Biology subjects

LIU, B.

Publications and source records attributed to LIU, B..

5 recordsLinked to original sources

bioRxiv2026

Whole-genome sequencing reveals variant associations with brain imaging phenotypes

Whole-genome sequencing (WGS) enables comprehensive discovery of genetic variation underlying brain imaging traits beyond the limits of SNP arrays, particularly for rare coding variants with potentially large effects. Here, we integrated WGS data from 45,755 UK Biobank participants with 4,016 derived imaging phenotypes (IDPs) spanning macrostructure (volumes, cortical thickness/area), microstructure (diffusion metrics), functional connectivity, and perfusion MRI measures. We performed variant-level association testing across 2,751,139 coding SNVs under dominant, genotypic, and recessive models. Then, we conducted gene-based rare-variant collapsing analyses across 18,762 genes using multiple qualifying-variant models to improve power for ultra-rare alleles and enhance biological interpretability. We detected 66,893 significant genotype-IDP associations at the variant level and 184 significant gene-IDP associations from collapsing analyses, including many signals driven by protein-truncating and damaging missense variants with larger effect sizes than common variants. Burden heritability analyses supported a contribution of rare coding variation to population variability in IDPs. This study provided a WGS framework for mapping rare coding variant effects on brain structure and function, advancing mechanistic insight into imaging endophenotypes relevant to neuropsychiatric and neurodegenerative disease.

genomics↗

bioRxiv2026

Genetics-informed bidirectional mapping of glycemic traits and brain phenotypes

Dysglycaemia is linked to brain atrophy, white-matter disruption and dementia risk, yet the directionality and mechanisms of glycemic-brain coupling remain unclear. Here we integrate large-scale GWAS of fasting glucose, fasting insulin, 2-hour glucose, HbA1c and type 2 diabetes with multimodal brain imaging phenotypes and major brain disorders using bidirectional two-sample Mendelian randomization. Across 4,040 tests, we identify 54 glycaemia and brain causal associations (FDR P < 0.05) and uncover a timescale-dependent hierarchy: short-term glycemic traits map to distributed macrostructure and functional-network, whereas long-term glycemic burden preferentially implicates long-range association and commissural white-matter pathways with focal prefrontal-paracentral vulnerability. Reverse analyses reveal 44 brain IDPs and glycaemia effects. Multi-trait Bayesian colocalization and tissue/cell-type eQTL integration nominate shared causal loci enriched in glial and neurovascular pathways. Individual-level UK Biobank analyses validated glycaemia-associated brain structural alterations and non-linear risk patterns for incident outcomes. Together, our results provide a genetically anchored atlas of bidirectional glycemic-neural relationships, linking metabolic dysregulation to multiscale brain vulnerability and disorder risk.

neuroscience↗

bioRxiv2025

Dissecting the Cellular Genetics of Cardiovascular Disease Through Endothelial and Immune Compartments Profiling

BackgroundNon-communicable diseases such as coronary artery disease, atrial fibrillation, type 2 diabetes, hypertension, and others share endothelial dysfunction as one of their underlying features. The endothelium, as the interface between blood and vasculature, shapes disease onset and progression through its response to environmental cues. However, while the genetic component of these diseases has been captured by genome wide association studies (GWAS), which also highlighted a shared immune component, it remains unclear which of these disease loci exerts their effects through endothelial cells. This study identifies, and quantifies, the genetic determinants of endothelial cells molecular traits and their overlap to the common genetic variation component of these diseases. MethodsWe generated genotype, RNA-sequencing, H3K27ac ChIP-sequencing, ATAC-sequencing, and endothelial cells barrier stimuli response measurements for 100 samples of human umbilical vein endothelial cells. These were used to identify quantitative trait loci (QTL) for gene expression, transcriptional isoform usage, splice junction usage, chromatin activity and barrier response. We applied statistical colocalisation to identify the overlap between data layers, and to explain molecular QTLs contribution to GWAS disease loci. ResultsWe used molecular QTLs to identify the regulatory features of 8,214 genes, representing 36% of all expressed genes in endothelial cells. We also identified the molecular mechanisms underlying 815 loci across 16 disease GWAS. These represent between 29% and 40% of all loci for each disease, compared to the previous average of 23%. This is due to the choice of a cell type often underrepresented in tissue level data, and the inclusion of isoform, splicing and chromatin activity datasets. Furthermore, we compared the endothelial cells molecular QTLs with similar datasets in monocytes, neutrophils and CD4 T lymphocytes to shed light on the interplay between the endothelial and the immune compartments in these diseases. We identified loci acting through both the endothelial and the immune compartment, mostly with the same directionality of effect, and endothelial specific ones. ConclusionsThis work expands the knowledge of the mechanisms and genes underlying the effect of common genetic variation on non-communicable diseases having endothelial dysfunction as a shared feature. It also illustrates the interplay between endothelial cells and immune cell types in these diseases, highlighting shared and unique pathways.

