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Results for “evolutionary conservation”

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PubMed2026

From pan-life phase insights to PhaseHub: Analyzing protein condensate complexity.

Intracellular biomolecular condensation forms multicomponent signaling hubs that regulate development, stress responses, and environmental adaptation. While the molecular grammar encoded within scaffold proteins defines the basal associative features driving condensation, heterotypic condensates are intrinsically dynamic, multicomponent, and far-from-equilibrium systems. Consequently, how condensates organize component composition, stoichiometry, and functional specificity in space and time under physiological conditions remains poorly understood. Addressing this challenge requires integrative frameworks that combine predictive biophysical features with experimental information on protein abundance, interaction networks, subcellular localization, and evolutionary conservation. In this study, we first analyzed phase separation (PS) proteins across the tree of life in 1106 species, revealing a stark contrast in computationally predicted PS propensity between eukaryotes and prokaryotes, with genome size as a key determinant. Through a broad analysis of amino acid homorepeat-containing proteins (HRPs) across all species, we uncovered how PS evolves via a balance between functional condensation and avoidance of harmful, aggregation-prone sequences. We further identified potential signaling hubs and components across kingdoms by integrating PS-positive proteins with experimentally derived abundance and interactome data from four model eukaryotic species. Using Arabidopsis as a model, we dissected the relationships among PS propensity, condensation hub prediction, HRPs, subcellular localization, and structural conservation. Finally, we developed PhaseHub, a user-friendly interface for exploring scaffold-client dynamics, PS components, sequence signatures within each PS protein, and hubs. Collectively, our work provides an evolutionary framework for understanding multicomponent PS hubs by integrating molecular grammar with physiological context, thereby facilitating hypothesis generation and rational design.

Phase Separation↗

PubMed2025

Conserved HSFA1-dependent chromatin dynamics drive heat stress responses in plants.

Eukaryotic organisms remodel chromatin landscapes to regulate gene expression in response to environmental stress. In plants, heat stress (HS) induces widespread chromatin changes, yet the role of heat shock transcription factors (HSFs) in chromatin remodeling and their evolutionary conservation remains unclear. Using Marchantia polymorpha Mphsf mutants and Arabidopsis thaliana Athsfa1s mutants, we identify HSFA1 as a key regulator of HS-induced cis-regulatory element (CRE) accessibility, a mechanism conserved across land plants, mice, and humans. Gene regulatory network modeling reveals parallel transcription factor subnetworks, with MpWRKY10 and MpABI5B acting as indirect and negative HS regulators. We further showed that ABA modulates gene expression in an HSFA1-dependent manner without inducing chromatin remodeling. Finally, we develop a machine learning framework integrating chromatin accessibility and CRE information to predict gene expression across species, revealing stress-responsive regulatory logic at the transcriptional level. These findings provide insights into how TFs coordinate chromatin architecture to drive stress adaptation.

Heat-Shock Response↗

PubMed2026

Base-pair resolution conservation data improves cell type specific sequence-to-expression prediction.

MOTIVATION: Genomic sequence-to-activity models can decipher gene regulatory mechanisms and predict the functional impact of regulatory variants. However, current models struggle to integrate information from sequences outside promoters, especially information from cell type specific regulatory elements. RESULTS: Here, we propose incorporating base-pair resolution evolutionary conservation data into genomic sequence-to-expression predictors. We explore two training strategies-training from scratch or fine-tuning an existing sequence-only model with additional conservation input. We find that in both cases, base-pair resolution conservation data improves cell type specific sequence-to-expression prediction, with training from scratch yielding the greatest benefit. The improvement in cell type specific expression prediction can be attributed in part to the fact that models trained on sequence and conservation data learn to better recognize cell type specific regulatory elements than models trained on sequence alone. AVAILABILITY: Code is available at https://github.com/ni-lab/basenji-phyloP.

