Exhaustive Circuit Mapping of a Single-Cell Foundation Model Reveals Massive Redundancy, Heavy-Tailed Hub Architecture, and Layer-Dependent Differentiation Control

TL;DR

This paper performs exhaustive circuit mapping of a single-cell foundation model, revealing significant redundancy, a heavy-tailed hub architecture, and layer-dependent control of cell differentiation, challenging prior biased interpretability methods.

Contribution

It introduces comprehensive circuit tracing and causal trajectory steering in Geneformer, uncovering systematic biases and layer-specific control mechanisms in the model.

Findings

Revealed 27-fold increase in downstream features through exhaustive tracing.

Identified 1.8% of features as disproportionate hubs, many unannotated.

Confirmed layer-dependent causal influence on cell differentiation.

Abstract

Mechanistic interpretability of biological foundation models has relied on selective feature sampling, pairwise interaction testing, and observational trajectory analysis. Each of these can introduce systematic bias. Here we present three experiments that address these limitations through exhaustive circuit tracing, higher order combinatorial ablation, and causal trajectory steering in Geneformer, a transformer based single cell foundation model. First, exhaustive tracing of all 4065 active sparse autoencoder features at layer 5 yields 1393850 significant downstream edges, a 27 fold expansion over selective sampling. This reveals a heavy tailed hub distribution in which 1.8 percent of features account for disproportionate connectivity and 40 percent of the top 20 hubs lack biological annotation. These results indicate systematic annotation bias in prior selective analyses. Second, three way combinatorial ablation across 8 feature triplets shows that redundancy deepens monotonically with interaction order, with a three way ratio of 0.59 versus a pairwise ratio of 0.74, and with zero synergy. This confirms that the model architecture is subadditive at all tested orders. Third, trajectory guided feature steering establishes a causal link between layer position and differentiation directionality. Late layer features at L17 consistently push cell states toward maturity, with fraction positive equal to 1.0. Early and mid layer features at L0 and L11 mostly push away from maturity, with fraction positive ranging from 0.00 to 0.58. Together these results move from correlation toward causal evidence for layer dependent control of cell state.