Biology subjects

Wong, I.

Publications and source records attributed to Wong, I..

11 recordsLinked to original sources

bioRxiv2026

Structural variants from donor-specific assemblies affect recurrent chromatin contact divergence in humans

Structural variants (SVs) are a major source of human genetic diversity, yet their contribution to three-dimensional (3D) genome organization remains difficult to resolve using a standard reference genome. Here, we integrate haplotype-resolved chromatin interaction maps across 354 human and 12 nonhuman ape haplotypes with matched genome assemblies and long-read transcriptomes to determine how inherited SVs influence chromatin organization. We observe significant improvements in contact mapping, with 13.2% of cis Hi-C contacts showing >25 kbp changes in inferred genomic separation and an additional 2.8% of valid contact pairs recovered when using donor-specific assemblies instead of standard references. We show that haplotype-specific chromatin differences are highly selective rather than pervasive, concentrating within 1,790 recurrent contact difference hotspots associated with a restricted subset of SVs. We identified 2,495 chromatin-structure-associated SVs that are enriched in regulatory genomic contexts and are linked to expression variation. Notably, more than 90% of these SVs are derived in the human lineage, consistent with recent remodeling of regulatory architecture at the population level. These findings highlight the importance of incorporating haplotype diversity from pangenomes into studies of chromatin organization and provide a framework for understanding how inherited genomic differences are linked to functional consequences across populations and evolution.

genomics↗

bioRxiv2026

Antiviral Sulfonated Polymersomes Inhibit Corona-, Influenza-, and Alphavirus

A broad-spectrum antiviral is required to enable rapid intervention against current, newly emerging and mutating viruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), Sindbis virus (SINV) and chikungunya virus (CHIKV) all engage negatively charged moieties on host cells, such as heparan sulfate (HS) and sialic acid, to facilitate attachment for entry and infection. We designed HS-mimetic nanoparticles in the form of polymer vesicles (polymersomes) by blending membrane-forming and sulfonated copolymers. These biocompatible polymersomes successfully inhibited host cell infection of HS-dependent SARS-CoV-2 and HS-independent IAV in vitro with sub-nanomolar potency. Multivalent interaction of several virus ligands with a single polymersome as quantified by fluorescence correlation spectroscopy likely contributes to their potency. The sulfonated polymersomes also functioned in vivo as demonstrated by a reduction in the spread of SINV, an alphavirus model for CHIKV, in zebrafish embryos, which led to a significantly increased survival. Hence, our polymersomes could form the basis for an urgently required multifunctional broad-spectrum antiviral nanomedicine.

bioengineering↗

bioRxiv2025

Tau oligomers modulate synapse fate by eliciting progressive bipartite synapse dysregulation and synapse loss

BackgroundSynapse function is critical for cognition, and synapse loss is highly correlated with cognitive decline in Alzheimers disease and related dementias. Tau oligomers, which accumulate in the brain in Alzheimers disease, can acutely inhibit synaptic plasticity and cause synapse loss. Coordinated presynaptic and postsynaptic function is essential for effective synaptic transmission, and both compartments can be dysregulated by pathogenic tau. However, the series of pathophysiological events triggered by tau oligomers to cause the dysfunction and deterioration of presynaptic terminals and postsynaptic sites remain unclear. MethodsWe developed a proximity labeling tool to map the postsynaptic proteome by fusing PSD-95 with APEX2 (APEX2-PSD-95) which was expressed in human induced pluripotent stem cell (iPSC)-derived neurons. We used APEX2-PSD-95 to map the dynamic changes in the postsynaptic proteome with precise temporal resolution after an acute exposure of human iPSC-derived neurons to recombinant tau oligomers for 30 min. Leveraging immunocytochemistry, electrophysiology and electron microscopy, we further delineated the impact of the acute tau oligomer exposure on presynaptic and postsynaptic compartments over time for up to 14 days. ResultsThe brief exposure of human iPSC-derived neurons to tau oligomers caused a progressive deterioration of synapses, marked by both presynaptic and postsynaptic dysregulation. Postsynaptic proteome mapping revealed an immediate tau oligomer-triggered downregulation of the postsynaptic actin motor proteins Myosin-Va and Myosin-10, which coincided with impaired AMPA receptor (AMPAR) trafficking during synaptic plasticity. This was followed 24 hours later by the upregulation of disease-related proteins, including GSK3{beta}, at postsynaptic sites. The loss of PSD-95-labeled postsynaptic sites at 7 days after tau oligomer exposure preceded the loss of Synapsin-labeled presynaptic terminals at 14 days. The postsynaptic sites that remained exhibited a long-term downregulation of postsynaptic AMPAR levels and sustained synaptic plasticity impairment. Moreover, the remaining presynaptic terminals contained less clusters of vesicles at the presynaptic active zone which was associated with reduced vesicle release probability at synapses. ConclusionOur findings reveal the series of events underlying tau oligomer-induced bipartite synapse deterioration. The progressive decline of synapses involves the emergence of two synapse fates. One synapse fate involves the persistent weakening of both presynaptic and postsynaptic function, and the other results in synaptic loss.

