A contextualised protein language model reveals the functional syntax of bacterial evolution

Wiatrak, M.; Vinas Torne, R.; Ntemourtsidou, M.; Dinan, A. M.; Abelson, D. C.; Arora, D.; Brbic, M.; Weimann, A.; Floto, R. A.

doi:10.1101/2025.07.20.665723

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bioRxiv · 10.1101/2025.07.20.665723

A contextualised protein language model reveals the functional syntax of bacterial evolution

Wiatrak, M.·Vinas Torne, R.·Ntemourtsidou, M.·Dinan, A. M.·Abelson, D. C.·Arora, D.·Brbic, M.·Weimann, A.·Floto, R. A.

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Abstract

Bacteria have evolved a vast diversity of functions and behaviours that are currently incompletely understood and poorly predicted from DNA sequence alone. To understand the syntax of bacterial evolution and discover genome-to-phenotype relationships, we curated over 1.3 million genomes spanning bacterial phylogenetic space, represented each as an ordered sequence of proteins, and used these sequences to train a transformer-based, contextualised protein language model, Bacformer. By pretraining on genome-wide evolutionary patterns, Bacformer captures the compositional and positional relationships of proteins and thereby provides a whole-genome framework for linking genomic organisation and content to measurable bacterial traits. We demonstrate the ability of Bacformer to accurately predict protein-protein interactions; uncover operon structure, which we validated experimentally; infer important phenotypic traits, including antimicrobial resistance, while revealing likely causal genes; and design template synthetic proteomes with desirable properties. Thus, Bacformer establishes a genomic foundation model that reveals the evolutionary rules governing bacterial gene organisation, function, and phenotype, opening a route to systematic whole-genome engineering.

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Wiatrak, M., Vinas Torne, R., Ntemourtsidou, M., Dinan, A. M., Abelson, D. C., Arora, D., Brbic, M., Weimann, A., Floto, R. A.. 2025-07-20. A contextualised protein language model reveals the functional syntax of bacterial evolution. https://doi.org/10.1101/2025.07.20.665723

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