Biology subjects

Liu, X.

Publications and source records attributed to Liu, X..

At least 451 records · Page 25Linked to original sources

bioRxiv2025

Beach sand beneath our feet: an overlooked reservoir of antibiotic resistance genes and pathogens, revealed by metagenomic evidence from Qingdao's recreational beaches

Coastal beach environments, especially those with heavy tourist activity, represent a dynamic interface between terrestrial and marine microbiomes. However, beach sand is rarely considered in surveillance of antibiotic resistance. In this study, we combined 16S rRNA gene sequencing and shotgun metagenomics to characterize microbial communities and antibiotic resistance genes (ARGs) at four popular recreational beaches in Qingdao, China. We show that beach sands harbor highly diverse bacterial communities with significantly greater richness than adjacent seawater. Beach sand near sewage discharge points had microbial profiles intermediate between raw sewage and open-ocean water, reflecting contributions from both sources. Metagenomic analysis identified a broad "resistome" of over 300 distinct ARGs in these beach and water samples, spanning 33 antibiotic classes and 6 resistance mechanism categories. Notably, the rifampicin resistance gene rpoB2 was the most abundant ARG, and genes conferring resistance to peptide antibiotics were prevalent. Sewage outfalls were found to be major contributors of ARGs, with waste-influenced sand containing a larger and more diverse ARG pool than sand farther from pollution sources. We also detected a high diversity of bacterial virulence factor genes, particularly in sand. Our findings highlight that tourist beaches can serve as reservoirs and mixing zones for antibiotic-resistant and potentially pathogenic bacteria from land-based pollution. This underscores the need to include beach sand in environmental monitoring for antibiotic resistance and to improve wastewater management at recreational coastlines to mitigate public health risks. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/661489v1_ufig1.gif" ALT="Figure 1"> View larger version (84K): org.highwire.dtl.DTLVardef@18705f3org.highwire.dtl.DTLVardef@1979f8forg.highwire.dtl.DTLVardef@16c9029org.highwire.dtl.DTLVardef@6c778d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Single-Cell and Population-Level Neuromodulation Dynamics in Dual-Electrode Intracortical Stimulation

In neuroprosthetics, intracortical microstimulation (ICMS) recruits cortical networks to evoke brain responses and sensory perceptions. However, multi-electrode ICMS often generates suboptimal percepts compared to single-electrode ICMS, suggesting nonlinear neuromodulation rather than simple summation by multi-electrode ICMS. Yet, the factors and mechanisms underlying this modulation remain poorly understood. To investigate multi-electrode ICMS, we combined two-photon calcium imaging with a well-controlled dual-electrode ICMS in the mouse visual cortex to investigate how neurons integrate converging ICMS inputs at varying intensities. We found that stimulation intensity significantly shapes neuromodulation at both single-cell and population levels. Specifically, low intensities (5-7 {micro}A) have a minimal effect on neural responses. At intermediate intensities (10-15 {micro}A), we observed diverse, nonlinear bipolar modulation--both enhancement and attenuation--at the single-cell level. However, we achieved net enhancement at the population level. At higher intensities (15-20 {micro}A), although the proportion of modulated neurons increased in both enhancement and attenuation directions, the net effect at the population level was neutral (zero modulation). Furthermore, neurons strongly responsive to single-electrode ICMS were more likely to be attenuated, while weaker responding cells exhibited enhanced modulation. The strongest neuromodulatory effects occur at intermediate spatial distances in between the two electrodes. Computational modeling based on spiking neural network composed of adaptive exponential integrate-and-field neurons implicated the importance of inhibitory network dynamics and network variability as key mechanisms. Our experimental data was used to train an advanced deep learning approach, which successfully predicted the neuromodulation patterns induced by dual-electrode ICMS. Our findings reveal intensity- and spatial-dependent rules of neuromodulation by ICMS, providing necessary insights to optimize multi-electrode ICMS for neuroprosthetic applications. Significance statementUnderstanding how cortical neurons integrate concurrent inputs from multi-electrode intracortical microstimulation (ICMS) is essential for advancing neuroprosthetic technologies. We show that dual-electrode ICMS evokes distinct, predictable neuromodulatory effects that depend on (i) stimulation intensity, (ii) a neurons baseline responsiveness to single electrode input, and (iii) its proximity to the electrodes. Low and intermediate intensity dual-electrode ICMS amplifies neural activity compared to single-electrode ICMS, whereas high-intensity stimulation leads to attenuation, limiting net activation.

