Genes最新文献

Background/objectives: Human-driven environmental change can promote cancer development in wild species, yet the pathophysiology of wildlife cancers remain largely unexplored. Urogenital carcinoma (UGC) in the California sea lion (CSL) (Zalophus californianus) is one of the most common cancer types documented in any wild mammal. The pathogenesis of UGC in CSLs is known to be multifactorial, with links to environmental contaminant exposure and infection by Otarine Herpesvirus-1 (OtHV-1); however, the genomic features of these cancers have not been thoroughly explored. Understanding UGC pathogenesis in the CSL has important implications for the health of humans and other species that share environment and diet.

Methods: We leveraged the evolutionary conservation between the domestic dog and CSL genomes to perform cross-species whole-exome sequencing (WES) of CSL UGC tumors and matched normal tissue pairs. We also used PCR and Sanger sequencing to investigate the prevalence of DNA from OtHV-1.

Results: Bioinformatic analyses identified shared somatic variants and DNA copy number aberrations in UGC tumor samples, including recurrent exonic single-nucleotide variants in CD274/PD-L1, and recurrent copy number gains in CD274/PD-L1, TNFRSF14, CD200, CDK4, and PLCG2. In an extended cohort of 70 CSLs (tumor, matched normals, and controls), a recurrent C > T single-nucleotide variant in exon 4 of CD274/PD-L1 was identified in 54 of 68 (79.4%) CSLs with diagnosed UGC. OtHV-1 DNA was detected in 67 of 70 individuals (95.8%).

Conclusions: These results demonstrate that cross-species exome capture provides a means to identify genomic alterations that may play a role in the molecular pathogenesis of UGC in the CSL and adds to the body of evidence for an association between OtHV-1 and UGC in this species.

Background/objectives: Females are generally more resistant to ischemia-related ferroptosis than males, due to differences in iron metabolism, antioxidant pathways, and sex hormone-mediated regulation of ferroptosis suppressors. This has not been systematically studied in a human donor liver model. To investigate the effect of sex on ferroptosis and oxidative stress pathways in non-utilized donor livers (NDLs), we assessed patterns of gene expression in NDLs under ex vivo normothermic machine perfusion (NMP).

Methods: We utilized the PROTECT dual-circuit ex vivo NMP system to assess three male and two female NDLs undergoing 6 h NMP. Perfusate and tissue samples were collected at baseline and 6 h of NMP. Malondialdehyde (MDA) levels were quantified as biochemical markers of iron overload and lipid peroxidation, respectively. Ferroptosis-related gene expression was assessed using molecular assays. Comparisons between male and female NDLs were used to determine the influence of sex on ferroptosis and oxidative injury during NMP.

Results: NMP was successfully performed on NDLs (n = 5) from three male (56.3 ± 5.7 years) and two female donors (46.5 ± 0.7 years, p = 0.15). The fold-change in the oxidative stress marker MDA was comparable between female (1.2 ± 0.6) and male (1.0 ± 0.4) NDLs after 6 h NMP (p = 0.76). All livers showed upregulation of ferroptosis-related genes (Hypoxia-inducible factor 1 alpha, Iron Responsive Binding Elements 2, Ribosomal Protein L8, Ferritin Heavy Chain 1, Acyl-CoA synthetase family member 2, ATP synthase membrane subunit c locus 3, Heme-oxygenase 1, NAD(P)H Quinone Dehydrogenase 1, Tetratricopeptide Repeat Domain 35, Nuclear Factor Erythroid 2 Related Factor 2). ACSF2 expression was significantly higher in female NDLs compared with males undergoing 6 h NMP (3.6 ± 3.0 vs. 1.0 ± 0.7-fold change, p = 0.04). There were no sex-based significant differences observed in the expression of other ferroptosis-related genes (HIF-1α, IREB2, RPL8, FTH-1, ATP5G3, HO-1, NQO1, TTC35, and NRF2) between male and female NDLs. No gene reached statistical significance after false-discovery-rate (FDR) correction.

