Search Results (3,022)

Background/Objectives: Candidozyma auris is the most frequent multidrug-resistant fungal infection in the Arabian Peninsula, with high mortality rates; therefore, new medications are in high demand. Microbes in marine habitats have genetically evolved to survive under a variety of adverse conditions, including severe temperatures, salinity, pH, and other stress factors, by generating various bioactive metabolites. These bioactive secondary metabolites have strong potential for use as antifungal agents. Due to the shortage of antifungal medications and the emergence of treatment resistance in C. auris, identifying new therapeutics from synthetic bacterial components or natural materials has become a necessity. Natural molecules have numerous advantages over synthetic substances, including structural variation and low toxicity. Few next-generation sequence-based investigations have been carried out on anti-Candidozyma auris bacterial species to identify potential therapeutic candidates. Therefore, the aim of this study is to identify biosynthetic gene clusters from marine bacteria using next-generation sequencing to discover novel drug compounds against multidrug-resistant C. auris. Methods: More than 68 isolates were collected from various marine environments using standard techniques. All isolates were tested against the multidrug-resistant C. auris. Scanning electron microscopy was utilized to investigate the cell membrane rupture caused by defused metabolites of the IRMCESH58L bacterium in C. auris. The Vibrio sp. IRMCESH58L genome was sequenced using long-read nanopore sequencing technology. Results: The bacterial strain IRMCESH58L, isolated from a fish liver sample, showed the highest and most constant activity against C. auris. An in vitro toxicity test found that IRMCESH58L had no cell cytotoxicity against HFF-1 cells. The assembled plasmid-free genome is 6,556,025 bp (48.93% G+C), with an N50 of 909243. Comparative analysis confirmed its relation to Vibrio alginolyticus. Conclusions: Whole-genome analysis of the native bacterial strain IRMCESH58L revealed various biosynthetic gene clusters, including those involved in surfactin’s biosynthesis of putative natural anti-C. auris chemicals, but no pathogenic protein-coding genes, emphasizing the importance of marine bacteria in the fight against C. auris. Following this in vivo study, therapeutic targets will later be selected for further pre-clinical studies. Full article

Distant hybridization induces genomic instability in offspring, driving the occurrence of gene recombination and mutation. Analysis of the genomic genetic composition can be used to infer the genetic evolutionary relationships between species. Based on the improved diploid carp (IDC) and the improved diploid scattered mirror carp (IDMC) lineages derived from distant hybridization between female common carp and male blunt snout bream, this study analyzed the genetic variation in their mitochondrial genomes to investigate the impact of distant hybridization on mitochondrial DNA (mtDNA) structural variation. Analysis of complete mitochondrial genome sequence structure and composition revealed subtle structural divergence across generations in both the IDC and IDMC lineages. Analysis of the protein-coding gene sequence structure demonstrated mitochondrial genome structure instability in nascent hybrid diploid lineages. Yet, subsequent self-crossing significantly narrowed the range of structural variation within each lineage. Furthermore, analysis of the genetic variation in the mitochondrial genome sequence structure revealed that paternal base insertions occurred in both F₁ lineages, accompanied by mutations predominantly consistent with those in crucian carp. The results of this study also indicated that the strictness of the paternal mtDNA elimination mechanism varied significantly among polymorphic individuals across different generations of the hybrid lineages, reflecting the randomness of paternal leakage. Full article

Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder characterized by autonomic dysfunction, Parkinsonism, and cerebellar ataxia. While the pathological hallmark of MSA is the accumulation of α-synuclein in oligodendrocytes and formation of glial cytoplasmic inclusions (GCIs), the precise etiopathogenesis, accurate biomarkers, and promising therapeutic targets remain elusive. This review synthesizes current evidence regarding the role of microRNAs (miRNAs) in MSA, focusing on how small non-coding RNAs mediate gene–environment interactions contributing to disease pathogenesis. We explore dysregulated miRNA profiles in MSA, their impact on α-synuclein aggregation, neuroinflammation, demyelinating process, and oligodendrocyte dysfunction, and their potential as biomarkers and therapeutic targets. Understanding the complex interplay between miRNAs, genetic susceptibility, and environmental factors may provide critical insights into MSA pathophysiology and open new avenues for therapeutic intervention. Full article

