DoFormer: Causal Transformer for Gene Perturbation

Abstract Learning causal gene regulatory mechanisms from single-cell data, and thereby predicting the effects of unseen perturbations, remains challenging. Observational RNA-seq data alone is insufficient for causal modeling, whereas perturbational data is essential. Classical causal inference methods often rely on unrealistic directed acyclic graph (DAG) assumptions and are not well suited to integrating multimodal data. Current transcriptomic foundation models also typically treat observational and perturbational data identically, limiting their ability to model perturbations. We present DoFormer, a causal multimodal Transformer that makes no DAG assumptions and leverages rich perturbational data to accurately predict previously unseen perturbations. DoFormer enables principled in silico perturbations by adapting the causal do-operator within the attention mechanism: the perturbed gene is set to the intervention value and prevented from attending to other genes, allowing the model to fully distinguish observational from interventional regimes. We train DoFormer using biologically informed loss functions and evaluate it with comprehensive perturbation prediction metrics. DoFormer substantially improves perturbation prediction relative to baseline and prior foundation models, underscoring the importance of intervention-aware architectures and biologically grounded objectives for causal modeling in single-cell genomics. Competing Interest Statement The authors have declared no competing interest.