Conserved Sequence↗

PubMed2025

Cross-Kingdom Genomic Conservation of Putative Human Sleep-Related Genes: Phylogenomic Evidence From Chlamydomonas reinhardtii.

Sleep is a widespread and evolutionarily conserved process observed in diverse organisms, from jellyfish to mammals, hinting at its origin as a life-supporting mechanism over 500 million years ago. Although its fundamental purpose and mechanisms remain unclear, sleep's evolution and adaptive significance continue to be debated. This study explores the evolutionary origins of sleep using Chlamydomonas reinhardtii as a model organism, identifying 112 putative sleep-related genes across species and highlighting the evolutionary conservation of sleep-regulatory pathways. Additionally, discovering uncharacterized proteins with high sequence similarity and significant e-values suggests unexplored roles in sleep regulation, underscoring the potential of C. reinhardtii to reveal new insights into the molecular basis of sleep. This study provides a foundation for identifying previously unknown sleep-associated proteins, particularly within single-celled organisms, which may offer novel perspectives on the biological role of sleep. The study demonstrates that phylogenomic analysis of diverse model organisms can expand our understanding of the evolutionary trajectory of sleep and its fundamental function, paving the way for further research in sleep biology and its health implications. Overall, the fundamental functions of sleep observed in higher animal phyla originated from its primordial activities, demonstrating an evolutionary continuum wherein more specialized tasks were integrated with sleep's essential restorative properties.

Chlamydomonas reinhardtii↗

PubMed2026

Genome-Wide Characterization of the Apple HD-Zip IV Gene Family and Functional Validation of MdHDZIV3 Under PEG-Induced Osmotic Stress.

The homeodomain-leucine zipper IV (HD-Zip IV) transcription factor subfamily plays essential roles in epidermal development, cuticle formation, lipid metabolism, and environmental adaptation in plants. Despite its biological importance, the HD-Zip IV family has not been systematically characterized in apple (Malus domestica). Here, we identified 17 apple HD-Zip IV genes and named them MdHDZIV1-MdHDZIV17 based on their locations on the chromosomes. The 17 genes showed a nonuniform distribution on eight chromosomes, while the occurrence of both tandem and segmental duplications indicated that family expansion involved more than one duplication mechanism. All MdHDZIV proteins contained the conserved HD, LZ, START, and SAD domains but lacked the MEKHLA domain, consistent with typical HD-Zip IV structural features. Phylogenetic analysis classified MdHDZIV proteins into five groups together with HD-Zip IV members from Arabidopsis thaliana and rice, indicating evolutionary conservation of this subfamily. Collinearity and Ka/Ks analyses revealed that duplicated MdHDZIV gene pairs were mainly subjected to purifying selection. Promoter scanning revealed diverse cis-regulatory motifs associated with hormonal signaling, environmental stress, light response, and epidermal regulation, including ABRE, ARE, W-box, MYC, G-box, and L1-box motifs. Integration of transcriptomic profiling with qRT-PCR validation revealed pronounced tissue-dependent differences in the expression of MdHDZIV genes in leaf, fruit skin, and branch bark. Under PEG6000-induced osmotic stress and NaCl-induced salt stress, 10 candidate MdHDZIV genes displayed gene-specific and stress type-specific expression patterns, with MdHDZIV3 showing strong induction under PEG6000 treatment. Functional validation in apple calli showed that MdHDZIV3 overexpression enhanced PEG tolerance, increased fresh weight, elevated SOD and POD activities, and reduced MDA accumulation under osmotic stress. These findings provide a genome-wide framework for understanding the apple HD-Zip IV gene family.

abiotic stress↗

PubMed2025

TRB proteins in moss reveal their evolutionarily conserved roles in plant development and telomere maintenance.

