Genes

14 pages, 2660 KB

Open AccessArticle

Phenotypic and Transcriptomic Analyses of Transgenic Arabidopsis thaliana Expressing Cotton Zinc Finger Protein8 (GhZFP8)

by Wenhan Cheng, Chen Rui, Yechuan Huang, Deyan Zhu and Yongchang Liu

Genes 2025, 16(9), 1119; https://doi.org/10.3390/genes16091119 - 22 Sep 2025

Viewed by 179

Abstract

Background: The functional role of GhZFP8 (a zinc finger protein gene) in plant growth and development remains unclear. Methods: This study investigated phenotypic and transcriptomic changes in GhZFP8-transgenic vs. wild-type Arabidopsis to clarify GhZFP8’s biological functions. Phenotypes of two transgenic lines [...] Read more.

Background: The functional role of GhZFP8 (a zinc finger protein gene) in plant growth and development remains unclear. Methods: This study investigated phenotypic and transcriptomic changes in GhZFP8-transgenic vs. wild-type Arabidopsis to clarify GhZFP8’s biological functions. Phenotypes of two transgenic lines (ZFP8_7, ZFP8_21) were observed. Transcriptome sequencing (ZFP8_7 vs. wild-type, 3 biological replicates/sample) was performed, with quality assessment (coverage, depth, alignment rate). Differential genes were screened by |log2(fold change)| > 1 and FDR < 0.05; GO/KEGG enrichment analyses were conducted. Results: Transgenic lines showed slower growth, higher trichome density, ectopic silique trichomes, and reduced fertility. Sequencing quality was satisfactory (97.42% exonic alignment). Most differential genes were highly expressed in wild-type plants, with more downregulated than upregulated genes. Upregulated genes enriched in stimulus response regulation, plant cell walls, and methyltransferase activity (GO); estrogen signaling/tyrosine metabolism (KEGG). Downregulated genes enriched in cell wall/phenylpropanoid biosynthesis (GO); glycosyltransferase/plant MAPK pathways (KEGG). Conclusions:GhZFP8 overexpression induces significant phenotypic changes and alters gene expression in Arabidopsis. Findings provide insights into GhZFP8’s effects, supporting further study of its functional mechanisms. Full article

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

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11 pages, 1613 KB

Open AccessArticle

Novel KIAA0825 Variants Underlie Nonsyndromic Postaxial Polydactyly

by Abdullah, Thashi Bharadwaj, Saffia Javed, Hammal Khan, Anushree Acharya, Weizhen Ji, Umm-e-Kalsoom, Hamid Ali, Isabelle Schrauwen, Wasim Ahmad, Saquib A. Lakhani and Suzanne M. Leal

Genes 2025, 16(9), 1118; https://doi.org/10.3390/genes16091118 - 21 Sep 2025

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Abstract

Background: Extra digits on the hands and/or feet are a frequent condition known as polydactyly. Twelve nonsyndromic polydactyly genes have been identified, including KIAA0825. Methods: Four consanguineous Pakistani families that segregate nonsyndromic postaxial polydactyly (PAP) with an autosomal recessive mode of inheritance [...] Read more.

Background: Extra digits on the hands and/or feet are a frequent condition known as polydactyly. Twelve nonsyndromic polydactyly genes have been identified, including KIAA0825. Methods: Four consanguineous Pakistani families that segregate nonsyndromic postaxial polydactyly (PAP) with an autosomal recessive mode of inheritance were clinically and genetically evaluated. Exome sequencing or genotyping of polymorphic microsatellite markers followed by Sanger sequencing were used to identify the variants underlying the PAP etiology. Results: Three novel KIAA0825 variants were identified that segregate with PAP: a nonsense variant c.2319G>A; p.(Trp773*) in two families; a missense variant c.970G>T; p.(Val324Phe) in one family; and a four amino acids in-frame deletion c.2743_2754del; p.(Gln915_Val918del) in one family. The nonsense variant segregated in families with PAP type B (PAPB), while the missense and the in-frame deletion variants segregated with PAP type A and B. Conclusions: The findings of this study expanded the clinical and genetic spectrum of PAP due to KIAA0825 variants including the first KIAA0825 variant specific to PAPB. Full article

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

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20 pages, 13395 KB

Open AccessArticle

Fine Mapping of a Major Locus for Leaf Sheath Hairiness in Wheat Identifies TaSAIN1-4D as a Candidate Gene

by Lijuan Wu, Jundong He, Shian Shen, Yulin Li, Jinbai He and Xinkun Hu

Genes 2025, 16(9), 1117; https://doi.org/10.3390/genes16091117 - 20 Sep 2025

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Abstract

Background/Objectives: Leaf sheath hairiness (LSH) is an adaptive trait in wheat that improves tolerance to biotic and abiotic stresses. Although trichome development has been extensively studied in model plants, the genetic basis of LSH in Triticeae crops remains poorly defined. Methods: [...] Read more.

Background/Objectives: Leaf sheath hairiness (LSH) is an adaptive trait in wheat that improves tolerance to biotic and abiotic stresses. Although trichome development has been extensively studied in model plants, the genetic basis of LSH in Triticeae crops remains poorly defined. Methods: In this study, the inheritance and genetic architecture of LSH were investigated. Two F₂ populations were used, derived from crosses between the glabrous lines ‘Shumai 830’ and ‘Shumai 2262’ and the hairy line ‘Zhongkelanmai 1’. BSA-seq was combined with KASP marker genotyping to map and refine the trait locus. Candidate genes were evaluated through comparative genomics; sequence variation; and subcellular localization prediction. Results: Phenotypic evaluation revealed that LSH is a dominant trait, segregating at a 3:1 ratio in F₂ populations. BSA-seq identified a major locus, QLsh.cwnu-4D, on chromosome 4DL. Fine mapping with KASP markers refined this region to a 1.67 Mb interval overlapping a 530 kb trichome-associated linkage disequilibrium block in Aegilops tauschii. Within this interval, TaSAIN1-4D, a salt-inducible protein unique to Triticeae, was identified as the strongest candidate gene. Extensive sequence variation among alleles (TaSAIN1-4Da; TaSAIN1-4Db; TaSAIN1-4Dc), including large insertions and multiple SNPs, indicated potential functional diversification. Predicted nuclear localization of TaSAIN1-4D supports a role in trichome regulation and stress adaptation. The co-dominant KASP marker K-cwnu-4D-502238348 was tightly linked to LSH and cosegregated perfectly, making it a reliable tool for marker-assisted selection. Conclusions: This study clarifies the genetic architecture of leaf sheath hairiness in wheat and identifies TaSAIN1-4D as a likely regulator. These findings provide a practical marker-assisted selection tool that can accelerate the development of improved wheat varieties with desirable leaf surface traits. Full article

(This article belongs to the Special Issue Genetic Research on Crop Stress Resistance and Quality Traits)

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11 pages, 233 KB

Open AccessArticle

The Polymorphism of Metabolic and Immune Mechanisms Controlling Genes in Type 2 Diabetes Mellitus

by Iuliana Shramko, Elizaveta Ageeva, Anatolii Kubishkin, Tatyana Makalish, Cyrill Tarimov and Dmitry Bondar’

Genes 2025, 16(9), 1116; https://doi.org/10.3390/genes16091116 - 20 Sep 2025

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Abstract

Background/Objectives: Most genes involved in the pathogenesis of Metabolic Syndrome (MS) and Type 2 Diabetes Mellitus (T2DM) are regulated by peroxisome proliferator-activated receptors (PPARs), which modulate the production of pro-inflammatory cytokines, with interleukin-6 (IL-6) playing a crucial role. The associations of single-nucleotide [...] Read more.

