Moirai: single-cell trajectory inference grounded in gene-level expression dynamics

Abstract

Underlying the development of multicellular organisms is the process of cell differentiation, which is governed by the concerted and sequential change in gene expression. Various methods have been developed that employ scRNA-seq data to infer the position of a cell along a pseudo-temporal axis and identify relevant genes involved in the process. These trajectory inference methods typically rely on global transcriptomic changes and mathematical methods. However, overemphasis on large-scale transcriptomic changes may impair sensitivity to identify branching points and convergent trajectories, which are rather governed by small-scale transcriptional events. Motivated by this, we developed Moirai, a graph-based trajectory inference method that identifies gene expression patterns that change dynamically over a developmental continuum and leverages these to define a common pseudotime axis between all cells. In doing so, Moirai shifts the focus to individual gene dynamics, which enhances its ability to detect putative branching points that are masked by global transcriptomic similarities. We apply Moirai to four developmental datasets, where we demonstrate its ability to recover gene expression patterns of genes with a known involvement in the respective developmental process, motivating their use for defining a cell's pseudotime. We furthermore show that Moirai can robustly infer gene expression patterns across different embedding approaches, highlighting the value of moving the focus of the inference process to the small-scale transcriptional dynamics.