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Results for “phenotypic trajectory”

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At least 19 recordsLinked to original sources

PubMed2025

Genotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study.

BACKGROUND: Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are neurodevelopmental conditions caused by genetic variants leading to upregulated signaling in the RAS-MAPK pathway. While previous research has focused on genetic variability in cognitive and cardiac phenotypes, behavioral phenotypes, and their correlations across genetic variants and within the PTPN11 gene remain poorly characterized. METHODS: This study included 121 individuals with NS (PTPN11: 88, SOS1: 18, RAF1: 6, KRAS: 2, RIT1: 3, NRAS: 2, LZTR1: 2, SOS2: 1) and seven individuals with NSML (PTPN11), compared to age- and sex-matched typically developing (TD) (N = 71). Behavioral questionnaires assessed social responsiveness and ASD-related traits (using SRS-2), and emotional problems (using CBCL) to identify genetic variant-specific behavioral profiles. Biochemical profiling of SHP2 activity in PTPN11-associated NS variants examined genotype-phenotype relationships. RESULTS: Compared to TD individuals, those with PTPN11-associated NS, NSML, and SOS1-associated NS exhibited clinically elevated scores, indicating increased ASD-related behaviors, poorer social functioning, and heightened emotional problems. Genetic variant comparisons revealed that individuals with PTPN11-associated NS and NSML exhibited greater ASD-related challenges than those with RAF1. Individuals with NSML exhibit elevated attention problems compared to all other genetic groups. Logistic regression results suggested each one-unit increase in SHP2 fold activation for PTPN11-associated NS corresponded to a 64% higher likelihood of markedly elevated restricted and repetitive behaviors, suggesting genotype-phenotype links. LIMITATIONS: Small sample sizes for rarer variants, leading to unequal group sizes across subgroups, with PTPN11 variants comprising most of the NS group. Future research should address these sampling constraints and conduct functional studies to clarify variant impacts. Longitudinal assessments could elucidate behavioral phenotype trajectories. CONCLUSIONS: This study underscores the importance of genetic variant-specific research to understand unique behavioral phenotypes in NS and NSML. Our findings indicate a higher risk for ASD-related symptoms in PTPN11-associated NS and NSML compared to other variants. Additionally, individuals with PTPN11-associated NS and higher SHP2 fold activation exhibited greater impairments in restricted and repetitive behaviors, suggesting SHP2 activation variations may contribute to phenotypic variability. By linking ASD-related symptoms to biochemical predictors in PTPN11-associated NS, this study may inform future targeted treatment approaches.

Humans↗

PubMed2026

Comparative whole-exome sequencing of ambulatory patients and transplant recipients with idiopathic dilated cardiomyopathy.

BACKGROUND: Idiopathic dilated cardiomyopathy (DCM) is a major cause of advanced heart failure and heart transplantation (HTx), yet the genetic correlates of progression to HTx and transplant-relevant arrhythmic phenotypes remain incompletely defined. We examined the genetics of idiopathic DCM in a Korean population, focusing on HTx/death and arrhythmic outcomes, to identify adverse outcome-linked genotype-phenotype associations. METHODS: Whole-exome sequencing was performed in 202 Korean patients with idiopathic DCM, including 56 HTx recipients and 146 ambulatory patients, and compared the findings with 1093 population-based controls. Genotype-phenotype correlations were analyzed for major clinical outcomes, including HTx, death, arrhythmias, and left ventricular functional recovery. RESULTS: Pathogenic/likely pathogenic variants were identified in 32% of patients (38% in HTx vs 30% in ambulatory patients). TTN was the most frequently affected gene overall (12%), but LMNA variants predominated in HTx recipients (20% vs 4%, p = 0.001). LMNA carriers showed substantially higher odds of HTx/death (OR 14.65, 95% CI 3.32-139.31; FDR p<0.001), and strong association with arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation. Both missense and loss-of-function LMNA variants were associated with adverse outcomes. In contrast, TNNT2 variants were observed exclusively in ambulatory patients and identified a favorable functional-recovery phenotype, with a greater likelihood of LVEF recovery ≥10 percentage points (OR 6.03, 95% CI 1.52-28.71; FDR p = 0.016). CONCLUSIONS: LMNA variants mark a high-risk transplant-trajectory phenotype in Korean idiopathic DCM. Genetic testing may aid early identification and management of candidates for advanced HF therapies, including HTx and durable MCS.

dilated cardiomyopathy↗

PubMed2023

Phenotypic presentation of Mendelian disease across the diagnostic trajectory in electronic health records.

