Biology subjects

Yap, D.

Publications and source records attributed to Yap, D..

6 recordsLinked to original sources

bioRxiv2026

G4SCOPE identifies sequence features and epigenetic contexts of chromatin G-quadruplexes

Cancer-associated epigenetic remodeling involves a complex interplay between DNA secondary structures and covalent cytosine modifications, yet predicting endogenously folded, chromatin-constrained G-quadruplex (G4) dynamics remains challenging. Here, we develop G4SCOPE, a multi-task deep learning framework that models chromatin-associated G4 occupancy and reconstructs quantitative high-resolution CUT&Tag profiles directly from primary DNA sequence alone. We initially trained G4SCOPE on genotype-stratified G4 enriched cut&tag landscapes generated across an isogenic series of human breast epithelial cells (WT, TP53-/-, TP53-/-;BRCA1-/-, and TP53-/-;BRCA2-/-). G4SCOPE integrates convolutional motif learning with transformer self-attention to decode long-range sequence contexts. The model robustly distinguishes chromatin-associated G4s from GC-matched loci with intrinsic in vitro folding potential, generalizes across distinct breast lineages, and transfers accurately to an independent K562 cellular context. Strikingly, genotype-resolved mapping reveals a profound divergence in genome maintenance states: BRCA1 deficiency indicated a global inflation of chromatin-embedded G4 density, whereas BRCA2 loss was associated with systemic, chromosome-wide structural depletion. Furthermore, unsupervised clustering of model-derived latent sequence representations identified distinct biological G4 subclasses that occupy unique regulatory class genomic environments associated with distinct local 5-methylcytosine and 5-hydroxymethylcytosine landscapes. Together, our framework decodes the primary sequence grammar governing cell-based G4 occupancy and demonstrates that sequence-defined G4 topologies harbor intrinsic and distinct local epigenetic features.

bioinformatics↗

bioRxiv2025

Somatic copy number mutations contribute to fitness in transplantation models of spontaneous human breast cancer metastasis

The contribution of somatic gene dosage mutations (CNA) to breast cancer metastasis remains poorly defined. Using 9 transplantable human neoadjuvant-naive triple-negative breast cancer xenografts, we studied the fitness of copy number clones in spontaneous metastasis from orthotopic transplant sites. Metastatic site preference was strongly patient-dependent, and the emergence of metastases exhibited a general trend toward slower growth at the orthotopic site. In our models, single-cell whole-genome sequencing of primary and metastatic sites showed that distant metastases were most often the result of minor prevalence clones at the orthotopic site, suggesting that some metastatic phenotypes may be weakly negatively fit at the primary site. We validated the existence of a fitness hierarchy of copy number clones using a previously established paradigm of remixing and retransplanting clones. Single-cell clone analysis of competitive repopulation and re-emergence of metastases showed that CNAs arising in cancer evolution can mediate metastatic fitness. Moreover, some clones displaying strong metastatic tendency exhibited weaker survival at the primary site, consistent with the notion that metastatic phenotypes could have a fitness cost at the primary site. Finally, we conducted RNA-seq analysis combined with DriverNet analysis to dissect the contribution of CNA-mediated versus genome-independent transcriptional states. CNA mutations appeared to contribute strongly to transcriptional differences between clones. Among clones of high metastatic potential, we observed CNA-mediated and CNA-independent convergence on pathways such as epithelial-mesenchymal transition (EMT), established as mediators of metastatic cell survival at distant sites. Taken together, our data point to a contribution of CNA-mediated cancer evolution to metastatic states and identify distant-site context as a key determinant of CNA-mediated fitness.

cancer biology↗

bioRxiv2024

Evaluating Physiological Indicators in Detecting Deception using the Comparison Question Test (CQT)

Despite significant advancements in deception detection, traditional methods often fall short in real-world applications. This study addresses these limitations by evaluating the effectiveness of various physiological measures -- pupil response, electrodermal activity (EDA), heart rate (HR), and facial temperature changes -- in predicting deception using the Comparison Question Test (CQT). It also fills a critical research gap by validating these methods within an Asian context. Employing a between-subjects design, data was collected from a diverse sample of 118 participants from Singapore, including Chinese, Indian, and Malay individuals. The research aims to identify which physiological indicators, in combination, offer the most robust predictions of deceptive behavior. Key innovations include the adaptation of the CQT with a modified directed lie paradigm and an expanded sample size to assess the relative importance of each physiological measure. The studys findings reveal that pupil response is the most significant predictor of deception, with EDA enhancing the models explanatory power. HR, while relevant, adds limited value when combined with pupil response and EDA, and facial temperature changes were statistically non-significant. The study highlights the need for further research into the interactions among physiological measures and their application in varied contexts. This research contributes valuable insights into improving deception detection methodologies and sets the stage for future investigations that could incorporate additional physiological indicators and explore real-world applications.