Background/Objectives: Most genes involved in the pathogenesis of Metabolic Syndrome (MS) and Type 2 Diabetes Mellitus (T2DM) are regulated by peroxisome proliferator-activated receptors (PPARs), which modulate the production of pro-inflammatory cytokines, with interleukin-6 (IL-6) playing a crucial role. The associations of single-nucleotide polymorphisms (SNPs) with MS and T2DM remain uncertain across populations. Therefore, we aimed to investigate the associations of PPAR-related SNPs in IL-6, LEP, ADIPOQ, ADIPOR1, and ADIPOR2 with MS and T2DM clinical features. Methods: Polymorphism analysis of IL-6, LEP, ADIPOQ, ADIPOR1, and ADIPOR2 genes was performed on isolated DNA from individuals diagnosed with T2DM and from healthy controls using real-time polymerase chain reaction (qPCR). Results: The IL-6-174G/C polymorphism shows that the CC genotype is associated with higher MS risk, whereas the GG genotype appears protective against metabolic disturbances. When the IL6 CC genotype is combined with ADIPOR2 GA or ADIPOR2 219 A/T, hyperglycemia is 1.3 times more frequent than with other IL6/ADIPOR2 genotype combinations. Conclusions: To develop informative genetic risk scores, future studies should include additional polymorphisms in key immune–metabolic pathway genes, such as AP-1, NF-κB, and FFAs. Full article

(This article belongs to the Section Genetic Diagnosis)

17 pages, 5748 KB

Open AccessArticle

Birth–Death Dynamics of Microsatellites: Mechanistic Insights from Orthologous Loci in Felidae

by Wenping Zhang, Mingchun Zhang and Hao Liu

Genes 2025, 16(9), 1115; https://doi.org/10.3390/genes16091115 - 19 Sep 2025

Viewed by 248

Abstract

Background/Objectives: The mutational dynamics of microsatellites over deep evolutionary timescales are poorly understood. This study aims to elucidate the life history of trinucleotide microsatellites by tracing orthologous loci across divergent vertebrate lineages and characterizing their mutational pathways. Methods: We developed a [...] Read more.

Background/Objectives: The mutational dynamics of microsatellites over deep evolutionary timescales are poorly understood. This study aims to elucidate the life history of trinucleotide microsatellites by tracing orthologous loci across divergent vertebrate lineages and characterizing their mutational pathways. Methods: We developed a bioinformatic framework for identifying orthologous microsatellite loci using conserved flanking sequences. This approach was applied to three trinucleotide microsatellites located in exonic, intronic, and intergenic regions, respectively. These loci were amplified and sequenced across 126 individuals representing 64 vertebrate species, whose divergence times range from 6 to 150 million years ago (MYA). Results: Flanking sequences proved essential for reliable orthology assignment, while repeat motifs revealed distinct mutational pathways. Microsatellite decay occurs through two primary mechanisms: the complete loss of dominant repeats or their progressive reduction to solitary units (≤1 repeat). This degeneration process is facilitated by cryptic simple sequences (CSS), which act as genomic catalysts promoting birth–death transitions. Large intra-motif deletions were identified as the key mutational event driving contractions and eventual locus degeneration. Furthermore, mutational patterns were highly locus-specific, influenced by genomic context. Conclusions: Although the study focused on only three loci, limiting broader generalizations, our findings provide mechanistic insights into microsatellite evolution. These results establish a foundation for modeling complex microsatellite life histories and highlight the role of CSS in facilitating evolutionary turnover. Full article

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

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19 pages, 965 KB

Open AccessArticle

GPBSO: Gene Pool-Based Brain Storm Optimization for SNP Epistasis Detection

by Liyan Sun, Yi Xin, Shen Qu, Linxuan Zheng and Linqing Jiang

Genes 2025, 16(9), 1114; https://doi.org/10.3390/genes16091114 - 19 Sep 2025

Viewed by 180

Abstract

Background/Objectives: Detecting high-order epistatic interactions in genome-wide association studies (GWAS) is essential for understanding complex diseases, yet most existing approaches are limited to pairwise interactions. We propose GPBSO (Gene Pool-Based Brain Storm Optimization for Epistasis Detection), a novel stochastic framework that integrates Brain [...] Read more.

Background/Objectives: Detecting high-order epistatic interactions in genome-wide association studies (GWAS) is essential for understanding complex diseases, yet most existing approaches are limited to pairwise interactions. We propose GPBSO (Gene Pool-Based Brain Storm Optimization for Epistasis Detection), a novel stochastic framework that integrates Brain Storm Optimization with a dynamic gene pool to efficiently explore high-order SNP combinations. Methods: Epistasis is evaluated using the k2 Bayesian network scoring criterion and the G-test, with iterative updates to the gene matrix enhancing search diversity. Results: Comparative experiments on simulated datasets generated from five epistatic models demonstrated that GPBSO consistently outperformed a set of well-established methods—DECMDR, SNPHarvester, AntEpiSeeker, HS-MMGKG, and SEE—in terms of F-measure and statistical power, particularly for third-order interactions. Conclusions: GPBSO provides an effective and scalable approach for detecting high-order epistatic interactions, offering methodological advancements for genetic epidemiology and complex disease analysis. Full article

(This article belongs to the Section Bioinformatics)

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14 pages, 933 KB

Open AccessArticle

Effects of the PCSK9 C378W Mutation on PCSK9 Levels and Lipid Profiles in Taiwanese Individuals: A Loss-of-Function Mutation with Potential Cardiovascular Benefits

by Semon Wu, Lung-An Hsu, Kuan-Hung Yeh and Yu-Lin Ko

Genes 2025, 16(9), 1113; https://doi.org/10.3390/genes16091113 - 19 Sep 2025

Viewed by 311

Abstract

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid metabolism. The rare PCSK9 C378W (rs776752113) mutation influences the level of low-density lipoprotein cholesterol (LDL-C); however, its association with PCSK9 levels remain unclear. Methods: This study investigates the [...] Read more.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid metabolism. The rare PCSK9 C378W (rs776752113) mutation influences the level of low-density lipoprotein cholesterol (LDL-C); however, its association with PCSK9 levels remain unclear. Methods: This study investigates the frequency of the C378W mutation and its effects on PCSK9 levels and lipid profiles in 5901 Taiwan Biobank participants, including 1486 individuals with available whole-genome sequencing data. The C378W mutations were detected using a TaqMan genotyping assay and confirmed using direct DNA sequencing. Results: Whole-genome sequencing data revealed a single carrier of the C378W mutation. The TaqMan assay identified seven carriers of the 378W allele (7/5901 [0.119%]). After the exclusion of an individual with a history of hyperlipidemia, six carriers exhibited significantly lower levels of LDL-C (−30.5%) and PCSK9 (−56.4%) than noncarriers (LDL-C: 81.17 ± 21.79 vs. 116.70 ± 30.70 mg/dL [p = 0.0005]; PCSK9: 67.20 ± 14.83 vs. 154.02 ± 45.52 ng/mL [p = 3.59 × 10⁻¹²]. Moreover, carriers exhibited significantly lower levels of total cholesterol (−18.6%) and non-high-density lipoprotein cholesterol (non-HDL-C; −28.4%) than noncarriers (total cholesterol: 157.17 ± 19.30 vs. 193.18 ± 35.22 mg/dL [p = 0.0035]; non-HDL-C: 99.50 ± 20.22 vs. 138.91 ± 34.97 mg/dL [p = 0.0005]). Mediation analysis suggests that the association between the C378W mutation and LDL-C levels persisted even after adjustment for PCSK9 levels. Functional characterization indicates that the C378W mutation impairs protein stability and function. Conclusion: In conclusion, the rare C378W mutation represents a loss-of-function mutation in the Taiwanese population. This variant is independently associated with reduced PCSK9 levels and improved lipid profiles, highlighting its potential cardioprotective role. Full article

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

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14 pages, 3712 KB

Open AccessArticle

Phosphatidic Acid Reverses Obesity Induced by a High-Fat, High-Sugar Diet at the Transcriptional Level

by Hao Xie, Qian Cheng, Xingyi Tian and Yanlin Liao

Genes 2025, 16(9), 1112; https://doi.org/10.3390/genes16091112 - 19 Sep 2025

Viewed by 338

Abstract

Background: Obesity poses a significant threat to human health and is commonly caused by excessive dietary intake. Phosphatidic acid (PA) is one of the simplest diacylglycerol phospholipids, serving as a crucial precursor for the synthesis of triglycerides and other complex phospholipids. PA is [...] Read more.

Background: Obesity poses a significant threat to human health and is commonly caused by excessive dietary intake. Phosphatidic acid (PA) is one of the simplest diacylglycerol phospholipids, serving as a crucial precursor for the synthesis of triglycerides and other complex phospholipids. PA is also an important intermediate product in the process of fat digestion and absorption. Studies have shown that PA has muscle-building and fat-reducing effects, but it is currently unclear whether it can combat obesity induced by a high-fat, high-sugar diet (HFD). Methods: Using a model of obesity induced by a high-fat high-sugar diet, we found that the addition of PA to food could reverse HFD-induced obesity. Results: Addition of PA to food can reverse obesity induced by a high-fat diet. Transcriptomic analysis results indicate that this reversal also takes place at the molecular level. Further analysis suggests that PA may regulate fat metabolism by reversing the PPAR signaling pathway. Conclusions: Our study provides molecular evidence for the use of PA as an effective additive in weight-loss food products. Full article

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

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20 pages, 8305 KB

Open AccessArticle

Machine Learning Identifies Shared Regulatory Mechanisms of Genes Associated with Ferroptosis in Major Depressive Disorder and Inflammatory Bowel Disease

by Jiyuan Shi, Luojin Wu, Lingxi Li, Ye Liu, Yuxuan Lu, Mengmeng Sang and Liming Mao

Genes 2025, 16(9), 1111; https://doi.org/10.3390/genes16091111 - 19 Sep 2025

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Abstract

Background: Major depressive disorder (MDD) and inflammatory bowel disease (IBD) form a “bidirectional vicious cycle” through the gut–brain axis: psychological and emotional abnormalities can induce intestinal inflammation, while intestinal inflammation can in turn exacerbate mental health disorders. Ferroptosis is an iron-dependent form of [...] Read more.

