Mix-Geneformer: Unified Representation Learning for Human and Mouse scRNA-seq Data

Abstract: Single-cell RNA sequencing (scRNA-seq) enables single-cell transcriptomic profiling, revealing cellular heterogeneity and rare populations. Recent deep learning models like Geneformer and Mouse-Geneformer perform well on tasks such as cell-type classification and in silico perturbation. However, their species-specific design limits cross-species generalization and translational applications, which are crucial for advancing translational research and drug discovery. We present Mix-Geneformer, a novel Transformer-based model that integrates human and mouse scRNA-seq data into a unified representation via a hybrid self-supervised approach combining Masked Language Modeling (MLM) and SimCSE-based contrastive loss to capture both shared and species-specific gene patterns. A rank-value encoding scheme further emphasizes high-variance gene signals during training. Trained on about 50 million cells from diverse human and mouse organs, Mix-Geneformer matched or outperformed state-of-the-art baselines in cell-type classification and in silico perturbation tasks, achieving 95.8% accuracy on mouse kidney data versus 94.9% from the best existing model. It also successfully identified key regulatory genes validated by in vivo studies. By enabling scalable cross-species transcriptomic modeling, Mix-Geneformer offers a powerful tool for comparative transcriptomics and translational applications. While our results demonstrate strong performance, we also acknowledge limitations, such as the computational cost and variability in zero-shot transfer.