neuroscience↗

bioRxiv2025

TaPGS1 Driven Flavonol Accumulation Delays Endosperm Cellularization and Enlarges Wheat Grains

Flavonols play a crucial role in seed development by regulating multiple physiological processes, including seed coat pigmentation, dormancy, fertilization, and endosperm formation. Notably, flavonols influence the polar transport of auxin, thereby affecting seed growth dynamics. In our previous work, we found that overexpression of the wheat bHLH transcription factor TaPGS1 results in increased grain size; however, the underlying mechanism remained unclear. In this study, metabolomic and transcriptomic analyses of TaPGS1 overexpressing wheat lines revealed enhanced flavonol accumulation and upregulation of key flavonol biosynthetic genes. Further investigations suggested that flavonol accumulation in the seed coat may disrupt auxin transport, leading to localized auxin buildup, delayed endosperm cellularization, and an increase in endosperm cell number. These changes collectively contribute to grain enlargement. Our findings uncover a TaPGS1 flavonol regulatory module that links auxin distribution to endosperm development and seed size control in wheat.

plant biology↗

bioRxiv2025

High-throughput Single-cell Proteomics Enabled by an Integrated Hyperplexing and Automatic Labelling Approach without Fractionation

Single-cell proteomics (scProteomics) enables comprehensive analysis of protein composition, expression and functions at the single-cell level. While label-free techniques have generated promising results, achieving high-throughput scProteomics remains a substantial challenge. In this study, we present an approach that increases scProteomics throughput by approximately 30-fold through the true integration of isobaric tags (IBT) with tandem mass tags (TMT), a method we term Integral-Hyperplex. Due to remarkable differences in signal response between TMT16 and IBT16 reporter ions, we implemented two normalization strategies to ensure accurate and integrated quantification: (1) the inclusion of a normalization channel in both IBT and TMT groups to serve as internal standards; and (2) the generation of protein-specific conversion factors between IBT16 and TMT16 signals. We validated the quantification accuracy of the Integral-Hyperplex method by labeling HeLa digests at varying ratios. Furthermore, we demonstrated fully automated labeling on the active-matrix digital microfluidics chip, consuming only 12 nL of labeling reagent per single cell and with a reaction volume as low as 20 nL. Our approach was validated through proof-of-principle quantification experiments across three types of single cells. Approximately 2,000 protein groups were quantified per cell, and the three cell types can be well clustered, confirming the reliability of the Integral-Hyperplex approach. Approximately 300 samples can be analyzed per day due to insufficient resolution of timsTOF SCP. Throughput can be further enhanced using TMT32, additional labeling reagents, and more advanced mass spectrometers such as Orbitrap Astral and timsTOF Ultra 2, and our approach is theoretically capable of analyzing up to [~]2,000 single cells per day.

