Genes

21 pages, 1677 KB

Open AccessReview

Genetics of Keratoconus: A Comprehensive Review

by Raul Hernan Barcelo-Canton, Darren S. J. Ting and Jodhbir S. Mehta

Genes 2025, 16(10), 1147; https://doi.org/10.3390/genes16101147 (registering DOI) - 27 Sep 2025

Keratoconus (KC) is a progressive, multifactorial corneal ectatic disorder characterized by localized stromal thinning and irregular astigmatism, with incidence and prevalence varying markedly among populations. These differences are influenced by environmental exposures, behavioral factors, and genetic predisposition. A positive family history is a [...] Read more.

Keratoconus (KC) is a progressive, multifactorial corneal ectatic disorder characterized by localized stromal thinning and irregular astigmatism, with incidence and prevalence varying markedly among populations. These differences are influenced by environmental exposures, behavioral factors, and genetic predisposition. A positive family history is a well-established high-risk factor, and KC has also been documented in association with syndromic disorders such as Down syndrome, connective tissue disorders, and certain metabolic diseases. Over the past decades, numerous candidate genes have been investigated, encompassing those involved in extracellular matrix (ECM) assembly, collagen synthesis and cross-linking, oxidative stress defense, wound healing, and transcriptional regulation. Modern genomic approaches, including genome-wide association studies (GWAS), linkage analyses, and next-generation sequencing, have identified multiple loci and variants with potential pathogenic roles. Nonetheless, several genes have also been systematically tested and found to show no association in specific populations, highlighting the genetic variability of KC and the potential influence of population-specific factors. This dual landscape of positive and negative genetic findings underscores the complexity of KC pathogenesis and the necessity for ethnically diverse cohorts. In this review, we synthesize current evidence on genes implicated in KC, integrating confirmed pathogenic variants, associations, and negative findings across diverse populations, to provide a comprehensive overview of the genetic architecture of KC and to outline priorities for future research aimed at improving diagnosis, risk stratification, and therapeutic development. Full article

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

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23 pages, 4673 KB

Open AccessArticle

Integrative Analysis of Biomarkers for Cancer Stem Cells in Bladder Cancer and Their Therapeutic Potential

by Jing Wu and Wei Liu

Genes 2025, 16(10), 1146; https://doi.org/10.3390/genes16101146 (registering DOI) - 27 Sep 2025

Abstract

Background: Cancer stem cells (CSCs) are key drivers of tumorigenesis and metastasis. However, the precise roles of CSC-associated genes in these processes remain unclear. Methods: This study integrates cancer stem cell biomarkers and clinical data from The Cancer Genome Atlas (TCGA) [...] Read more.

Background: Cancer stem cells (CSCs) are key drivers of tumorigenesis and metastasis. However, the precise roles of CSC-associated genes in these processes remain unclear. Methods: This study integrates cancer stem cell biomarkers and clinical data from The Cancer Genome Atlas (TCGA) specific to bladder cancer (BLCA). By combining differentially expressed genes (DEGs) from TCGA-BLCA samples with CSC-related biomarkers, we conducted comprehensive functional analyses and developed an 8-gene prognostic signature through Cox regression, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox regression. This model was validated with GEO datasets (GSE13507 and GSE32894), and the single-cell RNA seq dataset GSE222315 was subsequently analyzed to characterize the signature genes and elucidate their interactions. And a nomogram was created to stratify TCGA-BLCA patients into risk categories. The ‘oncoPredict’ algorithm based on the GDSC2 dataset assessed drug sensitivity in BLCA. Result: From the TCGA cohort, 665 CSC-related genes were identified, with 120 showing significant differential expression. The 8-gene signature (ALDH1A1, CBX7, CSPG4, DCN, FASN, INHBB, MYC, NCAM1) demonstrated strong predictive power for overall survival in both TCGA and GEO cohorts, as confirmed by Kaplan–Meier and ROC analyses. The nomogram, integrating age, tumor stage and risk scores, demonstrated high predictive accuracy. Additionally, the oncoPredict algorithm indicated varying drug sensitivities across patient groups. Based on retrospective data, we identified a novel CSC-related prognostic signature for BLCA. This finding suggests that targeting these genes could offer promising therapeutic strategies. Full article

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

16 pages, 4433 KB

Open AccessArticle

Comparative Analysis of Artemisia Plastomes, with Implications for Revealing Phylogenetic Incongruence and Evidence of Hybridization

by Xinqiang Guo, Yonghe Bai, Jing Ruan, Xin Jin, Shang Wang, Dawei Xue and Yuhuan Wu

Genes 2025, 16(10), 1145; https://doi.org/10.3390/genes16101145 (registering DOI) - 27 Sep 2025

Abstract

Background: With the advancement of the next-generation sequencing technology, it is becoming more cost-effective to obtain plastomes from genome skimming data at shallow sequencing depth. Artemisia is a species-rich genus, comprising species of great medicinal or economic value. However, plastomes of Artemisia [...] Read more.

Background: With the advancement of the next-generation sequencing technology, it is becoming more cost-effective to obtain plastomes from genome skimming data at shallow sequencing depth. Artemisia is a species-rich genus, comprising species of great medicinal or economic value. However, plastomes of Artemisia have not been thoroughly and comparatively analyzed, and the phylogenetic relationships within the genus are still not well resolved. Methods: In this study, 19 Artemisia plastomes were obtained from genome skimming data. Together with the plastomes retrieved from the public database, comparative analyses of their structure were also conducted. We further used sequences of plastomes and nuclear internal transcribed spacer sequences to conduct phylogenetic reconstruction. Results: The Artemisia plastomes are conserved in terms of structure, GC content, gene number, and order. Some regions, i.e., accD, ccsA, ndhE, ycf1, ccsA-ndhD, trnG^GCC-trnfM^CAU, were found to be variable and could be chosen as candidates for the DNA barcode. Phylogenetic analyses also confirmed that the four subgenera of Artemisia are not monophyletic. The incongruence between plastid and nuclear phylogenies indicated that hybridization events have occurred during the evolution of the genus. Conclusions: Reconstructed phylogenies using plastome sequences and nuclear internal transcribed spacers improved our understanding of the phylogenetic backbone of Artemisia. In the future, more taxa of Artemisia should be sequenced and analyzed to clarify the evolutionary history. Full article

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

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35 pages, 1982 KB

Open AccessArticle

In Silico Characterization of Pathogenic ESR2 Coding and UTR Variants as Oncogenic Potential Biomarkers in Hormone-Dependent Cancers

by Hakeemah Al-Nakhle, Zainab Almoerifi, Layan Alharbi, Mashael Alayoubi and Rawan Alharbi

Genes 2025, 16(10), 1144; https://doi.org/10.3390/genes16101144 - 26 Sep 2025

Abstract

Background: The ESR2 gene encodes Estrogen Receptor-β1 (ERβ1), a putative tumor suppressor in hormone-dependent malignancies. Although ERβ biology has been studied extensively at the expression level, the functional impact of nonsynonymous SNPs (nsSNPs) and untranslated-region (UTR) variants in ESR2 remains underexplored. Methods [...] Read more.