Telomere repeat binding (TRB) proteins are plant-specific proteins with a unique domain structure distinct from telomerebinding proteins in animals and yeast. While extensively studied in seed plants, their role in early-diverging plant lineages remains largely unexplored. Here, we investigate TRB proteins in a model moss, Physcomitrium patens, to assess their evolutionary conservation and functional significance. Functional analysis using single knockout mutants revealed that individual PpTRB genes are essential for normal development, with mutants exhibiting defects in the two-dimensional (protonemal) stage, and more prominently, in the formation of three-dimensional (gametophore) structures. Some double mutants displayed telomere shortening, a phenotype also observed in TRB-deficient seed plants, indicating a conserved role for TRBs in telomere maintenance. Transcriptome profiling of TRB mutants revealed altered expression of genes associated with transcriptional regulation and stimulus response in protonema. Subcellular localization studies across various plant cell types confirmed that PpTRBs, like their seed plant counterparts, localize prevalently to the plant nucleus and mutually interact. In bryophytes, TRBs form a monophyletic group that mirrors the species phylogeny, whereas in seed plants, TRBs have diversified into two distinct monophyletic groups. Our findings provide the first comprehensive characterization of TRB proteins in non-vascular plants and demonstrate their conserved roles in telomere maintenance, with additional implications for plant development and gene regulation across land plant lineages.

Bryopsida↗

PubMed2026

Stem Cell Differentiation Disperses Transcriptional Clusters via a Conserved Surface-Condensate Trajectory.

Stem cells exhibit exceptionally prominent transcriptional clusters, which dissolve with progressing differentiation. Although these clusters are assigned central roles in embryonic gene regulation, their formation and loss during differentiation remain poorly understood. This study reveals that these prominent clusters disperse along a conserved trajectory in mouse embryonic stem cells, fruit fly testes, and zebrafish embryos. Imaging and lattice simulations show that these clusters form via surface condensation on H3K27ac-marked super-enhancer regions, which act as genomic scaffolds. Upon differentiation, partial loss of these active epigenetic marks and transcription-driven unfolding lead to dispersal of the prominent clusters. The block copolymer-based lattice simulations explain this process as a conserved trajectory through a three-dimensional state space, governed by surface condensation principles that extend beyond canonical liquid-liquid phase separation. This work marks surface condensation as a biophysical mechanism for the dynamic organization of stem cell-specific transcriptional hubs and demonstrates evolutionary conservation in several organisms. By uncovering a conserved biophysical mechanism for transcriptional organization in development, our work illustrates how polymer properties can contribute to the control of cell identity and fate.

Animals↗

PubMed2026

The multilayered cuticle underlying structural coloration in red algae shares features with the metazoan extracellular matrix.

Structural coloration, a physical phenomenon observed in many living organisms, may arise from the interference of light with highly organized surface nanostructures. In some seaweeds, these nanostructures consist of cuticular lamellae in the outer part of the extracellular matrix (ECM) of the epidermis. However, the chemical composition of seaweed cuticles is poorly understood and the molecular components of lamellae remain unidentified. Here, we use integrated genomic, transcriptomic, proteomic, and metabolomic approaches together with analytical profiling of carbohydrates to determine the composition of the multilayered cuticle in the red alga Chondrus crispus and assess its evolutionary conservation. The structural assembly reveals common features with the ECM of animals. The carbohydrate fraction includes a complex mixture of carrageenans and glycosaminoglycan-like compositions. A major von Willebrand factor A domain protein, Lamellae Cohesive Protein, plays a critical role in protein-protein interactions and binding to sulfated polysaccharides. We have further identified the major proteins of the algal cuticle, providing a framework for addressing the evolutionary origins of the cuticle and raising important questions regarding its role, particularly across the red algal life cycle marked by major structural differences in its ECM.

Extracellular Matrix↗

PubMed2026

Genome-wide characterization of heat shock protein genes reveals thermal stress-responsive candidates in Litopenaeus vannamei.

