genetic architecture of hemiplegic migraine, identifying rare and potentially deleterious variants in SVD-related genes. These findings support the hypothesis that vascular and cellular maintenance pathways contribute to migraine susceptibility and may offer new targets for diagnosis and therapy. Full article

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

13 pages, 1507 KiB

Open AccessArticle

DNA Transfer Between Items Within an Evidence Package

by Yong Sheng Lee and Christopher Kiu-Choong Syn

Genes 2025, 16(8), 894; https://doi.org/10.3390/genes16080894 - 28 Jul 2025

Abstract

Background/Objectives: Advancements in DNA profiling have made it possible to retrieve intact DNA profiles from increasingly minute biological samples. This increased sensitivity in DNA detection has highlighted crucial considerations to be made when handling and packing items from the crime scene to [...] Read more.

Background/Objectives: Advancements in DNA profiling have made it possible to retrieve intact DNA profiles from increasingly minute biological samples. This increased sensitivity in DNA detection has highlighted crucial considerations to be made when handling and packing items from the crime scene to minimize potential contamination from either direct or indirect transfer of DNA. To investigate potential DNA transfer between items stored within the same evidence package, we conducted a simulation study with items commonly encountered during forensic casework. Methods: Participants were grouped in pairs, each of them handling the same type of item to simulate the activity conducted at the crime scene. The items were then collected from each pair of participants and stored in the same evidence package for 4 to 5 days. To evaluate the basal DNA transfer between items within the same package, the packed items were not subjected to friction, force, or long-distance movement in this study. Results: We have observed the occurrence of DNA transfer on 39% of the studied items inside the package, which changed the source attribution of the DNA profiles for 10% of the recovered samples. Our results showed that the types of items were associated with the number of transferred alleles and the amount of DNA recovered, while no association was found between the number of transferred alleles and the amount of DNA on the studied items. Conclusions: Taken together, the results from this study reiterate the importance of packing each item from the crime scene separately, especially when packing items together may impact the interpretation of source attribution. Full article

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

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13 pages, 634 KiB

Open AccessArticle

Rare Variant Burden and Behavioral Phenotypes in Children with Autism in Slovakia

by Gabriela Repiská, Michal Konečný, Gabriela Krasňanská, Hana Celušáková, Ivan Belica, Barbara Rašková, Mária Kopčíková, Petra Keményová, Daniela Ostatníková and Silvia Lakatošová

Genes 2025, 16(8), 893; https://doi.org/10.3390/genes16080893 - 28 Jul 2025

Abstract

Background: Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by a complex, multifactorial etiology with a strong genetic contribution. Our study aimed to evaluate the link between the burden of rare genetic variants within a specific panel of ASD [...] Read more.

Background: Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by a complex, multifactorial etiology with a strong genetic contribution. Our study aimed to evaluate the link between the burden of rare genetic variants within a specific panel of ASD and intellectual disability-associated genes and phenotypic variability in a cohort of children with autism in Slovakia. Methods: Gene burden scores were calculated based on pathogenic, likely pathogenic, and uncertain significance rare DNA variants identified by whole-exome sequencing. We then assessed the effect of three different scoring methods on the variance across 15 psycho-behavioral parameters describing the phenotypic profiles of 117 ASD probands. Results: The burden score showed a significant multivariate effect on the combination of psycho-behavioral parameters. This score was associated with the social affect of ADOS-2, as well as with the socialization domain, and total adaptive behavior scores from the Vineland Adaptive Behavior Scales-3 (VABS). While a score based solely on count of pathogenic and likely pathogenic variants did not show a multivariate effect, incorporating variants of uncertain significance revealed a multivariate effect on two adaptive behavior parameters: daily living skills and total adaptive behavior score (VABS). Conclusions: Our findings partially explain the variability in phenotypic manifestation in our ASD patient cohort, highlighting the importance of considering the cumulative effect of rare genetic variants, including those of uncertain significance, in shaping the diverse clinical presentation of ASD. Full article

