Phylogenetic tree inference from single-cell RNA sequencing data

Abstract

Single-cell RNA sequencing technologies enable the large-scale measurement of gene expression profiles at the individual cell level to assess cellular diversity and function. In oncology, leveraging these single-cell transcriptomic data to reconstruct the phylogenetic relationships among cancer cells can provide insights into tumor evolution, metastasis formation, and the development of treatment resistance. However, phylogenetic inference from single-cell RNA sequencing is challenging due to sparse and noisy data and large dataset sizes. We present a novel tree inference method designed for such data that takes reference and alternative read counts of single-nucleotide variants and reconstructs a phylogenetic tree of the sequenced cells via maximum likelihood using a random-scan greedy search. To overcome local optima in the search, our algorithm alternates between two different tree representations: cell lineage trees, where cells are represented by nodes and mutations are attached to edges, and mutation trees, where mutation nodes encode the mutational events and cells are attached to them. Because a local optimum in one tree space generally does not correspond to a local optimum in the other space, we maximize the likelihood by switching between the two tree spaces until convergence is achieved in both. We demonstrate superior performance of our approach on simulated data with complex clonal architectures compared to existing methods. Furthermore, we show its applicability to cancer single-cell RNA sequencing data, which allows us to link evolutionary trajectories of cells to their gene expression profiles.