Biology subjects

Qi, Y.

Publications and source records attributed to Qi, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Medial Olivocochlear Activity Modulates Central Auditory Synapse Structure and Function

In many mammals, the auditory system is immature at birth and undergoes activity-dependent refinement. The medial olivocochlear system (MOC) contributes to the maturation of central auditory connectivity by shaping spontaneous activity in the developing inner ear. Although altered MOC activity has been linked to electrical and synaptic dysfunctions in different central auditory nuclei, an in-depth analysis of the same synapse under conditions of absent versus enhanced MOC activity is lacking. In this work, we set out a physiological and structural analysis of the calyx of Held and the principal neurons of the medial nucleus of the trapezoid body (CH-MNTB) synapse at postnatal days 12-14 in three mouse models of either sex: wild-type (WT), 9 knock-in (9KI; with enhanced MOC activity), and 9 knock-out (9KO; which lacks MOC activity). Electrophysiological recordings in brain slices revealed a reduced synaptic strength efficacy in 9KI compared to WT, including smaller excitatory postsynaptic current (EPSC) amplitudes, stronger short-term depression during repetitive stimulation and a decrease readily releasable pool size. In contrast, 9KO mice showed minimal synaptic differences relative to WT. Serial block-face electron microscopy (SBEM) reconstructions demonstrated morphological alterations of the CH in both MOC-manipulated mouse models. However, 9KI mice exhibited the largest deviations, including fewer morphologically complex CHs and increased poly-innervation of MNTB cells. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Moreover, the enhancement of MOC activity drives more pronounced developmental changes in brainstem auditory circuitry than its absence. Significance StatementBefore hearing onset, inner hair cells in altricial mammals show spontaneous electrical activity crucial for proper auditory pathway development. This activity is finely regulated by descending efferent nerves from the central nervous system during a critical developmental period, ensuring precise auditory circuit formation. Our study shows that genetically manipulating efferent function --either by eliminating it or enhancing it-- leads to structural alterations and severe synaptic dysfunction within the auditory brainstem. These results indicate that transient, well-regulated efferent control of cochlear activity is crucial for establishing accurate central auditory connectivity. Importantly, enhancing efferent peripheral activity causes more pronounced central synaptic changes than its absence, highlighting the importance of balanced efferent modulation during early auditory system development for normal brainstem auditory function.

neuroscience↗

bioRxiv2026

UniWave: A Waveform-Based Encoding Framework for Nucleic Acid Feature Extraction

Nucleic acid sequence analysis constitutes a core research area in biomedical and health informatics, playing a critical role in infectious disease surveillance, epigenetic regulation, and genomic biomarker discovery. However, most existing sequence encoding methods rely on discrete representations, which are inadequate for capturing the intrinsic continuous structural properties of biological sequences. Inspired by waveform representations in modern physics, we propose UniWave, a novel encoding framework that converts discrete nucleotide sequences into biologically informative one-dimensional continuous waveforms through base mapping, windowed sinc interpolation, and wavelet-based downsampling. To enable more efficient spatiotemporal modeling, we design a learnable positional encoding module, WavePosition, which incorporates positional information to project the one-dimensional waveform into a two-dimensional continuous representation. In addition, we develop a lightweight dual-attention network, InceptionTime-ATT, to facilitate efficient multi-scale extraction of biological features. Experiments conducted on multiple representative genomic benchmark tasks demonstrate that UniWave consistently and significantly outperforms conventional encoding methods in viral genotype classification, cross-species enhancer identification, epigenetic modification site detection, and bacterial genome classification. Moreover, UniWave maintains excellent robustness under perturbation and noise stress tests, while its low-dimensional continuous representation further contributes to reduced model complexity. In summary, UniWave establishes a novel paradigm for biomedical nucleic acid sequenceencoding that is interpretable, noise-resilient, and computationally efficient, offering new avenues for uncovering disease-associated genomic patterns and advancing data-driven biomedical research.

bioinformatics↗

bioRxiv2026

EssTFNet: Integration of Adaptive Time - Frequency and DNA Language Models for Interpretable Human Essential Gene Prediction

