ArticlebioRxiv : the preprint server for biology2025
Evolutionary Reasoning Does Not Arise in Standard Usage of Protein Language Models.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Protein language models (PLMs) are often assumed to capture evolutionary information by training on large protein sequence datasets. Yet it remains unclear whether PLMs can reason about evolution-that is, infer evolutionary relationships between sequences. We test this capability by evaluating whether standard PLM usage, frozen or fine-tuned embeddings with distance-based comparison, supports evolutionary reasoning. Existing PLMs consistently fail to recover phylogenetic structure, despite strong performance on sequence-level tasks such as masked-token and contact prediction. We present Phyla, a hybrid state-space and transformer model that jointly processes multiple sequences and is trained using a tree-based objective across 3,000 phylogenies spanning diverse protein families. Phyla outperforms the next-best PLM by 9% on tree reconstruction and 23% on taxonomic clustering while remaining alignment- and guide-tree-free. Although classical alignment pipelines achieve higher absolute accuracy, Phyla narrows the gap and achieves markedly lower end-to-end runtime. Applied to real data, Phyla reconstructs biologically accurate clades in the tree of life and resolves genome-scale relationships among
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