The interpretation of genomic sequences is crucial for understanding biological processes. To handle the growing volume of DNA sequence data, Genomic Foundation Models (GFMs) have been developed by adapting architectures and training paradigms from Large Language Models (LLMs). Despite their remarkable performance in DNA sequence classification tasks, there remains a lack of systematic understanding regarding the training and task-adaptation processes of GFMs. Moreover, existing GFMs cannot achieve state-of-the-art performance on both short and long-context tasks and lacks multimodal abilities. By revisiting pre-training architectures and post-training techniques, we propose **Omni-DNA**, a family of models spanning 20M to 1.1B parameters that supports sequence understanding, long-context genomic reasoning, and natural-language annotation. **Omni-DNA** establishes new state-of-the-art results on 18 of 26 evaluations drawn from Nucleotide Transformer and Genomic Benchmarks. When jointly fine-tuning on biologically related tasks, **Omni-DNA** consistently outperform existing models and demonstrate multi-tasking abilities. To enable processing of arbitrary sequence lengths, we introduce **SEQPACK**—an adaptive compression operator that packs historical tokens into a learned synopsis using a position-aware learnable sampling mechanism, enabling transformer-based models to process ultra-long sequences with minimal memory and computational requirements. Our approach demonstrates superior performance on enhancer-target interaction tasks, capturing distant regulatory interactions at the 450kbp range more effectively than existing models. Finally, we present a new dataset termed **seq2func**, enabling Omni-DNA to generate accurate and functionally meaningful interpretations of DNA sequences, unlocking new possibilities for genomic analysis and discovery.

Genetic variants (GVs) are defined as differences in the DNA sequences among individuals and play a crucial role in diagnosing and treating genetic diseases. The rapid decrease in next generation sequencing cost, analogous to Moore’s Law, has led to an exponential increase in the availability of patient-level GV data. This growth poses a challenge for clinicians who must efficiently prioritize patient-specific GVs and integrate them with existing genomic databases to inform patient management. To addressing the interpretation of GVs, genomic foundation models (GFMs) have emerged. However, these models lack standardized performance assessments, leading to considerable variability in model evaluations. This poses the question: *How effectively do deep learning methods classify unknown GVs and align them with clinically-verified GVs?* We argue that representation learning, which transforms raw data into meaningful feature spaces, is an effective approach for addressing both indexing and classification challenges. We introduce a large-scale Genetic Variant dataset, named $\textsf{GV-Rep}$, featuring variable-length contexts and detailed annotations, designed for deep learning models to learn GV representations across various traits, diseases, tissue types, and experimental contexts. Our contributions are three-fold: (i) $\textbf{Construction}$ of a comprehensive dataset with 7 million records, each labeled with characteristics of the corresponding variants, alongside additional data from 17,548 gene knockout tests across 1,107 cell types, 1,808 variant combinations, and 156 unique clinically-verified GVs from real-world patients. (ii) $\textbf{Analysis}$ of the structure and properties of the dataset. (iii) $\textbf{Experimentation}$ of the dataset with pre-trained genomic foundation models (GFMs). The results highlight a significant disparity between the current capabilities of GFMs and the accurate representation of GVs. We hope this dataset will advance genomic deep learning to bridge this gap.