Background: The ESR2 gene encodes Estrogen Receptor-β1 (ERβ1), a putative tumor suppressor in hormone-dependent malignancies. Although ERβ biology has been studied extensively at the expression level, the functional impact of nonsynonymous SNPs (nsSNPs) and untranslated-region (UTR) variants in ESR2 remains underexplored. Methods: We retrieved variants from Ensembl and performed an integrative in silico assessment using PredictSNP, I-Mutant, MUpro, HOPE, MutPred2, and CScape for pathogenicity, oncogenicity and structural stability; STRING/KEGG/GO for pathway context; RegulomeDB and polymiRTS for regulatory effects; and cBioPortal for pan-cancer clinical outcomes (breast (BRCA), endometrial (UCEC), and ovarian (OV)). We evaluated effects of nsSNPs on ERβ1 stability, ligand-binding/DNA-binding domains, co-factor recruitment, and post-transcriptional regulation. Results: Across tools, 93 missense nsSNPs were consistently predicted to be deleterious. Notably, several variants were found to destabilize ERβ1, particularly within the ligand-binding domains (LBD) and DNA-binding domains (DBD). Putative oncogenic drivers R198P and D154N showed high CScape scores and very low population frequencies, consistent with pathogenicity. Several substitutions were predicted to impair coactivator binding and disrupt interactions with key transcriptional partners, including JUN, NCOA1, and SP1. At the post-transcriptional level, rs139004885 was predicted to disrupt miRNA binding, while 3′UTR rs4986938 showed strong regulatory potential and comparatively high population frequency; by contrast, most other identified SNPs were rare. Clinically, pan-cancer survival analyses indicated worse overall survival (OS) in BRCA for ESR2-Altered cases (HR ≈ 2.25; q < 0.001), but better OS in UCEC (HR ≈ 0.24; q ≈ 0.014) and OV (HR ≈ 0.29; q < 0.001), highlighting a tumor-type-specific association. Conclusions: This integrative analysis prioritizes high-impact ESR2 variants that likely impair ERβ1 structure and shows context-dependent clinical effects. Despite their generally low frequency (except for rs4986938), prospective validation linking variant class to ERβ expression and survival outcomes is needed to support biomarker development and therapeutic applications. Full article

(This article belongs to the Special Issue Genetic Biomarkers in Cancer: From Discovery to Clinical Application)

20 pages, 7315 KB

Open AccessArticle

GhTGA2, a Potential Key Regulator of Salt Stress Response: Insights from Genome-Wide Identification of TGA Family Genes Across Ten Cotton Species

by Lu Meng, Jiliang Fan, Shandang Shi, Faren Zhu, Ganggang Zhang, Junwei Wang, Zihan Li, Fei Wang and Hongbin Li

Genes 2025, 16(10), 1143; https://doi.org/10.3390/genes16101143 - 26 Sep 2025

Abstract

Background: The TGACG-BINDING FACTORS (TGA) gene family, a key subgroup of bZIP transcription factors, mediates plant stress responses and developmental processes by binding to the as-1 cis-element in target gene promoters to regulate transcriptional activation or repression. Despite its functional significance, systematic [...] Read more.

Background: The TGACG-BINDING FACTORS (TGA) gene family, a key subgroup of bZIP transcription factors, mediates plant stress responses and developmental processes by binding to the as-1 cis-element in target gene promoters to regulate transcriptional activation or repression. Despite its functional significance, systematic characterization of TGA genes in cotton (Gossypium spp.) remains insufficient. Methods: In this study, we performed a comprehensive genome-wide identification and phylogenetic analysis of TGA members across 10 Gossypium species and verified the functions of candidate genes using VIGS technology. Results: A total of 74 TGA homologous genes with conserved DOG1 and bZIP domains were identified. Evolutionary analysis revealed that the cotton TGA gene family can be classified into five distinct branches, suggesting functional diversification. Functional prediction analyses indicated these genes in cotton growth regulation and stress adaptation, potentially through hormone-mediated signaling pathways. Expression profiling demonstrated both tissue-specific expression patterns and salt-stress responsiveness in Gossypium hirsutum TGA genes, and GhTGA2 exhibited the most significant up-regulated expression under salt stress. Virus-induced gene silencing (VIGS)-mediated GhTGA2 silencing significantly reduced the salt tolerance in cotton. Conclusions: The TGA gene family is involved in regulating cotton growth, development, and stress responses, and plays a critical role in mediating salt stress tolerance in cotton. Our results provide mechanistic insights into cotton stress adaptation and establish a valuable genetic resource for developing elite salt-tolerant cotton cultivars, with direct implications for sustainable cotton production. Full article

(This article belongs to the Special Issue Molecular Genetics of Stress Response in Crops)

15 pages, 571 KB

Open AccessArticle

Plastid RNA Editing in Glycyrrhiza uralensis: Landscape Characterization and Comparative Assessment of RNA-Seq Library Strategies for Detection

by Hui Ma, Yixuan Rao, Yinxiao Lu, Na Fang, Yijia Huang and Lei Gong

Genes 2025, 16(10), 1142; https://doi.org/10.3390/genes16101142 - 26 Sep 2025

Abstract

Background: Plastid RNA editing is widespread in angiosperms yet remains underexplored in the medicinal non-model species Glycyrrhiza uralensis. This study aimed to (i) comprehensively identify plastid RNA editing sites in G. uralensis, and (ii) compare the detection performance of three library [...] Read more.

Background: Plastid RNA editing is widespread in angiosperms yet remains underexplored in the medicinal non-model species Glycyrrhiza uralensis. This study aimed to (i) comprehensively identify plastid RNA editing sites in G. uralensis, and (ii) compare the detection performance of three library construction strategies: total RNA-seq, rRNA-depleted RNA-seq, and mRNA-seq. Methods: Leaf tissue was used from three wild-sampled individual plants. Plastomes were assembled with GetOrganelle v1.7.0 and annotated using PGA. Strand-specific RNA-seq libraries were mapped to sample-matched plastomes using HISAT2 v2.2.1. Variants were identified using REDItools v2.0 under uniform thresholds. Candidate sites were visually verified in IGV v2.12.3, and read origins were confirmed by BLAST v2.13.0+; artifacts were removed via strand-specific filtering. Results: After stringent filtering, 38 high-confidence RNA editing sites were identified across 19 genes. Total RNA seq performed the best, detecting 37/38 sites consistently, whereas rRNA-depleted libraries detected fewer genuine sites and produced numerous rRNA-linked, noncanonical, noncoding-strand-dominant artifacts. Despite very low rates of plastid mapping, mRNA seq recovered a large fraction of bona fide sites under stringent, strand-aware filtering. Conclusions: We establish a set of 38 high-confidence plastid RNA editing sites in G. uralensis and suggest potential adaptive implications of editing in ndh-related genes. Methodologically, total RNA-seq is recommended for identification using de novo RNA editing due to its high sensitivity and low false-positive rate; publicly available poly(A)-selected mRNA-seq datasets can be repurposed to reliably retrieve plastid RNA editing sites when stringent strand-specific filtering is applied. Full article

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

15 pages, 944 KB

Open AccessArticle

Disentangling the Effects of Suicide Attempts and Psychiatric Diagnosis Based on a Genotype-Informed Dynamic Model of the Serotonin Presynapse

by Lana Radenković, Maja Pantović-Stefanović, Goran Brajušković, Maja Ivković, Dušanka Savić-Pavićević and Jovan Pešović

Genes 2025, 16(10), 1141; https://doi.org/10.3390/genes16101141 - 26 Sep 2025

Abstract

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying [...] Read more.

