MicroFuse: Protein-to-Genome Expert Fusion for Microbial Operon Reasoning

Identifying operons is a fundamental step in understanding prokaryotic gene regulation, as classifying genes into operons supports the reconstruction of regulatory networks, functional annotation of unannotated genes, and drug candidate development. Experimental approaches such as RT-PCR and RNA-seq provide precise evidence of operon structure, but are laborious and largely limited to well-studied model organisms, making scalable computational methods essential for genome-wide operon identification. Prior computational approaches have employed traditional classifiers such as logistic regression and decision trees, motivating our use of these as physicochemical baselines. The DGEB benchmark evaluates operonic pair classification by embedding each sequence independently with a pre-trained protein language model and computing pairwise cosine similarity. In contrast, our Siamese MLP learns a classifier over the fused embedding space, which is theoretically better motivated for binary classification, as cosine similarity can yield meaningless scores depending on the regularization of the embedding model. While protein language model embeddings substantially outperform physicochemical features in ROC-AUC, a learned Siamese MLP head does not significantly improve over unsupervised cosine similarity in Average Precision, suggesting that the geometry of the embedding space already captures the functional relationships needed for this task. Nonetheless, our Siamese MLP achieves a ROC-AUC of 0.71, competitive with state-of-the-art models on the DGEB leaderboard. These findings indicate that protein language model embeddings are a viable, scalable foundation for operonic pair classification across diverse microbial genomes, with implications for automated genome annotation, regulatory network reconstruction, and characterization of organisms lacking experimental operon annotations.

Protein sequence data from nature exhibits survivorship bias: we only observe data from those organisms that survive and reproduce, while non-functional protein mutations are eliminated by natural selection. Thus, predicting whether a protein sequence is functional often requires learning from positive examples alone. While positive-unlabeled (PU) learning frameworks offer a generic solution to this problem, existing PU methods ignore the evolutionary processes that shape sequence observability and cause survivorship bias. Consider a sequence that is one mutation away from a commonly-observed protein variant in a well-surveilled organism. If the sequence were functional, it would likely be observed. If it is not observed, this suggests non-functionality. In contrast, sequences that are unlikely to arise through mutation may be missing simply because they never arose. Thus, these two kinds of missing sequences should be treated differently when training models. In this work, we propose Evo-PU, a PU learning framework that uses a scientific understanding of nucleotide mutation to model survivorship bias for well-surveilled single-organism sequence data. On three prediction tasks using single-organism uniform-coverage surveillance data -- predicting results from held-out influenza and respiratory syncytial virus (RSV) mutagenesis studies, and predicting future SARS-CoV-2 variants -- Evo-PU outperforms standard PU learning, one-class classification (OCC), and protein language models (PLMs). On prediction tasks from multi-organism ProteinGym datasets with more heterogeneous surveillance coverage, we identify opportunities to generalize our approach.

Transformer models for high-dimensional omics analysis process thousands of genes or pathways, although only a subset requires deep computation. Mixture-of-Recursions (MoR) improves efficiency through adaptive token-choice or expert-choice routing. We propose bioMoR, which, to the best of our knowledge, is the first framework to apply MoR to gene-level and pathway-level learning. Our contributions include identifying three locations for integrating structured biological knowledge within an MoR backbone: graph-based information sharing refines token embeddings, a structural bias guides self-attention toward biologically related tokens, and a graph-aware router uses neighborhood information to determine each token's recursion depth. These techniques are centered on our insight that additional knowledge of token interaction can effectively help models construct embeddings and select which tokens should be learned more deeply. Across eight benchmarks spanning diverse omics data types and evaluated under a unified five-fold cross-validation protocol, bioMoR improves average macro-F1 by 8.2 percentage points and balanced accuracy by 7.1 percentage points over the strongest biology-agnostic MoR baseline while using 75 percent fewer parameters and up to 58 percent fewer FLOPs than a non-recursive Transformer. The selected marker genes or pathways provide biological interpretability, while their token-specific recursion depths reveal how computation is allocated.