Background: Major depressive disorder (MDD) and inflammatory bowel disease (IBD) form a “bidirectional vicious cycle” through the gut–brain axis: psychological and emotional abnormalities can induce intestinal inflammation, while intestinal inflammation can in turn exacerbate mental health disorders. Ferroptosis is an iron-dependent form of regulated cell death that is driven by lipid peroxidation. Although this process has been molecularly defined in recent years, its role in the context of IBD and MDD remains insufficiently investigated. This study investigates the molecular roles of ferroptosis-related genes (FRGs) in both conditions and explores potential therapeutic strategies targeting these genes. Methods: We first identified differentially expressed FRGs (DE-FRGs) by comparing normal and disease samples. Subsequently, we screened for DE-FRGs in both IBD and MDD and named them Co-DEGs. Correlation analyses of these co-FRGs were performed, including comparisons between disease and control groups, as well as associations between Co-DEGs and immune cell infiltrations. Four distinct machine learning algorithms were employed to identify the core Co-DEGs associated with both IBD and MDD. Moreover, analyses of drug sensitivity, molecular docking, and molecular dynamics simulations were carried out to predict potential therapeutic agents for both conditions. Finally, single-cell sequencing analysis was also performed. Results: We identified 29 Co-DEGs in both IBD and MDD. Machine learning analysis identified RPL8 as a key common biomarker exhibiting a consistent expression trend in both diseases. A predictive approach integrating molecular docking and molecular dynamics simulations indicated that LE135, a compound targeting RPL8, is the most promising therapeutic candidate. Conclusions: These discoveries enhance the understanding of the shared and distinct regulatory mechanisms of FRGs in gut–brain axis disorders. We have pinpointed key biomarkers and predicted potential therapeutic agents that may offer dual-targeting strategies for both IBD and MDD. Full article

(This article belongs to the Special Issue Machine Learning in Cancer and Disease Genomics)

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17 pages, 10380 KB

Open AccessArticle

Multidimensional Regulatory Mechanisms of LvChia2 on Growth in the Pacific White Shrimp (Litopenaeus vannamei)

by Shangyi Li, Yifan Lei, Qingyun Liu, Qiangyong Li, Chunling Yang, Yuliu Huang, Digang Zeng, Liping Zhou, Min Peng, Xiuli Chen, Fan Wang and Yongzhen Zhao

Genes 2025, 16(9), 1110; https://doi.org/10.3390/genes16091110 - 19 Sep 2025

Viewed by 231

Abstract

Background: As a globally significant aquaculture species, elucidating the molecular mechanisms underlying the regulation of the Pacific White Shrimp (Litopenaeus vannamei) growth holds substantial scientific and industrial value. This study systematically investigates the role of the LvChia2 gene in governing [...] Read more.

Background: As a globally significant aquaculture species, elucidating the molecular mechanisms underlying the regulation of the Pacific White Shrimp (Litopenaeus vannamei) growth holds substantial scientific and industrial value. This study systematically investigates the role of the LvChia2 gene in governing growth and development through a cross-tissue metabolic network approach. Methods: RNA knockdown (RNAi)-mediated knockdown of LvChia2 significantly impaired growth performance and triggered a tissue-specific metabolic compensation mechanism. Results: This mechanism was characterized by reduced crude lipid content in muscle and adaptive modulation of lipase (LPS) activities in hepatopancreatic and intestinal tissues, suggesting inter-tissue metabolic coordination. Transcriptomic profiling identified 610 differentially expressed genes (DEGs), forming a three-dimensional regulatory network encompassing “energy metabolism, molt regulation, and nutrient utilization.” Key mechanistic insights revealed the following: (1) Enhanced mitochondrial energy transduction through the upregulation of ATP synthase subunits and NADH dehydrogenase (ND-SGDH). (2) The disruption of ecdysteroid signaling pathways via suppression of Krueppel homolog 1 (Kr-h1). (3) The coordinated regulation of nitrogen metabolism through the downregulation of glutamine synthetase and secretory phospholipase A2. These molecular adaptations, coupled with tissue-specific oxidative stress responses, reflect an integrated physiological strategy for environmental adaptation. Conclusions: Notably, this study provides the first evidence in crustaceans of chitinase-mediated growth regulation through cross-tissue metabolic interactions and identifies six core functional genes (ATP5L, ATP5G, ND-SGDH, Kr-h1, GS, sPLA2) as potential targets for molecular breeding. A novel “gut-hepatopancreas axis” energy compensation mechanism is proposed, offering insights into resource allocation during metabolic stress. These findings advance our understanding of crustacean growth regulation and establish a theoretical foundation for precision aquaculture strategies, including genome editing and multi-trait genomic selection. Full article

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

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13 pages, 4440 KB

Open AccessArticle

Integrating Network Analysis and Machine Learning Identifies Key Autism Spectrum Disorder Genes Linked to Immune Dysregulation and Therapeutic Targets

by Haitang Wang, Xiaofeng Zhu, Hong Zhang and Weiwei Chen

Genes 2025, 16(9), 1109; https://doi.org/10.3390/genes16091109 - 19 Sep 2025

Viewed by 252

Abstract

Background: Understanding the genetic mechanisms and identifying potential therapeutic targets are essential for clarifying Autism Spectrum Disorder (ASD) etiology and improving treatments. This study aims to bridge the gap between basic transcriptomic discoveries and clinical applications in ASD research. Methods: Differentially expressed genes [...] Read more.

Background: Understanding the genetic mechanisms and identifying potential therapeutic targets are essential for clarifying Autism Spectrum Disorder (ASD) etiology and improving treatments. This study aims to bridge the gap between basic transcriptomic discoveries and clinical applications in ASD research. Methods: Differentially expressed genes (DEGs) of GSE18123 datase were identified. A protein–protein interaction (PPI) network was constructed. Functional enrichment analysis was performed to link genetic loci to relevant biological pathways. Connectivity Map (CMap) analysis was used to predict potential drugs. Furthermore, immune infiltration correlation analysis explored associations between key genes and immune cell subpopulations. Diagnostic performance of top genes was evaluated by receiver operating characteristic (ROC) analysis. Results: The functional enrichment analysis successfully revealed relevant biological processes associated with ASD, while the CMap analysis predicted potential drugs that were consistent with some clinical trial results. Random forest analysis selected ten key feature genes (SHANK3, NLRP3, SERAC1, TUBB2A, MGAT4C, TFAP2A, EVC, GABRE, TRAK1, and GPR161) with the highest importance scores for autism prediction. Immune infiltration analysis showed significant correlations in genes and multiple immune cell types, demonstrating complex pleiotropic associations within the immune microenvironment. ROC curve analysis indicated that most top genes had strong discriminatory power in differentiating ASD from controls, particularly MGAT4C (AUC = 0.730), highlighting its potential as a robust biomarker. Conclusions: This study effectively bridges the basic transcriptomic discoveries and clinical applications in ASD research. The findings contribute to a better understanding of the etiology of ASD and provide potential therapeutic leads. Future research could focus on validating these potential drugs in clinical studies, as well as further exploring the biological functions of the identified genes to develop more targeted and effective treatments for ASD. Full article

(This article belongs to the Section Bioinformatics)

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25 pages, 1851 KB

Open AccessArticle

Predicting Gene Expression Responses to Cold in Arabidopsis thaliana Using Natural Variation in DNA Sequence

by Margarita Takou, Emily S. Bellis and Jesse R. Lasky

Genes 2025, 16(9), 1108; https://doi.org/10.3390/genes16091108 - 19 Sep 2025

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Abstract

Background/Objectives: The evolution of gene expression responses is a critical component of population adaptation to variable environments. Predicting how DNA sequence influences expression is challenging because the genotype-to-phenotype map is not well resolved for cis-regulatory elements, transcription factor binding, regulatory interactions, [...] Read more.