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying psychiatric diagnosis. This study used a genotype-informed dynamic model of the 5-HT presynapse to disentangle the effects of suicide attempts and psychiatric diagnosis. Methods: We applied a personalized dynamic model of the 5-HT presynapse to 392 psychiatric patients (with BD, MDD, or SCH), categorized by suicide attempt status, and 140 unaffected individuals. The model incorporated five variants across TPH2, SLC6A4, and MAOA genes simulating individual-specific concentration changes of five 5-HT-related molecular species. Model outputs were summarized by six statistical measures (mean, median, maximum, standard deviation, skewness, and kurtosis) and compared across groups. Results: No significant differences were found across groups defined by suicide attempt status and unaffected individuals. However, diagnosis significantly influenced 5-hydroxyindoleacetic acid (5-HIAA) mean, median, maximum, and standard deviation (all p < 0.05). BD patients had lower 5-HIAA levels than SCH patients (mean: p = 0.013; median: p = 0.013; maximum: p = 0.014; standard deviation: p = 0.014). MDD patients also showed lower 5-HIAA levels than SCH patients for the same measures, with differences approaching significance. No significant difference was observed between BD and MDD patients. A diagnosis-by-suicide attempt status interaction was observed for 5-HIAA skewness (p = 0.013). Conclusions: Model-derived 5-HT profiles were shaped primarily by diagnosis, while temporal dynamics of 5-HIAA, rather than its absolute levels, was associated with suicide attempt status. Thus, personalized dynamic modeling incorporating genetic variants may aid in detecting subtle molecular signatures across diagnoses and suicidal behavior. Full article

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

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28 pages, 18004 KB

Open AccessArticle

Spotlight on FAM72B: Pan-Cancer Expression Profiles and Its Potential as a Prognostic and Immunotherapeutic Biomarker

by Anran Chu and Yuchan Wang

Genes 2025, 16(10), 1140; https://doi.org/10.3390/genes16101140 - 26 Sep 2025

Abstract

Background/Objectives: FAM72B (Family with sequence similarity 72 member B) is a gene whose function is not yet fully elucidated and which belongs to the FAM72 gene family. Recent studies have indicated that it is involved in the regulation of stem cell proliferation [...] Read more.

Background/Objectives: FAM72B (Family with sequence similarity 72 member B) is a gene whose function is not yet fully elucidated and which belongs to the FAM72 gene family. Recent studies have indicated that it is involved in the regulation of stem cell proliferation and DNA repair and serves as a valuable prognostic biomarker for a few types of cancer. This study aimed to systematically investigate the expression profile of FAM72B in pan-cancer, its role in the tumor immune microenvironment, and its potential as a prognostic and immunotherapeutic biomarker. Methods: Using bioinformatics tools such as SangerBox3.0, GEPIA2.0, Kaplan–Meier Plotter, and cBioPortal, we systematically analyzed the correlation of FAM72B expression levels with various cancer types, clinical pathological parameters, prognostic value, genetic mutations, genomic heterogeneity, immune checkpoint genes, immune cell infiltration levels, and single-cell-level characteristics. Results:FAM72B was found to be overexpressed in most cancers and significantly associated with poor prognosis, although it may exert a protective effect in some cancers like thymoma (THYM). Its expression level was positively correlated with tumor mutation burden (TMB), microsatellite instability (MSI), neoantigen (NEO) levels, and expression of immune checkpoint genes in most cancers, suggesting that patients with high FAM72B expression may respond better to immune checkpoint inhibitors. Moreover, FAM72B expression was significantly correlated with the infiltration levels of various immune cells in the tumor immune microenvironment across pan-cancer. Single-cell sequencing results also demonstrated a significant correlation between FAM72B and the biological functional states of multiple cancers. Conclusions:FAM72B holds promise as a potential pan-cancer prognostic biomarker and therapeutic target, providing a novel basis for the development of personalized treatment strategies. Full article

(This article belongs to the Section Bioinformatics)

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20 pages, 9291 KB

Open AccessArticle

Atad1 Is a Potential Candidate Gene for Prepulse Inhibition

by Akhilesh K. Bajpai, Timothy G. Freels, Lu Lu and Melloni N. Cook

Genes 2025, 16(10), 1139; https://doi.org/10.3390/genes16101139 - 26 Sep 2025

Abstract

Background/Objectives: Prepulse inhibition (PPI) is a robust, reproducible phenotype associated with schizophrenia and other psychiatric disorders. This study was carried out to identify gene(s) influencing PPI. Methods: We performed Quantitative Trait Locus (QTL) analysis of PPI in 59 strains from [...] Read more.

Background/Objectives: Prepulse inhibition (PPI) is a robust, reproducible phenotype associated with schizophrenia and other psychiatric disorders. This study was carried out to identify gene(s) influencing PPI. Methods: We performed Quantitative Trait Locus (QTL) analysis of PPI in 59 strains from the BXD recombinant inbred (BXD RI) mouse family and used a 2-LOD region for candidate gene identification. Genes significantly correlated with the candidate gene were identified based on genetic, partial, and literature correlation, and were further studied through gene enrichment and protein–protein interaction analyses. Phenome-wide association study (PheWAS) and differential expression analyses of the candidate gene were performed using human data. Results: We identified one significant (GN Trait 11428) and two suggestive male-specific QTLs (GN Traits 11426 and 11427) on Chromosome 19 between 27 and 36 Mb with peak LRS values of 19.2 (−logP = 4.2), 14.4 (−logP = 3.1), and 13.3 (−logP = 2.9), respectively. Atad1, ATPase family, AAA domain containing 1 was identified as the strongest candidate for the male-specific PPI loci. Atad1 expression in BXDs is strongly cis-modulated in the nucleus accumbens (NAc, LRS = 26.5 (−logP = 5.7). Many of the Atad1-correlated genes in the NAc were enriched in neurotransmission-related categories. Protein–protein interaction analysis suggested that ATAD1 functions through its direct partners, GRIA2 and ASNA1. PheWAS revealed significant associations between Atad1 and psychiatric traits, including schizophrenia. Analysis of a human RNA-seq dataset revealed differential expression of Atad1 between schizophrenia patients and the control group. Conclusions: Collectively, our analyses support Atad1 as a potential candidate gene for PPI and suggest that this gene should be further investigated for its involvement in psychiatric disorders. Full article

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

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19 pages, 1566 KB

Open AccessArticle

Genetic Diversity of Fresh Maize Germplasm Revealed by Morphological Traits and SSR Markers

by Suying Guo, Xin Zheng, Shuaiyi Wang, Yuran Ai, Rengui Zhao and Jinhao Lan

Genes 2025, 16(10), 1138; https://doi.org/10.3390/genes16101138 - 25 Sep 2025

Abstract

Background: This study aims to systematically evaluate the genetic divergence among 200 fresh maize inbred lines using both phenotypic and molecular markers, and to compare the efficacy of these two approaches for genetic classification. Methods: Phenotypic clustering analysis was conducted based on eight [...] Read more.

Background: This study aims to systematically evaluate the genetic divergence among 200 fresh maize inbred lines using both phenotypic and molecular markers, and to compare the efficacy of these two approaches for genetic classification. Methods: Phenotypic clustering analysis was conducted based on eight key agronomic traits, including plant height and ear length. Additionally, molecular analysis was performed using 40 Simple Sequence Repeat (SSR) primer pairs, resulting in the generation of 230 polymorphic alleles. The polymorphism information content (PIC) was calculated to evaluate the discriminatory power of the markers. Results: Phenotypic analysis categorized the inbred lines into four groups, comprising 25, 38, 97, and 40 lines, respectively, with benchmark lines distributed across Groups I and III. SSR analysis revealed a high level of genetic diversity, with an average of 5.75 alleles per locus and a mean polymorphic information content (PIC) of 0.70. Molecular grouping further divided the population into four distinct clusters, representing 26.5%, 51.0%, 14.0%, and 8.5% of the total, which exhibited different distribution patterns compared to the phenotypic grouping. The distribution of benchmark lines across various molecular groups confirmed their genetic divergence. Conclusions: SSR-based clustering demonstrated superior robustness and reliability compared to phenotypic grouping for genetic discrimination. These findings confirm the substantial genetic diversity present in fresh maize inbred lines and support the preferential use of SSR markers in maize breeding programs for precise genetic characterization. Full article

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

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13 pages, 670 KB

Open AccessReview

Characteristic Gene Alterations During Fatty Acid Metabolism in the Goose Liver

by Anna Koseniuk

Genes 2025, 16(10), 1137; https://doi.org/10.3390/genes16101137 - 25 Sep 2025

Abstract

The development of hepatic steatosis in geese is a complex, multistage process involving genes related to lipid synthesis, transport, storage, and metabolism. Key genes activated during this process include ME1 (malic enzyme 1), SCD1 (stearoyl-CoA desaturase), ACSL1 (acyl-CoA synthetase long-chain family member 1), [...] Read more.

