Search Results (645)

Genetic background strongly influences the penetrance and phenotypic expression of SMAD4-associated intestinal tumorigenesis, yet the underlying modifier loci remain poorly defined. To investigate the genetic architecture of tumor susceptibility and systemic physiology, we analyzed 260 Smad4⁺/⁻ × Collaborative Cross (CC)-F1 mice derived from 14 CC lines using 11 quantitative traits, including longitudinal body weight, adjusted organ weights, and intestinal polyp counts across anatomical regions. Principal component analysis reduced these traits to seven components explaining more than 85% of total phenotypic variance. PC1 represented a tumor burden–metabolic axis, whereas PC2 captured systemic organ-physiology variation. Genome-wide QTL mapping of principal component scores identified significant loci for PC1 on chromosomes 1 and 4 and a female-specific locus for PC5 on chromosome 10, with additional suggestive loci supporting a polygenic architecture. Founder-effect analysis revealed strong contributions from CAST/EiJ, 129S1/SvImJ, and WSB/EiJ haplotypes. Candidate gene annotation identified biologically relevant coding and noncoding loci, including Galnt7 and Galntl6, as well as regulatory regions with potential enhancer activity. Together, these findings indicate that intestinal tumor susceptibility in Smad4⁺/⁻ × CC-F1 mice is influenced by multiple coding and regulatory genetic modifiers with sex-dependent effects. This study demonstrates that integrating multivariate phenotyping with systems genetics analyses provides an effective framework for identifying the complex genetic networks underlying intestinal tumorigenesis and associated systemic physiological variation in genetically diverse mouse populations. Full article

Background/Objectives: The domestic yak (Bos grunniens) is a livestock species of major relevance in high-altitude environments and an important model for studying adaptation and reproductive isolation within Bovini. Despite its close phylogenetic relationship with cattle (Bos taurus), yak × cattle hybrids show a marked sex-biased fertility pattern, with fertile females and generally sterile F1 males, suggesting that subtle chromosomal or genomic differences may underlie post-zygotic reproductive barriers. In this study, we performed a cytogenetic characterization of eight adult yak bulls imported and reared in Central Italy using conventional and molecular cytogenetic approaches. Results: GTG-, RBG-, RBA- and CBA-banding confirmed the yak diploid number as 2n = 60 and the fundamental number as NF = 62, with banding patterns highly comparable to the standardized cattle karyotype. CBA-banding showed an X chromosome lacking evident constitutive heterochromatin and a Y chromosome with distal C-positive blocks. Chromosome instability was low, with 3.75% abnormal metaphases, mainly represented by chromatid and iso-chromatid breaks, while the mean sister chromatid exchange (SCE) rate was 5.19 ± 2.14 per cell. Sequential Ag-NOR/RBA staining localized nucleolar organizer regions (NORs) at the telomeres of autosomes 2, 3, 4, 11 and 25, as in cattle. Zoo-FISH using bovine chromosome paints for X, Y, 5 and 15 showed complete hybridization to the corresponding yak chromosomes, and BAC-FISH mapped the Y-linked ZFY and SRY genes to positions homologous to those reported in cattle. A comparative bioinformatics analysis of available yak genome assemblies confirmed the overall genome-wide correspondence with cattle, while revealing chromosome orientation issues and small local inconsistencies that may be relevant for comparative mapping and probe design. Conclusions: Overall, at the resolution tested, these findings support broad macrostructural conservation of yak and cattle karyotypes and provide cytogenetic reference data for yak populations reared outside of their traditional range. The persistence of F1 male sterility despite this large-scale chromosomal conservation suggests that fine-scale sex chromosome differences, particularly involving pseudoautosomal regions, recombination boundaries, or heterochromatin organization, may deserve targeted investigation. Full article

