Biology subjects

Yip, K.

Publications and source records attributed to Yip, K..

17 recordsLinked to original sources

bioRxiv2026

A Manifold-Based Measure of Transcriptional Entropy for Quantifying Aging in Single Cells

Aging reshapes tissues through changes in cellular composition, coordinated transcriptional reprogramming, and loss of transcriptional coordination. Whereas the first two have been characterized across aging tissues, the third remains difficult to quantify. We introduce an unsupervised, first-principles framework for measuring transcriptional dyscoordination in single cells as deviation from a learned, predictable structure accounting for technical noise. Orthogonal validation links transcriptional dyscoordination to classical intrinsic noise and distinguishes it from coordinated change. In controlled perturbations, dyscoordination rises after genotoxic injury and senescence induction, then falls following senolytic depletion. Across mouse, rat, and human tissues, dyscoordination increases with chronological age, especially in regenerative compartments. In human T cells, dyscoordination increases with clonal expansion and effector function yet declines within persisting clones after checkpoint blockade. Cross-modal analyses further link dyscoordination to chromatin-based mitotic age and genome instability. These results identify loss of transcriptional coordination as a distinct and dynamic feature of cellular aging.

genomics↗

bioRxiv2025

Aging-induced hepatocyte CD44 drives IL6/STAT3 signaling and associates with impaired neighboring T cell function.

Liver cancer incidences increase dramatically beyond 55 years of age, suggesting that age-associated changes contribute critically to tumor initiation. However, the mechanisms linking liver aging and cancer initiation are not well defined. This study investigates the role of CD44, a marker of liver tumor-initiating cells (TIC), in age-associated liver pathophysiology. Aged livers showed accumulation of CD44-expressing hepatocytes exhibiting enrichment of immune modulatory genes and activation of the immunosuppressive IL6/JAK/STAT3 pathway. Indeed, in adoptive transfer assays, antigen-exposed CD8+ T cells mounted a lower IFN-{gamma} response in aged livers than in young livers, indicating an immunosuppressive aged milieu. Concordantly, spatial analyses showed that the proximal neighbourhoods of Cd44-expressing hepatocytes are enriched in T cells exhibiting reduced cytokine and chemokine gene expression. Finally, hepatocyte-specific knock out of Cd44 mitigated the IL6/JAK/STAT3 gene signature in aged livers. Overall, these findings suggest that CD44 expression in aged hepatocytes promotes activation of the immunosuppressive IL6/JAK/STAT3 pathway and this is associated with impaired T cell effector function.

cell biology↗

bioRxiv2025

Mapping Structural Aging across Human Tissues reveals tissue-specific trajectories, coordinated deterioration and genetic determinants

1.Tissue structure, the organization of cells, vasculature and extracellular matrix, underpins organ function. Yet how it deteriorates with age remains largely uncharacterized. Current aging research focuses primarily on molecular changes, missing this structural dimension. Here we present PathStAR (Pathology-based Structural Aging Rate), a computational framework that quantifies tissue structural aging from histopathology images without training on chronological age. Applying PathStAR to 25,306 postmortem biopsies spanning 40 tissue types from 970 individuals aged 21-70, we show that structural aging unfolds through non-linear phases rather than gradual decline. We identify three distinct temporal programs: early-aging tissues (vascular system, peaking in the 30s), late-aging tissues (uterus and vagina, peaking around menopause) and biphasic-aging tissues (digestive and male reproductive organs, with two acceleration periods). During accelerated phases, tissues exhibit common molecular signature of increased inflammation, decreased energy production, regeneration and quality control alongside tissue-specific pathway disruptions related to its function: Artery-specific decline of peroxisomal function, responsible for fatty acid breakdown and testis-specific decline of spermatogenesis. Cross-organ analysis reveals coordinated deterioration within individuals, not only within expected organ systems but also unexpectedly between digestive and reproductive tissues, traced to shared sex hormone signaling. This reveals a role for sex hormones in maintaining structural integrity of non-reproductive organs during aging. Genome-wide association analysis identifies 123 germline variants associated with organ-specific accelerated structural aging, including variants in the longevity regulator SIRT6 linked specifically to vascular structural decline. As proof of concept, PathStAR captures the established non-linear functional decline of the ovary, fertility loss in the 30s and menopause in the 50s, that bulk transcriptomic and methylation profiles from matched samples fail to detect. PathStAR provides a systematic map of structural aging across the human body: when tissues structure decline, what molecular programs define each phase, and how organs deteriorate in coordination.