The development of hepatic steatosis in geese is a complex, multistage process involving genes related to lipid synthesis, transport, storage, and metabolism. Key genes activated during this process include ME1 (malic enzyme 1), SCD1 (stearoyl-CoA desaturase), ACSL1 (acyl-CoA synthetase long-chain family member 1), and ELOVL6 (elongation of very-long-chain fatty acids protein 6). The expression of these genes varies depending on the tissue, breed, and metabolic context. Geese possess a unique ability to develop hepatic steatosis (fatty liver) without accompanying inflammation or liver damage. This condition typically arises from overfeeding, either through carbohydrates or fats, leading to significant triglyceride accumulation in hepatocytes. Importantly, this state remains reversible and is considered non-pathological. The physiological and molecular changes observed in overfed geese, particularly regarding liver lipid accumulation and serum enzyme activity, closely resemble those found in human non-alcoholic fatty liver disease (NAFLD). This similarity makes geese an excellent biomedical model for studying NAFLD. Overfeeding initiates a cascade of enzymatic reactions that regulate lipid metabolism at the genetic level. These reactions decrease circulating free fatty acids and glucose while promoting triglyceride storage in the liver. The aim of this study is to synthesize current knowledge on the genetic regulation of fatty acid metabolism in geese, highlighting how these genes coordinate the processes of activation, desaturation, synthesis, and elongation during induced steatosis. Moreover, the summarized effects of different diet supplements will enhance goose feeding strategies for foie gras production. Full article

(This article belongs to the Special Issue Genetic Breeding of Poultry)

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17 pages, 7498 KB

Open AccessReview

A Recipe to Evolve Complex Life Chemically on Earth

by Lei Lei and Zachary Frome Burton

Genes 2025, 16(10), 1136; https://doi.org/10.3390/genes16101136 - 25 Sep 2025

Abstract

Sequences of tRNAs are highly patterned in easily identifiable RNA repeats and RNA inverted repeats (stem–loop–stems). Because of patterning, the multi-step evolution of tRNA can be described in remarkable detail. To evolve life on Earth or another planet or the moon requires the [...] Read more.

Sequences of tRNAs are highly patterned in easily identifiable RNA repeats and RNA inverted repeats (stem–loop–stems). Because of patterning, the multi-step evolution of tRNA can be described in remarkable detail. To evolve life on Earth or another planet or the moon requires the evolution of tRNA or a tRNA-like molecule to act as a genetic adapter. To replace tRNA with an alternate or improved genetic adapter is a remarkably challenging problem, indicating strong chemical selection of tRNA precursors in pre-life. The genetic code, translation systems, and first proteins coevolved with tRNAomes (all of the tRNAs of an organism). Because the tRNA sequence can be separated into component parts, a simple pathway for chemical evolution of life and genetic coding can be described in sufficient detail to allow the assembly of a living entity in laboratories. Full article

(This article belongs to the Special Issue Roles of RNAs in Biology)

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12 pages, 714 KB

Open AccessReview

MicroRNA-Induced Regulation of the IGF-1 System in Various Types of Cancer

by George Triantafyllou, Mary Kategianni, Maria Maridaki, Michael Koutsilieris and Anastassios Philippou

Genes 2025, 16(10), 1135; https://doi.org/10.3390/genes16101135 - 25 Sep 2025

Abstract

Insulin-like growth factor 1 (IGF-1) is an important endocrine and autocrine/paracrine factor that regulates various cellular responses in multiple biological systems. Its actions are mediated mainly via its binding to the type 1 IGF receptor (IGF-1R), while its bioactivity is also modulated by [...] Read more.

Insulin-like growth factor 1 (IGF-1) is an important endocrine and autocrine/paracrine factor that regulates various cellular responses in multiple biological systems. Its actions are mediated mainly via its binding to the type 1 IGF receptor (IGF-1R), while its bioactivity is also modulated by the IGF-binding proteins (IGFBPs). The IGF-1 system regulates cell growth, differentiation and energy metabolism and thus plays a crucial role in the modulation of key aspects of cancer biology, such as cancer cell growth, survival, transformation and invasion. The synthesis of IGF-1 is regulated, among other factors, by microRNAs (miRNAs), and it has been shown that the miRNA-induced regulation of IGF-1 is implicated in various stages of tumor development and/or progression in different types of cancer. The aim of this review was to identify and characterize the miRNA-induced regulation of the IGF-1 system in various types of cancer. It was revealed that many miRNAs can be used as potential biomarkers, while others may contribute to metastasis regulation, targeting components of the IGF-1 bioregulation system and being implicated in cancer staging and/or progression. Additional miRNAs and their role in IGF-1’s effects on other types of cancer have also been identified. Nevertheless, future studies are needed to expand the current knowledge on the role of miRNAs in the regulation of other components of the IGF-1 bioregulation system and in various types of cancer, contributing further to the characterization of the role of miRNAs and their target genes as pathogenic, therapeutic and diagnostic molecules for cancer in clinical practice. Full article

(This article belongs to the Special Issue Function and Regulatory Mechanism of MicroRNAs in Cancers)

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15 pages, 3846 KB

Open AccessArticle

Integrative Multi-Omics Characterization and Structural Insights into the Poorly Annotated Integrin ITGA6 X1X2 Isoform in Mammals

by Ximena Aixa Castro Naser, Alessandro Cestaro, Silvio C. E. Tosatto and Emanuela Leonardi

Genes 2025, 16(10), 1134; https://doi.org/10.3390/genes16101134 - 25 Sep 2025

Abstract

Background: Accurate annotation of gene isoforms remains one of the major obstacles in translating genomic data into meaningful biological insight. Laminin-binding integrins, particularly integrin α6 (ITGA6), exemplify this challenge through their complex splicing patterns. The rare ITGA6 X1X2 isoform, generated by the [...] Read more.

Background: Accurate annotation of gene isoforms remains one of the major obstacles in translating genomic data into meaningful biological insight. Laminin-binding integrins, particularly integrin α6 (ITGA6), exemplify this challenge through their complex splicing patterns. The rare ITGA6 X1X2 isoform, generated by the alternative inclusion of exons X1 and X2 within the β-propeller domain, has remained poorly characterized despite decades of integrin research. Methods: We combined comparative genomics across primates with targeted re-alignment to assess exon conservation and annotation fidelity; analyzed RNA-seq for exon-level usage; applied splice-site prediction to evaluate inclusion potential; surveyed cancer mutation resources for exon-specific variants; and used structural/disorder modeling to infer effects on the β-propeller. Results: Exon X2 is conserved at the genomic level but inconsistently annotated, reflecting the limitations of current annotation pipelines rather than genuine evolutionary loss. RNA-seq analyses reveal low but detectable expression of X2, consistent with weak splice site predictions that suggest strict regulatory control and condition-specific expression. Despite its rarity, recurrent mutations in exon X2 are reported in cancer datasets, implying possible roles in disease. Structural modeling further indicates that X2 contributes to a flexible, disordered region within the β-propeller domain, potentially influencing laminin binding or β-subunit dimerization. Conclusions: Altogether, our results suggest that ITGA6 X1X2 could be a rare, tightly regulated isoform with potential functional and pathological relevance. Full article

(This article belongs to the Section Bioinformatics)

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14 pages, 1716 KB

Open AccessArticle

Dna2 Responds to Endogenous and Exogenous Replication Stress in Drosophila melanogaster

by Ivan Rivera, Sabah Shammari, Hamiya Sohail, Christian Villegas, Zoha Wasim, Sze Hang Ip, Vada Becker, Kathryn P. Kohl, Eric P. Stoffregen, Christina I. Swanson and Elyse Bolterstein

Genes 2025, 16(10), 1133; https://doi.org/10.3390/genes16101133 - 25 Sep 2025

Abstract

Background/Objectives: DNA2 is a conserved nuclease–helicase that plays a crucial role in DNA replication and repair by responding to replication stress. Previous studies have established the role of DNA2 in Okazaki fragment processing, the recovery of stalled replication forks, and double-strand break [...] Read more.

