Summary
The broad application of single-cell RNA sequencing has revealed transcriptional cell state heterogeneity across diverse healthy and malignant somatic tissues. Recent advances in lineage tracing technologies have further enabled the simultaneous capture of cell transcriptional state along with cellular ancestry thus enabling the study of somatic evolution at an unprecedented resolution; however, new analytical approaches are needed to fully harness these data. Here we introduce PATH (the Phylogenetic Analysis of Transcriptional Heritability), an analytical framework, which draws upon classic approaches in species evolution, to quantify heritability and plasticity of somatic phenotypes, including transcriptional states. The PATH framework further allows for the inference of cell state transition dynamics by linking a model of cellular evolutionary dynamics with our measure of heritability versus plasticity. We evaluate the robustness of this approach by testing a range of biological and technical features in simulations of somatic evolution. We then apply PATH to characterize single-cell phylogenies, reconstructed from either native or artificial lineage markers, with matching transcriptional state profiling. PATH recovered known developmental relationships in mouse embryogenesis, and revealed how anatomic proximity influences neural relatedness in the developing zebrafish brain. In cancer, PATH dissected the heritability of the epithelial-to-mesenchymal transition in a mouse model of pancreatic cancer, and the heritability versus plasticity of transcriptionally-defined cell states in human glioblastoma.
Competing Interest Statement
MLS is equity holder, scientific co-founder, and advisory board member of Immunitas Therapeutics. DAL has served as a consultant for Abbvie, AstraZeneca and Illumina, and is on the Scientific Advisory Board of Mission Bio, Pangea, Alethiomics, and C2i Genomics; DAL has received prior research funding from BMS, 10x Genomics, Ultima Genomics, and Illumina unrelated to the current manuscript.