bioinformatics↗

bioRxiv2024

ecPath detects ecDNA in tumors from histopathology images

Circular extrachromosomal DNA (ecDNA) can drive tumor initiation, progression and resistance in some of the most aggressive cancers and is emerging as a promising anti-cancer target. However, detection currently requires costly whole-genome sequencing (WGS) or labor-intensive cytogenetic or FISH imaging, limiting its application in routine clinical diagnosis. To overcome this, we developed ecPath (ecDNA from histopathology), a computational method for predicting ecDNA status from routinely available hematoxylin and eosin (H&E) images. ecPath implements a deep-learning method we call transcriptomics-guided learning, which utilizes both transcriptomics and H&E images during the training phase to enable successful ecDNA prediction from H&E images alone, a task not achievable with models trained on H&E images only. It is trained on more than 6,000 tumor whole-slide images from the TCGA cohort with the best performance in predicting ecDNA status in brain and stomach tumors (average AUC=0.78). ecPath revealed that ecDNA-positive tumors are enriched with pleomorphic, larger and high-density nuclei. Testing in an independent cohort, ecPath predicted ecDNA status of 985 pediatric brain tumor patients with an AUC of 0.72. Finally, we applied ecPath to identify ecDNA-positive tumors in the TCGA cohort for which no WGS data were available. Like WGS-based ecDNA-positive labels, the predicted ecDNA-positive status also identify poor prognoses for low grade glioma patients. These results demonstrate that ecPath enables the detection of ecDNA from routinely available H&E imaging alone and help nominate aggressive tumors with ecDNA to study and target it.

pathology↗

bioRxiv2024

Epigenomic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potentials

Hepatocellular carcinoma (HCC) exhibits widespread epigenetic alterations, yet their impact on cis-regulatory elements (CREs) and retrotransposons remains poorly understood. Here, we present an integrated epigenomic and transcriptomic analysis of HCC tumors and matched tumor-adjacent normal tissues. We identified extensive DNA hypomethylation coupled with changes in histone modifications at partially methylated domains, CREs, and retrotransposons. These epigenetic aberrations were associated with dysregulated expression of genes involved in cell cycle regulation, immune response, and extracellular matrix organization. Notably, our findings revealed a novel mechanism for the transcriptional dysregulation of GPC3, a key HCC biomarker and immunotherapeutic target. We observed that GPC3 upregulation is driven by both the reactivation of a fetal liver super enhancer and hypomethylation of GPC3-associated CpG islands. Moreover, we found that DNA hypomethylation-driven aberrant expression of retrotransposons carries prognostic significance in HCC. Patients with high expression of a long non-coding RNA driven by a HERVE-int element exhibited more aggressive tumors, poorer clinical outcomes, and molecular features associated with favorable immunotherapy response. Together, our study provides a comprehensive resource for understanding the role of epigenetic dysregulation in HCC and identifies retrotransposon-associated transcripts as potential biomarkers.

genomics↗

bioRxiv2024

Chromosomal-level genome assembly and single-nucleotide polymorphism sites of black-faced spoonbill Platalea minor