Background/Objectives: DNA2 is a conserved nuclease–helicase that plays a crucial role in DNA replication and repair by responding to replication stress. Previous studies have established the role of DNA2 in Okazaki fragment processing, the recovery of stalled replication forks, and double-strand break repair. This study investigates the role of Drosophila melanogaster Dna2 in response to exogenous DNA damage and replication stress as well as during developmental stages involving intensive DNA replication. Methods: We used the Drosophila mutant alleles, Dna2^D1 and Dna2^D2, which differ in the presence of the helicase 1A domain, to assess sensitivity to mutagens that cause various types of replication stress and DNA damage. We examined reproductive fitness through Mendelian ratio calculations, fecundity, egg viability assays, and assessed DNA damage via immunostaining of ovarian germaria. Lifespan assays were also conducted to examine adult survival. Results: Dna2 mutants demonstrated significant sensitivity to replication stress induced by MMS, hydroxyurea, topotecan, and nitrogen mustard. Dna2^lS/S1 mutants exhibited higher survival than Dna2^lS/D2 upon exposure to topotecan and bleomycin, suggesting a possible helicase-specific role in damage response. Mutants exhibited decreased fecundity, reduced egg viability, and elevated DNA damage in mitotically active germline cells. Adult lifespan was not reduced in Dna2 mutants, implying potential compensatory stress-response mechanisms. Conclusions: Our findings support a requirement of Dna2 in managing replication stress during critical developmental phases in Drosophila. These insights clarify the nuanced contributions of the nuclease and helicase domains of DNA2, suggesting potential domain-specific functions in genomic stability and repair mechanisms. This work provides a foundation that will enable future researchers to further dissect the complex roles of DNA2 in replication and repair pathways. Full article

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

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12 pages, 1678 KB

Open AccessArticle

Development and Application of an SNP Marker for High-Throughput Detection and Utilization of the badh2 Gene in Rice Breeding

by Hao Fang, Huifang Huang, Lan Yu, Linyou Wang, Jue Lou and Yongbin Qi

Genes 2025, 16(10), 1132; https://doi.org/10.3390/genes16101132 - 25 Sep 2025

Abstract

Background: As a key rice breeding resource, aromatic rice is widely cultivated in agriculture due to its unique aroma. Badh2 mutations cause function loss, enabling rice’s characteristic aroma. Methods: In this study, we analyzed several badh2 mutation types across 8 japonica and [...] Read more.

Background: As a key rice breeding resource, aromatic rice is widely cultivated in agriculture due to its unique aroma. Badh2 mutations cause function loss, enabling rice’s characteristic aroma. Methods: In this study, we analyzed several badh2 mutation types across 8 japonica and 16 indica aromatic rice lines. Based on the 7 bp deletion in badh2-E2 identified in japonica aromatic lines, we developed a multiplex-ready PCR assay for badh2 genotyping. Additionally, leveraging the deletion mutation in badh2-E7 from the indica aromatic line Yexiang, we designed a KASP marker. Results: All 8 japonica aromatic lines carried a 7 bp deletion in badh2-E2, while 12 indica aromatic lines harbored an 8 bp deletion in badh2-E7, and 4 additional indica aromatic lines exhibited an 8 bp deletion in badh2-E2. The multiplex-ready PCR assay was used to screen 200 individual plants from the aromatic rice line Jia 58: 199 plants showed the expected results, while the remaining 1 exhibited two fluorescent signal peaks—suggesting that it may be a heterozygous individual. Using the KASP marker, we performed genotyping analysis on F₇ progeny individuals derived from the cross between Yexiang (aromatic line) and Yuenongsimiao (non-aromatic line). Combined with phenotypic observations, we successfully screened out an elite aromatic line named Zhexiangzhenhe, which not only possesses aroma but also maintains superior agronomic traits. Conclusions: The multiplex-ready PCR assay and KASP markers facilitate high-throughput genotyping in large-scale breeding populations, providing breeders with a rapid and efficient selection tool to accelerate aromatic trait improvement in rice. Full article

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

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15 pages, 746 KB

Open AccessArticle

Exploring Genetic Heterogeneity in Type 2 Diabetes Subtypes

by Yanina Timasheva, Olga Kochetova, Zhanna Balkhiyarova, Diana Avzaletdinova, Gulnaz Korytina, Tatiana Kochetova and Arie Nouwen

Genes 2025, 16(10), 1131; https://doi.org/10.3390/genes16101131 - 25 Sep 2025

Abstract

Background/Objectives: Type 2 diabetes (T2D) is a clinically and genetically heterogeneous disease. In this study, we aimed to stratify patients with T2D from the Volga-Ural region of Eurasia into distinct subgroups based on clinical characteristics and to investigate the genetic underpinnings of [...] Read more.

Background/Objectives: Type 2 diabetes (T2D) is a clinically and genetically heterogeneous disease. In this study, we aimed to stratify patients with T2D from the Volga-Ural region of Eurasia into distinct subgroups based on clinical characteristics and to investigate the genetic underpinnings of these clusters. Methods: A total of 254 Tatar individuals with T2D and 361 ethnically matched controls were recruited. Clinical clustering was performed using k-means and hierarchical algorithms on five variables: age at diagnosis, body mass index (BMI), glycated hemoglobin (HbA1c), insulin resistance (HOMA-IR), and β-cell function (HOMA-B). Genetic association analysis was conducted using logistic regression under an additive model, adjusted for age and sex, and corrected for multiple comparisons using the Benjamini–Hochberg method. Results: Four distinct T2D subtypes were identified—mild age-related diabetes (MARD, n = 25), mild obesity-related diabetes (MOD, n = 72), severe insulin-resistant diabetes (SIRD, n = 66), and severe insulin-deficient diabetes (SIDD, n = 52)—each with unique clinical and comorbidity profiles. SIDD patients exhibited the highest burden of microvascular complications and lowest estimated glomerular filtration rate. Nine genetic variants showed significant associations with T2D and/or specific subtypes, including loci in genes related to neurotransmission (e.g., HTR1B, CHRM5), appetite regulation (NPY2R), insulin signaling (TCF7L2, PTEN), and other metabolic pathways. Some variants demonstrated subtype-specific associations, underscoring the genetic heterogeneity of T2D. Conclusions: Our findings support the utility of clinical clustering in uncovering biologically and clinically meaningful T2D subtypes and reveal genetic variants that may contribute to this heterogeneity. These insights may inform future precision medicine approaches for T2D diagnosis and management. Full article

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

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31 pages, 1382 KB

Open AccessReview

Clinical Actionability of Genes in Gastrointestinal Tumors

by Nadia Saoudi Gonzalez, Giorgio Patelli and Giovanni Crisafulli

Genes 2025, 16(10), 1130; https://doi.org/10.3390/genes16101130 - 25 Sep 2025

Abstract

Precision oncology is witnessing an increasing number of molecular targets fueled by the continuous improvement of cancer genomics and drug development. Tumor genomic profiling is nowadays (August 2025) part of routine cancer patient care, guiding therapeutic decisions day by day. Nevertheless, implementing and [...] Read more.