PURPOSE: To investigate the phenotypic presentation of Mendelian disease across the diagnostic trajectory in the electronic health record (EHR). METHODS: We applied a conceptual model to delineate the diagnostic trajectory of Mendelian disease to the EHRs of patients affected by 1 of 9 Mendelian diseases. We assessed data availability and phenotype ascertainment across the diagnostic trajectory using phenotype risk scores and validated our findings via chart review of patients with hereditary connective tissue disorders. RESULTS: We identified 896 individuals with genetically confirmed diagnoses, 216 (24%) of whom had fully ascertained diagnostic trajectories. Phenotype risk scores increased following clinical suspicion and diagnosis (P < 1 × 10-4, Wilcoxon rank sum test). We found that of all International Classification of Disease-based phenotypes in the EHR, 66% were recorded after clinical suspicion, and manual chart review yielded consistent results. CONCLUSION: Using a novel conceptual model to study the diagnostic trajectory of genetic disease in the EHR, we demonstrated that phenotype ascertainment is, in large part, driven by the clinical examinations and studies prompted by clinical suspicion of a genetic disease, a process we term diagnostic convergence. Algorithms designed to detect undiagnosed genetic disease should consider censoring EHR data at the first date of clinical suspicion to avoid data leakage.

Humans↗

PubMed2025

SLB-msSIM: A Spectral Library-Based Multiplex Segmented SIM Platform for Single-Cell Proteomic Analysis.

Mass spectrometry (MS)-based single-cell proteomics, while highly challenging, offers unique potential for a wide range of applications to interrogate cellular heterogeneity, trajectories, and phenotypes at a functional level. We report here the development of the spectral library-based multiplex segmented selected ion monitoring (SLB-msSIM) method, a conceptually unique approach with significantly enhanced sensitivity and robustness for single-cell analysis. The single-cell MS data is acquired by a multiplex segmented selected ion monitoring (msSIM) technique, which sequentially applies multiple isolation cycles with the quadrupole using a wide isolation window in each cycle to accumulate and store precursor ions in the C-trap for a single scan in the Orbitrap. Proteomic identification is achieved through spectral matching using a well-defined spectral library. We applied the SLB-msSIM method to interrogate cellular heterogeneity in various pancreatic cancer cell lines, revealing common and distinct functional traits among PANC-1, MIA-PaCa2, AsPc-1, HPAF, and normal HPDE cells. Furthermore, for the first time, our novel data revealed the diverse cell trajectories of individual PANC-1 cells during the induction and reversal of epithelial-mesenchymal transition (EMT). Collectively, our results demonstrate that SLB-msSIM is a highly sensitive and robust platform, applicable to a wide range of instruments for single-cell proteomic studies. SUMMARY: We present the SLB-msSIM method, a conceptually unique approach in mass spectrometry-based single-cell proteomics that significantly enhances sensitivity and robustness. This innovative platform enables detailed analysis of the proteome landscape, capturing cellular heterogeneity, trajectories, and phenotypes at a single-cell resolution. Utilizing the SLB-msSIM technique, we identified both common and distinct functional traits among various pancreatic cancer cell lines and normal cells. Moreover, our study unveiled new insights into the diverse cell trajectories of individual cancer cells during the induction and reversal of epithelial-mesenchymal transition (EMT). In summary, the SLB-msSIM method offers a highly sensitive and robust platform for single-cell proteomic studies, with broad applicability across different instruments.

Single-Cell Analysis↗

PubMed1992

Anatomical and functional compartmentalization of the subparafascicular thalamic nucleus in the rat.

The localization and the transmitter phenotype of subparafascicular thalamic nucleus (Spf) neurons projecting to the inferior colliculus (IC) and to the spinal cord (Sp) were studied by using a retrograde fluorescent double labeling technique, and a combined technique of retrograde tracing and immunohistochemistry for tyrosine hydroxylase (TH) and glutamate decarboxylase (GAD). The cell population of Spf-IC neurons was totally differentiated from that of Spf-Sp neurons which have been reported to be dopaminergic. The former were densely distributed, small to medium sized cells and localized in the central portion of the Spf, while the latter were sparsely distributed, large cells and localized in the marginal portion of the Spf. Spf-IC neurons were completely devoid of TH immunoreactivity and, instead, approximately half of them showed GAD immunoreactivity. From these findings, it is concluded that the Spf is distinctly compartmentalized by the presence at least two separate neuronal subpopulations, which are distinguishable in terms of their cell size, distribution patterns, transmitter phenotypes and trajectories.