Conclusions: Normothermic machine perfusion of NDLs was feasible, and no sex-related differences were observed in MDA levels or most ferroptosis-related gene expression after 6 h. Although ACSF2 showed higher expression in female livers, this was not significant after multiple testing correction, highlighting the need for larger studies to explore sex-dependent ferroptosis signaling during liver preservation.

Background/Objectives: Arctic foxes (Vulpes lagopus) exemplify the vulnerability of Arctic species to global warming and anthropogenic impacts, including habitat loss, interspecific competition with temperate species, pollution (chemical and biological), and declining prey abundance. Despite their ecological importance, the evolutionary and demographic history of the species is still incompletely understood, and the colonization history of isolated island populations, such as the one on Iceland, remains unresolved. Methods: We analyzed 80 mitochondrial genomes from across the Holarctic, including 22 Icelandic individuals. We combined phylogenetic reconstruction, coalescence-dating, haplotype network analysis, and diversity metrics to infer matrilineal relationships and colonization history. Results: Seven distinct haplogroups (Hg.1-Hg.7) were identified, which diverged ≥65 thousand years ago (kya). Two haplogroups were broadly distributed across Fennoscandia, Russia, Iceland, and Canada, while others were region-specific: two in eastern Russia (respectively diverging ~171 kya and ~89 kya), one in central Russia (~66 kya), and two in Iceland (~95 kya and ~66 kya). Three haplogroups were detected in Iceland, and at least four unrelated founding females are required to explain the current matrilineal diversity. One haplogroup contained sufficient representatives for molecular dating, yielding a minimum colonization age of ~5600 years, assuming in situ diversification. Observed matrilineal diversity in Iceland does not uniquely identify a single geographic source. Conclusions: Arctic foxes' distribution and diversity reflect repeated cycles of isolation and expansion as circumpolar environments shifted. Broader sampling across the Nearctic is critical to clarify the timing, sources, and routes of Iceland's colonization, as Nearctic sampling was limited to a single Canadian mitogenome.

Background: The incidence and prevalence of type 2 diabetes mellitus (T2DM) has been increasing worldwide recently. Diabetic retinopathy (DR) is a major ocular complication of diabetes mellitus, and it is the leading cause of blindness and visual impairment. Sirtuin 1 (SIRT 1) is a NAD+-dependent deacetylase and is involved in stress responses such as hypoxic and genotoxic stress, inflammation and heat shock. Tumor necrosis factor α (TNF-α) is an important inflammatory mediator that is involved in the pathogenesis of T2DM. The purpose of our study was to investigate the relationship between the SIRT1 rs7069102 polymorphism and TNF- α rs1800629 polymorphisms and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

Materials and methods: We analyzed 1554 Slovenian (Caucasian) patients with T2DM of at least 10 years' duration, stratifying them into two groups: 577 patients with diabetic retinopathy (DR) and 977 patients without DR. Genotyping of SIRT1 rs7069102 and TNF-α rs1800629 polymorphisms was performed using the StepOne real-time PCR System with TaqMan SNP Genotyping Assays.

Results and conclusions: A significant difference in the distribution of SIRT1 rs7069102 genotypes and alleles was observed between the groups. Under the dominant inheritance model, patients with CC or CG genotypes were more likely to develop DR than those with the GG genotype (OR = 1.30; 95% CI = 1.02-1.65; p = 0.036). No significant association was found between TNF-α rs1800629 and DR.

Background/objectives: Interpreting missense variants in intrinsically disordered proteins (IDPs) remains a major challenge, as these proteins lack stable structure and are under-represented in experimental and clinical annotations. Variants occurring in IDPs are disproportionately classified as variants of uncertain significance (VUS), reflecting the absence of appropriate predictive tools rather than true biological neutrality. Here, we address this challenge using a curated dataset of neurodevelopmental disorder (NDD)-associated proteins.

