Echidna: A Bayesian framework for quantifying gene dosage effect impacting phenotypic plasticity
Year: 2024
Type: preprint
Abstract: Phenotypic plasticity, the ability of cells to adapt their behavior in response to genetic or environmental changes, is a fundamental biological process that drives cellular diversity in both normal and pathological contexts, including in tumor evolution. While chromosomal instability and somatic copy number alterations (CNAs) are known to influence cellular states, it remains difficult to separate genetic from cell non-autonomous mechanisms that govern transcriptional variability. Here, we present Echidna , a Bayesian hierarchical model that integrates single-cell RNA sequencing (scRNA-seq) and bulk whole-genome sequencing (WGS) data to quantify the impact of CNAs on gene expression dynamics. By jointly inferring clone-specific CNA profiles and uncovering clonal dependencies, Echidna bridges genomic and transcriptomic landscapes within and across multiple time points, enabling the decoupling of gene dosage effects from cell-extrinsic factors on phenotypic plasticity. Applying Echidna to patient tumor specimens, we demonstrate its superior performance in clonal reconstruction and derive insights into resistance mechanisms.
Authors: Joy Linyue Fan, Mingxuan Zhang, William O’Brien, Joshua D. Myers, Johannes C. Melms, Jana Biermann, Edridge D’Souza, Somnath Tagore, Nicolas Beltran-Velez, Kevin Hoffer-Hawlik, Alexander Preau, Isha Arora, Sharanya Chatterjee, Benjamin Izar, Elham Azizi
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G2587019979, Centers for Cancer Systems Therapeutics (CaST), Graduate Research Fellowship Program (GRFP), Computational toolbox for spatial transcriptomic analysis of complex tissues, Integrative framework for identifying dysregulated mechanisms in the tumor-immune microenvironment, Machine learning methods for interpreting spatial multi-omics data, Mechanisms of liver metastasis and associated resistance to immunotherapy, The role of the CD58:CD2 axis in cancer immune evasion and resistance to immunotherapy, Multi-cellular interactions defining the human brain metastatic niche
OpenAlex ID: W4405966574