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

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16 pages, 3919 KiB

Open AccessArticle

Autophagy and PXR Crosstalk in the Regulation of Cancer Drug Metabolism and Resistance According to Gene Mutational Status in Colorectal Cancer

by Evangelos Koustas, Panagiotis Sarantis, Eleni-Myrto Trifylli, Eleftheria Dikoglou-Tzanetatou, Evangelia Ioakeimidou, Ioanna A. Anastasiou, Michalis V. Karamouzis and Stamatios Theocharis

Genes 2025, 16(8), 892; https://doi.org/10.3390/genes16080892 - 28 Jul 2025

Abstract

Background and Objectives: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Although chemotherapy is an effective treatment for colorectal cancer (CRC), its effectiveness is frequently hindered by the emergence of resistant cancer cells. Studies have demonstrated a linkage between [...] Read more.

Background and Objectives: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Although chemotherapy is an effective treatment for colorectal cancer (CRC), its effectiveness is frequently hindered by the emergence of resistant cancer cells. Studies have demonstrated a linkage between drug resistance and the pregnane X receptor (PXR), which influences the metabolism and the transport of chemotherapeutic agents. Likewise, autophagy is also a well-established mechanism that contributes to chemotherapy resistance, and it is closely tied to tumor progression. This pre-clinical study aims to investigate the role of mtKRAS-dependent autophagy with PXR expression after treatment with Irinotecan in colorectal cancer. Methods: CRC lines were treated with specific inhibitors, such as 3-methyladeninee, hydroxychloroquine PI-103, and irinotecan hydrochloride, and subjected to various assays, including MTT for cell viability, Western blot for protein expression, siRNA-mediated PXR knock-out, and confocal microscopy for autophagic vacuole visualization. Protein quantification, gene knockdown, and subcellular localization studies were performed under standardized conditions to investigate treatment effects on autophagy and apoptosis pathways. Conclusions: Our experiments showed that PXR knockdown does not alter autophagy levels following Irinotecan treatment, but it promotes apoptotic cell death despite elevated autophagy. Moreover, late-stage autophagy inhibition reduces PXR expression, whereas induction through PI3K/AKT/mTOR inhibition leads to increased expression of PXR. Our experiments uncover a mechanism by which autophagy facilitates the nuclear translocation of the PXR, thereby promoting resistance to Irinotecan across multiple cell lines. Full article

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

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27 pages, 1010 KiB

Open AccessReview

The Multifaceted Role of IL-35 in Periodontal Disease and Beyond: From Genetic Polymorphisms to Biomarker Potential

by Zdravka Pashova-Tasseva, Antoaneta Mlachkova, Kamen Kotsilkov and Hristina Maynalovska

Genes 2025, 16(8), 891; https://doi.org/10.3390/genes16080891 - 28 Jul 2025

Abstract

Periodontitis is a prevalent chronic inflammatory disease with complex etiopathogenesis involving microbial dysbiosis, host immune response, environmental factors, and genetic susceptibility. Among the cytokines implicated in periodontal immunoregulation, interleukin-35 (IL-35) has emerged as a novel anti-inflammatory mediator with potential diagnostic and therapeutic relevance. [...] Read more.

