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Biology subjects

Jedryszek, P.

Publications and source records attributed to Jedryszek, P..

2 recordsLinked to original sources

Decode-gLM: Tools to Interpret, Audit, and Steer GenomicLanguage Models

While genomic language models are enabling the de novo design of entire genomes, they remain challenging to interpret, limiting their trustworthiness. Here, we show that sparse autoencoders (SAEs) trained on Nucleotide Transformer activations decompose hidden representations into interpretable biological features without supervision. Across layers and model sizes, SAEs identified over 60 diverse functional annotations encoded in the models activations. This included viral regulatory elements such as the CMV enhancer, despite viral genomes being excluded from training data. Tracing this signal revealed contamination in reference databases, demonstrating that interpretability methods can audit training data and identify hidden data leakage. We then show that Meta-SAEs, trained on the decoder weights of another SAE, can identify conceptual hierarchies encoded in the model, including a more abstract feature related to multiple HIV annotations. We confirmed that the features identified by our SAEs were learned during pretraining through probing a randomly initialised model. Finally, we demonstrate that our SAEs allow us to steer model predictions in biologically meaningful ways, showing that we can use an antibiotic-resistance SAE-feature to steer the model toward the A1408G aminoglycoside-resistance mutation in the ribosomal gene 16S rRNA. Together, these results establish SAEs as a method for both discovery and auditing, providing a toolkit for interpretable and trustworthy genomic foundation models. Readers can explore our findings at https://interpretglm.netlify.app/.

genomics↗

Plasmids link antibiotic resistance genes and phage defense systems in E. coli

Phage therapy has been proposed as an alternative to antibiotics to treat resistant infections. However, we have a limited understanding of how antibiotic resistance genes (ARGs) associate with bacterial phage defense systems (PDSs). Here, we explore the relationship between ARGs and PDSs in a sample of 2,559 plasmids originating from 1,044 E. coli isolates, representing a snapshot of clinical and non-clinical diversity in Oxfordshire, UK (2008-2020). In total, we identify 3,193 ARGs and 14,013 PDSs (180 unique types). We demonstrate that E. coli plasmids are enriched for ARGs and PDSs (both p<0.001), with a bias towards toxin-antitoxin/abortive-infection, TIR-domain and CBASS systems (all q<0.025). We proceed to show that ARGs and PDSs are physically linked by plasmids (p<0.001). Together, our results suggest that phage therapy may inadvertently select for antibiotic resistant bacteria, and that antibiotic use may similarly drive resistance to phage.

evolutionary biology↗