Frontiers in Genetics最新文献

Objectives: Hyperuricemia and gout are common public health problems, stemming from both genetic and lifestyle factors. Evidence from multi-ethnic regions in Yunnan Province remains limited. This preliminary study examined hyperuricemia and gout prevalence, related biomarkers, lifestyle patterns, and SLC2A9/SLC22A12 genetics variations among 88 participants from the Miao community in Yunnan Province China.

Methods: A cross-sectional survey and biochemical study were conducted. Demographic and lifestyle data were collected, and blood samples were analyzed for serum biochemical indicators. Eight SNPs in SLC2A9 and SLC22A12 were genotyped. Logistic regression models were applied to allele and genotype data.

Results: Demographic and clinical analyses for Miao villagers (n = 88) suggested that the morbidities of hyperuricemia and gout were more frequent in male and showed significant association with alcohol consumption, smoking, and elevated BMI. While dietary patterns showed no significant differences. Compared with non-hyperuricemia/non-gout individuals (n = 56), the hyperuricemia/gout group (n = 57) showed 56% higher uric acid (553.13 vs. 354.73 μmol/L), 37% elevated creatinine (84.66 vs. 61.80 μmol/L), and higher triglycerides (3.35 vs. 1.80 mmol/L), along with hematological abnormalities, e.g., elevated hemoglobin (162.77 vs. 147.50 g/L) and lower platelets counts (161.09 vs. 194.14 × 10⁹/L). Preliminary genetic analyses indicated a possible association between SLC2A9_rs10939650 and hyperuricemia/gout risk, whereas variant SLC22A12 polymorphisms showed no association. After Bonferroni correction, no SNPs remained statistically significant.

Conclusion: This preliminary study suggested that the relatively higher burden of hyperuricemia and gout in the Miao population may be influenced by ethnicity, sex, lifestyle factors, metabolic alteration, and potential genetic components. Given the small sample size, the genetic findings should be interpreted cautiously and validated in larger studies for that disease (hyperuricemia and gout) and for similar ethnic community.

Background: This study aimed to identify novel mutations associated with the progression of gastric cancer by establishing patient-derived xenograft (PDX) models and performing comprehensive genomic characterization of these PDX models and their corresponding primary tumors.

Methods: Fresh gastric cancer tissue samples were collected from 20 patients who underwent surgical resection at Shanxi Cancer Hospital and were subsequently implanted into NOD-SCID mice to establish PDX models. Histopathological features were evaluated using hematoxylin and eosin (H&E) staining. Whole-exome sequencing (WES) was performed on both primary tumors and their corresponding F1-PDX and F3-PDX tumors, focusing on mutations within 559 cancer-related genes. Predictive tools, including SIFT, Polyphen2_HVAR, Polyphen2_HDIV, and Mutation Taster, were utilized to identify potentially deleterious mutations, while I-Mutant and MUpro were employed to assess protein stability.

Results: Nine gastric cancer PDX models were successfully established, with seven models propagated to the third generation (F3-PDX), achieving an initial engraftment success rate of 45%. The latency of tumor establishment significantly decreased with each successive generation. The histological characteristics of the primary tumors were well preserved in the PDX models. WES of the three selected models revealed key mutated genes in primary tumors (F0), including IRS2, BLM, PDE4DIP, NUMA1, MYH9, TP53, PIK3CD, ERCC5, and ASXL1. A total of 28 somatic mutations were conserved across all three generations (F0, F1-PDX, and F3-PDX) in these models, representing a conservation rate of 43.75% (28/64). Among these conserved mutations, 10 were identified as potentially deleterious by multiple bioinformatics algorithms. Mutations in PTPRK (p.L988S), PIK3CB (p.F934L), LRP1B (p.A1912T), and IGF2R (p.G2052R) were predicted to significantly decrease protein stability.

Conclusion: This study demonstrated that PDX models effectively preserve the biological and genetic characteristics of primary gastric tumors, underscoring their utility in studying tumor heterogeneity. The integrated analysis of longitudinal WES data from primary tumors and matched PDXs enabled the identification of a core set of conserved, potentially deleterious mutations. The four prioritized mutations (PTPRK, PIK3CB, LRP1B, and IGF2R) provide new insights into the genetic landscape of gastric cancer and represent promising candidates for the development of targeted therapeutic strategies.

Introduction: The APOBEC3 family of cytidine deaminases induces somatic mutations that are highly prevalent in cancers, but the functional consequences remain largely unknown.

Methods: To determine these consequences, we exposed MCF7 tumorigenic breast epithelial cells to APOBEC3A, APOBEC3B or APOBEC3H Haplotype I.