Background/Objectives: Prenatal chromosomal assessment can benefit from the complementary use of non-invasive prenatal testing (NIPT), chromosomal microarray analysis (CMA), and karyotyping because each test provides different information. Methods: We retrospectively analyzed 14,011 fetus-specific amniotic fluid cases obtained through second-trimester amniocentesis between 2014 and 2023. The study included overlapping subgroups tested by NIPT and karyotyping (n = 1300), CMA and karyotyping (n = 444), or all three methods (n = 78). Results: Karyotyping identified fetal chromosomal abnormalities in 1288 cases (9.2%). Among 983 evaluable cases in the clinically selected NIPT–karyotyping subgroup referred for invasive diagnosis by amniocentesis, the positive predictive value was 88.8% for trisomy 21, 66.7% for trisomy 18, 21.4% for trisomy 13, and 37.0% for sex chromosome abnormalities. Because these estimates were derived from a highly selected referral cohort rather than an unselected prenatal screening population, the PPV and NPV values should be interpreted within this referral setting and should not be generalized to unselected prenatal screening populations. Low-risk or inconclusive NIPT results did not completely exclude fetal chromosomal abnormalities. CMA detected pathogenic or likely pathogenic copy-number findings in 17 of 397 cases with normal karyotypes and provided additional molecular information in selected cases with abnormal karyotypes. Conversely, karyotyping identified 11 abnormalities among 388 cases with only likely benign, benign, or normal CMA results, including 10 apparently balanced reciprocal translocations and one diploid–tetraploid mosaicism. Conclusions: These findings show that NIPT, CMA, and karyotyping provide complementary rather than interchangeable information. High-risk NIPT results should be confirmed by invasive diagnostic testing, while CMA and karyotyping should be selected according to the clinical indication and suspected type of abnormality. Full article

Glioblastoma (GBM) exhibits marked sex differences in incidence, outcome, and molecular regulation, yet the mechanisms underlying these disparities remain poorly defined. ZEB1 is a neurodevelopmental transcription factor implicated in GBM progression and cellular plasticity, but its prognostic and functional relevance may differ by sex. Here, we analyzed TCGA-GBM transcriptomic and clinical data to assess the relationship between ZEB1 expression, patient sex, and survival and to identify sex-specific transcriptional programs associated with ZEB1. Patients were stratified by ZEB1 expression and sex, followed by differential expression analysis, functional enrichment, and survival modeling. High ZEB1 expression was associated with improved overall survival in female patients but not in male patients. Sex-stratified transcriptomic analysis revealed distinct ZEB1-associated gene expression signatures, with enrichment of chromatin-modifying and demethylase-related pathways among male–female comparisons. Candidate Y-linked epigenetic regulators, including KDM5D and UTY, were differentially expressed in ZEB1-high male tumors. qPCR validation in male and female patient-derived GBM cell lines supported sex-dependent regulation of these candidates and showed that KDM5D and UTY expression was reduced following ZEB1 knockdown in male cells. Together, these findings identify a sex-dependent prognostic role for ZEB1 in GBM and suggest that ZEB1 interacts with sex-chromosome-linked epigenetic regulators to shape tumor transcriptional states. Full article

Aggression is a behavioral phenomenon observed not only in wild animals but also in companion animals, including the domestic cat. Although feline aggression represents a common welfare and public health concern, its genetic and environmental causes remain not fully understood. The aim of this systematic review was to identify and synthesize the current evidence regarding the genetic and environmental factors associated with aggressive behavior in domestic cats. Original articles published in English between 2005 and 2025 were retrieved from Scopus and PubMed using predefined search strategies. After a two-stage screening and eligibility assessment, 25 studies retrieved though the database searches met the inclusion criteria. One additional eligible study was identified through reference screening, resulting in a total of 26 included studies. No formal risk-of-bias assessment was performed. Findings were synthesized narratively because of the substantial heterogeneity in study design, behavioral assessment methods, and outcome measures. The available evidence indicates that feline aggression is influenced by a complex interaction between genetic predisposition and environmental factors. Associations have been reported with polymorphisms in genes such as OXTR and AR, chromosomal abnormalities, breed, sex, coat color, early-life experiences, owner management, and environmental conditions. Considerable variability in behavioral assessment methods and the absence of a universally accepted classification of feline aggression currently limit direct comparison across studies. Overall, feline aggression should be regarded as a multifactorial trait whose accurate interpretation requires consideration of both inherited and environmental influences. Full article