Periodontitis is a prevalent chronic inflammatory disease with complex etiopathogenesis involving microbial dysbiosis, host immune response, environmental factors, and genetic susceptibility. Among the cytokines implicated in periodontal immunoregulation, interleukin-35 (IL-35) has emerged as a novel anti-inflammatory mediator with potential diagnostic and therapeutic relevance. This narrative review evaluates the role of IL-35 in periodontal disease by exploring its local and systemic expression, response to non-surgical periodontal therapy (NSPT), and association with clinical disease severity. Additionally, current evidence regarding IL-35 gene polymorphisms and their potential contribution to individual susceptibility and disease progression, as well as their relevance in related systemic conditions, is assessed. A comprehensive review and synthesis of recent clinical and experimental studies were conducted, focusing on IL-35 levels in saliva, serum, and gingival crevicular fluid (GCF) among patients with healthy periodontium, gingivitis, and various stages of periodontitis, both before and after NSPT. Emphasis was placed on longitudinal studies evaluating IL-35 dynamics in correlation with periodontal parameters, as well as genetic association studies investigating IL-12A and EBI3 gene polymorphisms. IL-35 levels were generally found to be higher in healthy individuals and reduced in periodontitis patients, indicating a possible protective role in maintaining periodontal homeostasis. Following NSPT, IL-35 levels significantly increased, corresponding with clinical improvement and reduced inflammatory burden. Genetic studies revealed variable associations between IL-35 polymorphisms and susceptibility to periodontitis and related systemic conditions, although further research is needed for validation. IL-35 appears to function as a modulator of immune resolution in periodontal disease, with potential utility as a non-invasive biomarker for disease activity and therapeutic response. Its upregulation during periodontal healing supports its role in promoting tissue stabilization. The integration of cytokine profiling and genetic screening may enhance personalized risk assessment and targeted interventions in periodontal care. Full article

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

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12 pages, 910 KiB

Open AccessArticle

Unusual Profile of Germline Genetic Variants in Unselected Colorectal Cancer Patients from a High-Prevalence Region in Panama

by Iván Landires, José Pinto, Raúl Cumbrera, Alexandra Nieto, Gumercindo Pimentel-Peralta, Yennifer Alfaro and Virginia Núñez-Samudio

Genes 2025, 16(8), 890; https://doi.org/10.3390/genes16080890 - 28 Jul 2025

Abstract

Background: The profile of germline genetic variants among colorectal cancer patients in Panama has not yet been explored. Methods: We recruited 95 patients with colorectal cancer in an Oncology Reference Hospital Unit in the Azuero region of central Panama, which exhibited the highest [...] Read more.

Background: The profile of germline genetic variants among colorectal cancer patients in Panama has not yet been explored. Methods: We recruited 95 patients with colorectal cancer in an Oncology Reference Hospital Unit in the Azuero region of central Panama, which exhibited the highest prevalence of colorectal cancer in Panama. DNA analysis was performed with a panel of 113 genes with germline mutations for cancer (TruSight^® Cancer Sequencing Panel from Illumina, San Diego, CA, USA). Results: Among the 95 cases, 10 pathogenic/likely pathogenic variants (P/LP) were identified in the MUTYH, TP53, CHEK2, PALB2, ATM, and BARD1 genes, representing 10% of the total. The variant 1103G>A (p.Gly368Asp) in MUTYH was the most prevalent. The variant at c.1675_1676delCAinsTG (p.Gln559Ter) in PALB2 is new and is reported for the first time in this study. Variants were most frequently detected in the MUTYH and CHEK2 genes, affecting four and two patients, respectively. Notably, none of the 95 Panamanian patients in the initial colorectal cancer cohort had mutations in mismatch repair (MMR) genes. These genes are among the most frequently mutated in other cohorts around the world. Conclusions: The atypical profile of germline genetic variants in this population may be related to the unique characteristics of the Azuero population in Panama’s central region. This profile may partly explain the high prevalence of colorectal cancer among its inhabitants. Full article

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

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16 pages, 11910 KiB

Open AccessArticle

Characterization and Expression Analysis of β-Glucosidase Gene Under Abiotic Stresses in Pepper (Capsicum annuum L.)

by Jing Wang, Jiaxin Huang, Xu Jia, Zhenxin Hao, Yuancai Yang, Ruxia Tian and Yanping Liang

Genes 2025, 16(8), 889; https://doi.org/10.3390/genes16080889 - 27 Jul 2025

Abstract

Background: Pepper (Capsicum annuum L.) is highly susceptible to various abiotic stresses during their growth and development, leading to severe reductions in both yield and quality. β-Glucosidase (BGLU) is widely involved in plant growth and development, as well as in the [...] Read more.