Results: Comparative analysis between cells pre and post -APOBEC3 exposure revealed fewer deamination-dependent γH2AX foci post-APOBEC3 exposure, despite maintaining APOBEC3 protein expression. In a mouse xenograft model, high expressing, but not low expressing APOBEC3A-exposed cells caused increased tumor progression. In contrast, high expressing, but not low expressing APOBEC3B-exposed cells decreased tumor size. APOBEC3H Haplotype I-exposed cells stochastically increased tumor progression independent of expression levels. Consistent with tumor data, RNA-seq showed upregulation of tumor enhancing pathways only in cells that enhanced tumor progression.

Discussion: The results indicate that in a breast cancer xenograft model, APOBEC3A and APOBEC3H Haplotype I are more likely to contribute to enhanced tumor progression than APOBEC3B.

The Tylorrhynchus heterochaetus, a polychaete benthic invertebrate belonging to the Nereididae family, has emerged as a promising aquaculture species. It is highly regarded for its nutritional profile, with protein accounting for up to 60% of its dry weight, as well as its balanced amino acid composition. This has earned it the nickname "aquatic cordyceps". However, wild populations of this species have declined significantly due to environmental shifts and human activities, with local extinctions reported in certain regions. A critical barrier to advancing its population genetics and conservation biology has been the absence of a chromosomal-level reference genome for T. heterochaetus. To address this gap, we present the first chromosome-level genome assembly of T. heterochaetus, generated using PacBio HiFi sequencing data and Hi-C technology. The final assembly spans 782.25 Mb with a scaffold N50 of 75.39 Mb, successfully anchored to 11 pseudo-chromosomes. Repetitive sequences account for 428.09 Mb (54.73%) of the genome, and 20,145 protein-coding genes were annotated. This study provides foundational insights into the genetics, genomics, and evolutionary history of T. heterochaetus, laying a critical groundwork for future research and enabling the development of targeted genetic conservation strategies.

Background: Parkinson's disease (PD) is influenced by various factors, with lysosome function playing a critical role. However, the specific involvement of lysosome-related genes (LRGs) in PD remains unclear.

Objective: This study aims to identify biomarkers specific to PD that exhibit robust disease prediction capabilities.

Methods: Datasets for patients with PD, LRGs, and inflammation-related genes (IRGs) were retrieved from online databases. miRNAs and mRNAs within key modules were selected through Weighted Gene Co-expression Network Analysis (WGCNA), revealing strong associations with PD. A miRNA-mRNA network was constructed based on highly correlated PD-related LRGs (PD-LRGs) and miRNAs within these modules. Candidate genes were identified by intersecting target genes, differentially expressed genes (DEGs), PD-LRGs, and module-associated mRNAs. Machine learning and expression validation were employed to confirm these biomarkers. A nomogram was established, and its diagnostic performance was evaluated using a confusion matrix. Drug predictions were conducted based on these biomarkers. Spearman's correlation analyses were performed to assess the relationship between IRGs, freezing of gait (FOG)-related genes, and biomarkers. Molecular regulatory networks were constructed using datasets and online resources. Finally, clinical samples were collected for quantitative PCR (qPCR) validation of biomarker expression.

Results: Key modules related to PD were identified, comprising 190 miRNAs and 7,633 mRNAs. A miRNA-mRNA network was constructed based on 55 PD-LRGs and 181 miRNAs, resulting in the identification of 26 candidate genes strongly linked to lysosomal function. FGD4 and MAN2B1 were selected as biomarkers, and a gene expression-based risk prediction table was created. These biomarkers were significantly correlated with IRGs and several FOG-related genes. Gene localization analysis revealed that FGD4 and LRRK2, both critical to the FOG pathway, are located on chromosome 12. Drug prediction revealed that Tetrachlorodibenzodioxin and bisphenol A target both FGD4 and MAN2B1. qPCR analysis confirmed that FGD4 and MAN2B1 expression levels were significantly higher in patients with PD compared to healthy controls (p < 0.05).

Conclusion: FGD4 and MAN2B1 act as lysosomal biomarkers associated with PD and exhibit strong correlations with genes involved in PD-related freezing of gait. This study offers novel insights into PD diagnosis.