genomics↗

bioRxiv2025

Architecture and mechanism of a dual-enzyme retron system in prokaryotic immunity

Retrons are bacterial genetic retroelements encoding a reverse transcriptase (RT) and a non-coding RNA (ncRNA)-multi-copy single-stranded DNA (msDNA) hybrid. Diverse effector proteins or domains are found to associate with retrons, typically forming tripartite toxin-antitoxin systems involved in anti-phage defense. Although retrons have attracted growing interest in genome editing technologies, the mechanisms underlying most retron-mediated immune systems remain poorly understood. Here, we characterized a distinct quaternary retron system, Ec78, harboring a dual-enzymatic effector complex, in which the PtuA ATPase and PtuB nuclease act in concert to mediate phage clearance. The cryo-EM structure of the Ec78 complex adopts a flower-basket-like architecture, with two Ec78 retrons engaging the PtuAB effector complexes through a unique msDNA-insertion assembly mechanism. Interestingly, a sensing loop on the RT protein tightly monitors the length of the msDNA, which is likely responsible for phage detection and the subsequent release of the toxic effector complex. We further determined the cryo-EM structure of the retron-unbound effector complex, revealing an arginine-lysine finger loop on the PtuB nuclease that undergoes an ordered-to-disordered transition for enzymatic activation. Together, our work not only delineates the molecular basis underlying the Ec78 system in antiviral defense but also highlights the mechanistic diversity of retron systems in prokaryotic immunity.

biochemistry↗

bioRxiv2025

MsyB-HU Interaction Modulates a Two-Tiered Bacterial Stress Response by Regulating DNA Supercoiling

Bacteria respond to stressful conditions through multiple pathways, including changes in gene expression patterns and mutations for adaptation. DNA supercoiling is a fundamental regulatory principle of bacterial gene expression, controlled antagonistically by DNA gyrase and topoisomerase I. Nucleoid-associated proteins, such as HU, also regulate supercoiling through interactions with DNA. Here, we identify Escherichia coli protein MsyB as a HU inhibitor and a {beta}-clamp binder. MsyB is fine-tuned under various stressful conditions, where it modulates the population of DNA-bound HU by forming a HU-MsyB complex. Consequently, the balance between DNA-bound HU and MsyB-bound HU adjusts the DNA supercoiling state, thereby influencing transcription for adaptation. Additionally, under prolonged starvation during the stationary phase, sustained high level of MsyB increases DNA exposure to damaging factors, acting as a damage inducer. The HU/MsyB/{beta}-clamp interaction suggests a model in which MsyB coordinates with HU and the {beta}-clamp to facilitate damage acquisition and error-prone DNA repair. Thus, MsyB-dependent supercoiling regulation represents a novel two-tiered bacterial stress response mechanism in gene expression and adaptive mutation. Our findings reveal a previously unrecognized regulatory mechanism of bacterial supercoiling, positioning HU as a promising antibiotic target.

microbiology↗