Essential genes are defined as those that are indispensable for an organisms survival. The loss of function of these genes results in cell death or an inability to complete the normal life cycle. Research on essential genes is pivotal in elucidating the origin and evolution of life, as well as in identifying potential therapeutic targets. Therefore, accurately predicting essential genes is of great scientific importance and has many applications in basic research and the biomedical field. In this study, we propose EssTFNet, a novel and interpretable deep learning framework that combines adaptive time-frequency analysis with a DNA language model to achieve accurate prediction of human essential genes while enabling mechanistic biological interpretation. Specifically, EssTFNet leverages the architecture of ATFNet, which innovatively maps DNA and protein sequences into equivalent time-series signals to extract periodic and non-stationary features, thereby enhancing the models capacity to capture complex sequence patterns. Through effective feature selection and architectural optimization, EssTFNet strikes a favorable balance among prediction accuracy, model interpretability, and cross-tissues generalization capability, significantly outperforming current mainstream sequence-based deep learning methods with an AUC of 0.8336 and an AUPR of 0.8212. Additionally, the DeepLIFT attribution method was employed to identify functional motifs closely associated with gene essentiality, offering valuable insights for experimental validation. For the convenience of researchers, we have developed an easy-to-use web server and made it along with the source code in a GitHub repository: https://github.com/QIANJINYDX/EssTFNet. Overall, this study presents a potentially useful methodological framework for human essential genes prediction, which could provide valuable insights for future research and applications in this field.

bioinformatics↗

bioRxiv2026

Dendritic excitations primarily mediate back-propagation in CA1 pyramidal neurons during behavior

Dendrites integrate synaptic inputs to trigger action potentials, and dendrites carry back-propagating action potentials (bAPs) to synapses where these signals contribute to plasticity. Despite strong evidence for a rich repertoire of nonlinear dendritic excitations, the in vivo roles of these excitations in dendritic integration and back-propagation remain uncertain. Here, we used high-speed voltage imaging through a chronically implanted microprism to map membrane potential dynamics from basal to apical dendrites of CA1 neurons in mice navigating in a virtual reality environment. Despite complex dendritic branch morphology, the dynamics were largely captured by 2 or 3 electrical compartments: basal, soma, and apical. Fast dendritic spikes almost always started from bAPs, indicating that dendritic spikes are primarily a consequence rather than a cause of somatic spiking. These fast spikes sometimes triggered slower apical dendritic plateau depolarizations, which drove complex spikes at the soma. We found that the biophysics of dendritic excitability determined the distribution of simple and complex spikes across a place field. Our results show how CA1 pyramidal neurons convert synaptic inputs to spiking outputs and suggest a primary role of dendritic nonlinearities in mediating activity-dependent plasticity.

neuroscience↗

bioRxiv2026

Effects of atmospheric CO2 levels on the susceptibility of maize to diverse pathogens

Rising atmospheric CO2 has profound implications for crop productivity and food security. Based on studies in C3 plants, elevated CO2 (eCO2) can shape plant-pathogen interactions, although the outcomes are often variable. The question of how eCO2 influences immunity and disease development in C4 plants, such as the globally important cereal crop maize (Zea mays L.), has not been systematically examined. We challenged maize plants grown under ambient CO2 (aCO2, 420 ppm) and eCO2 (550 ppm) with bacterial, viral, fungal, and oomycete pathogens. Plants grown in eCO2 were more susceptible to sugarcane mosaic virus, suggesting compromised antiviral defenses, less susceptible to Clavibacter nebraskensis, Exserohilum turcicum, and Colletotrichum graminicola, and susceptibility to Puccinia sorghi and Pythium sylvaticum was unchanged. Reduced susceptibility to C. nebraskensis was associated with enhanced basal immune responses. These results establish a foundation for dissecting eCO2-responsive defense mechanisms, and they highlight a critical need to understand how eCO2 will impact plant responses to microbes, pests, and abiotic stresses under future conditions.

plant biology↗

bioRxiv2025

Detection of Mid-parent Heterosis Genes in Large-Scale Unreplicated RNA-Seq Experiments