Methods: We integrated curated and predicted disorder annotations from DisProt and MobiDB to characterize the structural landscape of 339 NDD-associated proteins. To quantify a regional genetic constraint, we recalculated the Missense Tolerance Ratio (MTR) using a published framework adapted to the recent gnomAD release (v4.1.0). Integration with 33,124 ClinVar-reported missense variants revealed that, while mean constraint levels differ only modestly across structural states, ordered and structural transition regions show the strongest depletion of missense variation.

Results: MTR identifies localized low-tolerance subregions within IDRs, indicating that these regions are not uniformly permissive and can harbor functionally essential elements.

Conclusions: Overall, our results demonstrate that missense constraint in NDD proteins is highly localized and context-dependent, and that integrating high-quality disorder annotations with updated MTR profiles can improve the prioritization and interpretation of missense variants in IDRs and IDPs.

Background/Objectives: Flea beetles (Coleoptera, Chrysomelidae: Alticinae) show extensive karyotypic diversity, yet cytogenetic and genomic data remain scarce for many taxa. Species of the genus Podagrica are characterized by unusually high chromosome numbers compared with the modal condition in Alticinae, suggesting a history of chromosomal fissions. This study aimed to characterize the karyotype and repetitive DNA composition of Podagrica fuscicornis, with special emphasis on the satellitome and its contribution to chromosome organization. Methods: Male specimens of P. fuscicornis collected in southern Spain were analyzed using conventional cytogenetic techniques, including Giemsa staining, DAPI staining, and C-banding. Fluorescence in situ hybridization was employed to map nucleolar organizer regions (NORs), telomeric repeats, and major satellite DNA (satDNA) families. The satellitome was characterized using Illumina short-read sequencing and analyzed with the RepeatExplorer2/TAREAN pipeline to identify satDNA families and estimate their genomic abundance and divergence. Results: The male karyotype of P. fuscicornis was 2n = 40 (38 + XY), with an Xy_p sex chromosome system. Constitutive heterochromatin was mainly pericentromeric, and the Y chromosome was largely heterochromatic. NORs were located on a single autosomal pair, and the ancestral insect telomeric motif (TTAGG)_n was detected at chromosome ends. The satellitome comprised at least 70 different satDNA families, representing 9.51% of the genome, some of them related to transposable elements. Ten of these 70 satDNAs are shared in other Alticinae species. The most abundant families were primarily localized in pericentromeric regions and showed differential distribution between autosomes and sex chromosomes. Conclusions: These results indicate that extensive chromosomal fissions and high satDNA dynamics could drive the high chromosome number and heterogeneous genome organization in P. fuscicornis, highlighting the role of repetitive DNA in karyotype evolution within Chrysomelidae.

Background: Fas/FasL-mediated apoptosis is central to immune homeostasis and is implicated in autoimmune lymphoproliferative syndrome (ALPS) and immune thrombocytopenia (ITP). We aimed to compare whole-blood transcriptional levels of CASP8 and CASP3 across ALPS, chronic ITP, and healthy controls.

Methods: CASP8 and CASP3 mRNA expression was quantified by real-time PCR in whole blood from clinically diagnosed ALPS patients, chronic ITP patients, and healthy controls.

Results: CASP8 mRNA expression was significantly increased in ALPS and ITP versus controls (p = 0.0009 and p < 0.0001, respectively) and was lower in ALPS than in ITP (p = 0.0265). CASP3 mRNA was also increased in both patient groups versus controls (ALPS: p = 0.0045; ITP: p < 0.0001), with no significant difference between ALPS and ITP (p = 0.1692).

Conclusions: ALPS and chronic ITP show distinct CASP8 transcriptional patterns and a shared upregulation of CASP3 at the whole-blood mRNA level. These findings are descriptive and do not directly assess caspase activation or apoptotic pathway activity; further protein- and cell subset-based studies are needed to clarify functional implications.

