Viola Chen will present her General Exam " Inferring Ancestral Cell States Using Transcriptome Geometry and Lineage Trees " on Thursday, May 8, 2025 at 10:30 AM in CS 302 . Committee Members: Benjamin Raphael (advisor), Mona Singh , Yuri Pritykin Abstract: Understanding how transcriptomic states evolve along a developmental lineage is a fundamental question in single-cell biology. While CRISPR-based lineage tracing technologies now enable high-resolution reconstruction of cell lineage trees, the transcriptomic states of internal (ancestral) nodes remain unobserved due to the destructive nature of sequencing. Existing methods for inferring these states either rely on strong parametric assumptions (e.g., Gaussian random walks in treeVAE) or discard true lineage information altogether (e.g., pseudotime methods). We present a geometry-aware parsimony framework for inferring ancestral transcriptomic states in cell lineage trees. Our approach leverages the principle of minimal transcriptomic change along a known tree structure, using either discrete or continuous representations of cell states. In the continuous case, we extend squared-change parsimony to non-Euclidean manifolds by computing Fréchet means under biologically meaningful distance metrics, such as graph geodesics derived from k-nearest neighbor (kNN) transcriptomic similarity graphs. We develop an efficient iterative optimization scheme, applicable to Euclidean, manifold, or graph-structured spaces, and benchmark our method on synthetic manifolds and real lineage-resolved datasets (e.g., C. elegans). Our results show improved recovery of internal cell states and differentiation trajectories compared to baseline methods. This framework provides a general and interpretable tool for reconstructing unobserved developmental states from lineage-traced single-cell data. Reading List: https://docs.google.com/document/d/1CtluDXuGFs2Z6IOfPlQg8gYGnNjemOPkjpYyuZZt... Everyone is invited to attend the talk, and those faculty wishing to remain for the oral exam following are welcome to do so.