Heat shock proteins (HSPs) are conserved molecular chaperones involved in protein folding, refolding, aggregation prevention, and degradation of damaged proteins. However, the genomic organization and thermal responsiveness of HSP genes in the Pacific white shrimp (Litopenaeus vannamei) remain incompletely understood. Here, we performed a genome-wide analysis of the HSP gene family and examined its phylogenetic relationships, structural features, duplication patterns, sequence variation, interaction networks, and transcriptional responses to acute heat stress. A total of 34 HSP genes were identified and classified into the HSP90, HSP70, HSP40/DNAJ, HSP60, and small HSP families. Phylogenetic, motif, gene structure, synteny, and subcellular localization analyses revealed evolutionary conservation and structural diversification among family members. Three duplicated gene pairs were identified, comprising two segmental duplications and one tandem duplication. All pairs exhibited Ka/Ks ratios below 1, consistent with purifying selection of varying strength. Sequence analysis identified 295 nonsynonymous single-nucleotide polymorphisms, of which 12 were consistently predicted to be deleterious by multiple algorithms. Protein-protein interaction analysis indicated enrichment of protein-folding and cellular stress-response functions. RT-qPCR analysis showed significant induction of HSPA4, HSP90AA1, TRAP1, BiP, and DNAJA1 after 6, 12, and 24 h of exposure to 34 °C, whereas DNAJC3 was significantly induced only at 12 h. All six genes reached their highest transcript abundance at 12 h. These findings may provide a genomic framework for HSP genes in L. vannamei and identify candidate genes and variants associated with thermal stress responses.

Animals↗

PubMed2024

Beyond antibiotic resistance: The whiB7 transcription factor coordinates an adaptive response to alanine starvation in mycobacteria.

Pathogenic mycobacteria are a significant cause of morbidity and mortality worldwide. The conserved whiB7 stress response reduces the effectiveness of antibiotic therapy by activating several intrinsic antibiotic resistance mechanisms. Despite our comprehensive biochemical understanding of WhiB7, the complex set of signals that induce whiB7 expression remain less clear. We employed a reporter-based, genome-wide CRISPRi epistasis screen to identify a diverse set of 150 mycobacterial genes whose inhibition results in constitutive whiB7 expression. We show that whiB7 expression is determined by the amino acid composition of the 5' regulatory uORF, thereby allowing whiB7 to sense amino acid starvation. Although deprivation of many amino acids can induce whiB7, whiB7 specifically coordinates an adaptive response to alanine starvation by engaging in a feedback loop with the alanine biosynthetic enzyme, aspC. These findings describe a metabolic function for whiB7 and help explain its evolutionary conservation across mycobacterial species occupying diverse ecological niches.

Transcription Factors↗

PubMed2026

Functional unknomics of the SAR11 clade reveal hidden genetic potential underlying adaptation to bottom-up and top-down pressures.

UNLABELLED: A substantial fraction of the genes in bacteria lack detectable sequence similarity to genes with known functions. These functionally uncharacterized genes-collectively referred to as the "unknome"-represent a largely unexplored genetic repertoire harboring insights into marine bacterial ecology. In this study, we explored the function of the unknome of the SAR11 clade, the most abundant bacterial lineage in the ocean, with a particular focus on genes that provide insight into its ecology. Based on the Clusters of Orthologous Genes and Kyoto Encyclopedia of Genes and Genomes classifications, approximately 56% of SAR11 ortholog groups were classified as members of the unknome. Among the SAR11 unknome, we successfully inferred the functions of 57 ortholog groups that are conserved in the SAR11 clade by protein structure similarity searches and genomic context analyses. These ortholog groups include putative transporter components, supporting the current ecological understanding that the SAR11 clade is specialized in substrate uptake to adapt to oligotrophic marine environments. Furthermore, structural analysis indicated that the DUF2237-containing protein, enriched in marine environments, may interact with purine nucleotide-containing compounds. This may suggest the existence of unique nucleotide utilization mechanisms in marine bacteria. In addition, we identified candidate viral defense systems within the unknome, indicating that diverse defense systems are present in at least one-third of cultured SAR11 strains. The presence of these defense systems, even within streamlined SAR11 genomes, suggests that they confer significant ecological advantages. Our analyses provide insights into the genetic basis of bottom-up processes (adaptation to oligotrophic environments) and top-down processes (antiviral defense strategy) contributing to ecological success. IMPORTANCE: Many microbial genes have no experimentally established function, limiting our ability to explain how microorganisms adapt to their environments. We examined this uncharacterized gene space, or "unknome" in SAR11, the most abundant bacterial clade in the ocean, by integrating evolutionary conservation, genomic context, predicted protein structure, and environmental distribution. This approach enabled us to prioritize components of the SAR11 unknome, including a core unknome conserved across the clade and genes enriched in specific lineages, and to identify several candidates with possible ecological roles in nutrient acquisition and defense against viruses. Our results suggest that the SAR11 unknome contains important clues to the ecological success of SAR11 rather than merely reflecting incomplete annotation or gene-prediction artifacts. Our study highlights the potential value of unknome analysis for identifying ecologically relevant genes in environmental microorganisms.