Background: Trisomy 18 (T18; Edwards syndrome) and Trisomy 13 (T13; Patau syndrome) are rare autosomal aneuploidies characterized by severe congenital anomalies, high neonatal mortality, and complex clinical trajectories. Objective: This study aimed to describe the clinical features, management approaches, and outcomes of genetically confirmed patients aged 0–18 years diagnosed with T18 or T13 in a tertiary care center. Methods: This retrospective study reviewed hospital records of genetically confirmed T18 and T13 cases identified through ICD-10 codes (Q91–Q92) between January 2015 and December 2024. Patients aged 0–18 years at diagnosis were included. Demographic, clinical, and interventional data were collected from electronic medical records. Survival analyses were conducted using the Kaplan–Meier method, with comparisons assessed using the log-rank test. Results: Among 29 patients, 23 had T18 and 6 had T13. Cardiovascular involvement was the most frequent anomaly, and overall mortality was high despite intensive care. Median survival was 90 days for T18 and 120 days for T13, with more than 80% surviving the first month but showing a steep decline thereafter. Most deaths were attributed to cardiopulmonary complications or sepsis secondary to prolonged intensive care. Kaplan–Meier analysis revealed marked early mortality in both groups, with no significant survival difference (log-rank p ≈ 0.3). A small subset demonstrated longer-term survival with heterogeneous clinical courses. Conclusions: T18 and T13 are associated with high early mortality driven by complex congenital heart disease, respiratory instability, and infection-related complications. Although the overall prognosis remains poor, a minority of patients achieve extended survival, highlighting variable trajectories. Early multidisciplinary care, individualized decision-making, and strict infection prevention remain essential to optimize outcomes and support families. Full article

Mutants with a bright green appearance due to wax synthesis or deposition defects have been reported in various plants such as Arabidopsis thaliana, corn, and rice, but they are relatively rare in broccoli (a brassicaceae crop). Here, we describe SY03, a natural mutant of broccoli with a glossy green phenotype owing to epidermal wax deficiency. Genetic analysis indicated that the leaf luster trait of SY03 was controlled by a single recessive gene. By using the F₂ generation and combining bulked segregant analysis and molecular marker techniques, the candidate gene BoFAR3a, homologous to the Arabidopsis FAR gene, was identified within a 96.678 kb interval of chromosome C01. The A→G point mutation in exon 1 of the BoFAR3a coding sequence substitutes the canonical ATG start codon with GTG, which is predicted to abrogate or severely reduce translation initiation. RT-qPCR indicated that the expression levels of BoFAR3a were significantly decreased in the leaves of the glossy green phenotype mutant. Heterologous expression of BoFAR3a in A. thaliana restored the phenotype of A. thaliana mutant FAR3. The discovery of BoFAR3a is of great significance for breeding lustrous and commercially appealing broccoli varieties. This study systematically analyzed the molecular basis of the lustrous green phenotype in broccoli, providing new insights into the epidermal waxy regulatory network of cruciferous crops. In the future, the wax synthesis pathway can be precisely improved through gene editing technology, achieving a coordinated enhancement of the appearance quality and stress resistance of broccoli. Full article

Yaks are important livestock in high-altitude regions, and their polled trait can effectively improve breeding and management efficiency. In this study, whole-genome resequencing combined with a GWAS was employed to identify a significantly associated region of approximately 273.6 kb on chromosome 1 (36,313,286–36,586,879 bp) in Xueduo yaks. This region contains 1001 significant single-nucleotide polymorphism (SNP) loci and is located within a long intergenic non-coding RNA (lincRNA) region. Candidate genes EPCIP, OLIG1 and PAXBP1 adjacent to this region were identified. Among these, the PAXBP1 gene plays a crucial role in neural crest development, suggesting that it may be a core gene regulating horn development in yaks. Further analysis of Ashdan yaks (a polled breed developed from Datong yaks) indicated that the two breeds share the same candidate genes and a subset of associated genetic variants for the polled trait, suggesting a degree of genetic conservation underlying this trait across yak breeds. This study provides a theoretical basis for polled yak breeding. Full article