Background/Objectives: The evolution of gene expression responses is a critical component of population adaptation to variable environments. Predicting how DNA sequence influences expression is challenging because the genotype-to-phenotype map is not well resolved for cis-regulatory elements, transcription factor binding, regulatory interactions, and epigenetic features, not to mention how these factors respond to the environment. Methods: We tested if flexible machine learning models could learn some of the underlying cis-regulatory genotype-to-phenotype map to predict expression response to a specific environment. We tested this approach using cold-responsive transcriptome profiles in five Arabidopsis thaliana natural accessions. Results: We first tested for evidence that cis regulation plays a role in environmental response, finding 14 and 15 motifs that were significantly enriched within the up- and downstream regions of cold-responsive differentially regulated genes (DEGs). We next applied convolutional neural networks (CNNs), which learn de novo cis-regulatory motifs in DNA sequences to predict expression response to cold. We found that CNNs predicted differential expression with moderate accuracy, with evidence that predictions were hindered by the biological complexity of regulation and the large potential regulatory code. Conclusions: Overall, approaches for predicting DEGs between specific environments based only on proximate DNA sequences require further development. It may be necessary to incorporate additional biological information into models to generate accurate predictions that will be useful to population biologists. Full article

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

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19 pages, 3450 KB

Open AccessArticle

De Novo Transcriptome Sequencing and Profiling of Ovarian Development of Argas persicus Along the Trophogonic Cycle

by Fen Yan, Deyong Duan, Jinzhu Meng and Tianyin Cheng

Genes 2025, 16(9), 1107; https://doi.org/10.3390/genes16091107 - 19 Sep 2025

Viewed by 257

Abstract

Background: Argas persicus is a hematophagous ectoparasite of poultry and is the vector of several agents infectious to poultry. This study aims to explore the key genes affecting the ovarian development of A. persicus. Methods: RNA-seq was performed on the [...] Read more.

Background: Argas persicus is a hematophagous ectoparasite of poultry and is the vector of several agents infectious to poultry. This study aims to explore the key genes affecting the ovarian development of A. persicus. Methods: RNA-seq was performed on the ovaries of A. persicus before blood-feeding, on the day of engorgement, and 6 days post-engorgement. Utilizing the threshold padj < 0.05 and|log₂(foldchange)| > 1, differentially expressed genes were identified, and hub genes were determined by constructing protein–protein interaction (PPI) networks. Results: A total of 1008 differentially expressed genes were obtained during the feeding period, including 448 up-regulated and 560 down-regulated genes. Further, 2179 differentially expressed genes were screened in the preoviposition stage, including 1957 up-regulated and 222 down-regulated genes. These genes are mainly annotated in functions such as peptidase activity (especially serine protease activity), protein folding, protein assembly, and cell component assembly, and enriched in pathways such as protein processing in endoplasmic reticulum, lysosome, glutathione metabolism, and sphingolipid metabolism. In addition, some proteins that are closely related to ovarian development, including heat shock protein 70, protein disulfide isomerase, paramyosin, troponin I, hexosaminidase, serine protease, Kunitz serine protease inhibitors, and vitellogenin, were obtained. Conclusions: These findings fill the gap in the biological data for the ovarian development of soft ticks, provide a reference database for subsequent proteomics research, and offer fundamental support for the screening and development of candidate antigens for anti-tick vaccines. Full article

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

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18 pages, 979 KB

Open AccessArticle

Genetic Diversity and Selection of MHC I-UAA in Clariid Catfish from Thailand: Implications for Breeding and Conservation

by Ton Huu Duc Nguyen, Piangjai Chalermwong, Chananya Patta, Wattanawan Jaito, Worapong Singchat, Thitipong Panthum, Trifan Budi, Kednapat Sriphairoj, Sittichai Hatachote, Prapansak Srisapoome, Narongrit Muangmai, Darren K. Griffin, Agostinho Antunes, Prateep Duengkae and Kornsorn Srikulnath

Genes 2025, 16(9), 1106; https://doi.org/10.3390/genes16091106 - 18 Sep 2025

Viewed by 295

Abstract

Background/Objectives: Understanding variabilities in the Major Histocompatibility Complex class I (MHC I) gene is essential for evaluating immunogenetic diversity in clariid catfish. MHC I plays a critical role in immune defense by presenting endogenous antigens to cytotoxic T cells. Therefore, we [...] Read more.

Background/Objectives: Understanding variabilities in the Major Histocompatibility Complex class I (MHC I) gene is essential for evaluating immunogenetic diversity in clariid catfish. MHC I plays a critical role in immune defense by presenting endogenous antigens to cytotoxic T cells. Therefore, we aimed to investigate the genetic diversity, selection patterns, and phylogenetic relationships of MHC I alleles in three important clariid catfish species (Clarias gariepinus, Clarias macrocephalus, and Clarias batrachus) across wild and hatchery populations in Thailand. Methods: Targeted next-generation sequencing of a 174 bp fragment partial exon 6 of MHC I-UAA gene was performed, along with phylogenetic analyses, neutrality tests and dN/dS analyses. Results: Overall, 91 novel alleles were identified in 674 individuals, all of which were novel (100% novelty), with none matching existing reference sequences, thereby revealing extensive variation in population-specific variants. Phylogenetic analyses revealed allele sharing among species, which was consistent with balanced selection. Neutrality tests and dN/dS analyses provided evidence of both purifying and diversifying selection, with episodic positive selection detected at multiple codon sites associated with the antigen-binding α1 domain. Distinct selection patterns among populations, influenced by local environmental conditions and human pressures, along with high allele richness, are reflected in the diversity of immunogenetic variations. Conclusions: These findings provide critical insights into immune adaptation and highlight the potential of MHC I as a functional marker for genetic monitoring. Although a causal relationship between MHC I polymorphism and disease resistance is debated, studies suggest associations with pathogen survival, indicating future implications for aquaculture breeding and conservation, particularly in marker-assisted selection for broodstock management in Thailand. Full article

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

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18 pages, 1498 KB

Open AccessArticle

Mixture Deconvolution with Massively Parallel Sequencing Data: Microhaplotypes Versus Short Tandem Repeats

by Monica Giuffrida, Pedro Rodrigues, Zehra Köksal, Carina G. Jønck, Vania Pereira and Claus Børsting

Genes 2025, 16(9), 1105; https://doi.org/10.3390/genes16091105 - 18 Sep 2025

Viewed by 354

Abstract

Background/Objectives: Interpretation of mixture profiles generated from crime scene samples is an important element in forensic genetics. Here, a workflow for mixture deconvolution of sequenced microhaplotypes (MHs) and STRs using the probabilistic genotyping software MPSproto v0.9.7 was developed, and the performance of the [...] Read more.

Background/Objectives: Interpretation of mixture profiles generated from crime scene samples is an important element in forensic genetics. Here, a workflow for mixture deconvolution of sequenced microhaplotypes (MHs) and STRs using the probabilistic genotyping software MPSproto v0.9.7 was developed, and the performance of the two types of loci was compared. Methods: Sequencing data from a custom panel of 74 MHs (the MH-74 plex) and a commercial kit with 26 autosomal STRs (the ForenSeq™ DNA Signature Prep Kit) were used. Single-source profiles were computationally combined to create 360 two-person and 336 three-person mixtures using the Python script MixtureSimulator v1.0. Additionally, 72 real mixtures typed with the MH-74 plex and 18 real mixtures typed with the ForenSeq Kit from a previous study were deconvoluted using MPSproto. Results: The deconvoluted MH profiles were more complete and had fewer wrong genotype calls than the deconvoluted STR profiles. The contributor proportion estimates were more accurate for MH profiles than for STR profiles. Wrong genotype calls were mostly caused by locus and heterozygous imbalances, noise reads, or an inaccurate contributor proportion estimation. The latter was especially problematic in STR sequencing data, when two contributors contributed equally to the mixture. A total of 34,800 deconvolutions of the simulated mixtures were performed with two defined hypotheses: H_p, “The sample consists of DNA from one/two unknown contributor(s) and the suspect” and H_d, “The sample consists of DNA from two/three unknown individuals”. All true contributors were identified (LR > 10¹⁵ for MHs and LR > 10⁹ for STRs) and all non-contributors excluded (LR < 10⁻⁶ for MHs and LR < 0.2 for STRs). Conclusions: In simulated and real mixtures, the MHs performed better than STRs. Full article

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

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10 pages, 245 KB

Open AccessArticle

hTERT Gene Expression and Athlete’s Heart: A Study in Middle-Aged Endurance Athletes

by Caglar Ozmen, Nihal Inandiklioglu, Ozgur Gunasti, Hatice Rahimova, Omer Tepe, Rabia Eker Akilli, Pinar Ozmen Yildiz, Sanli Sadi Kurdak and Mustafa Demirtas

Genes 2025, 16(9), 1104; https://doi.org/10.3390/genes16091104 - 18 Sep 2025

Viewed by 292

Abstract

Background/Objectives: Telomeres and the enzyme telomerase play essential roles in cellular aging and cardiovascular health. Physical activity is thought to influence telomere dynamics via upregulation of the hTERT gene, which encodes the catalytic subunit of telomerase. However, data on this relationship in middle-aged [...] Read more.