neuroscience↗

bioRxiv2025

Long-read sequencing of trios reveals increased germline and postzygotic mutation rates in repetitive DNA

Long-read sequencing (LRS) has improved sensitivity to discover variation in complex repetitive regions, assign parent-of-origin, and distinguish de novo germline from postzygotic mutations (PZMs). Most studies have been limited to population genetic surveys or a few families. We applied three orthogonal sequencing technologies--lIlumina, Oxford Nanopore Technologies, and Pacific Biosciences--to discover and validate de novo mutations (DNMs) in 73 children from 42 autism families (157 individuals). Assaying 2.77 Gbp of the human genome using read-based approaches, we discover on average 95 DNMs per transmission (87.5 de novo single-nucleotide variants and 7.8 indels), including sex chromosomes. We estimate that LRS increases DNM discovery by 20-40% over previous Illumina-based studies of the same families, and more than doubles the discoverable number of PZMs that emerged early in embryonic development. The strict germline mutation rate is 1.30x10-8 substitutions per base pair per generation, strongly driven by the fathers germline (3.95:1), while PZMs increase the rate by 0.23x10-8 with a modest but significant bias toward paternal haplotypes (1.15:1). We show that the mutation rate is significantly increased for classes of repetitive DNA, where segmental duplication (SD) mutation shows a dependence on the length and percent identity of the SD. We find that the mutation rate enrichment in repeats occurs predominantly postzygotically as opposed to in the germline, a likely result of faulty DNA repair and interlocus gene conversion.

genomics↗

bioRxiv2024

Bioinformatics Copilot 2.0 for Transcriptomic Data Analysis

Large language models, when integrated into bioinformatics tools, offer valuable support for biologists in the analysis of single-cell transcriptomic data. Here, we introduce Bioinformatics Copilot 2.0, an advanced tool that builds upon its predecessor with four significant enhancements: 1) Internal server processing: users can now process large datasets on an internal server, thereby ensuring data privacy. 2) User-controlled analysis: users can take control of their data analysis when tasks exceed the copilots capabilities.3) Real-time information access: users can access up-to-date information from online resources, such as gene function queries and recent publications, thus enhancing data interpretation. 4) Data analysis and result documentation: the copilot now supports the generation of PDFs that include images and detailed analysis. These advancements represent a step towards building a bioinformatics autopilot. Demonstration videos showcasing these features are available at www.biochemml.com/tools.

bioinformatics↗

bioRxiv2023

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimers disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase M{zeta} (PKM{zeta}) to maintain synaptic plasticity and memory despite tau mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

neuroscience↗

bioRxiv2022

GATK-gCNV: A Rare Copy Number Variant Discovery Algorithm and Its Application to Exome Sequencing in the UK Biobank

Copy number variants (CNVs) are major contributors to genetic diversity and disease. To date, exome sequencing (ES) has been generated for millions of individuals in international biobanks, human disease studies, and clinical diagnostic screening. While standardized methods exist for detecting short variants (single nucleotide and insertion/deletion variants) using tools such as the Genome Analysis ToolKit (GATK), technical challenges have confounded similarly uniform large-scale CNV analyses from ES data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, the lack of widely-adopted and robustly benchmarked rare CNV discovery tools has presented a barrier to routine exome-wide assessment of this critical class of variation. Here, we introduce GATK-gCNV, a flexible algorithm to discover rare CNVs from genome sequencing read-depth information, which we distribute as an open-source tool packaged in GATK. GATK-gCNV uses a probabilistic model and inference framework that accounts for technical biases while simultaneously predicting CNVs, which enables self-consistency between technical read-depth normalization and variant calling. We benchmarked GATK-gCNV in 7,962 exomes from individuals in quartet families with matched genome sequencing and microarray data. These analyses demonstrated 97% recall of rare ([≤]1% site frequency) coding CNVs detected by microarrays and 95% recall of rare coding CNVs discovered by genome sequencing at a resolution of more than two exons. We applied GATK-gCNV to generate a reference catalog of rare coding CNVs in 197,306 individuals with ES from the UK Biobank. We observed strong correlations between CNV rates per gene and measures of mutational constraint, as well as rare CNV associations with multiple traits. In summary, GATK-gCNV is a tunable approach for sensitive and specific CNV discovery in ES, which can easily be applied across trait association and clinical screening.

