GenomeHarness: Harnessing Al Agents for Reliable Adaptation of Genome Language Models

Abstract

Pretrained genome language models provide reusable representations for DNA sequence analysis, but turning them into reliable downstream predictors remains non-trivial. Their practical performance depends strongly on fine-tuning recipes, and default recipes reported in prior studies may be suboptimal for new tasks or model backbones, making weak downstream results difficult to interpret. These requirements place a substantial operational burden on many intended users, whose expertise is often centered on biological questions and interpretation rather than machine-learning engineering. Reliable use of genome language models therefore requires more than conventional AutoML-style tuning: it requires a systematic, budget-aware, and auditable procedure that lowers the barrier to downstream adaptation. We present GenomeHarness, an agentic harness for adapting genome language models through controlled search over fine-tuning recipes. GenomeHarness combines an AI agent for proposing and repairing recipe edits, a harness for protocol-constrained execution, resource management, and test isolation, and a Monte Carlo tree search controller for allocating search effort across recipe lineages. We evaluate GenomeHarness on DNABERT2 and NTv2-100M-Multi across the NT Benchmark and Genomic Benchmarks. Final evaluation is performed using three random seeds after recipe freezing. Across 52 model-task settings, GenomeHarness improves mean test MCC in 47 settings, including 24 of 26 DNABERT2 settings and 23 of 26 NTv2-100M-Multi settings. The gains are especially pronounced on Genomic Benchmarks and on tasks where the root recipe is unstable or poorly matched, such as human ocr ensembl task. Search traces further show that GenomeHarness progressively identifies stronger recipes, turning downstream adaptation into a controlled and auditable workflow rather than a manual tuning process.