Causal Circuit Tracing Reveals Distinct Computational Architectures in Single-Cell Foundation Models: Inhibitory Dominance, Biological Coherence, and Cross-Model Convergence

Motivation: Sparse autoencoders (SAEs) decompose foundation model activations into interpretable features, but causal feature-to-feature interactions across network depth remain unknown for biological foundation models. Results: We introduce causal circuit tracing by ablating SAE features and measuring downstream responses, and apply it to Geneformer V2-316M and scGPT whole-human across four conditions (96,892 edges, 80,191 forward passes). Both models show approximately 53 percent biological coherence and 65 to 89 percent inhibitory dominance, invariant to architecture and cell type. scGPT produces stronger effects (mean absolute d = 1.40 vs. 1.05) with more balanced dynamics. Cross-model consensus yields 1,142 conserved domain pairs (10.6x enrichment, p < 0.001). Disease-associated domains are 3.59x more likely to be consensus. Gene-level CRISPRi validation shows 56.4 percent directional accuracy, confirming co-expression rather than causal encoding.

Source: arXiv:2603.01752v1 - http://arxiv.org/abs/2603.01752v1 PDF: https://arxiv.org/pdf/2603.01752v1 Original Link: http://arxiv.org/abs/2603.01752v1