genomics↗

bioRxiv2021

Chromatin alterations in the aging lung change progenitor cell activity

The lung contains multiple progenitor cell types that respond to damage, but how their responses are choreographed and why they decline with age is poorly understood. We report that histone H3 lysine 9 di-methylation (K9me2), mediated by histone methyltransferase G9a, regulates the dynamics of lung epithelial progenitor cells, and this regulation deteriorates with age. In aged mouse lungs, K9me2 loss coincided with lower frequency and activity of alveolar type 2 (AT2) cell progenitors. In contrast, K9me2 loss resulted in increased frequency and activity of multipotent progenitor cells with bronchiolar and alveolar potential (BASCs) and bronchiolar progenitors. K9me2 depletion in young mice through deletion or inhibition of G9a decreased AT2 progenitor activity and impaired alveolar injury regeneration. Conversely, K9me2 depletion increased chromatin accessibility of bronchiolar cell genes, increased BASC frequency and accelerated bronchiolar repair. K9me2 depletion also resulted in increased bronchiolar cell expression of the SARS-CoV2 receptor Ace2 in aged lungs. These data point to K9me2 and G9a as a critical regulator of the balance of lung progenitor cell regenerative responses and prevention of susceptibility to age-related lung diseases. These findings indicate that epigenetic regulation coordinates progenitor cell populations to expedite regeneration in the most efficient manner and disruption of this regulation presents significant challenges to lung health.

molecular biology↗

bioRxiv2021

High-throughput, label-free and slide-free histological imaging by computational microscopy and unsupervised learning

Rapid and high-resolution histological imaging with minimal tissue preparation has long been a challenging and yet captivating medical pursue. Here, we propose a promising and transformative histological imaging method, termed computational high-throughput autofluorescence microscopy by pattern illumination (CHAMP). With the assistance of computational microscopy, CHAMP enables high-throughput and label-free imaging of thick and unprocessed tissues with large surface irregularity at an acquisition speed of 10 mm2/10 seconds with 1.1-{micro}m lateral resolution. Moreover, the CHAMP image can be transformed into a virtually stained histological image (Deep-CHAMP) through unsupervised learning within 15 seconds, where significant cellular features are quantitatively extracted with high accuracy. The versatility of CHAMP is experimentally demonstrated using mouse brain/kidney tissues prepared with various clinical protocols, which enables a rapid and accurate intraoperative/postoperative pathological examination without tissue processing or staining, demonstrating its great potential as an assistive imaging platform for surgeons and pathologists to provide optimal adjuvant treatment.

bioengineering↗

bioRxiv2019

Dynamic evolution of euchromatic satellites on the X chromosome in Drosophila melanogaster and the simulans clade

Satellite DNAs (satDNAs) are among the most dynamically evolving components of eukaryotic genomes and play important roles in genome regulation, genome evolution, and speciation. Despite their abundance and functional impact, we know little about the evolutionary dynamics and molecular mechanisms that shape satDNA distributions in genomes. Here we use high-quality genome assemblies to study evolutionary dynamics of two complex satDNAs, Rsp-like and 1.688 gm/cm3, in Drosophila melanogaster and its three nearest relatives in the simulans clade. We show that large blocks of these repeats are highly dynamic in the heterochromatin, where their genomic location varies across species. We discovered that small blocks of satDNA that are abundant in X chromosome euchromatin are similarly dynamic, with repeats changing in abundance, location, and composition among species. We detail the proliferation of a rare satellite (Rsp-like) across the X chromosome in D. simulans and D. mauritiana. Rsp-like spreads by inserting into existing clusters of the older, more abundant 1.688 satellite, in events that were likely facilitated by microhomology-mediated repair pathways. We show that Rsp-like is abundant on extrachromosomal circular DNA in D. simulans, which may have contributed to its dynamic evolution. Intralocus satDNA expansions via unequal exchange and the movement of higher-order repeats also contribute to the fluidity of the repeat landscape. We find evidence that euchromatic satDNA repeats experience cycles of proliferation and diversification somewhat analogous to bursts of transposable element proliferation. Our study lays a foundation for mechanistic studies of satDNA proliferation and the functional and evolutionary consequences of satDNA movement.

genomics↗

bioRxiv2017

Firefly genomes illuminate the origin and evolution of bioluminescence

Fireflies are among the best-studied of the bioluminescent organisms. Despite longterm interest in the biochemistry, neurobiology, and evolution of firefly flash signals and the widespread biotechnological applications of firefly luciferase, only a limited set of genes related to this complex trait have been described. To investigate the genetic basis of firefly bioluminescence, we generated a high-quality reference genome for the Big Dipper firefly Photinus pyralis, from which the first laboratory luciferase was cloned, using long-read (PacBio), short-read (Illumina), and Hi-C sequencing technologies. To facilitate comparative genomics, we also generated short-read genome assemblies for a Japanese firefly Aquatica lateralis and a bioluminescent click beetle, Ignelater luminosus. Analyses of these genomic datasets supports at least two independent gains of luminescence in beetles, and provides new insights into the evolution of beetle bioluminescence and chemical defenses that likely co-evolved over their 100 million years of evolution.

genomics↗