Background/Objectives: Telomeres and the enzyme telomerase play essential roles in cellular aging and cardiovascular health. Physical activity is thought to influence telomere dynamics via upregulation of the hTERT gene, which encodes the catalytic subunit of telomerase. However, data on this relationship in middle-aged endurance athletes remain limited. This study aimed to investigate the association between long-term endurance training, cardiac structural adaptations, and hTERT gene expression in middle-aged elite athletes. Methods: A total of 38 middle-aged elite runners and 37 age-matched sedentary controls were enrolled. Echocardiographic assessments, VO₂peak measurements, and hTERT gene expression analysis using RT-PCR were conducted. Left ventricular mass (LVM), wall thicknesses, and cardiac volumes were compared, and correlations with hTERT expression were analyzed. Results: Athletes demonstrated significantly higher VO₂peak and echocardiographic parameters including LVEDD, LV mass, and wall thicknesses (p < 0.05). hTERT gene expression was 2.06-fold higher in athletes compared to controls. Significant positive correlations were observed between hTERT expression and VO₂peak, LVM, LV wall thicknesses, and right ventricular parameters. Conclusions: These findings suggest that regular aerobic exercise may contribute to both improved cardiovascular performance and cellular longevity by enhancing telomerase-related mechanisms. Full article

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

20 pages, 2713 KB

Open AccessArticle

Molecular Structure, Comparative Analysis, and Phylogenetic Insights into the Complete Chloroplast Genomes of Fissidens crispulus

by Yun-Qi Song, Kai-Li Kang, Jin Chen, Yu-Mei Wei, You-Liang Xiang and Tao Peng

Genes 2025, 16(9), 1103; https://doi.org/10.3390/genes16091103 - 18 Sep 2025

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Abstract

Background/Objectives: Fissidens crispulus Brid. is a dioicous moss with conspicuous axillary hyaline nodules and serrulate leaf margins. It features Neoamblyothallia-type peristome teeth and serves as an ecologically significant model for studying adaptation in the hyperdiverse genus Fissidens (>440 species). Methods: In this [...] Read more.

Background/Objectives: Fissidens crispulus Brid. is a dioicous moss with conspicuous axillary hyaline nodules and serrulate leaf margins. It features Neoamblyothallia-type peristome teeth and serves as an ecologically significant model for studying adaptation in the hyperdiverse genus Fissidens (>440 species). Methods: In this study, the complete chloroplast genome of F. crispulus was sequenced and de novo assembled, enabling detailed comparative genomic, phylogenetic, and codon usage bias studies. Results: As the third fully sequenced member of Fissidentaceae, this study deciphers its 124,264–124,440 bp quadripartite genome encoding 129 genes (83 CDS, 32 tRNAs, 8 rRNAs). Repeat analysis identified 125–127 SSRs, dominated by mono-/di-nucleotide A/T repeats (>70%), and dispersed repeats predominantly forward (F) and palindromic (P) (>85%), confirming profound AT-biased composition (GC content: 28.7%). We established 7 hypervariable loci (matK, ycf2, etc.) as novel Dicranidae-wide phylogenetic markers. Codon usage exhibited significant A/U-ending preference, with 12 optimal codons (e.g., GCA, UGU, UUU) determined. Maximum likelihood analyses resolved F. crispulus and F. protonematicola as sister groups with high support value (MBP = 100%). Conclusions: This work provides the foundational cpDNA resource for Fissidens, filling a major gap in bryophyte chloroplast genomics and establishing a framework for resolving the genus’s infrageneric conflicts. Furthermore, it offers critical insights into bryophyte plastome evolution and enables future codon-optimized biotechnological applications. Full article

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

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16 pages, 5035 KB

Open AccessArticle

Phylo-Epigenetic Conservation and CpG Erosion in OCT4, SOX2, and hTERT Intragenic CpG Islands: A Waddingtonian Perspective on Mammalian Developmental Evolution

by Simeon Santourlidis

Genes 2025, 16(9), 1102; https://doi.org/10.3390/genes16091102 - 18 Sep 2025

Viewed by 268

Abstract

Background/Objectives: Developmental biologist Conrad Waddington proposed that evolution is shaped not only by genetic mutations and natural selection but also by environmentally responsive developmental mechanisms. Building on this premise, the epigenetic regulation of three master genes central to mammalian embryogenesis—OCT4, SOX2 [...] Read more.

Background/Objectives: Developmental biologist Conrad Waddington proposed that evolution is shaped not only by genetic mutations and natural selection but also by environmentally responsive developmental mechanisms. Building on this premise, the epigenetic regulation of three master genes central to mammalian embryogenesis—OCT4, SOX2, and hTERT—focusing on their intragenic CpG islands (iCpGIs), which are crucial for transcriptional control and chromatin state modulation, were investigated. Methods: By performing a phylo-epigenetic comparison across 12 primate species, strong conservation of CpG-rich regions, punctuated by lineage-specific CpG transitions, particularly CpG→TpG and CpG→CpA was identified. Results: These mutational patterns align with methylation-dependent deamination mechanisms and highlight iCpGIs as evolutionarily constrained, epigenetically plastic elements. Notably, CpG variation alone recapitulated known primate phylogenies, suggesting that methylation-sensitive sites within iCpGIs encode both developmental and evolutionary information. Conclusions: It is proposed that such sites are prone to Environmentally Determined Epimutations (EDEMs)—methylation-driven, nutrition-sensitive changes that persist across generations and modulate gene regulatory capacity. This integrative framework advances Waddington’s concept of canalization by providing a molecular mechanism through which environmental factors can reshape developmental trajectories and contribute to evolutionary innovation. Full article

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

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48 pages, 557 KB

Open AccessReview

Molecular Signatures of Obesity-Associated Infertility in Polycystic Ovary Syndrome: The Emerging Role of Exosomal microRNAs and Non-Coding RNAs

by Charalampos Voros, Georgios Papadimas, Despoina Mavrogianni, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Dimitrios Vaitsis, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Vasileios Topalis, Marianna Theodora, Nikolaos Thomakos, Fotios Chatzinikolaou, Panagiotis Antsaklis, Dimitrios Loutradis, Evangelos Menenakos and Georgios Daskalakis

Genes 2025, 16(9), 1101; https://doi.org/10.3390/genes16091101 - 17 Sep 2025

Viewed by 328

Abstract

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine and metabolic conditions affecting women of reproductive age. This condition affects around 20% of this demographic and is characterized by polycystic ovarian morphology, hyperandrogenism, and chronic anovulation. Obesity, impacting 40–85% of women [...] Read more.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine and metabolic conditions affecting women of reproductive age. This condition affects around 20% of this demographic and is characterized by polycystic ovarian morphology, hyperandrogenism, and chronic anovulation. Obesity, impacting 40–85% of women with PCOS, exacerbates insulin resistance, increases insulin levels, and intensifies low-grade inflammation. This exacerbates the reproductive and metabolic complications associated with the condition. Recent advancements in molecular biology have underscored the significance of non-coding RNAs, including as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), as crucial regulators of gene expression and prospective biomarkers for PCOS. Exosome-derived microRNAs (ex-miRNAs) have emerged as compelling candidates due to their stability in body fluids and their capacity to promote intercellular communication among adipose tissue, the ovary, and the endometrium. Research, encompassing both experimental and clinical studies, has shown that ex-miRNAs display differing expression levels in women with obesity-related PCOS. Several of these ex-miRNAs are associated with networks that govern inflammation, glucose metabolism, steroidogenesis, and folliculogenesis. Moreover, the encapsulation of these chemicals within exosomes safeguards them from enzymatic breakdown, hence augmenting their potential as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring. Despite the initial results being encouraging, challenges remain in standardising exosome separation, quantifying miRNA, and analyzing functional data within the complex pathophysiology of PCOS. This narrative review consolidates existing evidence regarding the molecular signatures of obesity-related infertility in PCOS, emphasising the growing significance of exosomal miRNAs and other non-coding RNAs, while examining their translational potential for early diagnosis and personalised therapeutic approaches. Full article