Endoreduplication and mixoploidy are widespread but poorly characterized phenomena in Cannabis sativa, a species notable for its rapid growth and high morphological variability. In this study, we analyzed 12 accessions using flow cytometry, chromosome counts, and fluorochrome banding to investigate organ-specific patterns of endopolyploidy and the occurrence of mixoploidy. Roots and cotyledons consistently exhibited high levels of endoreduplication, with substantial proportions of 8C nuclei and above, whereas the first pair of leaves displayed a profile similar to that of adult foliage, dominated by 2C nuclei. Cycle value and endocycle index calculations confirmed significant differences among organs, with roots and cotyledons showing markedly higher endoreduplication levels than leaves. Chromosome counts revealed the expected diploid number (2n = 20), but we also detected triploid and tetraploid cells in several accessions, indicating somatic mixoploidy. The presence of endoreduplication and mixoploidy suggests that C. sativa exhibits complex cell cycle regulation during early development. Fluorochrome banding revealed GC- and AT-rich DNA regions. Sex chromosome candidates are heterochromatic and contain AT-rich DNA. These findings expand the cytogenetic knowledge of the species and provide a basis for future studies on the developmental and evolutionary significance of somatic genome variation in C. sativa. Full article

Most studies involving genomic data in animal breeding use only the effects of autosomal chromosome markers, excluding the sex chromosomes. However, the X chromosome is the second-largest chromosome in the bovine genome, and several economically important traits are sexually dimorphic, such as those related to growth. Therefore, the objective of this study was to evaluate whether there are predictive advantages for genetic parameters when including genomic markers from the X chromosome for yearling weight (YW) and postweaning gain (PWG) in Nellore cattle. Genetic parameter estimates were obtained under three scenarios: (1) only pedigree and phenotypic information; (2) pedigree, phenotypes, and autosomal chromosome markers; and (3) pedigree, phenotypes, autosomal chromosome markers, and X chromosome markers. Analyses were carried out using Bayesian inference with BLUPF90 family software version 2025. The heritability estimates obtained and their respective standard errors were 0.41 ± 0.004 for YW and 0.21 ± 0.004 for PWG. No differences were observed among the three scenarios tested for either trait. Therefore, the inclusion of the X chromosome did not influence the estimates of genetic parameters for these growth traits in Nellore cattle. Nevertheless, further molecular and genomic studies on the bovine X chromosome are still needed to explain the genetic effects and biological functions associated with this chromosome and with different traits of economic interest, as well as to justify whether to include the X chromosome in genomic prediction analyses. Full article

Background: Monochorionic twin pregnancies provide a unique model to investigate fetal phenotypic discordance, because both fetuses share a single placenta and interconnected vascular circulation. Although most monochorionic twins are monozygotic, clinically relevant differences may arise through genetic, epigenetic, placental, and stochastic developmental mechanisms. Methods: This systematic review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD420261432361). PubMed/MEDLINE, Embase, and Scopus were searched from inception to June 2026. Eligible studies included monochorionic monozygotic twin pairs with discordant congenital, developmental, or syndromic phenotypes, confirmed or clearly inferable monochorionicity, and at least one genomic, cytogenetic, or epigenetic investigation; studies describing confirmed monochorionic dizygotic twinning were excluded. Findings were synthesized qualitatively. Results: The search identified 1357 records. After duplicate removal and screening, 48 studies fulfilled the eligibility criteria, comprising 441 monozygotic twin pairs; 37 were single-pair case reports, whereas one large retrospective cohort study alone contributed 193 pairs (44% of the entire pooled sample). Reported phenotypes included congenital heart disease, chromosomal abnormalities, disorders of sex development, imprinting disorders, neurodevelopmental disease, endocrine disorders, renal anomalies, skeletal disorders, and multisystem malformations. Molecular methods included karyotyping, FISH, chromosomal microarray, array-CGH, CNV analysis, WES, WGS, targeted sequencing, and methylation profiling. Proposed mechanisms included postzygotic chromosomal errors, somatic mutations, tissue-specific mosaicism, discordant or shared CNVs, differential methylation, imprinting defects, variable expressivity, blood chimerism, unequal placental sharing, TTTS, TAPS, sFGR, and uteroplacental insufficiency. Conclusions: Phenotypic discordance in monochorionic twins is rarely explained by a single mechanism. Available evidence supports a multifactorial model in which postzygotic genetic events, epigenetic regulation, placental vascular factors, and stochastic developmental processes interact. Full article