biochemistry↗

bioRxiv2025

Neurogranin Unlocks the L-type Ca2+ Channel and Directs Calmodulin Delivery

Neurogranin (Ng) is enriched in the postsynaptic density, with mounting evidence of its importance to neural pathophysiology. Ng has long been recognized as a dedicated calmodulin (CaM)- binding/buffering protein. This study demonstrates that Ng, through its CaM-binding IQ domain, directly binds the distal C-terminus (DCT) of the L-type Ca2+ (CaV1) channel, as a de novo mechanism regulating excitation-transcription coupling. The Ng/DCT interaction attenuates autonomous C- terminus-mediated inhibition and promotes specific CaM delivery to CaV1, cooperatively enhancing channel gating (activation and inactivation), Ca2+ influx and downstream neuronal signaling. Phosphorylation of Ng leads to the dissociation of the CaM C-lobe, while transiently forming the linkage with the CaM N-lobe. In contrast to neurodegenerative disease-related Ng mutants, WT Ng, within the above transient complex, enables the "targeted CaM transfer" to the proximal C-terminus of CaV1. Collective evidence from electrophysiology, binding assays, structural modeling and Ca2+ imaging supports a paradigm of dynamic intra- and inter-molecular interactions/facilitations underlying Ng and CaV1, both of which are representative CaM-binding proteins. This work proposes a mechanistic scheme potentially applicable to a broad scope of CaM-related physiology.

biophysics↗

bioRxiv2025

Predicting the Evolutionary and Functional Landscapes of Viruses with a Unified Nucleotide-Protein Language Model: LucaVirus

Predicting viral evolution and function remains a central challenge in biology, hindered by high sequence divergence and limited knowledge compared to cellular organisms. Here, we introduce LucaVirus, a multi-modal foundation model for viruses, trained on 25.4 billion nucleotide and amino acid tokens covering nearly all known viruses. LucaVirus learns biologically meaningful representations capturing relationships between sequences, protein/gene homology, and evolutionary divergence. Using these embeddings, we developed downstream models that address key virology tasks: identifying hidden viruses in genomic "dark matter", annotating enzymatic activities of uncharacterized proteins, predicting viral evolvability, and identifying antibody candidates for emerging viruses. LucaVirus achieves state-of-the-art results in three tasks and matches leading models in the fourth with one-third the parameters. Together, these findings demonstrate the power of a unified foundation model to comprehensively decode the viral world and establish LucaVirus as an efficient and versatile platform for AI-driven virology, from virus discovery to functional and therapeutic predictions.

bioinformatics↗

bioRxiv2025

Nanopore Sequencing Unveils Somatic Structural Variations as Biomarkers in Laryngeal squamous cell carcinoma Genomes

Laryngeal squamous cell carcinoma (LSCC) is an aggressive cancer with poor quality of life, largely due to the absence of reliable molecular biomarkers for early diagnosis and prognosis. While somatic structural variations (SVs) have been documented in LSCC, conventional short-read sequencing approaches are inherently limited in detecting of large-scale somatic SVs, which are critical to understanding tumorigenesis. Here, we presented SomaGauss-SV, a somatic SVs detection workflow leveraging nanopore long-read sequencing data. Benchmarking against five paired tumor cell line datasets showed SomaGauss-SV consistently achieves a balanced high precision and recall. SomaGauss-SV applied to 15 paired LSCC tumor-blood samples uncovered a comprehensive SVs landscape and a significant positive correlation between somatic deletion burden and smoking intensity. Furthermore, a high-frequency somatic simple repeat expansion was identified in 20/27 (74.1%) of LSCC patients, upregulating the expression of genes TP53BP2 and FBXO28 through spatial proximity. These findings underscore the potential of long-read sequencing and SomaGauss-SV in uncovering previously unexplored genomic rearrangements in LSCC, providing valuable resources for biomarker discovery.

bioinformatics↗

bioRxiv2025

Rapid acquisition of HIV-1 neutralization breadth in a rhesus V2 apex germline antibody mouse model after a single bolus immunization

Current vaccine strategies to elicit broadly neutralizing antibodies (bnAbs) against HIV-1 generally propose complex, multi-boost immunization regimens. In rhesus macaques, SHIV infection has been observed to rapidly drive the development of some classes of bnAbs that share structural similarities with those in humans. Here, we generated a knockin mouse model with B cells bearing the unmutated common ancestor (UCA) of the V2 apex-targeted bnAb lineage, V033-a. A single immunization of mice with a germline-targeting native-like trimer was sufficient to recapitulate the ontogeny of the mature rhesus bnAb in knockin mice--including rare, disfavored somatic mutations--leading to the induction of antibodies that exhibited potent neutralization against both autologous and heterologous tier 2 viruses. A boost with Env escape mutant trimers further improved breadth and potency, and cryo-EM structure revealed the structural basis for heterologous neutralization breadth. Non-human primate and mouse models can thus combine with structure to serve as a platform for identifying and confirming immunogens that streamline HIV-vaccination regimens.