Background: Pepper (Capsicum annuum L.) is highly susceptible to various abiotic stresses during their growth and development, leading to severe reductions in both yield and quality. β-Glucosidase (BGLU) is widely involved in plant growth and development, as well as in the response to abiotic stress. Methods: We performed a genome-wide identification of pepper BGLU (CaBGLU) genes. Phylogenetic analysis included BGLU proteins from Arabidopsis, tomato, and pepper. Gene structures, conserved motifs, and promoter cis-elements were analyzed bioinformatically. Synteny within the pepper genome was assessed. Protein-protein interaction potential was predicted. Gene expression patterns were analyzed across tissues and under abiotic stresses using transcriptomic data and qRT-PCR. Subcellular localization of a key candidate protein CaBGLU21 was confirmed experimentally. Results: We identified 32 CaBGLU genes unevenly distributed across eight chromosomes. Phylogenetic classification of 99 BGLU proteins into 12 subfamilies revealed an uneven distribution of CaBGLUs across six subfamilies. Proteins within subfamilies shared conserved motifs and gene structures. CaBGLU promoters harbored abundant light-, hormone- (MeJA, ABA, SA, GA), and stress-responsive elements (including low temperature). A duplicated gene pair (CaBGLU19/CaBGLU24) was identified. 27 CaBGLU proteins showed potential for interactions. Expression analysis indicated CaBGLU5 and CaBGLU30 were mesophyll-specific, while CaBGLU21 was constitutively high in non-leaf tissues. CaBGLU21 was consistently upregulated by cold, heat, and ABA. Subcellular localization confirmed CaBGLU21 resides in the tonoplast. Conclusions: This comprehensive analysis characterizes the pepper BGLU gene family. CaBGLU21, exhibiting constitutive expression in non-leaf tissues, strong upregulation under multiple stresses, and tonoplast localization, emerges as a prime candidate gene for further investigation into abiotic stress tolerance mechanisms in pepper. The findings provide a foundation for future functional studies and stress-resistant pepper breeding. Full article

(This article belongs to the Special Issue Molecular Adaptation and Evolutionary Genetics in Plants)

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18 pages, 1956 KiB

Open AccessArticle

Panel-Based Genetic Testing in a Consecutive Series of Individuals with Inherited Retinal Diseases in Australia: Identifying Predictors of a Diagnosis

by Alexis Ceecee Britten-Jones, Doron G. Hickey, Thomas L. Edwards and Lauren N. Ayton

Genes 2025, 16(8), 888; https://doi.org/10.3390/genes16080888 - 27 Jul 2025

Abstract

Background/Objectives: Genetic testing is important for diagnosing inherited retinal diseases (IRDs), but further evidence is needed on the utility of singleton genetic testing in an Australian cohort. Methods: A consecutive series of individuals with clinically diagnosed IRDs without prior genetic testing [...] Read more.

Background/Objectives: Genetic testing is important for diagnosing inherited retinal diseases (IRDs), but further evidence is needed on the utility of singleton genetic testing in an Australian cohort. Methods: A consecutive series of individuals with clinically diagnosed IRDs without prior genetic testing underwent commercial panel-based sequencing (Invitae or Blueprint Genetics), clinical assessment, and multimodal imaging. Retinal images were graded using the Human Phenotype Ontology terms. Binary logistic regression was used to evaluate clinical predictors of a positive molecular diagnosis. Results: Among 140 participants (mean age 49 ± 19 years), genetic testing was undertaken, on average, 23 ± 17 years after the initial clinical IRD diagnosis. Of the 60% who received a probable molecular diagnosis, 40% require further phase testing, highlighting the limitations of singleton genetic testing. USH2A, ABCA4, and RPGR were the most common encountered genes; 67% of the probably solved participants had causative genes with targeted experimental treatments in ongoing human clinical trials. Symptom onset before the age of 30 (OR = 3.06 [95% CI: 1.34–7.18]) and a positive IRD family history (OR = 2.87 [95% CI: 1.27–6.78]) were each associated with higher odds of receiving a molecular diagnosis. Diagnostic rates were comparable across retinal imaging phenotypes (atrophy and autofluorescence patterns in widespread IRD, and the extent of dystrophy in macular IRDs). Conclusions: In an Australian IRD population without prior genetic testing, commercial panels yielded higher diagnostic rates in individuals with IRD onset before the age of 30 and those with an IRD family history. Further research is needed to understand the genetic basis of IRDs, especially isolated and late-onset cases, to improve diagnosis and access to emerging therapies. Full article