Pelagibacterales↗

PubMed2026

Crosstalk between the Wnt pathway and other signaling pathways.

The Wnt/β-catenin signaling pathway is a deeply conserved regulatory network that governs embryonic development, stem cell maintenance, and tissue homeostasis. Aberrant activation of the Wingless/Integrated protein (Wnt) signaling is a hallmark of numerous human diseases, most prominently in colorectal cancer, where it cooperates with additional oncogenic pathways to drive tumor initiation, progression, and therapeutic resistance (See Supplementary Table 1 for a list of the abbreviations used in this manuscript and their definitions.). Increasing evidence indicates that Wnt signaling does not function as an isolated linear cascade but rather as an integrative signaling hub that dynamically interfaces with major signaling pathways, including the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. Rat Sarcoma protein (RAS)- Rapidly Accelerated Fibrosarcoma protein (RAF)- Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)- Ak strain transforming protein (AKT)- Mechanistic Target of Rapamycin (mTOR) pathways. These interactions occur at multiple molecular levels, encompassing shared kinases, transcriptional regulators, metabolic nodes, and cytoskeletal components, thereby coordinating proliferative, metabolic, and migratory programs. In this review, we synthesize current mechanistic and clinical insights into the crosstalk between Wnt signaling and the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways, with particular emphasis on colorectal cancer. We discuss how these signaling networks converge to regulate β-catenin stability, transcriptional activity, cell adhesion, and metabolic reprogramming, thereby generating oncogenic phenotypes that cannot be explained by activation of individual pathways alone. To illustrate the evolutionary conservation and biological significance of these interactions, we integrate developmental paradigms from early Xenopus embryogenesis, where Wnt signaling governs zygotic genome activation, body axis formation, and the regulation of cell growth, protein stability, and biomass accumulation. Finally, we examine how an improved understanding of Wnt-centered signaling networks is informing emerging therapeutic strategies, including combinatorial pathway inhibition and nanoparticle-based drug delivery. Collectively, this review highlights Wnt signaling as a central integrator of developmental and oncogenic programs, providing a conceptual framework for understanding signaling network crosstalk and identifying new therapeutic opportunities in cancer.

Humans↗

PubMed2026

Compound Heterozygous PCDH15 Variants Associated With Cone-Rod Dystrophy in a Chinese Pedigree.