immunology↗

bioRxiv2025

Histo-LCM-Hi-C reveals the 3D chromatin conformation of spatially localized rare cells in tissues at high resolution

It is now well established that an understanding of the chromatin structure is essential to delineate the mechanisms underlying genomic processes. However, while methods to obtain this information from cells in vitro are widely available, there is presently a significant lack of techniques that can acquire this data from cells in the tissue. Such a capability is critical to determine the dependence of the local tissue environment on cell functioning. Further, this ability is particularly necessary for cells that are a significant minority of the total tissue population, which are often obscured in data dominated by more abundant tissue cells. Here we have developed Histological Laser Capture Microdissection Hi-C (Histo-LCM-Hi-C) to enable the characterization of chromatin architecture of phenotype-defined, spatially localized cells within intact tissue sections from as few as about 300 cells. We demonstrate the effectiveness of this approach with the generation of the first 3D Hi-C map of the tissue-resident macrophages of the liver, the Kupffer cells (KC), which are a minor cell population in the normal liver. As expected, owing to their relative rarity, these KC maps are significantly different from those obtained from whole liver, revealing distant contacts between putative enhancers and genes involved in key KC functions as well as significant differences with that of in vitro induced bone-marrow derived macrophages. We anticipate that this method will prove to be an indispensable technique in the growing repertoire of methodologies used for the characterization of the genomic properties of cells within their native environment.

genomics↗

bioRxiv2025

Structural Determinants and Biochemical Characterization of LORELEI as a GPI-Anchored Protein

Glycosylphosphatidylinositol-anchored proteins play critical roles in plant development, reproduction, and environmental responses. However, their biochemical characterization in plants remains limited. LORELEI, a putative glycosylphosphatidylinositol-anchored protein involved in pollen tube reception and early seed development in Arabidopsis thaliana, has lacked direct biochemical evidence confirming its glycosylphosphatidylinositol anchoring. This study employed biochemical approaches to validate LORELEI as a glycosylphosphatidylinositol-anchored protein. We demonstrate that ectopic expression of wild-type LORELEI fused to a reporter protein in vegetative tissues associates with a detergent-resistant membrane fraction and is sensitive to glycosylphosphatidylinositol-specific cleavage enzymes, thereby confirming that it is a glycosylphosphatidylinositol-anchored protein. Moreover, we show that mutations in the {omega}-sites or the glycosylphosphatidylinositol attachment signal of LORELEI disrupt its membrane localization, highlighting the necessity of these structural elements for proper glycosylphosphatidylinositol anchoring. Analysis of a reporter-fused LORELEI protein in the loss of function mutant of glycosylphosphatidylinositol 8, which encodes the catalytic subunit of glycosylphosphatidylinositol transamidase complex involved in glycosylphosphatidylinositol anchor addition, results in the appearance of prominent higher molecular weight bands, further supporting its role in glycosylphosphatidylinositol anchoring of the LORELEI protein. This study provides direct biochemical evidence confirming LORELEI as a glycosylphosphatidylinositol-anchored protein and sheds light on the structural determinants required for its glycosylphosphatidylinositol anchoring. Additionally, our study demonstrates that heterologous ectopic expression of LORELEI in vegetative tissues provides a viable alternative for the biochemical characterization of glycosylphosphatidylinositol-anchored proteins predominantly expressed in hard-to-access and small-sized female gametophytes. Our findings underscore the role of GPI anchoring in membrane localization and biosynthesis of GPI-anchored proteins in plants.