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

The European Union (EU) Green Deal (EGD) aims to significantly transform and modernize the EU economy, while at the same time envisioning significant changes in agricultural production, especially in livestock farming. Generally, EU Member States implement specific measures that contribute to the achievement of various EGD objectives. Most often, these are part of the national strategies of the EU Common Agricultural Policy. At the same time, it is important to identify the available scientific information on measures that contribute to the achievement of the EGD goals and their various impacts. Usually, each individual measure or practice is aimed at achieving one of the ESD goals, for example, reducing GHG emissions, but in practice, these create multiple side effects that can promote or hinder the achievement of other sustainability goals. This study focuses on the livestock sector and outlines key areas where intervention must occur: feeding, housing, grassland/pasture management, manure management, breeding and genetics—these factors interact and contribute to the achievement of EGD targets. At the same time, this research takes a holistic view of the EGD demands on livestock. In this study, the authors use pictograms and a color-coding system that broadens the scope of impact communication. It translates complex, scientific data into a format that is accessible and easily understood by a wider audience. The results of this study reveal that systematic research is needed to examine livestock farming measures that could change agricultural policies in the long term—from supporting existing measures to creating appropriate sustainable farming systems. Full article

The Sharpchin Slickhead, Bajacalifornia burragei, is a rarely collected bathypelagic fish endemic to the eastern tropical Pacific Ocean, and its genetic diversity remains undocumented. This study characterizes mitochondrial diversity in a localized deep-basin collection from the Carmen Basin of the Gulf of California by sequencing complete mitochondrial genomes from four individuals collected simultaneously at 1300 m in a single Tucker trawl. A high-quality reference mitogenome was assembled using PacBio HiFi long reads, and three additional mitogenomes were generated from Illumina PE150 libraries mapped to this reference. The mitogenome of B. burragei exhibits the canonical 37 gene architecture and conserved gene order typical of teleost mitogenomes. Overall mitogenome divergence was low (Range: 0.21–0.29%), with most protein-coding and rRNA genes exceeding 99.5% identity. Slightly elevated variation occurred in atp8, nad6, and several tRNA genes. This study provides the first genetic characterization of B. burragei and establishes a baseline for evaluating mitochondrial diversity within a localized collection of individuals and provides a point of comparison for future studies assessing connectivity among deep basins. Full article

Early-onset breast cancer (EOBC) is disproportionately common in Saudi Arabia, where women present nearly a decade earlier than in Western countries, suggesting unique inherited susceptibility. While BRCA1/2 explain part of the hereditary risk, the contribution of rare coding variants in Arab EOBC remains unclear. Whole-exome sequencing was performed on germline DNA from 102 unrelated Saudi EOBC patients and 1395 cancer-free controls recruited from the same national Saudi cohort. Rare variants were defined by stringent frequency and quality thresholds and classified as rare loss-of-function (RLOF) or rare predicted damaging variants (RPDVs). Gene-level case–control analyses were conducted using burden tests, with exome-wide significance set at p < 2.5 × 10⁻⁶. RLOF variants in BRCA1 (6.9% of EOBC vs. 0.14% of controls; OR = 51.3; p < 1.0 × 10⁻¹⁰) and RPDVs in TP53 (4.9% vs. 0.36%; OR = 14.3; p = 5.39 × 10⁻⁸) demonstrated strong associations. Sequence Kernel Association Test (SKAT) analysis identified NOTCH4 and OR12D3 and reinforced burden-based significance in GUCY2F, FRMPD3, and SHROOM2. No enriched signaling pathway emerged, indicating heterogeneous rare-variant mechanisms. This first germline exome-wide rare-variant association study in Saudi EOBC identifies substantial enrichment driven by BRCA1, TP53, and additional candidate genes, supporting population-specific genetic risk evaluation and the need for replication in larger Arab cohorts. Full article