BACKGROUND: This study aimed to characterize the clinical and genetic features of a Chinese family with cone-rod dystrophy in which compound heterozygous PCDH15 variants were identified. METHODS: A Chinese pedigree with autosomal recessive cone-rod dystrophy was investigated. A comprehensive ophthalmic assessment was performed in the proband, a 42-year-old woman, together with genetic evaluation of her family members. Candidate variants were identified using whole-exome sequencing and subsequently assessed by Sanger sequencing and family segregation analysis. RESULTS: Ophthalmoscopic examination revealed pigmentary changes and atrophic lesions affecting the posterior pole and peripapillary area bilaterally. Optical coherence tomography (OCT) demonstrated bilateral outer retinal layer atrophy with disruption of the ellipsoid zone at the posterior pole. Multifocal electroretinography (mfERG) revealed attenuated central responses, while full-field electroretinography (ffERG) documented a more pronounced reduction in cone-mediated (photopic) responses. Two novel compound heterozygous variants in PCDH15, namely c.4903_4906del (p.Glu1635Lysfs*4) and c.3470C>A (p.Ala1157Glu), were identified in this autosomal recessive cone-rod dystrophy pedigree. Family co-segregation analysis provided supportive evidence for their potential association with the disease phenotype. Cross-species analysis revealed high evolutionary conservation of the PCDH15 protein. Three-dimensional structural modeling predicted potential alterations in protein structure. CONCLUSION: To our knowledge, this is the first report describing an association between compound heterozygous PCDH15 variants and cone-rod dystrophy, thereby providing preliminary evidence that may broaden the mutational spectrum associated with this gene.

Adult↗

PubMed1977

Serum esterase genetics in rabbits. IV. The prealbumin and beta-globulin systems.

Discontinuous starch gel electrophoresis revealed a fourth allele of rabbit pre-albumin serum esterase at locus Est-2. This allele is designated Est-2f and appears to be silent. In addition to the prealbumin serum esterases, another serum esterase system was studied in rabbits. This system is localized in the beta-globulin region. Genetic analysis indicated that one locus with two codominant alleles controls the variation in this region. Linkage of this system with Est-1 and Est-2 of the prealbumin serum esterases was demonstrated. Comparison of the arrangement of these esterase loci on linkage group VI with the esterase loci on chromosome 8 of the mouse gives additional support for the theory of evolutionary conservation of chromosomal segments coding for mammalian esterases.

Alleles↗

PubMed2026

CgMYC2 directly activates jasmonate-induced naringin biosynthesis in Citrus grandis 'Tomentosa'.

CgMYC2 links jasmonate signaling to naringin biosynthesis by binding G-box motifs and activating flavonoid-pathway promoters in Citrus grandis 'Tomentosa' Naringin, the predominant bitter-flavanone glycoside in Citrus grandis 'Tomentosa', has well-characterized biosynthetic enzymes, yet the transcriptional regulators coupling hormonal signals to pathway activation remain poorly understood. We demonstrate that CgMYC2, a jasmonate-responsive bHLH transcription factor, functions as a central activator of naringin biosynthesis. Exogenous methyl jasmonate (MeJA) treatment increased naringin content 3.45-fold in seedlings, coinciding with a rapid 6.6-fold induction of CgMYC2 that preceded the peak transcription of five core biosynthetic genes (CgPAL5, CgCHS, CgFNS, Cg7GlcT, and Cg1,2RhaT). Physical interaction between CgMYC2 and the JAZ protein CgJAZ3 was confirmed by pull-down and Co-IP assays, placing CgMYC2 within the canonical jasmonate signaling cascade. Y1H confirmed CgMYC2 binding to the Cg1,2RhaT promoter, EMSA demonstrated direct G-box-dependent binding to all five pathway promoters, and dual-luciferase assays showed transactivation of all five promoters, with the strongest activation for CgCHS. As complementary chromatin-level support, a single-sample CUT&Tag profile revealed G-box-enriched CgMYC2-associated chromatin regions across jasmonate-responsive and secondary-metabolic loci. Virus-induced gene silencing (VIGS) of CgMYC2 reduced naringin content by ~21% and suppressed biosynthetic gene expression, supporting its positive contribution. Furthermore, heterologous overexpression in tomato activated the flavonoid pathway and elevated 16 flavonoid compounds, consistent with evolutionary conservation of the MYC2-G-box regulatory logic. These findings establish CgMYC2 as a central, JA-responsive activator bridging jasmonate perception and naringin biosynthesis, providing a molecular framework for the targeted improvement of bitter-flavonoid traits in citrus.