bioengineering↗

bioRxiv2021

Evolutionary tracking of cancer haplotypes at single-cell resolution

Cancer genomes exhibit extensive chromosomal copy number changes and structural variation, yet how allele specific alterations drive cancer genome evolution remains unclear. Here, through application of a new computational approach we report allele specific copy number alterations in 11,097 single cell whole genomes from genetically engineered mammary epithelial cells and 21,852 cells from high grade serous ovarian and triple negative breast cancers. Resolving single cell copy number profiles to individual alleles uncovered genomic background distributions of gains, losses and loss of heterozygosity, yielding evidence of positive selection of specific chromosomal alterations. In addition specific genomic loci in maternal and paternal alleles were commonly found to be altered in parallel with convergent phenotypic transcriptional effects. Finally we show that haplotype specific alterations trace the cyclical etiology of high level amplifications and reveal clonal haplotype decomposition of complex structures. Together, our results illuminate how allele and haplotype specific alterations, here determined across thousands of single cell cancer genomes, impact the etiology and evolution of structural variations in human tumours.

cancer biology↗

bioRxiv2021

The impact of mutational processes on structural genomic plasticity in cancer cells

Structural genome alterations are determinants of cancer ontogeny and therapeutic response. While bulk genome sequencing has enabled delineation of structural variation (SV) mutational processes which generate patterns of DNA damage, we have little understanding of how these processes lead to cell-to-cell variations which underlie selection and rates of accrual of different genomic lesions. We analysed 309 high grade serous ovarian and triple negative breast cancer genomes to determine their mutational processes, selecting 22 from which we sequenced >22,000 single cell whole genomes across a spectrum of mutational processes. We show that distinct patterns of cell-to-cell variation in aneuploidy, copy number alteration (CNA) and segment length occur in homologous recombination deficiency (HRD) and fold-back inversion (FBI) phenotypes. Widespread aneuploidy through induction of HRD through BRCA1 and BRCA2 inactivation was mirrored by continuous whole genome duplication in HRD tumours, contrasted with early ploidy fixation in FBI. FBI tumours exhibited copy number distributions skewed towards gains, widespread clone-specific variation in amplitude of high-level amplifications, often impacting oncogenes, and break-point variability consistent with progressive genomic diversification, which we termed serriform structural variation (SSV). SSVs were consistent with a CNA-based molecular clock reflecting a continual and distributed process across clones within tumours. These observations reveal previously obscured genome plasticity and evolutionary properties with implications for cancer evolution, therapeutic targeting and response.

cancer biology↗

bioRxiv2017

EIF4A3 associated splicing and nonsense mediated decay defined by a systems analysis with novel small molecule inhibitors

Chemical biology approaches to the global functions of splicing reactions are gaining momentum, with an increasing repertoire of small molecule probes becoming available. Here we map the association of eIF4A3 with transcript expression, NMD and alternative splicing using a set of selective novel small molecule allosteric helicase inhibitors whose synthesis and chemical properties we have recently described. We show through analysis of dose monotonic transcriptional responses to increasing inhibition that both full length and NMD prone transcripts link eIF4A3 to normal functioning of cell division including chromosome segregation and cell cycle checkpoints, pointing to a conserved role of splicing and transcript quality processing in cell cycle functions. Cell cycle analysis and microscopy of inhibitor treated cells demonstrates chromosome mis-segregation and spindle defects, associated with a G2/M arrest, validating this observation. Through analysis of conserved alternative splicing patterns exhibiting monotonic responses, we find that eIF4A3 dependent alternative splicing involves exons that are longer and introns that are shorter than transcripts not modulated by eIF4A3. Moreover we observe conservation of over/under representation of RBP binding motif density over introns and exons implicated eIF4A3 modulated skipped exon and retained introns. The distribution of motif densities over 5 and branch intron sites and 5 exons is consistent with function of the exon-junction complex. Taken together we have defined a fraction of the transcrip-tome dependent on eIF4A3 functions and revealed a link between eIF4A3 and cell cycle regulation. The systems approach described here suggests additional avenues for therapeutic exploitation of eIF4A3 functions in cancer and related diseases.

genomics↗