Animals↗

PubMed2026

Proteomics as a theranostic compass in BCR::ABL1-negative myeloproliferative neoplasms: Integrating biomarker discovery with therapeutic stratification.

Classic BCR::ABL1-negative myeloproliferative neoplasms (MPNs)-polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis-are clonal haematopoietic stem cell disorders with marked heterogeneity in clinical phenotype, disease trajectory, and therapeutic response. Genomic stratification by driver and cooperating mutations only partially accounts for this variability, leaving gaps in predicting thrombotic risk, fibrotic progression, leukaemic transformation, and treatment benefit. Proteomics bridges this gap by providing function-proximal readouts of protein abundance, post-translational modifications, pathway activity, and intercellular signalling that genomics and transcriptomics cannot capture, positioning it as a theranostic platform in which the same molecular readouts simultaneously inform diagnostic stratification and therapeutic decision-making. We propose a five-stage translational framework spanning from discovery-scale mass spectrometry and affinity-based plasma profiling to targeted validation, multicentre standardisation, and machine learning-integrated clinical panels. Proteomic evidence is synthesised across the following four disease axes: clonal fitness in haematopoietic stem and progenitor cells; bone marrow microenvironmental remodelling and fibrosis; chronic inflammation and thrombosis; and leukaemic transformation. We further describe how phosphoproteomics reveals resistance mechanisms to JAK inhibitors, including AXL-MAPK bypass and PP2A-autophagy-mediated tolerance, and how protein-level biomarkers (BCL2-BCL-XL, RAS-ERK, CAMK2G, and ROCK1/2) can guide individualised therapeutic selection. Affinity-based platforms (Olink PEA and SomaScan) and spatially resolved technologies (CODEX and single-cell proteomics) complement discovery proteomics. At present, however, this evidence base is constrained by small and heterogeneous cohorts, limited cross-platform reproducibility, and a scarcity of independent external validation for candidate protein panels. Realising this vision will require multicentre standardisation, analytically validated panel assays, and prospective clinical studies that translate molecular findings into decision-grade tools for patients with MPNs.

Humans↗

PubMed2024

Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenesis.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we profiled genome-wide histone modifications and found that a decrease in histone H3 acetylation (ac) at downregulated genes is among the earliest molecular changes occurring well before any measurable deficiencies in electrophysiology and neurological function. These data reveal a molecular cascade that drives disease independent of any developmental contributions or secondary pathogenesis.

Animals↗

PubMed2026

Genetic and epigenetic determinants of cytochrome P450 activity in psychopharmacology: from pharmacogenetics to functional pharmacogenomics.

Classical pharmacogenetics has explained interindividual variability in psychotropic drug response primarily through inherited polymorphisms in cytochrome P450 enzymes. This framework successfully identified extreme metabolizer phenotypes and informed genotype-guided dosing recommendations. However, genotype-based predictions frequently correlate more strongly with pharmacokinetic parameters than with clinical outcomes. Patients sharing similar CYP genotypes often exhibit divergent therapeutic trajectories, while metabolic phenotypes may change during treatment without corresponding alterations in DNA sequence. These observations suggest the existence of a genotype-phenotype gap mediated by regulatory processes not captured by genotyping alone. Evidence from epigenetic regulation, environmental modulation of pharmacogene expression, and phenoconversion indicates that metabolic capacity is better understood as a dynamic functional state rather than a fixed inherited trait. This review examines the role of these mechanisms in psychiatric pharmacotherapy and explores the implications of shifting the predictive focus of precision medicine from static genotype to functional state.

Humans↗

PubMed2025

Evolutionary Diversification and Functions of the Candidate Male Killing Gene wmk.