Citrus↗

PubMed2025

Phosphorylation as a regulatory mechanism of HP1 protein multifunctionality.

The Heterochromatin Protein 1 (HP1) family proteins are key regulators of chromatin structure and genome function, acting as "reader" proteins that recognize and bind to histone H3 lysine 9 methylation (H3K9me). Beyond their canonical role in heterochromatin formation and transcriptional repression, HP1 proteins exhibit functional versatility, participating in transcriptional activation, RNA processing, DNA repair, and chromosome segregation. This multifunctionality is mediated partially by post-translational modifications (PTMs), with phosphorylation emerging as a central regulatory mechanism. This review explores the diverse effects of HP1 phosphorylation on protein function and chromatin interactions, focusing on Drosophila melanogaster HP1a and its orthologs, mammalian HP1α and S. pombe Swi6. Phosphorylation in the N-terminal tail enhances HP1's affinity for H3K9me, promoting transcriptional silencing. Mitotic phosphorylation of serine residues in the hinge region, regulated by kinases such as AURKB and NDR1/2, leads to chromatin release and relocalization to the kinetochore, enabling proper chromosome segregation. Additionally, phosphorylation modulates HP1 phase separation dynamics, influencing nuclear compartmentalization and chromatin condensation. These findings highlight phosphorylation as a versatile molecular switch that enables HP1 proteins to transition between structural and regulatory roles, contributing to their evolutionary conserved multifunctionality in genome regulation and cell division. Further investigation into HP1 phosphorylation across species and contexts is essential to fully understand its contributions to chromatin biology.

Phosphorylation↗

PubMed2026

Whole-Genome Deep Learning Predicts Chemotherapy Response in Colorectal Cancer.

Chemotherapy response in colorectal cancer (CRC) exhibits significant heterogeneity, with current clinical predictors failing to capture complex genomic determinants of resistance. We developed a hybrid deep learning framework integrating convolutional neural networks (CNNs) and bidirectional long short-term memory (BiLSTM) networks to analyze whole-genome somatic mutations, evolutionary conservation, chromatin accessibility, and 3D genome architecture in 2,546 TCGA patients. An attention mechanism identified predictive genomic regions. The model achieved an AUC of 0.92 (95% CI: 0.89-0.94) in cross-validation and 0.88 (95% CI: 0.85-0.91) in independent validation, outperforming clinical models (ΔAUC = +0.18, p < 0.001). Key predictors included non-coding variants in TP53, KRAS, and PIK3CA regulatory regions. Triple-positive patients (mutations in all 3 regions) had significantly worse progression-free survival (HR = 4.7, p < 0.001). Our framework enables accurate chemotherapy response prediction and reveals novel non-coding resistance mechanisms, advancing precision oncology in CRC.

Humans↗

PubMed2026

Divergent PXR function in seals: Endocrine adaptation or functional loss?

Seals accumulate xenobiotics through dietary biomagnification and exposure to polluted marine environments, with contaminants concentrating in their blubber. Biotransformation mitigates xenobiotic toxicity by converting lipophilic compounds into excretable hydrophilic metabolites, a process coordinated by nuclear receptors including the Pregnane X Receptor (PXR), whose plastic ligand-binding domain enables broad xenobiotic sensing. By examining PXR in pinnipeds, we investigated the evolutionary conservation and functional characterization of PXR using genomic sequence analysis, protein structural prediction, and transactivation assays, revealing broadly conserved structural features alongside species-specific functional divergence in receptor responsiveness to environmental stressors. Specifically, the obtained results highlight divergent gene and functional landscapes with ORF-disrupting mutations identified in Monachus monachus and Neomonachus schauinslandi that abolish receptor activation toward known PXR ligands. In contrast, Leptonychotes weddelli retained an intact PXR ORF but showed reduced receptor activity, revealing functional divergence in PXR among pinnipeds.

Biotransformation↗