The starch content of lotus (Nelumbo nucifera) rhizomes is a key determinant of their taste and overall quality. In our previous work, a candidate transcription factor, NnAP2, was identified and its coding-region single-nucleotide polymorphisms (SNPs) were significantly associated with rhizome enlargement and carbohydrate-related traits. Owing to limitations in stable genetic transformation systems in lotus, potato (Solanum tuberosum) was employed as a heterologous model to investigate the regulatory role of NnAP2 in starch and soluble sugar metabolism. Overexpression of two allelic variants of the NnAP2 transcription factor (CC and TT) in potato resulted in pronounced differences between CC- and TT-overexpressing lines (NnAP2^CC-OE and NnAP2^TT-OE) in microtuber carbohydrate composition and proteome dynamics, accompanied by divergence in transgene copy number and substantial variation in transgene expression levels among independent lines. Six months after planting transgenic lines NnAP2^CC-OE and NnAP2^TT-OE, the NnAP2^CC-OE micro-tubers exhibited significantly higher starch content and lower soluble sugar levels compared with NnAP2^TT-OE. To uncover the underlying molecular basis, profiling of proteoforms was conducted on leaves, stems and tubers of both genotypes through a label-free proteomic strategy. A total of 51,299 peptides matched to 7292 proteins. Principal component analysis demonstrated clear separation of treatment groups, indicating robust differential accumulation of proteoforms. In total, 1715 differentially expressed proteins (DEPs) were identified across tissues (fold change ≥ 1.5 or ≤0.67, p  <  0.05), of which 1516 (88.4%) were tissue-specific. GO and KEGG enrichment analyses revealed that in leaves, DEPs were enriched for amino sugar metabolism, protein transporter activity and cell-wall macromolecule modification; in stems, enrichment included response to biotic stimulus, defense response and transporter activity; in tubers, DEPs were strongly enriched for carbohydrate metabolic processes, starch and sucrose metabolism, the TCA cycle and nucleotide sugar biosynthesis. Key starch-biosynthetic enzymes (e.g., ADP-glucose pyrophosphorylase, UDP-glucose-4-epimerase) were up-regulated in NnAP2^CC-OE tubers relative to NnAP2^TT-OE, while soluble sugar synthesis pathways (e.g., trehalose-6-phosphate synthase) were down-regulated. Together, these data suggest that elevated NnAP2^CC expression in transgenic potato is associated with allele-dependent shifts in central carbon allocation between starch and soluble sugar pathways, as revealed by comparative analyses between NnAP2^CC-OE and NnAP2^TT-OE. This study provides a comprehensive proteoform framework for allelic variation in an AP2 transcription factor involved in source–sink carbon partitioning and tuber starch accumulation in potato. Full article

The post-genomic era, defined by large-scale sequencing initiatives, has generated an unprecedented catalogue of human genetic variation. Yet, the vast majority of genetic variants remain classified as variants of uncertain significance or are located within poorly characterized non-coding regions, thereby hindering the effective translation of genomic data into meaningful biological understanding and clinical application. Bridging this genotype-to-phenotype gap requires precise, high-throughput functional genomics. Early CRISPR–Cas9 knockout and CRISPR interference/activation (CRISPRi/a) screens mapped gene-level functions but could not assess single nucleotide variants (SNVs). Bridging this genotype-to-phenotype gap demands precise, high-throughput functional genomics. Multiplexed assays of variant effect (MAVEs), like saturation genome editing, systematically test all possible mutations using CRISPR–Cas9 and donor libraries. Base editors allow targeted single-base changes without double-strand breaks but are limited in scope, while prime editing can introduce any small substitution, insertion, or deletion without double-strand breaks (DSBs) or donor templates. This review traces the evolution of functional screens from gene-level knockouts to saturation genomic editing (SGE), and highlights how prime editing is driving a new paradigm for the systematic functional characterization of thousands of variants across disease-relevant genes. We also detail the architecture, mechanism, and progressive optimization of PE systems and their delivery methods. Collectively, prime editing stands as a transformative platform poised to accelerate precision functional genomics and advance the diagnosis and treatment of genetic diseases. Full article

Coding transcripts-derived small interfering RNAs (ct-siRNAs) have emerged as a special class of endogenous siRNAs and have been implicated in the regulation of gene expression in plants, particularly under conditions where RNA metabolic pathways are perturbed. When the RNA quality control (RQC) system is impaired, the aberrant mRNA fragments were converted to double stranded forms by RNA-directed RNA polymerase 6 (RDR6) with the assistance of Suppressor of Gene Silencing 3 (SGS3) and subsequently processed by DICER-LIKE proteins into 21-nt and 22-nt ct-siRNAs. The accumulation of ct-siRNAs and the resulting suppression of their cognate genes are usually associated with altered plant growth and stress response. In this review, we summarize our current understanding of the ct-siRNAs, particularly their biogenesis under different RNA metabolic defective conditions. Comparative analysis of these genetic contexts indicates that ct-siRNAs act through translation inhibition and/or mRNA cleavage, with regulatory outcomes influenced by siRNA length and genetic background. We further summarize the biological consequence of ct-siRNA accumulation, which are frequently associated with impaired plant growth and stress adaptation. Finally, we discuss current controversies on ct-siRNAs research and highlight key unsolved questions for future investigation. Collectively, this review highlights ct-siRNAs as a link between impaired RNA metabolisms and post-transcriptional gene silencing, with context-dependent effects on plant growth and stress responses. Full article