Symbiont-mediated male killing (MK) is a mechanism that selectively eliminates male offspring, often by disrupting sex-specific developmental processes. In Drosophila melanogaster, the WO-mediated killing gene wmk from Wolbachia prophage WO transgenically reproduces the MK phenotype, yet how the gene evolves and functions across diverse Wolbachia has not been systematically investigated. We analyzed 32 Wolbachia genomes available in the NCBI database to study wmk homologs across different arthropod hosts, reproductive parasitism functions, and Wolbachia supergroups. First, we report at least five distinct wmk phylogenetic clusters (Types I to V), often organized in multigenic dyads or triads. Second, among MK Wolbachia, there is a significantly higher number of wmk genes and diversity in Lepidoptera strains than in Drosophila strains, which exclusively harbor wmk Types I and III. Third, there are three patterns of wmk sequence and genomic organizational changes in Drosophila MK strains that associate with different evolutionary trajectories underpinning the MK phenotype. Fourth, single and combinatory transgenic expression of Types I and III in D. melanogaster uncovers male-biased lethality associated with Type I; however, dual expression of the Types together elicits a major reduction in offspring number. Fifth, wmk genes have low expression level across D. melanogaster developmental stages relative to the cifA and cifB genes, which could explain why cytoplasmic incompatibility is expressed in this system. These findings establish a complex and phylogenetically informed genetic basis of wmk-induced lethality, highlighting the role of gene copy number and expression, wmk Types, and host background in shaping the phenotype.

Animals↗

PubMed2026

Population and landscape genomics provide insights into the adaptive genetic variation and future climate-induced vulnerability of the endangered tree species Phoebe bournei.

Elucidating the genomic underpinnings of adaptive variation is highly important for the conservation, landscape application, and management of ornamental trees against the backdrop of global climate change. However, research on the genetic mechanisms underlying climate adaptation in Phoebe bournei-a near-threatened subtropical tree species endemic to China, which is endowed with exceptionally high ornamental and ecological value-remains scarce. Whole-genome resequencing was conducted on 362 individuals from 27 natural populations across the geographical range of the species. Genome-environment association analyses were employed to identify 1556 climate-associated variants and 167 candidate genes associated with temperature and precipitation variables. Through functional annotation and expression profiling, pivotal genes, including TRX-M4 and FBD1, were identified as integral to drought and heat stress responses, with adaptive alleles displaying distinct geographic frequency distributions and significant phenotypic differentiation. Divergent evolutionary trajectories were deduced among populations, with southeastern populations distinguished by elevated genetic diversity and strong signatures of local adaptation. Nevertheless, projections derived from the Risk of Non-Adaptedness and gradient forest models suggest that these southeastern populations will face substantial genomic offset under future climate scenarios, signaling heightened vulnerability and the need for prioritized conservation and management. This study provides the first genome-wide perspective into the adaptive evolution of P. bournei and offers a robust foundation for its conservation and climate-resilient management.

Journal Article↗

PubMed2024

Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.

PURPOSE: Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. METHODS: A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. RESULTS: The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. CONCLUSION: Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.

Humans↗

PubMed2026

Time- and Dose-Resolved DIA-PASEF Proteomics Maps the Transition from Adaptive Stress to Apoptotic Collapse in Melittin-Treated MDA-MB-231 Cells.

Melittin, the cytolytic peptide of honeybee venom, exhibits potent anticancer activity in triple-negative breast cancer (TNBC), yet the molecular programs underlying its cytotoxic effects remain incompletely defined. To address this gap, MDA-MB-231 TNBC cells were exposed to melittin at half-maximal inhibitory concentration(half IC50) and IC50 across early(0.5, 1, and 2 h), mid(3, 4 h), and late (12, 24 h) time windows. Proteomic profiling was performed using label-free data-independent acquisition(DIA) parallel accumulation-serial fragmentation(PASEF). Approximately 5800 proteins were quantified, revealing distinct dose-dependent stress responses. An integrative exploratory framework combining time-resolved log2 fold-change trajectories, area-under-the-curve(AUC) based temporal prioritization, and independent heatmap visualization identified proteins associated with melittin-induced stress remodeling. Half IC50 exposure showed a transient stress-adaptive signature characterized by chromatin remodeling(HMGN2, H2AZ1), structural and RNA-associated buffering(LRRC7), and indirect mitochondrial quality-control signaling(CPAMD8, SPATA4), which progressively weakened over time. In contrast, IC50 treatment induced rapid chromatin remodeling dominated by histone H1 variants(H1.4, H1.2), early RNA instability(LRRC7), and late-stage cytoskeletal disassembly marked by MICAL3 induction, consistent with progression toward apoptosis. These trajectories paralleled dose-dependent apoptotic phenotypes. Overall, data suggest that melittin elicits dose- and time-dependent proteomic stress responses in TNBC cells and identify candidate trajectory-associated proteins and pathways linked to adaptive stress remodeling or progression toward cytotoxic collapse.

Melitten↗

PubMed2026

Hologenomic interactions promote the higher-order evolvability of phenotypic complexity.