Geleophysic dysplasia represents an exceedingly uncommon autosomal recessive skeletal disorder marked by profound growth restriction, contractures affecting multiple joints, and cardiac valve abnormalities. The molecular foundation involves ADAMTSL2 gene mutations disrupting extracellular matrix architecture. We document a 29-year-old Taiwanese woman followed longitudinally for 25 years, presenting with severe short stature measuring 141.2 cm, widespread joint contractures, thoracolumbar scoliosis, and distinctive gait abnormalities. Whole-exome sequencing identified compound heterozygous ADAMTSL2 mutations: c.286C>T resulting in p. Arg96Trp and c.454_459del causing p. Cys152_Thr153del deletion. The clinical course revealed musculoskeletal deterioration alongside mild mitral valve involvement and os odontoideum. Bilateral glaucoma, consistent with previously reported ocular manifestations in geleophysic dysplasia, was diagnosed at age 26. Notably, recent ophthalmologic evaluation revealed keratoconus-like corneal ectasia with paradoxically increased central corneal thickness measuring 690-693 μm bilaterally, substantially exceeding normal values of 520-560 μm. This paradoxical corneal thickening, contrasting with the stromal thinning characteristic of classical keratoconus, represents a novel ADAMTSL2-related corneal phenotype. The patient maintained normal intellectual capacity despite physical limitations, contrasting with published early mortality rates approaching 33%. This extended clinical documentation establishes keratoconus-like corneal ectasia with paradoxical corneal thickening as a novel ophthalmologic manifestation in geleophysic dysplasia, while adding to prior reports of glaucoma in this condition. These findings emphasize the necessity for comprehensive ophthalmologic monitoring in ADAMTSL2-related disorders and supporting multidisciplinary management strategies.

The FK506 Binding Protein 5 (FKBP5) gene encodes a protein that binds to the immunosuppressive agent FK506. FKBP5 expression is regulated by genetic variation and epigenetic mechanisms, including DNA methylation (DNAm). This gene regulates the glucocorticoid receptor (GR), and aberrant FKBP5 methylation is associated with psychiatric and metabolic disorders. Recent evidence also indicates that FKBP5 methylation significantly influences malignant tumors. The methylation status of FKBP5 not only modulates its own expression but also contributes to disease pathogenesis by regulating downstream signaling pathways. Despite extensive research on FKBP5 in individual disease contexts, a critical gap remains in understanding how its DNAm serves as a unifying epigenetic mechanism across psychiatric, metabolic, and neoplastic disorders. Existing reviews often focus on single disease domains or on genetic and protein-level regulation, lacking a systematic, horizontal integration analysis centered on DNAm-a dynamic and reversible modification. This review aims to fill this gap by proposing a coherent "epigenetic regulatory framework" that elucidates how tissue-and site-specific FKBP5 DNAm patterns, through modulating glucocorticoid (GC) signaling, stress responses, and inflammatory pathways (e.g., NF-κB), contribute to divergent pathological outcomes. By integrating evidence from disparate fields, this review summarizes the role of FKBP5 DNAm in disease biology, its functions across various disorders, and its potential as a biomarker and therapeutic target, aiming to provide a theoretical foundation and strategic insights for disease diagnosis and treatment.

Individuals with rare genetic diseases collectively comprise 3.5%-5.9% of the population, roughly 400 million people worldwide. Undiagnosed rare disease programs have leveraged next-generation sequencing technologies to facilitate genetic diagnoses, thereby shortening the complex diagnostic odysseys that many of these patients and their families endure. However, enrollment data suggest disparities in access to undiagnosed genetic disease programs among racial and ethnic minorities. To better understand this issue, we conducted a retrospective review of our rare undiagnosed disease program to assess whether referral route was a determinant of disparities for minoritized racial and ethnic communities. Participants enrolled in the Yale Pediatric Genomics Discovery Program from 2016 to 2022 were self-categorized into four racial and ethnic groups: Hispanic/Latinx (any race), non-Hispanic White, non-Hispanic Black/African American, non-Hispanic Other. Route of referral was classified as Inpatient, Outpatient, or Outside/Self referrals. Completion rates were the percentage of participants who completed enrollment compared to their respective group. Demographics for program participants were different from Yale-New Haven Children's Hospital demographics, with over-representation of non-Hispanics Whites. Direct inpatient recruitment had a higher yield of Hispanic individuals, which was offset by under-representation of minoritized individuals in the Outside/Self setting. Inpatients had lower referral completion rates compared to Outpatient and Outside/Self referrals. These data suggest that the route of referral may represent different levels of access to care, and inpatient recruitment may be leveraged to promote participation by some minoritized communities. We encourage other programs to examine their cohorts for representation and identify strategies for improving participation.

Elective Genomic Testing (EGT) can identify individuals at risk for actionable conditions that would not come to clinical attention following current testing guidelines. We describe the results of a checkup unit from a leading Spanish University hospital (Clínica Universidad de Navarra, Spain) that has incorporated EGT to their regular clinical practice. Medical anamnesis, biochemistry, low-intensity whole body scan and EGT with interpretation of over 560 genes related to actionable adult-onset diseases (Veritas Intercontinental, Spain) was performed in 400 participants, including medical consultation before and after the checkup. Clinically relevant variants were identified in 79/400 participants (19.8%). Thirteen individuals (3.3%) presented with clinical variants included in the American College of Medical Genetics and Genomics secondary finding list (ACMG SF list); 69.2% of these variants showed potential association with personal or family history (PFH). The study presents the results of the first hospital integrating EGT into the checkup unit.