Platalea minor, the black-faced spoonbill (Threskiornithidae) is a wading bird that is confined to coastal areas in East Asia. Due to habitat destruction, it has been classified by The International Union for Conservation of Nature (IUCN) as globally endangered species. Nevertheless, the lack of its genomic resources hinders our understanding of their biology, diversity, as well as carrying out conservation measures based on genetic information or markers. Here, we report the first chromosomal-level genome assembly of P. minor using a combination of PacBio SMRT and Omni-C scaffolding technologies. The assembled genome (1.24 Gb) contains 95.33% of the sequences anchored to 31 pseudomolecules. The genome assembly also has high sequence continuity with scaffold length N50 = 53 Mb. A total of 18,780 protein-coding genes were predicted, and high BUSCO score completeness (93.7% of BUSCO metazoa_odb10 genes) was also revealed. A total of 6,155,417 bi-allelic SNPs were also revealed from 13 P. minor individuals, accounting for [~]5% of the genome. The resource generated in this study offers the new opportunity for studying the black-faced spoonbill, as well as carrying out conservation measures of this ecologically important spoonbill species.

genomics↗

bioRxiv2024

Commonly used software tools produce conflicting and overly-optimistic AUPRC values

The precision-recall curve (PRC) and the area under it (AUPRC) are useful for quantifying classification performance. They are commonly used in situations with imbalanced classes, such as cancer diagnosis and cell type annotation. We evaluated 10 popular tools for plotting PRC and computing AUPRC, which were collectively used in >3,000 published studies. We found the AUPRC values computed by the tools rank classifiers differently and some tools produce overly-optimistic results.

bioinformatics↗

bioRxiv2024

Genome assembly of the edible jelly fungus Dacryopinax spathularia (Dacrymycetaceae)

The edible jelly fungus Dacryopinax spathularia (Dacrymycetaceae) is wood-decaying and can be commonly found worldwide. It has also been used in food additives given its ability to synthesize long-chain glycolipids. In this study, we present the genome assembly of D. spathularia using a combination of PacBio HiFi reads and Omni-C data. The genome size of D. spathularia is 29.2 Mb and in high sequence contiguity and completeness, including scaffold N50 of 1.925 Mb and 92.0% BUSCO score, respectively. A total of 11,510 protein-coding genes, and 474.7 kb repeats accounting for 1.62% of the genome, were also predicted. The D. spathularia genome assembly generated in this study provides a valuable resource for understanding their ecology such as wood decaying capability, evolutionary relationships with other fungus, as well as their unique biology and applications in the food industry.

genomics↗

bioRxiv2024

Chromosomal-level genome assembly of the long-spined sea urchin Diadema setosum (Leske, 1778)

The long-spined sea urchin Diadema setosum is an algal and coral feeder widely distributed in the Indo-Pacific and can cause severe bioerosion on the reef community. Nevertheless, the lack of genomic information has hindered the study its ecology and evolution. Here, we report the chromosomal-level genome (885.8 Mb) of the long-spined sea urchin D. setosum using a combination of PacBio long-read sequencing and Omni-C scaffolding technology. The assembled genome contained scaffold N50 length of 38.3 Mb, 98.1 % of BUSCO (Geno, metazoa_odb10) genes, and with 98.6% of the sequences anchored to 22 pseudo-molecules/chromosomes. A total of 27,478 genes including 23,030 protein-coding genes were annotated. The high-quality genome of D. setosum presented here provides a significant resource for further understanding on the ecological and evolutionary studies of this coral reef associated sea urchin.

genomics↗

bioRxiv2024

Genome assembly of the rare and endangered Grantham's camellia, Camellia granthamiana