Current models for evolvability and complexity generally focus on mutational and regulatory processes in the host genome alone, limiting their ability to explain the origin, inheritance, and dynamics of many phenotypes. We describe a framework treating multigenome interactions in the holobiont as a central process that impacts the genotype-phenotype map, expanding the dimensionality of mechanisms producing heritable variation, generating novel traits, and exploring adaptive trajectories. These mechanisms can promote both complex phenotypic innovation and evolutionary systems drift. Many evolutionary pathways and novelties cannot be fully understood from host data alone but require consideration of hologenomic targets of selection. We outline hypotheses and methods to quantify and evaluate their impacts as a fundamental macroevolutionary process.

cellular innovation↗

PubMed2025

Resource presentation dictates genetic and phenotypic adaptation in yeast.

BACKGROUND: Environments shape adaptive trajectories of populations, often leading to adaptive parallelism in identical, and divergence in different environments. However, how does the likelihood of these possibilities change with minute changes in the environment remain unclear. RESULTS: In this study, we evolved Saccharomyces cerevisiae in environments which differed only in the manner in which the sugar source is presented to the population. In one set of populations, carbon was presented as a mixture of glucose-galactose, and in the other, as melibiose, a glucose-galactose disaccharide. Since the two environments differed in how the two monosaccharides are packaged, we call these environments 'synonymous'. Our results show that even subtle environmental differences can lead to differing phenotypic responses between the two sets of evolved populations. However, despite different adaptive responses, pleiotropic effects of adaptation are largely predictable. We also show that distinct genomic targets of adaptation between the two sets of evolved populations are functionally convergent. CONCLUSION: This study highlights how subtle environmental differences dictate phenotypic and genetic adaptation of populations. Additionally, these results also suggest the predictive potential of ancestor's fitness in understanding pleiotropic responses. Our work underscores the importance of studying more such environments to understand the generality of adaptive responses in populations.

Saccharomyces cerevisiae↗

PubMed2026

Sex-specific ethylene responses drive floral sexual plasticity in Cannabis sativa.

Cannabis sativa L. exhibits pronounced sexual plasticity in which both XX and XY plants can undergo floral phenotypic sex reversal in response to ethylene modulation, yet the underlying molecular mechanisms remain poorly defined. Here, we present the most extensive multi-omic analysis of ethylene-induced sex change in C. sativa to date, integrating over 130 RNA-seq libraries, ethylene pathway metabolite quantification, and whole-genome sequencing across three XX and XY genotypes. Treatments with silver thiosulfate and ethephon induced more than 80% phenotypic conversion, but transcriptomic responses diverged sharply between XX and XY plants. Profiling 47 ERGs revealed 14 high-confidence candidates, including CsACS1, CsACO5, CsERF1, and CsMTN, with sex-specific and temporal expression patterns that show dynamic ethylene mediation of plasticity. Early transcriptional activation occurred prior to the emergence of flowers, within 18 h of sex-change treatments and the photoperiod-induced transition to flowering. As opposite-sex floral tissues emerged, ethylene-related gene expression shifted accordingly within developing floral organs, with distinct sets of genes stabilizing the opposite-sex phenotype in XX and XY plants. Several candidates were located in non-recombining regions of the X chromosome or were absent from the Y chromosome, and most exhibited low nucleotide diversity, consistent with functional constraint. These results provide a high-resolution view of ethylene-responsive sexual plasticity in cannabis and show that the shared capacity for sex reversal in XX and XY plants is implemented through distinct regulatory trajectories that produce opposite-sex floral phenotypes. This work expands the mechanistic understanding of sex expression in dioecious species and identifies candidate genes relevant to the development of sex-stable cultivars.

Ethylenes↗

PubMed2026

Virulent Parasites Emerge in Hosts With Rising Temperatures.

Climate change is increasing the risk of emerging parasites. However, whether more virulent variants will spread during climate-driven outbreaks remains unclear. Here, we aimed to explore the short-term trajectory of parasite evolution-at the phenotypic and genomic scales-across environmentally relevant temperatures in a thermally mismatched host-parasite interaction. We experimentally evolved a wild parasitic bacterium (Leucobacter musarum), across the thermal range (20°C-30°C) and extremes (35°C) of Cabo Verde-the site of field collection-in a Caenorhabditis elegans host strain. Starting from a single bacterial isolate, we then tracked phenotypic and de novo genomic changes that arose across replicate populations following ten passages of experimental evolution. We found that at 25°C, warm for the host but an average temperature for the parasite, host-mediated selection favoured higher virulence and genomic diversification by the end of the experiment. At hot temperatures, towards the limit of host survival, virulence was maintained across all parasite populations. Parasites evolved at hot temperatures also displayed a latent virulence boost, deadlier once hosts experienced a heatwave. Patterns of molecular evolution were constrained to parallel changes in fewer loci at extreme temperatures. Our findings suggest that shifting environmental temperatures will leave phenotypic and genomic signatures on evolving parasites.