plant biology↗

bioRxiv2025

Occludin Acts as a Dynein Adaptor Regulating Permeability and Collateral Angiogenesis

Previous studies of the tight junction protein occludin (OCLN) suggest that multiple phosphorylation sites on the carboxy-terminal domain contribute a regulatory role in vascular barrier properties. However, gene deletion studies failed to identify a clear functional role for OCLN, despite multiple phenotypic alterations. Importantly, previous studies targeting exon 3 allowed expression of a splice variant starting at exon 4, (isoform 4) that expresses the full carboxy-terminal tail. Here we show that the OCLN carboxy-terminus forms a complex with the light intermediate chain (LIC) of dynein to link tight junction cargo to the minus end directed motor protein. Mutational analysis revealed S471 phosphorylation is required for binding to the LIC while S490 phosphorylation is required for trafficking. Expressing OCLN S490A mutant prevented endothelial cell proliferation and collateral angiogenesis. OCLN gene deletion targeting exon 5, preventing full length and isoform 4 expression, resulted in embryonic lethality. In summary, OCLN links tight junction cargo to the dynein motor, regulating trafficking in a phosphorylation dependent manner and contributing to both VEGF-induced vascular permeability and collateral angiogenesis.

cell biology↗

bioRxiv2025

Desert Hedgehog mediates stem Leydig cell differentiation through Ptch2/Gli1/Sf1 signaling axis

Desert Hedgehog (Dhh) mutations cause Leydig cell dysfunction, yet the mechanisms governing Leydig lineage commitment through Dhh-mediated receptor selectivity, transcriptional effector specificity, and steroidogenic coupling remain elusive. In this study, using CRISPR/Cas9-mediated gene knockout and stem Leydig cells (SLCs) transplantation, we identified a critical Dhh/Patched 2 (Ptch2)/Glioma-associated oncogene homolog 1 (Gli1)/steroidogenic factor 1 (Sf1) signaling axis essential for SLC differentiation in Nile tilapia (Oreochromis niloticus). Dhh deficiency resulted in defective adult Leydig cells and androgen insufficiency. Rescue experiments involving 11-ketotestosterone administration and a Dhh agonist treatment, combined with SLCs transplantation, demonstrated that Dhh regulates SLC differentiation, not survival. In vitro knockout of ptch1 and ptch2 in SLCs revealed that Ptch2 likely acts as the functional receptor for Dhh. This was further supported by in vivo genetic rescue experiments, where ptch2 mutation did not impair testicular development, yet completely rescued the testicular defects in dhh mutants--consistent with Ptch2 acting as an inhibitory receptor whose loss alleviates Dhh pathway suppression. Luciferase assays in Gli-knockout SLCs demonstrated that Gli1 acts as the primary transcriptional effector, and transactivates sf1 expression. Additionally, functional transplantation assays confirmed that Sf1 is indispensable for SLCs differentiation, as Sf1-overexpressing SLCs rescued differentiation, whereas sf1-mutant SLCs failed. Overall, our work delineates the Dhh-Ptch2-Gli1-Sf1 axis and provides fundamental insights into the endocrine regulation of Leydig cell lineage development. HighlightsO_LIDhh regulates the differentiation of SLCs rather than their survival C_LIO_LIPtch2 acts as the functional receptor for Dhh signaling in SLCs C_LIO_LIGli1 is the principal transcriptional activator for Dhh signaling in SLCs C_LIO_LISf1 is the critical downstream effector of Gli1 in SLCs differentiation C_LI

developmental biology↗

bioRxiv2025

Metagenomic Analysis Reveals Northwest Pacific Ocean as a Reservoir and Evolutionary Hub of Antibiotic Resistance Genes

