Single-cell foundation models transfer across deep evolutionary distances

Abstract

Single-cell foundation models are trained mostly on human and other vertebrate cells, yet are proposed as general-purpose models. Whether they transfer far beyond their training species is unknown. We evaluated zero-shot embeddings from Geneformer, scGPT and UCE against PCA and scVI in developmental atlases of Dictyostelium discoideum and Caenorhabditis elegans, separated from humans by 1.2 billion and 600 million years. Without retraining, the models recovered developmental order and preserved organism-specific cell identities. UCE encodes genes by protein sequence and could use 97% of measured genes, whereas Geneformer and scGPT, after ortholog mapping, used under one-fifth. UCE performed most consistently, often exceeding species-native baselines. Restricted to ortholog-mappable genes, it still scored above vocabulary-based models on five of six annotation tasks, some narrowly. Foundation models can thus yield informative cell embeddings across more than a billion years of evolution, and protein-sequence gene representations make these embeddings more complete and often more accurate.