Mid-parent heterosis (MPH), characterized by hybrid trait values deviating from the mid-parent average, is a well-documented phenomenon whose genetic basis remains poorly understood. Identifying genes associated with MPH is crucial for uncovering the molecular mechanisms underlying heterosis. Recent large-scale RNA-sequencing (RNA-seq) experiments enable the evaluation of heterosis genes across numerous families; however, replication is often infeasible due to cost and labor constraints, resulting in unreplicated large-scale datasets and posing statistical challenges for dispersion estimation and reliable inference. To address this issue, we propose a novel two-stage likelihood ratio test (2sLRT) for detecting MPH genes in unreplicated RNA-seq experiments. In the first stage, genes and families without evidence of differential expression across varieties are identified, and the corresponding varieties are used as pseudo-replicates to estimate dispersion. In the second stage, a likelihood ratio test based on the negative binomial distribution is employed to test for MPH. Simulation studies demonstrate that 2sLRT achieves higher power and better false discovery rate control compared to existing approaches. Application of 2sLRT to a maize RNA-seq dataset with 599 families further highlights the methods effectiveness in revealing meaningful patterns of MPH gene expression.

plant biology↗

bioRxiv2025

Multimodal analysis defines GNG4 as a distinguishing feature of germinal center-positioned CD4 T follicular helper cells in humans

CD4 T follicular helper (Tfh) cells coordinate humoral immune responses within germinal centers (GC) of lymphoid tissue. Despite their critical roles in vaccination and autoimmunity, the gene expression programs that define functionally distinct human Tfh states-- and the molecular pathways engaged by Tfh positioned within the GC niche--remain incompletely understood. This gap has limited translational efforts to monitor or therapeutically target specific Tfh states for clinical benefit. Here, we delineate human CD4 T cell heterogeneity in tonsils and peripheral blood using trimodal single-cell sequencing and spectral flow cytometry to define epigenomic, transcriptional, and proteomic features of distinct Tfh states. Tfh with a GC-like phenotype exhibited markedly increased chromatin accessibility and both mRNA and protein expression of G protein subunit gamma 4 (GNG4). In tonsil, single-cell spatial transcriptomics defined GNG4 expression as a distinguishing feature of activated Tfh states within spatially demarcated GC compartments, with greater specificity than conventionally GC-associated features such as BCL6, TOX2, and S1PR2. In contrast, GNG4- Tfh primarily localized to nonGC regions and exhibited a resting, Th17-polarized phenotype. Together, these data highlight GNG4 as a central feature of activated, GC-positioned Tfh cell identity in humans. One Sentence SummaryGNG4 expression defines activated CD4 T follicular helper cells localized to the germinal center of human lymphoid tissue.

immunology↗

bioRxiv2025

The Human Hippocampus Is Involved in Auditory Short-Term Memory Trace Formation

The human hippocampus has been claimed to play an important role in long-term memory, or episodic memory, but its contribution to short-term memory remains debated. Here, we demonstrate human hippocampal involvement in auditory short-term memory (ASTM) trace formation. We used a classic oddball paradigm and intracranial recordings across various human brain areas. High frequency activities evoked by deviant stimuli in subjects indicate the generation of ASTM trace. Analysis of auditory response latencies across the hippocampus, insula, and temporal, parietal, and frontal lobes revealed the early processing of ASTM trace at a pre-attention stage. Granger causality analysis further showed that ASTM trace processing engages hierarchical cortical areas and clarified their interactions. Bottom-up signals flow from the insula and auditory temporal regions to the frontal lobe early on, followed by top-down information from the frontal lobe to the hippocampus, inferior temporal lobe, and insula at a later pre-attentive stage. Critically, Bayesian model selection of dynamic causal modeling revealed that deviant stimuli selectively enhanced the effectiveness of top-down connections to the hippocampus, thereby facilitating ASTM trace formation. These results provide compelling evidence that the human hippocampus contributes to auditory short-term memory at a pre-attention stage and suggests a challenge to entrenched beliefs in the classification of memory systems.

neuroscience↗

bioRxiv2025

Mechanical Disturbance of Trichomes Enhances Cd2+ Uptake via Malate-Mediated Stomatal Opening in Arabidopsis