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/659680v1_ufig1.gif" ALT="Figure 1"> View larger version (81K): org.highwire.dtl.DTLVardef@139e191org.highwire.dtl.DTLVardef@10834c4org.highwire.dtl.DTLVardef@1c0544aorg.highwire.dtl.DTLVardef@1ddfd8a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG Antibiotic resistance genes (ARGs) were identified as a novel type of environmental contaminants. Ocean is thought to be one of the ultimate environments where ARGs gathered. Marine ecosystems represent vast reservoirs of ARGs, yet their dynamics in open-ocean environments remain poorly characterized. Through large-scale metagenomic profiling of the Kuroshio Extension, a hydrographically dynamic region in the Northwest Pacific, we identified a striking enrichment of ARGs (1.81 x 10-3 ppm) at a frontal zone site (S30). The ARG abundance at this site exceeded coastal levels by 90-fold. Notably, multidrug resistance genes dominated this hotspot, with efflux pumps contributing 62% of the resistance mechanisms, a pattern distinct from the target-alteration strategies prevalent in other regions. The site exhibited unique microbial consortia, including pathogenic Acinetobacter (30.2% abundance) carrying clinically critical determinants (blaOXA-23, adeJ). Co-occurrence networks revealed horizontal transfer risks, linking pelagic Sphingobium to terrestrial-derived {beta}-lactamase variants. Crucially, we discovered three novel plasmid-borne resistance genes circulating in >15% of microbial populations, demonstrating open-ocean ARG diversification independent of direct anthropogenic inputs. These findings redefine oceanic frontiers as crucibles of resistance evolution, demanding urgent integration into global antimicrobial stewardship strategies.

microbiology↗

bioRxiv2025

Multi-omics profiling reveals atypical sugar utilization and identifies a key membrane composition regulator in Streptococcus pneumoniae

The human body comprises many different microenvironments, each with their own challenges for microorganisms to overcome in order to survive, and possibly cause infection. The human pathogen Streptococcus pneumoniae is notoriously flexible in this regard, and can adapt to a wide range of host niches, including the nasopharynx, lungs, and cerebrospinal fluid. However, the molecular and genetic underpinnings of this ability remain largely obscure. In this work, using infection-mimicking growth conditions we demonstrate that niche adaptation imposes genome-wide changes on multiple levels, including gene essentiality, expression and membrane lipid composition. In general, we show that gene expression and fitness profiling couple orthogonal sets of genes to environmental stimuli. For instance, N-acetylglucosamine (GlcNAc) import (manLMN) and catabolism (nagAB) genes were required for growth on this sugar, but not differentially expressed in its presence, whereas other amino sugar metabolism pathways were upregulated, but not essential. Surprisingly, we found that pneumococci do not necessarily prefer glucose over GlcNAc and that uptake of GlcNAc in absence of subsequent catabolism was toxic. Moreover, we identified a previously overlooked fatty acid saturation regulator, FasR, controlling membrane composition, rendering it important during heat stress. A fundamental understanding of how genes contribute to bacterial niche adaptation, including nutrient availability or temperature fluctuations, is crucial for understanding successful antibiotic therapy and vaccination strategies and the development of novel anti-infectives.

microbiology↗

bioRxiv2025

Analysis of protein aging reveals rates of subcellular organelle renewal and selective post-translational modification in Arabidopsis

The cellular proteome represents a mixture of older and newer copies of each protein type and turnover of this mixture occurs by cycles of protein synthesis and degradation. There is considerable research on new protein synthesis, the nature of nascent proteins and cellular machinery of protein degradation. However, we have limited insights into older proteins or the protein aging process in plants at scale. In this study we use pulse chase biorthogonal non-canonical amino acid tagging (BONCAT) in Arabidopsis cells coupled to affinity purification to capture and analyse snapshots of the cellular proteome as it ages over a two-week period. Each snapshot was subjected to peptide mass spectrometry-based identification, quantitation and characterisation. We show that there are a broad range of lifespans among the 1688 proteins studied and that their subcellular location correlates strongly with protein longevity. Mitochondria, plastids and the extracellular environment contained the longest lived sub-proteomes while the vesicular pathway to ER, PM and peroxisomes contained the shortest-lived protein sets. Abundant primary metabolic enzymes have considerable longevity, while kinases and ubiquitination machinery do not. Through analysis of the aging profiles, we demonstrate that many proteins selectively accumulate posttranslational modifications (PTMs) as they age and that these are mostly oxidative in nature. We show by analysis of exemplar proteins that distinct PTM profiles and proportional changes with age exist between proteins, likely dictated by differences in subcellular environment and protein function. Implications of these insights for understanding cellular function and for biotechnological modification of the plant proteome are discussed.

