JEPA-DNA: Grounding Genomic Foundation Models through Joint-Embedding Predictive Architectures

Contemporary Genomic Foundation Models (GFMs) rely on a DNA-as-a-string paradigm that employs masked token prediction objectives for pretraining. However, this abstraction does not explicitly model the biochemical, structural, and physical properties essential to biological function. Many molecular properties can be estimated from sequence using established biophysical models, so their utility lies not in providing an independent modality, but in introducing priors that training objectives can explicitly exploit. We introduce VANDAM, a framework that extends the training of GFMs with DNA molecular priors. In self-supervised training, VANDAM predicts regional molecular properties from pooled representations. When functional labels are available and can reward retaining molecular priors, local features are additionally injected at the input. VANDAM consistently improves downstream performance across four architecture families and nine held-out genomic tasks by complementing token-based objectives. Probing experiments further demonstrate that the use of molecular priors generalizes to other unseen molecular properties.

Genomic foundation models increasingly adopt large language model architectures, yet almost universally rely on fixed tokenization schemes such as $k$-mers, BPE, or single nucleotides, which impose arbitrary sequence boundaries that may obscure biologically relevant structure. We present LDARNet, a 120M-parameter hierarchical genomic foundation model that adapts H-Net-style dynamic chunking from autoregressive generation to masked language modeling, combining BiMamba-2 state-space layers with local attention, bidirectional routing, and a ratio-based regularizer to induce adaptive token boundaries without supervision. Fine-tuned on 27 tasks from the Nucleotide Transformer and Genomic Benchmarks suites, LDARNet achieves 11/18 wins among compact models ($<$300M parameters) and state-of-the-art results on 5 histone modification tasks, outperforming models up to 20$\times$ larger. A FLOPs-matched controlled experiment isolates learned routing as the source of these gains: learned boundaries beat fixed-grid boundaries by up to 14 percentage points on histone tasks at identical compute. Nucleotide-resolution analysis further shows that the learned boundaries align with canonical promoter motifs and splice junctions without supervision, providing a biological interpretation for adaptive tokenization in genomic foundation models.

Foundation models in genomics have shown mixed success compared to their counterparts in natural language processing. Yet, the reasons for their limited effectiveness remain poorly understood. In this work, we investigate the role of entropy as a fundamental factor limiting the capacities of such models to learn from their training data and develop foundational capabilities. We train ensembles of models on text and DNA sequences and analyze their predictions, static embeddings, and empirical Fisher information flow. We show that the high entropy of genomic sequences -- from the point of view of unseen token prediction -- leads to near-uniform output distributions, disagreement across models, and unstable static embeddings, even for models that are matched in architecture, training and data. We then demonstrate that models trained on DNA concentrate Fisher information in embedding layers, seemingly failing to exploit inter-token relationships. Our results suggest that self-supervised training from sequences alone may not be applicable to genomic data, calling into question the assumptions underlying current methodologies for training genomic foundation models.