Precision oncology is witnessing an increasing number of molecular targets fueled by the continuous improvement of cancer genomics and drug development. Tumor genomic profiling is nowadays (August 2025) part of routine cancer patient care, guiding therapeutic decisions day by day. Nevertheless, implementing and distilling the increasing number of potential gene targets and possible precision drugs into therapeutically relevant actions is a challenge. The availability of prescreening programs for clinical trials has expanded the description of the genomic landscape of gastrointestinal tumors. The selection of the genomic test to use in each clinical situation, the correct interpretation of the results, and ensuring clinically meaningful implications in the context of diverse geographical drug accessibility, economic cost, and access to clinical trials are daily challenges of personalized medicine. In this context, well-established negative predictive biomarkers, such as extended RAS extended mutations for anti-EGFR therapy in colorectal cancer, and positive predictive biomarkers, such as MSI status, BRAF p.V600E hotspot mutation, ERBB2 amplification, or even NTRK1, NTRK2, NTRK3, RET, and NRG1 fusions across gastrointestinal cancers, are mandatory to provide tailored clinical care, improve patient selection for treatment and clinical trials, maximize therapeutic benefit, and minimize unnecessary toxicity. In this review, we provide an updated overview of actionable genomic alterations in GI cancers and discuss their implications for clinical decision making. Full article

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

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12 pages, 349 KB

Open AccessReview

Drug-Induced Epigenetic Alterations: A Set of Forensic Toxicological Fingerprints?

by Simone Grassi, Andrea Costantino, Alexandra Dimitrova, Emma Beatrice Croce, Francesca Iasi, Alessandra Puggioni, Francesco De Micco and Fabio Vaiano

Genes 2025, 16(10), 1129; https://doi.org/10.3390/genes16101129 - 25 Sep 2025

Abstract

Background/Objectives: Epigenetics refers to heritable modifications in gene expression that do not involve changes to the DNA sequence. Among these, DNA methylation, histone modifications, and non-coding RNAs play a key role in regulating gene activity and are influenced by environmental factors, including exposure [...] Read more.

Background/Objectives: Epigenetics refers to heritable modifications in gene expression that do not involve changes to the DNA sequence. Among these, DNA methylation, histone modifications, and non-coding RNAs play a key role in regulating gene activity and are influenced by environmental factors, including exposure to psychoactive substances. In recent years, it has been hypothesized that such alterations may serve as molecular markers with forensic relevance. This systematic review aims to evaluate whether current evidence supports the use of drug-induced epigenetic changes as potential toxicological fingerprints in human subjects. Methods: A systematic literature search was conducted following PRISMA guidelines, including articles published on PubMed between 1 January, 2010, and 31 December, 2025. Only studies conducted on human samples and published in English were considered; animal studies and articles lacking epigenetic data were excluded. Results: Forty-two studies met the inclusion criteria. The most commonly investigated substances (alcohol, cocaine, methamphetamine, cannabis, and opioids) were found to induce specific and, in some cases, persistent epigenetic changes. These include alterations in CpG methylation in promoter regions, variations in miRNA expression, and modulation of epigenetic enzymes. Such changes were observed in brain tissue, blood cells, and semen, with evidence of persistence even after drug cessation. Conclusions: Current evidence confirms that psychoactive substance use is associated with specific epigenetic modifications. However, forensic application remains limited due to confounding factors such as age, co-exposures, and post-mortem interval. Further standardized research is necessary to validate their use as forensic biomarkers. Full article

(This article belongs to the Special Issue Novel Insights into Forensic Genetics)

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16 pages, 459 KB

Open AccessArticle

Associations Between Polygenic Risk for Alzheimer’s Disease and Grey Matter Volume Are Dependent on APOE, Pathological and Diagnostic Status

by Valerio Nocella, Riccardo Manca and Annalena Venneri

Genes 2025, 16(10), 1128; https://doi.org/10.3390/genes16101128 - 25 Sep 2025

Abstract

Background/Objectives: Studies have shown that higher polygenic risk scores (PRSs) for Alzheimer’s disease (AD) are associated with smaller volumes in temporal brain regions typically affected by this disease. These effects have also been found in cognitively unimpaired (CU) older adults. This study aimed [...] Read more.

Background/Objectives: Studies have shown that higher polygenic risk scores (PRSs) for Alzheimer’s disease (AD) are associated with smaller volumes in temporal brain regions typically affected by this disease. These effects have also been found in cognitively unimpaired (CU) older adults. This study aimed to investigate the relationship between PRSs and brain volumes in specific areas associated with early AD. Methods: 342 participants were selected from the Alzheimer’s Disease Neuroimaging Initiative and stratified into three groups: 114 amyloid-positive atrophic (A+N+), 114 amyloid-negative non-atrophic (A−N−), and 114 amyloid-positive non-atrophic (A+N−) people. Linear regressions were performed within each group to investigate associations between PRSs and regional grey matter volumes. Analyses were also repeated after stratifying groups by APOE status and clinical diagnosis. Two sensitivity analyses were run to investigate the impact of APOE and amyloid status and concordance across biomarkers. Multiplicity was controlled for using the Benjamini–Hochberg false discovery rate (FDR) approach. Results: Negative associations were observed between PRSs and volumes of the left amygdala and hippocampus in A+N+, right hippocampus in A+N−, and right posterior cingulate cortex in A−N− participants. Associations were found especially in A−N− participants, both ε4 allele carriers and non-carriers, and mostly confirmed in sensitivity analyses. Associations emerged only in CU and AD participants, but not in people with MCI. None of these findings survived correction for FDR. Conclusions: These findings highlight the potential of PRSs as novel biological indicators for a deeper characterisation of AD-related neural alterations. Full article

(This article belongs to the Section Neurogenomics)

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15 pages, 1225 KB

Open AccessArticle

Genetic Characteristics of Brazilian Patients with MH History

by Helga C. A. Silva, Daniela C. Mendonça, Brandow W. Souza, Joilson M. Santos, Lucas S. Souza, Antonio F. R. Junior, Felipe T. G. R. Vasconcelos, Pamela V. Andrade, Acary S. B. Oliveira and Mariz Vainzof

Genes 2025, 16(10), 1127; https://doi.org/10.3390/genes16101127 - 25 Sep 2025

Abstract

Background/Objectives: Malignant hyperthermia (MH) is a pharmacogenetic hypermetabolic syndrome triggered by halogenated agents/succinylcholine. Most families present variants in the RYR1 and, rarely, in other genes (CACNA1S/STAC3/ASPH). However, each country or region presents differences in the type and [...] Read more.

Background/Objectives: Malignant hyperthermia (MH) is a pharmacogenetic hypermetabolic syndrome triggered by halogenated agents/succinylcholine. Most families present variants in the RYR1 and, rarely, in other genes (CACNA1S/STAC3/ASPH). However, each country or region presents differences in the type and frequency of MH variants. Objective: To present the genetic characteristics of Brazilian individuals with MH history. Methods: We reviewed clinical and laboratory data from all families referred for evaluation in the Brazilian MH unit due to a personal or family history of MH during anesthesia. Demographic and clinical data were collected, as well as serum creatine kinase (CK) levels, in vitro contracture test (IVCT) results, and the results of anatomopathological studies of skeletal muscle. Molecular analysis was performed using whole-exome sequencing (WES). Patients with and without variants were compared. Results: WES analysis was available for 61 patients (29 patients who survived an MH crisis and 32 relatives). Variants in the RYR1 were found in 38 patients (62.2%), and no variants were identified in 20 patients (32.7%). More than one variant in the RYR1 was found in six individuals. Variants in the CACNA1S were found in three patients (4.9%), all of them with concomitant variants in the RYR1. Three patients presented variants in the STAC3 (4.9%). Comparing the groups of patients with variants in the RYR1 with the one with no variants in this gene, it was observed that the first group showed higher levels of serum CK, a greater frequency of ptosis, strabismus, and cores, and a higher amplitude of contracture in the IVCT after caffeine or halothane. Conclusion: In this preliminary evaluation of Brazilian individuals with MH history, the frequency of RYR1 variants was similar to those of previous reports in other countries, but there was a higher frequency of STAC3 and CACNA1S variants. Full article

(This article belongs to the Special Issue Molecular Genetics of Malignant Hyperthermia Susceptibility and Related Diseases)

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15 pages, 2041 KB

Open AccessArticle

Association of IL-23R rs1569922 and Other Probable Frequent Etiological Factors with Legg–Calvé–Perthes Disease in Mexican Patients

by Armando Odiseo Rodríguez-Olivas, Elba Reyes-Maldonado, Leonora Casas-Ávila, Marlene Alejandra Galicia-Alvarado, Erika Rosales-Cruz, Cesar Zavala-Hernández and Edgar Hernández-Zamora

Genes 2025, 16(10), 1126; https://doi.org/10.3390/genes16101126 - 24 Sep 2025

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Abstract

Background: Legg–Calvé–Perthes disease (LCPD) is a rare avascular osteonecrosis of the proximal femoral epiphysis and typically occurs during the childhood growth phase. LCPD is a complex illness of unknown origin, which is considered the main difficulty in the study of this disease. Various [...] Read more.