Phytoremediation of cadmium-contaminated soils relies on efficient metal uptake and translocation in plants. We previously found that gentle mechanical stimulation of non-glandular trichomes by brushing significantly enhances shoot Cd{superscript 2} accumulation in Arabidopsis thaliana, although the underlying physiological mechanism remained unclear. Here, we demonstrate that trichome brushing specifically induces stomatal opening, elevates transpiration, and promotes Cd{superscript 2} uptake, as evidenced by measurements of stomatal aperture, stomatal conductance, transpiration rate, and Cd{superscript 2} concentration in wild-type and mutant leaves. These responses are absent in the glabrous gl1-1 mutant and are not elicited by brushing epidermal pavement cells, indicating a trichome-specific mechanosensory pathway. Mechanistically, this pathway requires MPK3/MPK6 activity and employs malic acid as a key regulator of stomatal aperture, functioning independently of canonical ABA signaling. Our findings uncover a previously unrecognized trichome-to-stomatal signaling cascade that links trichome mechanostimulation to enhanced heavy metal accumulation.

plant biology↗

bioRxiv2025

Ion-Pair-Free Nanoflow HILIC-MS With RNase Benchmarking for Native RNA

RNA modifications play crucial roles in regulating cellular processes, but comprehensive mapping of the human RNome still remains limited by technological challenges. Mass spectrometry (MS) is a valuable tool to analyse RNA modifications complementing sequencing-based analysis. Current MS-based oligonucleotide workflows have limited sensitivity, requiring micrograms of RNA inputs and thus hindering studies on native RNAs. Additionally, environmentally toxic ion-pairing reagents are often required. Here, we report a highly sensitive, broadly applicable oligonucleotide-MS workflow that enables analysis of nanogram-scale RNA hydrolysates and we benchmark the substrate specificity of three nucleases: RNase T1, RNase 4, and colicin E5. We developed a nano-flow hydrophilic interaction liquid chromatography (HILIC) setup compatible with common MS buffers and coupled this with high-resolution MS. Using modified NucleicAcidSearchEngine (NASE), we confidently assigned RNA hydrolysates with diverse 3-end chemistries. Furthermore, we demonstrate that RNase 4 and colicin E5 efficiently cleave modified RNAs including pseudouridine-containing transcripts, enabling high sequence coverages. Using this workflow, we successfully mapped modifications in 25 ng of native yeast tRNAPhe and verified the sequence of 250 ng of a synthetic mRNA. Overall, our method provides a sensitive, high-resolution platform for oligonucleotide mass spectrometry, facilitating comprehensive analysis of RNA modifications and advancing efforts toward complete epitranscriptomic mapping. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=58 SRC="FIGDIR/small/689004v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@ed3dc3org.highwire.dtl.DTLVardef@171d3d6org.highwire.dtl.DTLVardef@a9ce2org.highwire.dtl.DTLVardef@c1d940_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Hippo signaling regulates cuticle pigmentation and dopamine metabolism in Drosophila

Pigmentation plays multiple important roles in development, physiology and evolution. Melanization of the insect cuticle requires dopamine as a precursor of melanin and involves key enzymes in dopamine biosynthesis including Tyrosine hydroxylase (TH) and Dopa decarboxylase (Ddc). Some studies have hinted that disruption of the evolutionarily conserved Hippo signaling pathway, which has been primarily studied in the context of tissue growth, may lead to changes in cuticle pigmentation in the fruit fly Drosophila melanogaster. However, to our knowledge, there have not been any systematic investigations into their potential mechanistic links. In this study, we identified that all genes that comprise the canonical Hippo signaling pathway [hippo (hpo), salvador (sav), mats, warts (wts), yorkie (yki) and scalloped (sd)] are involved in cuticle pigmentation in the fly notum based on tissue-specific gene knock-down/out experiments and epistatic analysis. Despite the notable divergence of pigmentation mechanisms between invertebrates and vertebrates, these phenotypes can often be rescued by the human orthologs of corresponding fly genes. While we find that manipulation of Hippo signaling in dopaminergic neurons does not affect global dopamine levels in the fly brain, developmental inhibition of this pathway can increase dopamine levels in the fly head, indicating that the mechanism by which dopamine levels are regulated in the nervous system is distinct from that in epithelial cells. Through single nuclei RNA sequencing of the developing fly nota and subsequent functional studies of differentially expressed genes that are altered upon inhibition of Hippo signaling, we found many genes that contribute to cuticle pigmentation downstream of Hippo signaling. We conclude that regulation of cuticle pigmentation by canonical Hippo signaling acts through multiple downstream genes rather than directly through TH and Ddc. We also propose that the Drosophila melanogaster cuticle may serve as a useful platform to identify previously uncharacterized mediators of Hippo signaling as well as an in vivo experimental system to test the functionality of rare genetic variants found in human Hippo signaling orthologs associated with a variety of diseases.