Animals↗

PubMed2026

Mirror worlds: The shared regulatory architecture of cell fate in development and cancer.

Lineage plasticity has emerged as a central mechanism through which cancer cells adapt to therapeutic pressure, evade immune surveillance, and acquire aggressive phenotypes. Although recognized across tumor types, the regulatory principles governing how cancer cells reprogram cellular identity remain incompletely understood. In this review, we propose that lineage plasticity in cancer reflects the redeployment of regulatory frameworks established during normal development. Rather than representing a stochastic byproduct of genomic instability, cancer plasticity frequently unfolds within gene regulatory architectures that also govern cell fate specification, lineage commitment, and controlled state transitions during embryogenesis and tissue homeostasis. Developmental transcription factors, including members of the SOX family, FOXA1, ASCL1, NKX2-1, and epithelial-mesenchymal transition regulators, function as lineage gatekeepers during development but are repurposed in cancer to destabilize lineage commitment and enable phenotypic switching. Similarly, epigenetic regulators that guide developmental trajectories, including chromatin remodeling complexes, Polycomb group proteins, and DNA methylation machinery, are frequently dysregulated or redistributed in tumors, altering the repression of lineage-stabilizing and alternative lineage programs and thereby weakening epigenetic barriers to lineage transitions. Together, these observations support a model in which development and cancer operate as mirror regulatory systems: one establishing and stabilizing cellular identity, the other exploiting the same regulatory architecture to permit adaptive reprogramming under selective pressure. We further discuss how emerging single-cell and spatial multi-omics technologies, integrated with artificial intelligence-based modeling, enable mapping of cell state landscapes and transitional trajectories, transforming lineage plasticity from a descriptive phenomenon into a measurable and predictable property of tumor evolution.

Humans↗

PubMed2026

Phylogeographic epidemiology of Dabie bandavirus in East Asia: divergent transmission networks and genotype‑linked clinical severity.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS), caused by Dabie bandavirus (SFTSV), exhibits geographically decoupled incidence and fatality patterns across East Asia. We aimed to elucidate the distinct ecological drivers and phylogeographic dynamics underlying this inland-coastal epidemiological divergence. METHODS: Integrating 1820 high-quality global genomes of SFTSV with well-characterized clinical cohorts (936 patients) and nationwide surveillance data (27,457 cases) from China, we constructed a comprehensive analytical framework. Ecological modeling, Bayesian phylogeography, and genotype-phenotype association analyses were employed to trace the evolutionary trajectories and clinical implications of the virus. RESULTS: A pronounced "inland-high-incidence vs. coastal-high-fatality" pattern of SFTS was identified. The incidence of SFTS exhibited divergent sensitivities to meteorological factors; inland transmission was sensitive to thermal fluctuations, whereas coastal dynamics were constrained by a sunshine threshold (> 200 h/month). In contrast, spatial divergence in clinical severity correlated with the distribution of regional viral genetic structures. Inland regions mainly co-circulated genotypes A, C, and D, while coastal regions were dominated by genotype B. Zhejiang province was identified as a genetic hub with significantly higher recombination frequencies than inland regions (11.0% vs. 3.5%, P < 0.001). Bayesian phylogeographic inference indicated frequent lineage exchange of Zhejiang province in China with the Republic of Korea and Japan. Clinically, genotypes B and D were associated with elevated mortality in coastal and inland regions, respectively, suggesting that the severe coastal phenotype is shaped by its genotype B-dominated structure. Additionally, the RdRp-N828S mutation emerged as a robust molecular correlate of fatal outcomes, warranting further functional validation. CONCLUSIONS: Divergent meteorological factors and plausible maritime transmission networks may underlie the geographically decoupled epidemiology of SFTS. These findings highlight that risk assessment must extend beyond incidence alone and provide a phylogeographically informed framework for targeted surveillance and genotype-specific interventions in high-risk hotspots.

Humans↗