(This article belongs to the Section Genetic Diagnosis)

15 pages, 1654 KB

Open AccessArticle

Genetic, Clinical, and Sociodemographic Profile of Individuals with Diagnosis or Family History of Hypertrophic Cardiomyopathy: Insights from a Prospective Cohort

by Emerson de Santana Santos, Gabriel da Costa Kuhn, Antônio Guilherme Cunha de Almeida, João Victor Andrade Pimentel, Newton Vital Figueiredo Neto, Larissa Rebeca da Silva Tavares, Bárbara Letícia Lima dos Santos, Ana Beatriz Leite Aragão, Beatriz Carolina de Araujo Pereira, Caio da Silva Ferreira, Willian Moreira Leão e Silva, Cardiogenetics Research Group of Sergipe, Enaldo Vieira de Melo, Irlaneide da Silva Tavares, Antônio Carlos Sobral Sousa and Joselina Luzia Menezes Oliveira

Genes 2025, 16(9), 1100; https://doi.org/10.3390/genes16091100 - 17 Sep 2025

Viewed by 278

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy in the absence of secondary causes. This study aimed to investigate the genetic, clinical, and epidemiological profile of individuals with clinical HCM or a family history of sudden [...] Read more.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy in the absence of secondary causes. This study aimed to investigate the genetic, clinical, and epidemiological profile of individuals with clinical HCM or a family history of sudden cardiac death (SCD). Methods: A total of 200 participants (58% male, median age 52 years) underwent genetic testing using a 19-gene panel associated with HCM and phenocopies. Variants were classified as pathogenic/likely pathogenic (P/LP), variants of uncertain significance (VUS), or negative. Clinical and imaging data were correlated with genetic findings. Results: P/LP variants were identified in 31% of individuals, while 40.5% carried VUS, and 28.5% tested negative. A positive genotype was more frequent among patients with clinical HCM (37.7%) than among those with only a family history (18.6%, p = 0.006). Sarcomeric mutations represented 77.4% of positive results, while 22.6% involved phenocopy genes, notably TTR (amyloidosis). Positive genotypes were significantly associated with a family history of SCD (68% vs. 46%, p = 0.004) and with greater interventricular septal thickness (17 mm vs. 15 mm, p < 0.001). Conclusions: Septal thickness >17 mm and family history of SCD were strong predictors of positive genetic results. These findings emphasize the importance of genetic screening and counseling in high-risk individuals and highlight the value of integrating genetic testing into clinical practice for diagnosis, risk stratification, and family management. Full article

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

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36 pages, 369 KB

Open AccessArticle

De Novo Variants Predominate in Autism Spectrum Disorder

by Richard G. Boles, Omri Bar, Philip T. Boles, Zoë R. Hill and Richard E. Frye

Genes 2025, 16(9), 1099; https://doi.org/10.3390/genes16091099 - 17 Sep 2025

Viewed by 359

Abstract

Background: Autism spectrum disorder (ASD) is a common condition with substantial personal and financial burdens of lifelong implication. Multiple twin studies have confirmed a genetic or inherited component at ~80%, higher than any other common condition. However, ASD’s rapidly accelerating prevalence, now at [...] Read more.

Background: Autism spectrum disorder (ASD) is a common condition with substantial personal and financial burdens of lifelong implication. Multiple twin studies have confirmed a genetic or inherited component at ~80%, higher than any other common condition. However, ASD’s rapidly accelerating prevalence, now at 1 in 31 in the USA, appears to defy a predominantly genetic basis and implicate our rapidly changing environment. A potential explanation for this paradox is a recent increase in de novo variants (DNVs), which are “new” mutations present in the patient yet absent in both parents. The present authors recently reported using trio whole-genome sequencing (trio-WGS) that DNVs highly likely to be highly disease-associated (“Principal Diagnostic Variants”, PDVs), mostly missense variants, were present in (25/50) 50% of the ASD patients clinically evaluated by our team. Methods: The current study was designed to support this observation with trio-WGS in 100 additional unrelated ASD patients. Results: De novo PDVs were identified in 47/100 (47%) of cases, in close approximation to our previous work. Using non-transcribed (up and downstream) variants for all genes as a control group, these DNV-PDVs were far more likely (p < 0.0001, OR 5.8, 95% C.I. 2.9–11) to be in SFARI-listed genes associated with ASD. Consistent with the emerging polygenic model, using the same analyses, inherited missense variants were also associated with ASD (p < 0.0001). Highly unexpectedly, silent variants, both inherited (p < 0.0001) and de novo (p < 0.007), were also statistically associated with ASD, and, among inherited variants, silent variants were more associated with ASD than were missense variants (p < 0.0001). Adding silent DNVs as PDVs increases the proportion of our subjects with at least one DNV-PDV to 55% of the subjects. Conclusions: Our proposed model for ASD, with prominent DNVs in most that are genetic yet not inherited, predicts the known predominant genetic pathogenesis and the accelerating prevalence of ASD, possibly from environmental factors, including insufficient nutrients and toxicant exposures, and/or the disrupted folate metabolism known to be associated with ASD. Limitations to this study include predominant inclusion of severely affected individuals and the lack of an unaffected control group and functional validation of variant pathogenicity. Full article

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

20 pages, 4850 KB

Open AccessArticle

Neonative Diploid-Polyploid Hotspots of Paspalum notatum: Identifying Novel Genetic Diversity for Conservation in South America

by Lucas M. Escobar, Anna Verena Reutemann, María C. Perichon, Juan S. Schneider, Carolina A. Sartor, Clarisse Chaparro, Julio R. Daviña, José F. M. Valls, Eric J. Martínez and Ana I. Honfi

Genes 2025, 16(9), 1098; https://doi.org/10.3390/genes16091098 - 16 Sep 2025

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Abstract

Background: Bahiagrass (Paspalum notatum), a key cultivated grass worldwide, includes both sexual diploid and apomictic tetraploid cytotypes. Finding new diploid populations is crucial for the species’ genetic improvement and conservation. Objectives: We aimed to determine the ploidy levels of [...] Read more.

Background: Bahiagrass (Paspalum notatum), a key cultivated grass worldwide, includes both sexual diploid and apomictic tetraploid cytotypes. Finding new diploid populations is crucial for the species’ genetic improvement and conservation. Objectives: We aimed to determine the ploidy levels of 168 P. notatum accessions from subtropical South America, analyze the geographic distribution of cytotype diversity, and identify new diploid zones. Methods: Using chromosome counts and flow cytometry, we georeferenced our data with existing literature to map cytotype distribution. Results: We discovered five previously unknown diploid centers in Argentina, Brazil, and Paraguay, two of which resulted from the naturalization of diploid cultivars. One location hosted a mixed-ploidy population (diploid, tetraploid, and pentaploid), confirming ongoing hybridization. Our results show that human activity actively creates new centers of genetic diversity, serving as a dynamic source of raw material for crop resilience. These neonative diversification zones are not only of scientific interest but also vital, evolving hotspots for germplasm conservation. Conclusions: This study presents a new framework for understanding the interactions between crop and wild relatives and highlights the urgent need for conservation in the rapidly changing South American grasslands. Full article

(This article belongs to the Special Issue Plant Genetics, Evolution, Cytogenetics and Cytogenomics for Biodiversity Conservation)

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13 pages, 265 KB

Open AccessArticle

Correlation Analysis of CXCL10, FOS, HOXC13, and WNT4 Gene Polymorphisms with Key Economic Traits—Initial Population Screening for Jiangnan Cashmere Goats

by Gvlnigar Amar, Qingwei Lu, Asma Anwar, Sen Tang, Qingfa Yan, Cuiling Wu and Xuefeng Fu

Genes 2025, 16(9), 1097; https://doi.org/10.3390/genes16091097 - 16 Sep 2025

Viewed by 252

Abstract

Background/Objectives: The Jiangnan cashmere goat is a newly developed national cashmere goat breed in China, and the genetic stability of its traits is the core of breeding work. Methods: This study used 353 Jiangnan cashmere goats as research subjects. Descriptive statistics [...] Read more.