(This article belongs to the Special Issue Inherited Retinal Diseases: Genetic Research and Novel Therapeutic Prospects)

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15 pages, 1388 KiB

Open AccessArticle

SLC39A14 Is a Potential Therapy Target and Prognostic Biomarker for Acute Myeloid Leukemia

by Yun Li and Liming Shan

Genes 2025, 16(8), 887; https://doi.org/10.3390/genes16080887 - 27 Jul 2025

Abstract

Background: Programmed cell death-related genes (PCDRGs) have been reported to play an important role in diagnosis, treatment and immunity regarding cancer, but their prognostic value and therapeutic potential in acute myeloid leukemia (AML) patients still need to be fully explored. Methods: [...] Read more.

Background: Programmed cell death-related genes (PCDRGs) have been reported to play an important role in diagnosis, treatment and immunity regarding cancer, but their prognostic value and therapeutic potential in acute myeloid leukemia (AML) patients still need to be fully explored. Methods: Cox regression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) analysis were used to identify PCDRGs significantly associated with the prognosis of AML patients. Furthermore, a prognostic risk model for AML patients was constructed based on the selected PCDRGs, and their immune microenvironment and biological pathways were analyzed. Cell experiments ultimately confirmed the potential role of PCDRGs in AML. Results: The results yielded four PCDRGs that were used to develop a prognostic risk model, and the prognostic significance of this model was confirmed using an independent external AML patient cohort. This prognostic risk model provides an independent prognostic risk factor for AML patients. This prognostic feature is related to immune cell infiltration in AML patients. The inhibition of solute carrier family 39 member 14 (SLC39A14) expression enhanced apoptosis and inhibited cell cycle progression in AML cells. Conclusions: This study integrates bioinformatics analysis and cellular experiments to reveal potential gene therapy targets and prognostic gene markers in AML. Full article

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

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10 pages, 226 KiB

Open AccessArticle

Association of SIRT1 Promoter Polymorphisms with Type 2 Diabetes Mellitus and Pregnancy-Related Complications in the Greek Population

by Sophia Letsiou, Eirini Prountzou, Despina Vougiouklaki, Maria Trapali, Michail Papapanou, Zoe Siateli, Konstantinos Ladias, Dimitra Houhoula and Panagiotis Halvatsiotis

Genes 2025, 16(8), 886; https://doi.org/10.3390/genes16080886 - 27 Jul 2025

Abstract

Background/Objectives: SIRT1 is a NAD⁺-dependent protein deacetylase regulating metabolic and stress response pathways. Genetic variations in the SIRT1 gene may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This case–control study investigates the associations of two SIRT1 promoter polymorphisms, [...] Read more.

Background/Objectives: SIRT1 is a NAD⁺-dependent protein deacetylase regulating metabolic and stress response pathways. Genetic variations in the SIRT1 gene may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This case–control study investigates the associations of two SIRT1 promoter polymorphisms, rs12778366 and rs3758391, in patients with type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), preeclampsia, and healthy controls. Methods: This case–control study compared the genotypes between T2DM and pregnant and non-pregnant controls. We also compared genotypes between pregnant women with T2DM, GDM, preeclampsia, and healthy pregnant controls. Genomic DNA was extracted and analyzed using PCR-RFLP for the detection of rs12778366 and rs3758391 polymorphisms. Genotype frequencies were compared using chi-square tests, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: The study included 66 patients with T2DM, 36 with GDM, 12 with preeclampsia, and 81 pregnant and non-pregnant controls (33 pregnant controls). Although rs3758391 was more frequent in T2DM, the difference was not statistically significant between SIRT1 polymorphisms and T2DM. The CT genotype was more prevalent in T2DM (54.5%) compared to controls (33.4%); however, this difference was not significant. We finally found no significant association of the investigated SIRT1 polymorphisms with any of the conditions studied. In addition, the small sample size, especially for preeclampsia cases, limits the statistical power to detect significant associations. Conclusions: Although no significant association was observed between SIRT1 polymorphisms and diabetes, the findings of our study underscore the need for further studies examining SIRT1 polymorphisms in various ethnic groups, with a focus on leveraging these genetic variations in diabetes pathophysiology. Larger studies in the Greek population could also provide additional meaningful findings. Full article