genetics↗

bioRxiv2025

CREG1 promotes autophagy and protects the heart against nutritional stress-induced injury and age-associated hypertrophy, fibrosis and diastolic dysfunction

BackgroundCellular repressor of E1A-stimulated genes 1 (CREG1) is an evolutionarily conserved endolysosomal glycoprotein that enhances lysosomal biogenesis and autophagy, suppresses proliferation, and promotes differentiation. A prior gene targeting strategy that produced truncated N-terminal fragments resulted in embryonic lethality, limiting the ability to assess the physiological role of complete CREG1 loss. We hypothesized that CREG1 regulates cardiac autophagy, thereby maintaining cardiac structure and function under both physiological and stress conditions. MethodsWe generated true Creg1 knockout (KO) mice by deleting the entire open reading frame and established a gain-of-function model by inserting human CREG1 into the Rosa26 locus. Cardiac structure and function were assessed in global and cardiomyocyte-specific Creg1 knockout (cmCreg1KO) and knock-in (cmCREG1KI) mice. Autophagy was evaluated using biochemical assays, immunofluorescence, electron microscopy, and the CAG-EGFP-RFP-LC3 reporter analysis. ResultsGlobal Creg1 knockout mice developed progressive cardiac hypertrophy, fibrosis, and diastolic dysfunction at [~]80 weeks of age. At younger ages, CREG1 deficiency increased susceptibility to nutritional stress, resulting in mitochondrial damage and myofiber disruption in cardiomyocytes. cmCreg1KO mice exhibited dilated cardiomyopathy, left atrial thrombosis, and lethality around 50 weeks of age; however, interpretation of disease severity is confounded by Myh6-Cre-associated cardiotoxicity, which may mask additional pathogenic effects attributable to CREG1 loss. In contrast, cmCREG1KI mice demonstrated enhanced exercise capacity under nutritional stress. Mechanistically, CREG1 was localized to endolysosomal and autophagosomal compartments. Loss of CREG1 impaired autophagy flux and mitophagy, likely due to defective autophagosome membrane expansion and degradation. In contrast, CREG1 overexpression enhanced autophagy in cardiomyocytes. ConclusionsCREG1 is a key regulator of cardiac autophagy, protecting the heart against nutritional stress-induced injury and age-associated cardiac hypertrophy, fibrosis, and diastolic dysfunction. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/687936v1_ufig1.gif" ALT="Figure 1000"> View larger version (60K): org.highwire.dtl.DTLVardef@1b9fc05org.highwire.dtl.DTLVardef@150e48aorg.highwire.dtl.DTLVardef@1cc47adorg.highwire.dtl.DTLVardef@75ed53_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Neuropathological Correlates of Apathy Progression in Alzheimer's Disease and Related Dementias: A Longitudinal NACC Cohort Study

ObjectiveApathy is a prevalent and disabling symptom in Alzheimers disease and related dementias, yet its progression across neuropathological subtypes remains incompletely understood. This cohort study investigates longitudinal changes in apathy and their associations with major neuropathologies using data from the National Alzheimers Coordinating Center. MethodsWe analyzed 1,488 participants with autopsy-confirmed neuropathology and at least two caregiver-reported NPI-Q assessments. Generalized linear mixed models were used to assess associations between apathy and six neuropathologies--Alzheimers disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration (FTLD), hippocampal sclerosis (HS), cerebrovascular disease (CVD), and cerebral amyloid angiopathy (CAA). with time modeled as years to death and including interaction terms. Sex-stratified analyses were also conducted. All models were adjusted for age at death, sex, and NPI-Q total score excluding apathy. ResultsApathy prevalence increased over time across all pathology groups. FTLD (OR = 2.11, 95% CI: 1.32-3.39) and HS (OR = 2.23, 95% CI: 1.38-3.60) were consistently associated with higher odds of apathy throughout the disease course. No significant interaction effect was observed in any of the neuropathologies. In sex-stratified analyses, FTLD (OR=2.58, 95% CI 1.40-4.77), HS (OR=2.48, 95% CI 1.29-4.77), and LBD (OR=1.64, 95% CI 1.03-2.61) were significantly associated with apathy in males, while only HS (OR=2.18, 95% CI 1.06-4.47) remained significant in females. InterpretationApathy severity varied by neuropathologies but progressed similarly over time. The elevated burden in FTLD and HS, particularly among males, underscores the importance of stratified approaches to early detection and intervention targeting apathy in ADRDs.