Background: Legg–Calvé–Perthes disease (LCPD) is a rare avascular osteonecrosis of the proximal femoral epiphysis and typically occurs during the childhood growth phase. LCPD is a complex illness of unknown origin, which is considered the main difficulty in the study of this disease. Various theories on LCPD etiology have been proposed; however, no consensus has been reached about its origin. Our research objective was to evaluate the polymorphisms FVL rs6025, FVIII rs5987061, FIX Malmö rs6048, PAI-1 rs1799889, eNOS rs17899983/rs2070744, IL-23R rs1569922/rs154655686/7539625, and TNF-α rs180062, and their relationship with LCPD. Methods: A blood sample was taken from each study participant. Complete blood count, coagulation times and factors, antithrombotic proteins, and homocysteine (Hcy) were determined using a coagulometric method. DNA was obtained and genotyped using real-time PCR with TaqMan probes. Genotypic and allelic distributions were analyzed using comparative analysis, the Hardy–Weinberg equilibrium, and OR. Results: This study included 46 children: 23 with LCPD (cases) and 23 without (controls). Statistically significant differences were found in Prothrombin Time, Factor V, and Factor IX activity, as well as Hcy concentration; these values suggest the presence of hypercoagulable states in patients, which can cause thrombotic events. On the other hand, significant differences were also found in the neutrophil–lymphocyte ratio and systemic immune-inflammation index, showing major inflammation states in the patient group. Moreover, statistically significant differences were found in the IL-23R rs1569922 polymorphism; it was found that carriers of the T/T and C/T genotypes have an increased risk of developing LCPD. Conclusions: Our results show greater hemostatic activity and inflammation in the group of patients included in this study, supporting various theories previously proposed. Therefore, we believe that LCPD is a multifactorial condition in which hemostatic, inflammatory, and genetic factors play a central and triggering role in the disease. Full article

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

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18 pages, 2657 KB

Open AccessArticle

GRE: A Framework for Significant SNP Identification Associated with Wheat Yield Leveraging GWAS–Random Forest Joint Feature Selection and Explainable Machine Learning Genomic Selection Algorithm

by Mei Song, Shanghui Zhang, Shijie Qiu, Ran Qin, Chunhua Zhao, Yongzhen Wu, Han Sun, Guangchen Liu and Fa Cui

Genes 2025, 16(10), 1125; https://doi.org/10.3390/genes16101125 - 24 Sep 2025

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Abstract

Background: Facing global wheat production pressures such as environmental degradation and reduced cultivated land, breeding innovation is urgent to boost yields. Genomic selection (GS) is a useful wheat breeding technology to make the breeding process more efficient, increasing the genetic gain per [...] Read more.

Background: Facing global wheat production pressures such as environmental degradation and reduced cultivated land, breeding innovation is urgent to boost yields. Genomic selection (GS) is a useful wheat breeding technology to make the breeding process more efficient, increasing the genetic gain per unit time and cost. Precise genomic estimated breeding value (GEBV) via genome-wide markers is usually hampered by high-dimensional genomic data. Methods: To address this, we propose GRE, a framework combining genome-wide association study (GWAS)’s biological significance and random forest (RF)’s prediction efficiency for an explainable machine learning GS model. First, GRE identifies significant SNPs affecting wheat yield traits by comparison of the constructed 24 SNP subsets (intersection/union) selected by leveraging GWAS and RF, to analyze the marker scale’s impact. Furthermore, GRE compares six GS algorithms (GBLUP and five machine learning models), evaluating performance via prediction accuracy (Pearson correlation coefficient, PCC) and error. Additionally, GRE leverages Shapley additive explanations (SHAP) explainable techniques to overcome traditional GS models’ “black box” limitation, enabling cross-scale quantitative analysis and revealing how significant SNPs affect yield traits. Results: Results show that XGBoost and ElasticNet perform best in the union (383 SNPs) of GWAS and RF’s TOP 200 SNPs, with high accuracy (PCC > 0.864) and stability (standard deviation, SD < 0.005), and the significant SNPs identified by XGBoost are precisely explained by their main and interaction effects on wheat yield by SHAP. Conclusions: This study provides tool support for intelligent breeding chip design, important trait gene mining, and GS technology field transformation, aiding global agricultural sustainable productivity. Full article

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

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22 pages, 3795 KB

Open AccessArticle

Comparative Analysis of the Chloroplast Genomes of Grewia tembensis Fresen and Closely Related Species of Grewioideae Hochr: A Phylogenetic and Conservation Perspective

by Widad S. AL-Juhani

Genes 2025, 16(10), 1124; https://doi.org/10.3390/genes16101124 - 23 Sep 2025

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Abstract

Background: Grewia is a genus of flowering plants belonging to the Malvaceae family. Grewia tembensis is used in traditional medicine for the treatment of several microbial diseases as well as a livestock feed. Methods: In the current study, the complete chloroplast (cp) genome [...] Read more.

Background: Grewia is a genus of flowering plants belonging to the Malvaceae family. Grewia tembensis is used in traditional medicine for the treatment of several microbial diseases as well as a livestock feed. Methods: In the current study, the complete chloroplast (cp) genome of G. tembensis was constructed using data derived from high-throughput sequencing, followed by comprehensive analyses and comparison with phylogenetically related species. Results: The chloroplast genome of G. tembensis is 158,040 bp long and has the typical quadripartite structure found in angiosperms. The large single-copy (LSC) segment measures 86,956 bp, whereas the small single-copy (SSC) regions encompass 20,142 bp. The two inverted repeat (IRa and IRb) regions have an identical length of 25,471 bp and display a higher degree of conservation relative to the single-copy (SC) regions based on nucleotide diversity analysis. The genome of G. tembensis possesses 130 genes. The simple sequence repeat (SSR) numbers ranged between 202 and 234 repeats in Grewioideae subfamily species under this study. Furthermore, nucleotide diversity analysis demonstrated a marked elevation in polymorphism information (Pi) values across 30 genes in Grewioideae. Conclusions: cpSSRs can be used for the examination of population genetic variability within and between Grewia species, as well as the categorization of populations and their biogeographical distribution. In addition, loci with high Pi values can contribute substantial genetic variability, which is crucial for addressing taxonomic dilemmas in phylogenetic investigations. Full article

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

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10 pages, 1018 KB

Open AccessArticle

Somatic TEK Mutation Identified in a Patient with Calvarial Venous Malformations

by Baojian Fan, Evan Dennis, Neel H. Mehta, William Davalan, Carla Fortes, Aditi Swamy, William Muñoz, Camilo Jaimes, Andrew T. Hale and Kristopher T. Kahle

Genes 2025, 16(10), 1123; https://doi.org/10.3390/genes16101123 - 23 Sep 2025

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Abstract

Background: Calvarial venous malformations (VMs) are rare and genetically understudied. While somatic TEK receptor tyrosine kinase (TEK) mutations drive sporadic VMs, their role in scalp–calvarial VMs is unknown. We report the first pediatric case of a calvarial VM with a [...] Read more.