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

16 pages, 2138 KiB

Open AccessArticle

Precise Identification of Higher-Order Repeats (HORs) in T2T-CHM13 Assembly of Human Chromosome 21—Novel 52mer HOR and Failures of Hg38 Assembly

by Matko Glunčić, Ines Vlahović, Marija Rosandić and Vladimir Paar

Genes 2025, 16(8), 885; https://doi.org/10.3390/genes16080885 - 27 Jul 2025

Abstract

Background: Centromeric alpha satellite DNA is organized into higher-order repeats (HORs), whose precise structure is often difficult to resolve in standard genome assemblies. The recent telomere-to-telomere (T2T) assembly of the human genome enables complete analysis of centromeric regions, including the full structure of [...] Read more.

Background: Centromeric alpha satellite DNA is organized into higher-order repeats (HORs), whose precise structure is often difficult to resolve in standard genome assemblies. The recent telomere-to-telomere (T2T) assembly of the human genome enables complete analysis of centromeric regions, including the full structure of HOR arrays. Methods: We applied the novel high-precision GRMhor algorithm to the complete T2T-CHM13 assembly of human chromosome 21. GRMhor integrates global repeat map (GRM) and monomer distance (MD) diagrams to accurately identify, classify, and visualize HORs and their subfragments. Results: The analysis revealed a novel Cascading 11mer HOR array, in which each canonical HOR copy comprises 11 monomers belonging to 10 different monomer types. Subfragments with periodicities of 4, 7, 9, and 20 were identified within the array. A second, complex 23/25mer HOR array of mixed Willard’s/Cascading type was also detected. In contrast to the hg38 assembly, where a dominant 8mer and 33mer HOR were previously annotated, these structures were absent in the T2T-CHM13 assembly, highlighting the limitations of hg38. Notably, we discovered a novel 52mer HOR—the longest alpha satellite HOR unit reported in the human genome to date. Several subfragment repeats correspond to alphoid subfamilies previously identified using restriction enzyme digestion, but are here resolved with higher structural precision. Conclusions: Our findings demonstrate the power of GRMhor in resolving complex and previously undetected alpha satellite architectures, including the longest canonical HOR unit identified in the human genome. The precise delineation of superHORs, Cascading structures, and HOR subfragments provides unprecedented insight into the fine-scale organization of the centromeric region of chromosome 21. These results highlight both the inadequacy of earlier assemblies, such as hg38, and the critical importance of complete telomere-to-telomere assemblies for accurately characterizing centromeric DNA. Full article

(This article belongs to the Section Cytogenomics)

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12 pages, 1442 KiB

Open AccessArticle

Does BRCA Mutation Status Influence Ovarian Cancer Onset Timing and Patients’ Treatment Outcomes?

by Kaja Michalczyk, Agata Mokrzycka, Marianna Rudzińska, Barbara Michalczyk, Janusz Menkiszak and Anita Chudecka-Głaz

Genes 2025, 16(8), 883; https://doi.org/10.3390/genes16080883 - 27 Jul 2025

Abstract

Background/Objectives: Mutations in the BRCA1 and BRCA2 genes are well-known risk factors for ovarian cancer. They are also associated with response to platinum-based chemotherapy; however, their definitive impact on patient prognosis remains not fully understood. This study aimed to investigate the influence of [...] Read more.