The Granthams camellia (Camellia granthamiana Sealy) is a rare and endangered tea species that is endemic to southern China, and was first discovered in Hong Kong in 1955. Despite its high conservation value, genomic resources of C. granthamiana remain limited. Here, we present a chromosome-scale draft genome of the tetraploid C. granthamiana (2n = 4x = 60) using a combination of PacBio long read sequencing and Omni-C data. The assembled genome size is [~]2.4 Gb with most sequences anchored to 15 pseudochromosomes that resemble a monoploid genome. The genome is of high contiguity, with a scaffold N50 of 139.7 Mb, and high completeness with a 97.8% BUSCO score. Gene model prediction resulted in a total 76,992 protein-coding genes with a BUSCO score of 85.9%. 1.65 Gb of repeat content was annotated, which accounts for 68.48% of the genome. The Granthams camellia genome assembly provides a valuable resource for future investigations on its biology, ecology, phylogenomic relationships with other Camellia species, as well as set up a foundation for further conservation measures.

plant biology↗

bioRxiv2024

Chromosome-level genome assembly of the common chiton, Liolophura japonica (Lischke, 1873)

Chitons (Polyplacophora) are marine molluscs that can be found worldwide from cold waters to the tropics, and play important ecological roles in the environment. Nevertheless, there remains only two chiton genomes sequenced to date. The chiton Liolophura japonica (Lischke, 1873) is one of the most abundant polyplacophorans found throughout East Asia. Our PacBio HiFi reads and Omni-C sequencing data resulted in a high-quality near chromosome-level genome assembly of [~]609 Mb with a scaffold N50 length of 37.34 Mb (96.1% BUSCO). A total of 28,233 genes were predicted, including 28,010 protein-coding genes. The repeat content (27.89%) was similar to the other Chitonidae species and approximately three times lower than in the genome of the Hanleyidae chiton. The genomic resources provided in this work will help to expand our understanding of the evolution of molluscs and the ecological adaptation of chitons.

genomics↗

bioRxiv2024

Genome assembly of the milky mangrove Excoecaria agallocha

The milky mangrove Excoecaria agallocha is a latex-secreting mangrove that are distributed in tropical and subtropical regions. While its poisonous latex is regarded as a potential source of phytochemicals for biomedical applications, the genomic resources of E. agallocha remains limited. Here, we present a chromosomal level genome of E. agallocha, assembled from the combination of PacBio long-read sequencing and Omni-C data. The resulting assembly size is 1,332.45 Mb and has high contiguity and completeness with a scaffold N50 of 58.9 Mb and a BUSCO score of 98.4 %. 73,740 protein-coding genes were also predicted. The milky mangrove genome provides a useful resource for further understanding the biosynthesis of phytochemical compounds in E. agallocha.

genomics↗

bioRxiv2024

Chromosomal-level genome assembly of golden birdwing Troides aeacus (Felder & Felder, 1860)

Troides aeacus, the golden birdwing (Lepidoptera, Papilionidae) is a large swallowtail butterfly widely distributed in Asia. Despite its occurrence, T. aeacus has been assigned as a major protective species in many places given the loss of their native habitats under urbanisation and anthropogenic activities. Nevertheless, the lack of its genomic resources hinders our understanding of their biology, diversity, as well as carrying out conservation measures based on genetic information or markers. Here, we report the first chromosomal-level genome assembly of T. aeacus using a combination of PacBio SMRT and Omni-C scaffolding technologies. The assembled genome (351 Mb) contains 98.94% of the sequences anchored to 30 pseudo-molecules. The genome assembly also has high sequence continuity with scaffold length N50 = 12.2 Mb. A total of 28,749 protein-coding genes were predicted, and high BUSCO score completeness (98.9% of BUSCO metazoa_odb10 genes) was also revealed. This high-quality genome offers a new and significant resource for understanding the swallowtail butterfly biology, as well as carrying out conservation measures of this ecologically important lepidopteran species.

genomics↗

bioRxiv2023

Linked-Pair Long-Read Sequencing Strategy for Targeted Resequencing and Enrichment