Sex- and gender-based immune differences have often been interpreted through a male–female biological binary, overlooking how endocrine signaling dynamically shapes immune function. Gender-affirming hormone therapy (GAHT) offers a unique physiological model to disentangle the effects of sex steroids from chromosomal background and examine immune plasticity in contexts relevant to reproductive health. This hormone-informed framework proposes that estradiol and testosterone regulate immune set-points across innate, adaptive, metabolic, and mucosal compartments. Through genomic and non-genomic signaling via androgen and estrogen receptors (AR, ERα/β), these hormones drive distinct immune outcomes: testosterone dampens type I interferon responses in plasmacytoid dendritic cells and reshapes monocyte inflammatory profiles, while estradiol promotes macrophage polarization and enhances T helper1 (Th1) responses. Hormonal effects are closely coupled to cellular metabolism: androgen signaling acts as a “metabolic brake” on Th17 cells by limiting glutaminolysis, a process reinforced by epigenetic remodeling, and is reflected in shifts in the circulating metabolome, positioning metabolomics as a sensitive tool for monitoring hormone-driven immune adaptation. Regardless, hormones also reshape mucosal barriers and reproductive microbiome composition. GAHT alters vaginal and gut microbial communities and their metabolism, influencing mucosal immunity, local inflammation, and reproductive tract homeostasis, with potential implications for fertility preservation, susceptibility to reproductive tract infections, and long-term genital mucosal health. Collectively, this evidence underscores that human immunity is highly responsive to endocrine context. This review synthesizes evidence linking endocrine trajectories, tissue microenvironments, reproductive biology, and social determinants of health, aiming to advance understanding of immune plasticity and contribute to a more inclusive framework of human immune diversity. Full article

Early sex identification is essential for the propagation, cultivation, quality improvement, and germplasm management of dioecious horticultural plants and related functionally dioecious systems, particularly in perennial species with long juvenile phases. However, the reliability and transferability of sex-identification technologies depend strongly on the underlying sex-determining mechanism. Here, we synthesize recent advances in plant sex determination and diagnostic technologies, ranging from morphological and biochemical traits to molecular markers, high-throughput sequencing, structural-variant detection, and emerging non-invasive phenotyping. We propose that sex-identification strategies should be selected according to the biological target generated by each mechanism, including heteromorphic sex chromosomes, homomorphic sex-determining regions (SDRs), functional sex-determining genes, sex chromosome turnover, dosage-dependent systems, and environmentally labile sex expression. We further distinguish genetic, developmental, physiological, and phenotypic layers of plant sex, emphasizing that DNA markers and spectral phenotyping provide complementary information. Genomic markers and non-invasive phenotyping are expected to be consistent when genetic sex is stably expressed, but they may become inconsistent when sex expression is developmentally, hormonally, or environmentally modulated. While molecular markers remain the most reliable tools for confirmatory genotyping, Raman spectroscopy, surface-enhanced Raman scattering (SERS), hyperspectral imaging, and machine learning may serve as rapid prescreening tools in large breeding populations, although their application remains at the proof-of-concept stage. Finally, we present a mechanism-guided decision framework for integrating genomic markers and non-invasive phenotyping to support early sex screening, propagation planning, planting-material optimization, and marker-assisted improvement in dioecious horticultural plants. Full article