neuroscience↗

bioRxiv2025

ALKBH1 activity in vitro and human cell lines by isotope dilution mass spectrometry

AlkB homolog 1 (ALKBH1) is a member of the AlkB family of Fe(II) and -ketoglutarate (-KG)-dependent dioxygenases, known for its enzymatic activity on various nucleic acid substrates. Its known targets include N1-methyladenosine (m1A), N6-methyladenosine (m6A), N3-methylcytidine (m3C), and 5-methylcytosine (m5C) in RNA, as well as N6-methyladenine (N6-mA, 6mA) in DNA and the histone protein H2A. Moreover, dysregulation or dysfunction of ALKBH1 has been implicated in a broad spectrum of human diseases. In order to shed further light on the substrate scope and role of ALKBH1, we used quantitative mass spectrometry to assess its activity in vitro and in human cell lines. To study ALKBH1 activity on defined substrates in vitro, we enzymatically generated tRNAs specifically carrying the m3C32 (tRNA-ThrUGU and tRNA-SerUCN) and i6A37 (tRNA-SerUCN) modifications. Here we show that ALKBH1 reduces m3C, m1A and m5C in vitro in total extracts of tRNAs, but does not impact on rRNA modifications in human cell lines. However, upon overexpression or siRNA-mediated knock-down of alkbh1 in human cell lines no impact on the modification of total tRNA extracts or specifically enriched RNAs could be observed. In addition, varying the glucose and fetal bovine serum (FBS) concentration in the growth medium of HEK293T cells, in combination with alkbh1 siRNA-mediated knock-down, also shows no impact on the tRNA modification spectra. Based on our data, we conclude that in human cells lines grown under optimal conditions ALKBH1 does not play an important role in the demethylation of tRNAs.

biochemistry↗

bioRxiv2025

Pro4S: prediction of protein solubility by fusing sequence, structure, and surface

Protein solubility is a critical physicochemical property influencing protein stability, therapeutic efficacy, and overall developability in drug discovery. However, traditional experimental methods for assessing solubility are often resource-intensive and time-consuming. To address these limitations, computational approaches leveraging artificial intelligence have emerged, yet current models generally treat qualitative classification and quantitative regression as separate tasks and rely predominantly on sequence-based information, neglecting crucial structural and surface characteristics. Here, we introduce Pro4S, a novel multimodal predictive model that integrates protein language models, structural data, and surface descriptors using advanced contrastive learning techniques. Our unified framework achieves significant improvements in prediction accuracy, robustness, and generalizability for both qualitative and quantitative solubility assessments. Benchmark comparisons demonstrate that Pro4S consistently outperforms existing state-of-the-art predictors across diverse datasets. Furthermore, by applying Pro4S to the emerging area of de novo protein design, we validated a strong correlation between predicted solubility and experimental expression levels, reducing the proportion of non-expressed proteins by 52.7% while retaining 96.7% of highly expressed proteins. This highlights Pro4Ss potential to serve as a reliable upfront screening tool for increasing expression success rates and accelerating rational protein engineering.

bioinformatics↗

bioRxiv2025

The dominance of gene expression controlled by trans-eQTL hotspots contributes to phenotypic heterosis in maize