Background/Objectives: Mutations in the BRCA1 and BRCA2 genes are well-known risk factors for ovarian cancer. They are also associated with response to platinum-based chemotherapy; however, their definitive impact on patient prognosis remains not fully understood. This study aimed to investigate the influence of BRCA mutation status on the age of ovarian cancer onset and on treatment outcomes in patients with high-grade serous ovarian cancer. Methods: This single-center retrospective analysis included newly diagnosed FIGO stage III and IV HGSOC patients treated between June 2018 and April 2023. Patients’ age, tumor histology, CA125 levels, BRCA mutation status, type of treatment (neoadjuvant or adjuvant chemotherapy), and surgical outcomes were collected and analyzed. Survival analyses were performed using the Kaplan–Meier method and log-rank test. Results: Pathogenic mutations were identified in 25 patients (15 in BRCA1, 10 in BRCA2). Patients with a BRCA mutation were diagnosed at a significantly younger age (median 58.78 years) compared to non-carriers (66.81 years; p < 0.001), with BRCA1 carriers being diagnosed the youngest (median 46.52 years). The study found no statistically significant difference in progression-free survival (PFS) between BRCA carriers and non-carriers. However, a significant improvement in overall survival (OS) was observed for patients with a BRCA1 mutation (p = 0.036). No significant OS difference was found for BRCA2 carriers. Conclusions: BRCA mutations, particularly in the BRCA1 gene, are associated with an earlier onset ovarian cancer. BRCA1 mutation appears to be a favorable prognostic factor for overall survival in patients with HGSOC. Our findings demonstrate the clinical implications of different BRCA mutations and support the need for further research in larger cohorts to confirm their influence on prognostic effects. Full article

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

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21 pages, 606 KiB

Open AccessReview

Genomics in Pancreas–Kidney Transplantation: From Risk Stratification to Personalized Medicine

by Hande Aypek, Ozan Aygormez and Yasar Caliskan

Genes 2025, 16(8), 884; https://doi.org/10.3390/genes16080884 - 26 Jul 2025

Abstract

Background: Pancreas and pancreas–kidney transplantation are well-established therapeutic options for patients with type 1 diabetes mellitus (T1DM) and end-stage kidney disease (ESKD), offering the potential to restore endogenous insulin production and kidney function. It improves metabolic control, quality of life, and long-term survival. [...] Read more.

Background: Pancreas and pancreas–kidney transplantation are well-established therapeutic options for patients with type 1 diabetes mellitus (T1DM) and end-stage kidney disease (ESKD), offering the potential to restore endogenous insulin production and kidney function. It improves metabolic control, quality of life, and long-term survival. While surgical techniques and immunosuppressive strategies have advanced considerably, graft rejection and limited long-term graft survival remain significant clinical challenges. Method: To better understand these risks, the genetic and immunological factors that influence transplant outcomes are examined. Beyond traditional human leukocyte antigen (HLA) matching, non-HLA genetic variants such as gene deletions and single-nucleotide polymorphisms (SNPs) have emerged as contributors to alloimmune activation and graft failure. Result: Polymorphisms in cytokine genes, minor histocompatibility antigens, and immune-regulatory pathways have been implicated in transplant outcomes. However, the integration of such genomic data into clinical practice remains limited due to underexplored gene targets, variability in study results, and the lack of large, diverse, and well-characterized patient cohorts. Initiatives like the International Genetics & Translational Research in Transplantation Network (iGeneTRAiN) are addressing these limitations by aggregating genome-wide data from thousands of transplant donors and recipients across multiple centers. These large-scale collaborative efforts aim to identify clinically actionable genetic markers and support the development of personalized immunosuppressive strategies. Conclusions: Overall, genetic testing and genomics hold great promise in advancing precision medicine in pancreas and pancreas–kidney transplantation. Full article

(This article belongs to the Special Issue Genetics in Transplantation)

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