The carob tree (Ceratonia siliqua L., Fabaceae) is an ecologically and economically significant species of the Mediterranean basin, yet its cytogenetic and genomic organisation have remained largely uncharacterised. Here we present the first comprehensive molecular cytogenetic characterisation of C. siliqua, combining conventional karyotyping, fluorochrome banding, fluorescence in situ hybridisation (FISH), and flow cytometric genome size estimation across 29 accessions spanning the Mediterranean basin. A uniform diploid chromosome number of 2n = 24 was confirmed across all 14 populations examined, including Algerian, French, and Lebanese accessions, with no karyotypic variation detected regardless of geographic origin, altitude, or cultivation status. Karyotype analysis revealed a bimodal chromosome set comprising two large metacentric pairs and ten smaller pairs, with an intermediate asymmetry class (AsI = 60.09; R = 2.71). Physical mapping of ribosomal RNA gene families by FISH identified three chromosome pairs bearing 35S rDNA loci, all co-localising with GC-rich CMA₃-positive heterochromatin at satellite regions, and a single 5S rDNA locus at the telomeric region of a distinct chromosome pair, corresponding to the S-type arrangement. DAPI staining revealed an additional class of AT-rich constitutive heterochromatin at centromeric positions, compositionally and positionally independent of the rDNA arrays. Genome size was strikingly conserved across all 23 accessions assessed (2C = 1.10–1.23 pg; overall mean 1.14 ± 0.03 pg), with no significant variation attributable to geographic origin, altitude along an Algerian gradient (162–950 m a.s.l.), cultivation status, or sex. The near-identical genome sizes recorded in female and male individuals provide no cytometric evidence for heteromorphic sex chromosomes in this dioecious species. These results establish a stable genomic and cytogenetic baseline for C. siliqua across its Mediterranean range and provide a reference framework for future comparative cytogenetics, molecular marker development, and breeding programmes targeting this increasingly valued climate-resilient crop. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of coronavirus disease 2019 (COVID-19). Toll-like receptor 8 (TLR8), which is located on the X chromosome, plays as a key mediator of the innate immune response. Genetic variation in the form of single-nucleotide polymorphisms (SNPs) within TLR8 has been linked to changes in the transcriptional activity of this gene. Thus, we aimed to identify TLR8 SNPs in the proximal promoter region and investigate whether these SNPs are associated with COVID-19 case status in a Korean population. We performed amplicon sequencing to investigate the genotypes and allele frequencies of regulatory SNPs in COVID-19 patients (n = 191) and the control group (n = 173). Four polymorphic sites, rs5741883, rs186566524, rs3764879, and rs3764880, were identified within the TLR8 proximal promoter. Given the X-linked nature of this locus, allele and genotype frequencies were computed independently by sex. Notably, the minor C allele at rs3764879 occurred at a markedly reduced rate among male patients (10%) relative to male controls (24%), corresponding to an OR of 0.35 (95% CI 0.15–0.8; p = 0.018; q = 0.036). A parallel pattern emerged for rs3764880, where the minor A allele was likewise underrepresented in male patients (9%) versus male controls (24%), yielding an OR of 0.3 (95% CI 0.12–0.7; p = 0.01; q = 0.036). By contrast, neither genotype nor allele distributions differed significantly between female patients and female controls for any of the four variants. These results indicate that the TLR8 polymorphisms rs3764879 and rs3764880 may be associated with COVID-19 case status among Korean males, although further validation in larger, independent cohorts is required. Full article

Research has shown a sex-specific immune response, with males having a worse prognosis in acute inflammatory diseases. While these disparities were initially attributed to sex hormones, increasing evidence points to a predominant role for X-linked genetic factors. Toll-like receptors and several components of their signaling pathway are encoded on the X chromosome and may contribute to these differences. We investigated whether increase in circulating oestradiol influences TLR-dependent immune response. Sixteen women undergoing controlled ovarian hyperstimulation for in vitro fertilisation were studied. Whole blood collected before treatment, during stimulation and at ovulation triggering was stimulated with ligands targeting TLR2/6, TLR1/2, TLR4 and TLR7/8. TLR2, TLR4 and CD99 expression, intracellular phosphorylated NF-κB p65, ERK1/2 and p38 MAPK, and cytokine production were assessed. Oestradiol levels increased markedly during treatment (48.1 to 1819.5 pg/mL; p < 0.001). Despite this rise, no or minimal impact on TLR2/4 and CD99 expression, intracellular signalling or cytokine release was detected. Only IL-6 and IL-10 in response to TLR2/6 stimulation increased significantly, with IL-6 positively associated with oestradiol variation. These findings indicate that oestradiol exerts a limited influence on TLR-dependent immune responses, supporting our view that sex-based immune differences are driven primarily by genetic rather than hormonal factors. Full article