Heterosis, or hybrid vigor, is a key phenomenon in genetics research and agricultural production, and has been primarily attributed to non-additive genetic effects such as dominance -- a prevailing consensus shaped by decades of empirical research and theoretical debate. Although dominance may arguably arise from distal modifiers, their selective advantage is debated due to presumably small individual effects. To address this long-standing question, particularly how genetic dominance manifests at the transcriptomic level and contributes to phenotypic heterosis, we integrated transcriptomic and phenotypic data from a large population of maize hybrids and their inbred parents. We found that [~] 30% of the expressed seedling genes in a significant proportion of hybrids exhibited expression patterns deviating from the average of the two parents, indicative of non-additivity. Further analysis suggests that while hybrid gene expression per se is primarily regulated by cis-eQTLs, expression dominance (or non-additivity) is disproportionately controlled by trans-eQTLs. These trans-eQTLs cluster into hotspots that regulate the non-additivity of hundreds of target genes, mostly within co-expression networks, and are notably enriched for transcription factors (TFs). Focusing on one such hotspot, we functionally validated a classical maize gene ZmR1, a basic helix-loop-helix (bHLH) TF associated with multiple seedling trait heterosis, as a candidate regulator of expression dominance across hundreds of genes. Overexpression of ZmR1 enhances expression dominance of downstream genes and increases phenotypic heterosis in both seedling and adult traits. Further experiments confirmed its direct regulatory role in modulating genes involved in anthocyanin biosynthesis and lignin metabolism, driving transcriptome-level dominance. These results provide empirical support for the modifier hypothesis under an omnigenic model, suggesting that heterosis arises not from the modification of a single genes inheritance but through the coordinated regulation of hundreds of phenotype-associated genes, thereby helping to reconcile the long-standing debate over the genetic basis of dominance in heterosis.

genetics↗

bioRxiv2025

A blueprint for mutation-defined hallmark vulnerabilities across human cancers

Hallmark gene mutations shape cancer cell vulnerabilities and inform drug discovery1-3. A systematic map of hallmark gene mutation-defined cancer dependencies and therapeutic responses is essential to uncover novel targets and refine therapeutic strategies. Here, we present the first pan-cancer blueprint of hallmark vulnerabilities, systematically linking hallmark gene mutation markers to cancer cell dependencies and drug sensitivities across 22 cancer cohorts. We integrated multi-omics data from patient tumours with large-scale CRISPR-Cas9 screens and pharmacologic profiling of over a thousand cancer cell lines. Our analysis revealed the cancer type-specific nature of hallmark gene expression programs, uncovered previously unrecognised mutation-target gene dependencies, and highlighted metabolic programs as a dominant class of functional vulnerabilities. Notably, we identified oxidative phosphorylation (OXPHOS) addiction in CDKN2A-loss lung squamous cell carcinoma (LUSC) and experimentally validated this dependency. Our validation highlights the greater selectivity of CDKN2A-loss LUSC cells to metformin, an FDA-approved antidiabetic drug known for its OXPHOS inhibitory activity. Proteogenomic integration further prioritised targets overexpressed in mutant tumours, constituting therapeutic windows. Pharmacologic profiling identified both oncology and non-oncology agents with selective activity in mutation-defined subgroups, revealing opportunities for drug repurposing. Our machine learning framework, Comet-X, for the first time fully leveraged gene mutation combinations to predict these target dependencies and drug responses. The resulting pan-cancer mutation-dependency map provides a comprehensive resource of hallmark gene targets and candidate therapeutics, stratified by mutation markers, to pave the way for drug development, clinical trial design and discovery research.

cancer biology↗

bioRxiv2025

In-situ glial cell-surface proteomics identifies pro-longevity factors in Drosophila

Much focus has shifted towards understanding how glial dysfunction contributes to age-related neurodegeneration due to the critical roles glial cells play in maintaining healthy brain function. Cell-cell interactions, which are largely mediated by cell-surface proteins, control many critical aspects of development and physiology; as such, dysregulation of glial cell-surface proteins in particular is hypothesized to play an important role in age-related neurodegeneration. However, it remains technically difficult to profile glial cell-surface proteins in intact brains. Here, we applied a cell-surface proteomic profiling method to glial cells from intact brains in Drosophila, which enabled us to fully profile cell-surface proteomes in-situ, preserving native cell-cell interactions that would otherwise be omitted using traditional proteomics methods. Applying this platform to young and old flies, we investigated how glial cell-surface proteomes change during aging. We identified candidate genes predicted to be involved in brain aging, including several associated with neural development and synapse wiring molecules not previously thought to be particularly active in glia. Through a functional genetic screen, we identified one surface protein, DIP-{beta}, which is down-regulated in old flies and can increase fly lifespan when overexpressed in adult glial cells. We further performed whole-head single-nucleus RNA-seq and revealed that DIP-{beta} overexpression mainly impacts glial and fat cells. We also found that glial DIP-{beta} overexpression was associated with improved cell-cell communication, which may contribute to the observed lifespan extension. Our study is the first to apply in-situ cell-surface proteomics to glial cells in Drosophila, and to identify DIP-{beta} as a potential glial regulator of brain aging.

neuroscience↗