Background: Calvarial venous malformations (VMs) are rare and genetically understudied. While somatic TEK receptor tyrosine kinase (TEK) mutations drive sporadic VMs, their role in scalp–calvarial VMs is unknown. We report the first pediatric case of a calvarial VM with a pathogenic somatic TEK mutation and its molecular implications. Methods: A 16-year-old female with a symptomatic parietal scalp VM underwent neurosurgical resection. Exome sequencing was performed on both lesional and blood DNA. Single-cell RNA sequencing (scRNA-seq) data from normal brain vasculature were analyzed for TEK expression and pathway enrichment. Results: A novel somatic TEK L914F mutation (chr9:27212760-C-T [GRCh38]), absent in germline DNA and population databases, was identified and predicted to be deleterious (CADD: 24). scRNA-seq data analysis revealed TEK enrichment in endothelial cells, particularly in fetal and arterial subtypes, and implicated angiogenesis and PI3K/Rho signaling as potential downstream phenotypic and molecular consequences. Conclusions: This first pediatric scalp VM with a somatic TEK L914F mutation expands the phenotypes associated with TEK-related vascular anomalies. These findings emphasize the role of somatic TEK mutation in diverse VMs and support genetic testing in sporadic cases. Further studies are needed to define therapeutic targets. Full article

(This article belongs to the Section Neurogenomics)

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11 pages, 225 KB

Open AccessArticle

Lack of Association Between COL1A1 rs1800012 Polymorphism and Anterior Open Bite Malocclusion in a Turkish Case–Control Cohort

by Tolga Polat, Özlem Özge Yılmaz, Elvan Önem Özbilen and Beste Tacal Aslan

Genes 2025, 16(10), 1122; https://doi.org/10.3390/genes16101122 - 23 Sep 2025

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Abstract

Background/Objectives: Anterior open bite is a multifact orial malocclusion influenced by genetic and environmental factors. Variants in the Collagen type I, alpha 1 (COL1A1) gene, particularly rs1800012, have been implicated in bone quality, but their role in craniofacial anomalies remains unclear. [...] Read more.

Background/Objectives: Anterior open bite is a multifact orial malocclusion influenced by genetic and environmental factors. Variants in the Collagen type I, alpha 1 (COL1A1) gene, particularly rs1800012, have been implicated in bone quality, but their role in craniofacial anomalies remains unclear. Methods: A case–control study was conducted with 60 participants (30 anterior open bite cases; 30 matched controls). DNA was extracted from buccal swabs, and rs1800012 genotyping was performed using TaqMan assays. Genotype and allele distributions were compared with chi-square and Fisher’s exact tests; Hardy–Weinberg equilibrium was assessed in controls. Results: Genotype (GG/GT/TT: 53.3/40.0/6.7% vs. 60.0/33.3/6.7%) and allele (T allele: 26.7% vs. 23.3%) frequencies did not differ significantly between cases and controls. No association was detected under additive, dominant, or recessive models (all p > 0.05). Wide confidence intervals indicated limited precision of effect estimates. Conclusions: This study provides no evidence of association between COL1A1 rs1800012 and anterior open bite in this Turkish cohort. The relatively small sample size, the rarity of the TT genotype, and the multifactorial nature of craniofacial development represent important limitations. Larger, multi-gene, and functionally integrated studies are required to clarify the genetic architecture of open bite malocclusion. Full article

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

18 pages, 1635 KB

Open AccessArticle

Alcohol Preference Impacts Multi-Organ Transcriptome in MetALD

by Saumya Sikhwal, Tyler C. Gripshover, Rui S. Treves and Josiah E. Hardesty

Genes 2025, 16(10), 1121; https://doi.org/10.3390/genes16101121 - 23 Sep 2025

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Abstract

Background/Objectives: Alcohol use disorder (AUD) is a major public health issue with rising global occurrence and metabolic consequences. Modeling the addictive behaviors associated with AUD remains inadequate and elusive. Even more so, models that are representative of AUD in concert with excessive caloric [...] Read more.

Background/Objectives: Alcohol use disorder (AUD) is a major public health issue with rising global occurrence and metabolic consequences. Modeling the addictive behaviors associated with AUD remains inadequate and elusive. Even more so, models that are representative of AUD in concert with excessive caloric intake are limited. Some consequences of chronic alcohol use overlap with the metabolic phenotype of hypercaloric diets. Recently characterized metabolic dysfunction-associated steatotic liver disease with increased alcohol intake (MetALD) helps to differentiate these conditions. This study aims to investigate metabolic phenotypes and gene expression alterations in MetALD mice that are grouped by alcohol preference based on blood phosphatidylethanol levels and alcohol consumption. Methods: Mice were fed high-fat and chow diets, with water and 10% EtOH, for 13 weeks. mRNA sequencing was performed across multiple tissues including brain, liver, skeletal muscle, ileum, and white adipose tissue, and gut microbiome diversity was evaluated via 16S sequencing. Results: Key findings included reduced glucagon in alcohol-preferring mice with no significant differences in dyslipidemia and hepatic steatosis. Additionally, we observed reduced gut microbiome diversity and Wnt signaling with elevated acute-phase response genes in ileum tissue. Reduced Wnt and Hippo signaling in the brain and liver, respectively, was also revealed. Other gene ontologies discovered included increased neural inflammation and adipose mitochondrial translation. Nek3, Ntf3, Cux1, and Irf6 expression changes were shared across at least three tissues and may be potential biomarkers of alcohol addiction. Conclusions: This novel model assists future intervention research in the characterization of MetALD and identifies potential biomarkers of alcohol preference. Full article

(This article belongs to the Topic Genetics and Epigenetics of Substance Use Disorders)

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13 pages, 1498 KB

Open AccessArticle

Expanding the Clinical and Molecular Spectrum of Primary Autosomal Recessive Microcephaly: Novel CDK5RAP2 Gene Variants and Functional Insights on the Intronic Variants

by Burcu Yeter, Yasemin Kendir Demirkol, Esra Usluer, İpek Görüşen Kavak, Sena Gjota Ergin and Nursel H. Elçioğlu

Genes 2025, 16(10), 1120; https://doi.org/10.3390/genes16101120 - 23 Sep 2025

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Abstract

Background/Objectives: Autosomal recessive primary microcephaly is a rare and genetically heterogeneous disorder characterized by congenital non-syndromic microcephaly, with at least 28 causative genes identified to date. Biallelic variants in the CDK5RAP2 gene, an ultra-rare cause of autosomal recessive primary microcephaly, lead to [...] Read more.

Background/Objectives: Autosomal recessive primary microcephaly is a rare and genetically heterogeneous disorder characterized by congenital non-syndromic microcephaly, with at least 28 causative genes identified to date. Biallelic variants in the CDK5RAP2 gene, an ultra-rare cause of autosomal recessive primary microcephaly, lead to Primary Autosomal Recessive Microcephaly 3 (MCPH3). Methods: We present seven patients from six families diagnosed with MCPH3 in light of clinical and molecular findings using whole-exome sequencing (WES). Furthermore, we investigated the effects of the identified intronic variants on splicing through RNA analysis. Results: Almost all patients had severe microcephaly, mild to moderate intellectual disability, speech delay, and cutaneous pigmentary abnormalities. Four patients presented with postnatal short stature, and two showed weight deficiency. Dysmorphic evaluation revealed that the most prominent features included brachycephaly, hypertelorism, epicanthus, high-arched eyebrows, prominent nasal bridge, and micrognathia. We identified five distinct homozygous CDK5RAP2 variants in our patients, including four novel variants. Segregation analysis verified that the parents were carriers. Two of these variants were intronic (c.3148+5G>C and c.383+4dupA), two were frameshift (c.3168del), and one was a nonsense variant (c.1591C>T). Both intronic variants disrupted splicing, generating a premature stop codon and resulting in a truncated protein. Conclusions: This study broadens the mutational landscape of CDK5RAP2. We also sought to demonstrate the functional consequences of the CDK5RAP2 intronic variants on gene function using RNA analysis. The identification of four novel variants underscores the importance of molecular diagnostics in patients with primary microcephaly and provides valuable data for genetic counseling and future functional studies. Full article

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

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