Evolutionary Reasoning Does Not Arise in Standard Usage of Protein Language Models

Yasha Ektefaie, Andrew Shen, Lavik Jain, Maha Farhat, Marinka Zitnik

Keywords: Protein Language Models, Reasoning, Sequence Modeling, Evolution

TL;DR: State-of-the-art protein language models, under standard usage, cannot infer evolutionary relationships so we introduce Phyla, a model explicitly trained for evolutionary reasoning that achieves state-of-the-art phylogenetic performance.

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 Mycobacterium tuberculosis isolates. These findings suggest that, under standard usage, evolutionary reasoning does not reliably emerge from large-scale sequence modeling. Instead, Phyla shows that models trained with phylogenetic supervision can reason about evolution more effectively, offering a biologically grounded path toward evolutionary foundation models.

Primary Area: Machine learning for sciences (e.g. climate, health, life sciences, physics, social sciences)

Submission Number: 25465