In this report, we present linked-pair sequencing, a novel strategy to construct a long-read sequencing library such that adjacent fragments are linked with end-terminal duplications. We use the CRISPR-Cas9 nickase enzyme and a pool of multiple sgRNAs to perform non-random fragmentation of targeted long DNA molecules (>300kb) into smaller library-sized fragments (about 20 kbp) in a manner so as to retain physical linkage information (up to 1000 bp) between adjacent fragments. DNA molecules targeted for fragmentation are preferentially ligated with adaptors for sequencing, so this method can enrich targeted regions while taking advantage of the long-read sequencing platforms. This enables the sequencing of target regions with significantly lower total coverage, and the genome sequence within linker regions provides information for assembly and phasing. We demonstrated the validity and efficacy of the method first using phage and then by sequencing a panel of 100 full-length cancer-related genes (including both exons and introns) in the human genome. When the designed linkers contained heterozygous genetic variants, long haplotypes could be established. This sequencing strategy can be readily applied in both PacBio and Oxford Nanopore platforms. This economically viable approach is useful for targeted enrichment of hundreds of target genomic regions and where long no-gap contigs need deep sequencing.

genomics↗

bioRxiv2021

Deep learning identifies and quantifies recombination hotspot determinants

Recombination is one of the essential genetic processes for sexually reproducing organisms, which can happen more frequently in some regions, called recombination hotspots. Although several factors, such as PRDM9 binding motifs, are known to be related to the hotspots, their contributions to the recombination hotspots have not been quantified, and other determinants are yet to be elucidated. Here, we develop a computational method, RHSNet, based on deep learning and signal processing, to identify and quantify the hotspot determinants in a purely data-driven manner, utilizing datasets from various studies, populations, sexes, and species. In addition to being able to identify hotspot regions and the well-known determinants accurately, RHSNet is sensitive to the difference between different PRDM9 alleles and different sexes, and can generalize to PRDM9-lacking species. The cross-sex, cross-population, and cross-species studies suggest that the proposed method has the potential to identify and quantify the evolutionary determinant motifs. TeaserRHSNet can accurately identify and quantify recombination hotspot determinants across different studies, sexes, populations, and species.

bioinformatics↗

bioRxiv2018

A cross-organism framework for supervised enhancer prediction with epigenetic pattern recognition and targeted validation

Enhancers are important noncoding elements, but they have been traditionally hard to characterize experimentally. Only a few mammalian enhancers have been validated, making it difficult to train statistical models for their identification properly. Instead, postulated patterns of genomic features have been used heuristically for identification. The development of massively parallel assays allows for the characterization of large numbers of enhancers for the first time. Here, we developed a framework that uses Drosophila STARR-seq data to create shape-matching filters based on enhancer-associated meta-profiles of epigenetic features. We combined these features with supervised machine learning algorithms (e.g., support vector machines) to predict enhancers. We demonstrated that our model could be applied to predict enhancers in mammalian species (i.e., mouse and human). We comprehensively validated the predictions using a combination of in vivo and in vitro approaches, involving transgenic assays in mouse and transduction-based reporter assays in human cell lines. Overall, the validations involved 153 enhancers in 6 mouse tissues and 4 human cell lines. The results confirmed that our model can accurately predict enhancers in different species without re-parameterization. Finally, we examined the transcription-factor binding patterns at predicted enhancers and promoters in human cell lines. We demonstrated that these patterns enable the construction of a secondary model effectively discriminating between enhancers and promoters.

bioinformatics↗

bioRxiv2018

Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis

Neutrophil extracellular traps (NETs) entrap circulating tumor cells (CTCs) and promote metastasis within distant organs in preclinical models1,2. In these models, NETosis is triggered by exogenous massive inflammatory stimuli, and thus it remains unknown whether cancer hosts under physiologic inflammation-free conditions experience NETosis and consequent cancer metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis and cancer metastasis specifically in the lungs. Albumin is the major source of free thiol that maintains redox balance in vitro and in vivo. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of CTCs leading to pulmonary metastases in mouse models. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation and the resultant decline of plasma free thiol are associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression.

cancer biology↗