Background/Objectives: The Jiangnan cashmere goat is a newly developed national cashmere goat breed in China, and the genetic stability of its traits is the core of breeding work. Methods: This study used 353 Jiangnan cashmere goats as research subjects. Descriptive statistics were performed on the key economic traits of the experimental population. Polymorphisms in the CXCL10, FOS, HOXC13, and WNT4 genes were detected using multiplex PCR. The correlation between single-nucleotide polymorphism (SNP) loci and key economic traits was analyzed using the least squares variance method in SAS 9.4 software. Results: A total of 14 SNP loci were detected in the four genes, of which 5 were in the CXCL10 gene. Three SNPs were detected in the FOS, HOXC13, and WNT4 genes. SNP3, SNP4, SNP6, SNP10, SNP11, SNP12, SNP13, and SNP14 were in Hardy–Weinberg equilibrium. The results of the correlation analysis showed that SNP9 of the HOXC13 gene was significantly correlated with birth weight (BW) and mean fiber diameter (MFD), SNP10 of the HOXC13 gene was significantly correlated with yearling weight (YW), and SNP14 of the WNT4 gene was significantly correlated with birth weight (BW) (p < 0.05). Conclusions: The results of this study provide molecular markers for cashmere goat breeding and an experimental basis for accelerating the cultivation of new strains, which is conducive to further optimizing the economic traits of the Jiangnan cashmere goat and ensuring the stable inheritance of its economic traits through molecular breeding. Full article

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

32 pages, 1038 KB

Open AccessReview

Precision Medicine for Diabetic Retinopathy: Integrating Genetics, Biomarkers, Lifestyle, and AI

by Connor Kaurich, Neha Mahajan and Ashay D. Bhatwadekar

Genes 2025, 16(9), 1096; https://doi.org/10.3390/genes16091096 - 16 Sep 2025

Viewed by 506

Abstract

Diabetic retinopathy (DR) is a common sight-threatening complication of diabetes. Overall, 26% of the 37 million Americans with diabetes suffer from DR, and 5% of people with diabetes suffer from vision-threatening DR. DR is a heterogeneous disease; thus, it is essential to acknowledge [...] Read more.

Diabetic retinopathy (DR) is a common sight-threatening complication of diabetes. Overall, 26% of the 37 million Americans with diabetes suffer from DR, and 5% of people with diabetes suffer from vision-threatening DR. DR is a heterogeneous disease; thus, it is essential to acknowledge this diversity as we advance toward precision medicine. The current classification for DR primarily focuses on the microvascular component of disease progression, which does not fully capture the heterogeneity of disease etiology in different patients. Further, researchers in the field have suggested renewed interest in improving diagnosis and treatment modalities for personalized care in DR management. Moreover, genetic factors, lifestyle, and environmental variation strongly affect the disease outcome. It is important to emphasize that various ocular and peripheral biomarkers, along with imaging techniques, significantly influence the diagnosis of DR. Therefore, in this review, we explore the heterogeneity of DR, genetic variations or polymorphism, lifestyle and environmental factors, and how these factors may affect the development of precision medicine for DR. First, we provide a rationale for the necessity of a multifaceted understanding of disease etiology. Next, we discuss different aspects of DR diagnosis, emphasizing the need for further stratification of patient populations to facilitate personalized treatment. We then discuss different genetics, race, sex, lifestyle, and environmental factors that could help personalize treatments for DR. Lastly, we summarize the available literature to elaborate how artificial intelligence can enhance diagnostics and disease classification and create personalized treatments, ultimately improving disease outcomes in DR patients who do not respond to first-line care. Full article

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

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16 pages, 2537 KB

Open AccessArticle

Transcriptome of Sterile Testes in dnd-Depleted Atlantic Salmon (Salmo salar L.) Highlights Genes Involved in Gonadal and Brain Development

by Aleksei Krasnov, Sergey Afanasyev, Jens-Erik Dessen, Marianne H. S. Hansen, Marianne Vaadal, Helge Tveiten and Øivind Andersen

Genes 2025, 16(9), 1095; https://doi.org/10.3390/genes16091095 - 16 Sep 2025

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Abstract

Background/Objectives: Inactivation of the dnd gene involved in the development of primordial germ cells (PGCs) leads to the loss of gametes and halts reproductive development. Studies on sterile fish allow for the identification of genes and processes associated with GC differentiation. Methods: Atlantic [...] Read more.

Background/Objectives: Inactivation of the dnd gene involved in the development of primordial germ cells (PGCs) leads to the loss of gametes and halts reproductive development. Studies on sterile fish allow for the identification of genes and processes associated with GC differentiation. Methods: Atlantic salmon with GC-ablated testes were produced by temporal silencing of dnd. Gene expression was analyzed in sterile and fertile testes using 44k microarray and qPCR. Results: In sterile testes, transcripts of several GC markers were detected at low levels, suggesting the presence of cells with a GC-related expression profile that failed to initiate spermatogenesis. Expression of 260 genes was undetectable in the gonads of sterile males and females, and 61.5% of these were also inactivated during first maturation of fertile testes. This group was enriched with genes highly expressed in the brain, including those involved in endocrine and paracrine regulation, synaptic transmission, and numerous genes critical for brain development; among them, 45 genes encoding homeobox proteins. Another group of 229 genes showed increased expression in developing testes and included genes involved in neurosecretion and brain development regulation. GC-ablated testes showed increased expression of reproductive regulators such as amh and sdy and numerous immune genes, suggesting a reprogramming of GC-depleted testes. Temporal silencing of dnd indicated common developmental processes in the brains and gonads of Atlantic salmon testis that become inactive in testes at first maturation. These processes may play roles in PGC homing, the creation of a specific environment required for spermatogenesis, or facilitating communication between the gonads. Full article

(This article belongs to the Special Issue The 15th Anniversary of Genes: Feature Papers in the "Animal Genetics and Genomics" Section)

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12 pages, 2341 KB

Open AccessArticle

Updated Sequence and Annotation of the Broad Host Range Rhizobial Symbiont Sinorhizobium fredii HH103 Genome

by Francisco Fuentes-Romero, Francisco-Javier López-Baena, José-María Vinardell and Sebastián Acosta-Jurado

Genes 2025, 16(9), 1094; https://doi.org/10.3390/genes16091094 - 16 Sep 2025

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Abstract

Background: Sinorhizobium fredii HH103 is a fast-growing rhizobial strain capable of infecting a broad range of legumes, including plants forming determinate and indeterminate nodules, such as Glycine max (its natural host) and Glycyrrhiza uralensis, respectively. Previous studies reported the sequence and [...] Read more.

Background: Sinorhizobium fredii HH103 is a fast-growing rhizobial strain capable of infecting a broad range of legumes, including plants forming determinate and indeterminate nodules, such as Glycine max (its natural host) and Glycyrrhiza uralensis, respectively. Previous studies reported the sequence and annotation of the genome of this strain (7.25 Mb), showing the most complex S. fredii genome sequenced to date. It comprises seven replicons: one chromosome and six plasmids. Among these plasmids, pSfHH103d, also known as the symbiotic plasmid pSymA, harbors most of the genes involved in symbiosis. Due to limitations of the sequencing technology used at the time and the presence of high number of clusters of transposable elements, this plasmid could only be partially assembled as four separated contigs. Methods: In this work, we have used a combination of PacBio and Illumina sequencing technologies to resolve these complex regions, obtaining an updated genome sequence (7.27 Mb). Results: This updated version includes an increase in size of the largest replicons (chromosome, pSfHH103d, and pSfHH103e) and a complete and closed symbiotic plasmid (pSfHH103d or pSymA). Additionally, we carried out a re-annotation of the updated genome, merging the previous annotation and the new one found in the remaining gaps. Notably, we found a high number of transposable elements in the HH103 genome, especially in three plasmids (pSfHH103b, pSfHH103c, and pSymA), a feature that is common among S. fredii strains. Conclusions: The combination of PacBio and Illumina sequencing technologies has allowed us to obtain a complete version of the HH103 pSymA. The presence of a high number of mobile elements seems to be a general characteristic among S. fredii strains, a fact that might be related to a high genome plasticity. Full article

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

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16 pages, 8433 KB

Open AccessArticle

Hi-C Technology Reveals Actionable Gene Fusions and Rearrangements in Diffuse Large B-Cell Lymphoma Unidentified by Conventional FISH

by Sichen Liang, Candice Ament, Melanie Klausner, Victoria Stinnett, Laura Morsberger, Jen Ghabrial, William Middlezong, Anthony D. Schmitt, Alex R. Hastie and Ying S. Zou

Genes 2025, 16(9), 1093; https://doi.org/10.3390/genes16091093 - 16 Sep 2025

Viewed by 339

Abstract

Background/Objectives: Fluorescence in situ hybridization (FISH) is a standard diagnostic tool for detecting gene fusions and rearrangements in lymphomas but is limited by incomplete genomic coverage, dependence on predefined probes, and difficulty identifying atypical or noncanonical fusion partners. These constraints often result in [...] Read more.