Background: Cholesterol imbalances and elevated blood pressure (BP) are closely interrelated risk factors for cardiovascular disease (CVD) and are subject to genetic influences. We sought to identify novel associations between candidate genetic coding variants and CVD traits in our isolated study cohort and validate them in a general population cohort. Methods: We leveraged the population genetic features of the Norfolk Island Health Study (NIHS, n = 601), to identify candidate functional variants which were analysed for association with CVD and metabolic syndrome traits. We followed up suggestive variant-trait associations in the 2022 release of UK Biobank whole exome data (n = 200,625). Results: We identified a novel ten-base-pair in-frame missense multi-nucleotide variant (MNV), tagged by rs35724886, in the lipid metabolism gene ACOT4, which was associated with cholesterol levels and blood pressure. The MNV was associated with a lower incidence of ‘elevated BP’—systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg—(OR: 0.70; 95% CI: 0.51, 0.97; p = 0.03), and higher total cholesterol levels (β = 0.08; p = 0.04) in the NIHS. Validation in the UK Biobank revealed consistent associations between the MNV (proxied by rs35725886) and lower incidence of ‘elevated BP’ (p = 0.0001), higher total cholesterol (p = 0.01), and reduced use of medication for managing blood pressure (p = 1.8 × 10⁻⁶) and cholesterol (p = 0.002). Structural modelling and in-silico predictions suggested that the MNV introduced destabilising changes in the ACOT4 protein, likely influencing peroxisomal lipid metabolism pathways critical to CVD risk. Conclusions: This study identified a coding MNV with potential implications for understanding the genetic regulation of lipid metabolism and its impact on cardiovascular health. Full article

Background: Haemoglobinopathies such as beta-thalassemia (β-thal), alpha-thalassemia (α-thal) and sickle cell disease (SCD) are characterised by pathogenic gene variations (mutations) in the globin genes. Patients with haemoglobinopathies have the same disease-causing coding variations with very different disease phenotypes, from requiring blood transfusions to being non-symptomatic. The gap between the expected clinical outcomes based on primary coding mutations (the genotype) and the actual observed symptoms (the phenotype) often remains unexplained. We refer to the contribution of secondary genetic modifiers—specifically, non-coding variants of the genome that alter globin gene expression and pathophysiology—as the “missing heritability” of the clinical presentation [Primary Mutation + Missing Heritability (Non-Coding Variants) = Actual Clinical Phenotype]. Objectives: This systematic review aims to find evidence connecting genetic differences outside of the protein-coding region, as in promoters, enhancers or untranslated regions (UTRs), to the clinical severity (phenotype) of beta-thalassemia, alpha-thalassaemia and SCD. We summarise the molecular basis of phenotypic variation among haemoglobinopathy patients with identical variations to reveal their missing heritability and to enhance our understanding of prognostic strategies. Methods: This systematic review was performed in accordance with the PRISMA 2020 guidelines. We used search terms related to haemoglobinopathies, non-coding variation, SNP, promoters, enhancers and clinical severity to search major databases (PubMed and Google Scholar) as of October 2025. A total of 527 (out of 572) abstracts were fit for initial screening to identify the eligible reports. Due to heterogeneity in study designs and reported outcomes, findings were synthesised descriptively and grouped by variant mechanism (cis-acting and trans-acting). The final analysis included 89 articles that demonstrated a direct association between a non-coding genomic variant and a quantitative measure of clinical severity. Results: Two main groups of non-coding variants (NCVs) that modulate foetal haemoglobin (HbF) induction were identified. The first major group comprises cis-acting variants within globin gene clusters (HBG2 promoter XmnI polymorphism, HBB promoter mutations and α-globin enhancer variants), while the second major group comprises trans-acting quantitative trait loci (QTLs) (BCL11A and HBS1L-MYB loci). Non-globin NCVs in the UGT1A1 promoter were also found to influence the severity measures in β-thal and SCD. NCVs primarily alter the binding of transcription factors and the looping dynamics of chromatin, modulating the α/β chain balance ratio and γ-globin repression. The XmnI polymorphism is the most prominent cis-acting modifier associated with β-thal intermedia. The promoter polymorphisms in TNF-α and VCAM1 are associated with vascular complications in SCD. Conclusions: NCVs are fundamental when determining the clinical measures of haemoglobinopathies, in addition to coding variants. NCV screening should be integrated for clinical prognosis for the accurate prediction of haemoglobinopathy severity and associated high-risk complications. NCVs may represent promising targets for next-generation gene editing and therapeutic intervention strategies aimed at modifying the severity of β-thal, α-thal and SCD. Full article