plant biology↗

bioRxiv2025

Multimodal Evidence for Hippocampal Engagement and Modulation by Functional Connectivity-Guided Parietal TMS

Hippocampal activity supports memory and many other brain functions. Transcranial magnetic stimulation (TMS) guided by hippocampal functional connectivity (FC) shows promise in improving memory, but direct neural evidence of its capacity to engage and modulate hippocampal activity is lacking. Here we combined TMS with intracranial electroencephalography (iEEG) in 8 neurosurgical patients and with functional magnetic resonance imaging (fMRI) in 79 neurologically healthy participants. We identified that (1) single-pulse TMS to individualized parietal cortex guided by hippocampal-FC preferentially evoked distinct temporal and spectral activity patterns in the hippocampus, (2) variability in TMS-evoked hippocampal responses related to individual differences in parietal-hippocampus FC strength, and (3) repetitive TMS to hippocampal-FC-guided parietal cortex selectively suppressed hippocampal theta oscillations. These findings provide multimodal causal neural evidence and important mechanistic insights supporting the development of personalized neuromodulation strategies aimed at improving hippocampus-dependent functions.

neuroscience↗

bioRxiv2025

Improved chromatin QTL mapping with CACTI

Mapping chromatin quantitative trait loci (cQTLs) is crucial for elucidating the regulatory mechanisms governing gene expression and complex traits. However, current cQTL mapping methods suffer from limited detection power, particularly at existing sample sizes, and are constrained by peak-calling accuracy. To address these limitations, we present CACTI, a novel method that improves cQTL mapping by leveraging correlations between neighboring regulatory elements. Across diverse histone marks (H3K4me1, H3K4me3, H3K27ac, H3K27me3 and H3K36me3) and cell types, CACTI identifies 51%-255% more cQTL signals compared to traditional single-peak-based approaches. Using CACTI, we generate a comprehensive cQTL map for the five histone marks across multiple cell types and perform colocalization analyses with GWAS loci from 44 complex traits. CACTI cQTLs colocalize with 6%-47% of GWAS loci, which is on average 15%-424% more than the standard cQTL mapping method across different marks. 24%-75% of colocalized GWAS loci show no colocalization with eQTLs. This underscores CACTIs unique ability to uncover regulatory mechanisms that would otherwise remain undetected by eQTL analysis alone, significantly improving the functional interpretation of GWAS findings.

genetics↗

bioRxiv2025

Uncovering Heterogeneous Effects via Localized Feature Selection

Identifying features that interact to trigger disease, while accounting for heterogeneity across diverse populations, is essential for the development of precision and targeted medicine. Despite the availability of vast and complex health-related datasets, most existing works focus on identifying disease-associated features at the population level or within a few subpopulations, often overlooking individual-level heterogeneity within these groups. To address this limitation, we propose a novel framework that utilizes localized test statistics to identify disease-associated features tailored to individual profiles. Our method leverages the recently developed knockoffs methodology to control the noise level of the selection set so that the results are replicable. Moreover, it allows for the discovery of hidden heterogeneous effects within the data, as demonstrated in an application to single-cell RNA sequencing data for Alzheimers disease. By aggregating localized feature selection results, our framework also enables powerful population-level feature selection. Our framework provides a powerful tool for exploratory studies of precision medicine, offering the potential to generate novel hypotheses for confirmatory biological experiments.

bioinformatics↗