Background/Objectives: Fluorescence in situ hybridization (FISH) is a standard diagnostic tool for detecting gene fusions and rearrangements in lymphomas but is limited by incomplete genomic coverage, dependence on predefined probes, and difficulty identifying atypical or noncanonical fusion partners. These constraints often result in inconclusive diagnoses in complex lymphoma cases. This study evaluates a novel Hi-C-based sequencing assay from formalin-fixed paraffin-embedded (FFPE) samples to detect clinically significant gene fusions and rearrangements in cases where conventional FISH was inconclusive or expected biomarkers were not detected. Methods: Five diffuse large B-cell lymphoma cases with previously atypical gene fusions or rearrangements by FISH were analyzed using both standard FISH and a Hi-C-based lymphoma assay. Standard FISH was performed using break-apart probes targeting MYC, BCL2, and BCL6, and dual-fusion probes targeting IGH::MYC and IGH::BCL2. The Hi-C assay utilized high-resolution sequencing of FFPE tissue to map chromatin interactions and identify structural variations across the genome and assessment of their clinical relevance. Results: In this series of five lymphoma cases, Hi-C detected additional structural variants beyond those identified by FISH. It identified typical and atypical translocation partners of key oncogenes (MYC, BCL2, BCL6), cryptic breakpoints, and novel genomic events, including TP53 loss, KMT2A amplification, and complex rearrangements, which were undetectable by FISH. The Hi-C assay’s whole-genome coverage enabled comprehensive profiling. Conclusions: The Hi-C-based lymphoma assay offers a transformative diagnostic tool, overcoming FISH limitations by providing unbiased, high-resolution detection of structural variations. This approach enhances diagnostic accuracy and supports personalized therapeutic strategies in lymphoma management, warranting further validation for clinical adoption. Full article

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

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14 pages, 291 KB

Open AccessArticle

Association Study of the Heat Shock Protein 90 Alpha (HSP90AA1) Gene Polymorphisms with Schizophrenia in a Polish Population

by Malgorzata Kowalczyk, Aleksander J. Owczarek, Krzysztof Kucia, Maja Hasterok, Renata Suchanek-Raif, Monika Paul-Samojedny, Weronika Lakomy and Jan Kowalski

Genes 2025, 16(9), 1092; https://doi.org/10.3390/genes16091092 - 16 Sep 2025

Viewed by 362

Abstract

Background/Objectives: Schizophrenia (SCZ) is a highly heritable mental disorder with a complex polygenic genetic architecture. The heat shock protein 90 alpha (HSP90α), encoded by the HSP90AA1 gene, is a molecular chaperone that is required for the proper folding and activity of many of [...] Read more.

Background/Objectives: Schizophrenia (SCZ) is a highly heritable mental disorder with a complex polygenic genetic architecture. The heat shock protein 90 alpha (HSP90α), encoded by the HSP90AA1 gene, is a molecular chaperone that is required for the proper folding and activity of many of the client proteins that are involved in numerous essential cellular pathways. In addition to its general chaperone activity, HSP90α plays a role in other neuronal contexts and was found to have an altered expression in SCZ, which makes HSP90AA1 an attractive gene for association studies. The aim of this study was to determine whether the HSP90AA1 polymorphisms (rs8005905, rs10873531, rs11621560, rs4947 and rs2298877) are involved in the risk of developing SCZ and its clinical picture in a Polish Caucasian population. Methods: A total of 1088 unrelated subjects (409 patients and 679 healthy controls) were included in the study. The SNPs were genotyped using a TaqMan 5′-exonuclease allelic discrimination assay. The results of the Positive and Negative Syndrome Scale (PANSS) were presented in the five-dimensional model. Results: None of the SNPs were associated with a predisposition to developing SCZ in either the single-marker or haplotype analysis including the results of gender-stratified analyses. However, the genotypes of rs11621560, rs4947 and rs2298877 SNPs were associated with the emotional distress (EMO) dimension score. Conclusions: The results of the present study indicate that HSP90AA1 variants may have an impact on the psychopathology of SCZ, although larger studies are needed to clarify these findings. Full article

(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)

15 pages, 2187 KB

Open AccessArticle

The Phenotype of Physcomitrium patens SMC6 Mutant with Interrupted Hinge Interactions

by Karel J. Angelis, Marcela Holá, Radka Vágnerová, Jitka Vaculíková and Jan J. Paleček

Genes 2025, 16(9), 1091; https://doi.org/10.3390/genes16091091 - 16 Sep 2025

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Abstract

Background/Objectives: The Structural Maintenance of Chromosomes (SMC) proteins form essential heterocomplexes for the preservation of DNA structure and its functions, and hence cell viability. The SMC5/6 dimer is assembled by direct interactions of ATP heads via the kleisin NSE4 bridge and by [...] Read more.

Background/Objectives: The Structural Maintenance of Chromosomes (SMC) proteins form essential heterocomplexes for the preservation of DNA structure and its functions, and hence cell viability. The SMC5/6 dimer is assembled by direct interactions of ATP heads via the kleisin NSE4 bridge and by SMC hinges. The structure might be interrupted by a single point mutation within a conserved motif of the SMC6-hinge. We describe the phenomena associated with the impairment of the SMC5/6 complex with morphology, repair of DNA double strand breaks (DSB), mutagenesis, recombination and gene targeting (GT) in the moss Physcomitrium patens (P. patens). Methods: Using CRISPR/Cas9-directed oligonucleotide replacement, we have introduced two close G to R point mutations in the hinge domain of SMC6 of P. patens and show that both mutations are not toxic and allow viability of mutant lines. Results: The G514R mutation fully prevents the interaction of SMC6 not only with SMC5, but also with NSE5 and NSE6, while the mutation at G517R has no effect. The Ppsmc6_G514R line has aberrant morphology, spontaneous and bleomycin-induced mutagenesis, and maintenance of the number of rDNA copies. The most unique feature is the interference with gene targeting (GT), which is completely abolished. In contrast, the Ppsmc6_G517R line is close to WT in many aspects. Surprisingly, both mutations have no direct effect on the rate of DSB repair in dividing and differentiated cells. Conclusions: Abolished interactions of SMC6 with SMC5 and NSE5,6 partners, which allow DSB repair, but impair other repair and recombination functions, suggests also regulatory role for SMC6. Full article

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

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14 pages, 2882 KB

Open AccessArticle

Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy

by Dovilė Žebrauskienė, Eglė Sadauskienė, Roma Puronaitė, Rūta Masiulienė, Ramunė Vaišnorė, Nomeda Bratčikovienė, Nomeda Valevičienė, Jūratė Barysienė, Audronė Jakaitienė and Eglė Preikšaitienė

Genes 2025, 16(9), 1090; https://doi.org/10.3390/genes16091090 - 16 Sep 2025

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Abstract

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is an inherited disease with genetic and phenotypic variability and an unclear genotype–clinical course relationship. The aim of our study was to assess the phenotypic and molecular characteristics of patients with HCM. Methods: Clinical and genetic data from adult [...] Read more.

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is an inherited disease with genetic and phenotypic variability and an unclear genotype–clinical course relationship. The aim of our study was to assess the phenotypic and molecular characteristics of patients with HCM. Methods: Clinical and genetic data from adult HCM patients treated at a university hospital between 2005 and 2024 were analysed. A comparative analysis of probands with a single pathogenic/likely pathogenic (P/LP) variant and without a P/LP variant was performed. Results: The analysis involved 214 individuals with HCM, 42.1% being females. The median age at HCM diagnosis was 52 (38–62) years. P/LP variants were identified in 92 (43.0%) individuals. Compared to patients without an identified genetic cause, individuals with P/LP variants had a significantly earlier HCM diagnosis (43.5 (32.3–58.0) vs. 54.0 (45.8–65.0) years, p < 0.001) and higher maximal thickness on cardiac imaging (17.5 (15.0–21.0) vs. 17.0 (15.0–19.0) mm, p = 0.009 on transthoracic echocardiography and 21.0 (18.0–23.0) vs. 18.0 (16.0–20.0) mm, p < 0.001 on cardiac magnetic resonance imaging). During the median follow-up of 4.2 (1.6–6.8) years, individuals with P/LP HCM variants had earlier onset of atrial fibrillation (p = 0.021), ventricular tachycardia (p = 0.004), heart failure composite (p = 0.006), and overall composite outcome (p = 0.002). No difference between the groups was observed when hazard ratios for clinical outcomes were adjusted by age at HCM diagnosis and gender. Conclusions: Genotype influences HCM phenotype, as patients with P/LP variants experience earlier onset and more pronounced hypertrophy. However, once diagnosed, genotype may not predict the outcomes of HCM. Full article

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

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