Background/Objectives: Hypermobile Ehlers-Danlos syndrome (hEDS) remains genetically unexplained despite decades of clinical investigation, with the molecular basis undefined for the vast majority of cases. This study employs integrated machine learning approaches with rigorous subject-level statistical methods to decode the genetic architecture underlying hEDS. Methods: We analyzed 35,923 rare genetic variants (gnomAD MAF < 0.2) across 116 subjects from 43 families (86 hEDS patients diagnosed per 2017 international criteria; 30 unaffected intrafamilial controls) using whole-exome sequencing. Machine learning analysis employed Random Forest feature selection, deep neural networks, and ensemble methods with subject-stratified cross-validation to prevent data leakage. Statistical association testing used subject-level Fisher's exact tests with Bonferroni correction (α = 3.77 × 10^-6 for 13,281 genes). Sensitivity analyses assessed robustness to family structure. Results: Subject-level analysis identified statistically significant enrichment in variants associated with three major biological systems: (1) collagen biosynthesis pathway variants (present in 63% of hEDS subjects vs. 17% of controls, Fisher's p = 1.06 × 10^-5, OR = 8.4), predominantly affecting COL5A1, COL18A1, COL17A1, and post-translational modification enzymes; (2) HLA/adaptive immune axis variants (74% of hEDS vs. 30% of controls, p = 2.23 × 10^-5, OR = 6.8), involving HLA-B, HLA-A, HLA-C, and TAP transporters; (3) mitochondrial respiratory chain variants (34% of hEDS vs. 7% of controls, p = 2.29 × 10^-3, OR = 7.1), with striking 4.2-fold enrichment in pediatric fracture cases (52% vs. 21%, p = 0.021, 95% CI: 1.2-14.6). These associations require independent validation and functional studies to determine their mechanistic relevance. Genome-wide analysis identified seven genes achieving Bonferroni significance (p < 3.77 × 10^-6), all encoding structural/cytoskeletal proteins. Machine learning models with proper subject-stratified cross-validation achieved 80% accuracy (95% CI: 73-86%, sensitivity = 82%, specificity = 77%). Conclusions: Our findings suggest that hEDS may involve genetic variation across multiple biological systems beyond classical collagen pathways. These hypothesis-generating associations require validation in independent cohorts and functional studies before mechanistic or clinical conclusions can be drawn.

Background/objectives: Ram fertility is essential for sheep production, influenced by genetic, physiological, behavioral, and environmental factors. This narrative review synthesizes findings from over 190 peer-reviewed publications to evaluate the phenotypic indicators, genetic architecture, molecular candidates, and management conditions influencing testicular development, semen quality, and reproductive performance in rams.

Methods: A narrative synthesis of peer-reviewed studies was conducted, integrating findings from quantitative genetics, genome-wide association studies, transcriptomics, and controlled environmental and management experiments. Emphasis was placed on studies evaluating fertility-related traits across breeds, ages, and production systems.

Results: Recent genomic and transcriptomic studies have identified potential biomarkers (e.g., IGF1, IGFALS, FOXO1) and gene networks linked to ram fertility, including semen quality, scrotal circumference, and endocrine regulation. For instance, genome-wide association studies (GWASs) have identified candidate genes such as SLC2A8 and MAPK3, which are associated with spermatogenesis and semen quality. Additionally, Y-linked SNPs such as ZFY16: g.146 C > T have been linked to testicular development. Genetic potential is heavily modulated by environmental constraints. Heat stress emerges as a disruptor of testicular thermoregulation, with recent evidence highlighting the vulnerability of spermatogenesis even in adapted breeds. Management interventions, specifically nutritional supplementation and hormonal modulation via melatonin, are discussed as effective strategies to mitigate environmental impacts.

Conclusion: Improving ram fertility will require an approach that prioritizes phenotypic traits supported by candidate genes identified through transcriptomic analyses and GWASs. Integrating these genetic tools together with cost-effective nutritional and hormonal management strategies can further improve semen quality, libido, and testicular traits, thereby enhancing fertility gains while maintaining sheep breed adaptability across production systems.