Explaining deep neural network predictions on genome sequences enables biological insight and hypothesis generation-often of greater interest than predictive performance alone. While explanations of convolutional neural networks (CNNs) have been shown to capture relevant patterns in genome sequences, it is unclear whether this transfers to more expressive Transformer-based genome language models (gLMs). To answer this question, we adapt AttnLRP, an extension of layer-wise relevance propagation to the attention mechanism, and apply it to the state-of-the-art gLM DNABERT-2. Thereby, we propose strategies to transfer explanations from token and nucleotide level. We evaluate the adaption of AttnLRP on genomic datasets using multiple metrics. Further, we provide an extensive comparison between the explanations of DNABERT-2 and a baseline CNN. Our results demonstrate that AttnLRP yields reliable explanations corresponding to known biological patterns. Hence, like CNNs, gLMs can also help derive biological insights. This work contributes to the explainability of gLMs and addresses the comparability of relevance attributions across different architectures.
Deep neural networks have achieved strong performance in genomic sequence classification; however, relating their predictions to biologically meaningful sequence patterns remains challenging. In this work, we present AttnGen, an attention-guided training framework that embeds interpretability directly into the optimization process. AttnGen computes nucleotide-level importance scores using an attention mechanism and progressively suppresses low-contribution positions during training. This encourages the model to focus its predictions on a compact set of informative regions while reducing reliance on noisy sequence elements. We evaluate AttnGen on the standardized demo_human_or_worm benchmark, a binary classification task over 200-nucleotide sequences. With moderate masking, AttnGen achieves a validation accuracy of 96.73%, outperforming a conventional CNN baseline with 95.83% accuracy, while also exhibiting faster convergence and improved training stability. To assess whether the learned importance scores reflect functionally relevant signal, we conduct perturbation-based analysis by removing high-saliency nucleotides. This causes accuracy to drop from 96.9% to near chance level on a 3,000-sequence evaluation set, indicating that the model relies on a relatively small subset of informative positions. Our analysis shows that masking 10--20% of positions provides the most favorable trade-off between predictive performance and interpretability. These results suggest that attention-guided masking not only improves classification performance but also reshapes how models distribute importance across sequence positions. Although this study focuses on short genomic sequences, the proposed approach may extend to more complex interpretable sequence modeling settings.
Recent breakthroughs in foundation models and Large Language Models (LLMs) have introduced new opportunities for studying and decoding genomic sequences. Several state-of-the-art approaches, such as DNABERT2, rely on transformer-based architectures, while others, such as ConvNova, still build upon more conventional convolutional models. However, systematic benchmark comparisons across these methods remain scarce. Given that transformer-based models require extensive and costly pretraining, it is crucial to evaluate whether their performance gains justify this overhead. Moreover, LLMs such as DNABERT2 typically rely on Byte Pair Encoding (BPE) tokenization, whose relevance for DNA sequence representation is still debated within the genomics community. In this work, we investigate three key questions: (i) do transformer-based models provide sufficient improvements on fine-tuning tasks upon heavy pretraining, (ii) what is the actual contribution of pretraining in this setting, and (iii) how does BPE tokenization impact performance on genomics-related tasks?
In a feature-tokenized transformer (arXiv:2106.11959) such as BiomeGPT (doi:10.64898/2026.01.05.697599), each input token is built by fusing a fixed identity with a sample-specific measurement: a fixed species and a variable abundance, T = S + A. To interpret downstream classification in such models, prior work inspects the attention weights of the special [CLS] token (arXiv:2106.11959, arXiv:1810.04805, BiomeGPT) to rank sample tokens by importance. These weights have two critical limitations: they are nonnegative, so they cannot separate disease-supporting from health-supporting evidence (arXiv:2201.12114), and they act after token fusion, obscuring how the input sources S and A each affect the output. To address this we use Integrated Gradients (arXiv:1703.01365), a signed, fusion-aware attribution method, and propose a source-derived baseline T' = S + A_0 for feature-tokenized models such as BiomeGPT, which preserves species identity as a fixed biological coordinate while isolating the effect of abundance variation. Applied to a disease-versus-health decision margin, it yields polarity that explicitly separates pathogenic from protective microbial signals. We show that this gradient-based approach uncovers species-abundance directional relationships and sensitivity diagnostics entirely obscured by unsigned [CLS] attention weights. We further recommend second-order Integrated Hessians (arXiv:2002.04138) to expose microbiome community interaction rules: how a perturbation in one member alters the model's sensitivity to another, and which other species drive ambiguous cases toward disease or health at a given abundance level. This provides a principled approach to explainability in BiomeGPT that generalizes to other smooth and differentiable feature-tokenized transformers. Code is available at https://github.com/nohren/token-source-attribution