Background and Objectives: Sex differences are well recognized in the epidemiology and clinical manifestations of knee osteoarthritis (OA), with women exhibiting a higher prevalence and greater disease severity than men. Although synovial inflammation is increasingly recognized as a key contributor to OA pathology, the molecular mechanisms underlying sex-related differences in OA synovium remain incompletely understood. Materials and Methods: Synovial tissues were obtained from patients with knee OA undergoing total knee arthroplasty. RNA sequencing (RNA-seq) was initially performed using synovial samples from five female and five male patients to identify differentially expressed genes (DEGs) associated with sex. Candidate genes identified by RNA-seq were subsequently validated by quantitative PCR (qPCR) using an independent cohort consisting of 78 female and 27 male patients. Multivariable analyses adjusted for age, body mass index (BMI), and Kellgren–Lawrence (KL) grade were performed to evaluate the independent association between gene expression and sex. Results: RNA-seq analysis identified 12 female-upregulated genes and 13 male-upregulated genes. Several Y chromosome-related genes showed marked male-specific expression and were excluded from downstream validation analyses. qPCR validation demonstrated significantly higher expression of CAPN6, COL6A6, EGFL6, LAMP3, and MMD in female synovial tissues. After adjustment for age, BMI, and KL grade, EGFL6 (β = 0.829, p = 0.004), LAMP3 (β = 0.596, p = 0.029), and MMD (β = 0.698, p = 0.014) remained significantly associated with female sex. In contrast, DAW1 became significantly associated with male sex after multivariable adjustment (β = 0.753, p = 0.009). Conclusions: Distinct sex-related synovial gene expression profiles were identified in knee OA. In particular, EGFL6, LAMP3, and MMD were independently associated with female sex, suggesting potential sex-related pathology in OA synovium. These findings provide new insight into the molecular basis of sex differences in OA and may contribute to the development of sex-specific therapeutic strategies. Full article

Reliable preimplantation embryo sexing is relevant in cattle breeding; however, PCR-based Y-marker detection may be sensitive to limited DNA input and sample-type-specific properties of embryo-derived material. In this observational study, we examined assay-output patterns in a low-input multiplex PCR workflow targeting a male-specific Y-chromosome marker (MSY) together with an autosomal internal control targeting cyclin-dependent kinase 1 (CDK1). A total of 141 bovine embryo-derived samples were analyzed across three sample categories: whole embryos, cleavage-stage blastomere biopsies, and blastocyst-stage trophectoderm biopsies. Assay evaluability differed across sample categories, being highest in blastocyst-stage biopsy samples (90.6%, 29/32), intermediate in whole embryos (82.9%, 58/70), and lowest in blastomere-biopsy samples (64.1%, 25/39). Among technically evaluable CDK1-positive samples, apparent MSY-positive classification also differed across categories, with rates of 55.2% (32/58) in whole embryos, 52.0% (13/25) in blastomere-biopsy samples, and 6.9% (2/29) in blastocyst-stage biopsy samples. In a same-lysate repeat-amplification subset, overall evaluability concordance was 92.5% and overall apparent MSY-based classification concordance was 88.2%, although subgroup sizes were limited. Because no independent reference method for true embryo sex was available and sample category was structurally confounded with developmental stage, semen type, sire, and partly PCR-date structure, the findings should be interpreted as assay-output observations rather than measures of biological sex ratio or diagnostic sexing accuracy. Overall, embryo-derived sample categories showed differing assay evaluability and apparent MSY-classification patterns within this low-input PCR setting, supporting the need for sample-type-specific validation when low-cell embryo-derived samples are used. Full article