GiantHost: a domain-adaptive and uncertainty-aware framework for giant virus host prediction.

MOTIVATION: Nucleocytoplasmic large DNA viruses (NCLDVs) play crucial roles in global ecosystems. Although metagenomics has vastly accelerated the discovery of novel NCLDVs, predicting their hosts from fragmented contigs remains a critical bottleneck, with no dedicated end-to-end computational tools currently available. Addressing this gap requires overcoming three fundamental challenges: the extreme scarcity of labeled reference genomes, the severe domain shift between laboratory isolates and diverse environmental metagenomes, and the inability of traditional deterministic models to quantify prediction uncertainty-a crucial requirement for reliable ecological profiling where novel, divergent viruses are prevalent. RESULTS: We present GiantHost, the first NCLDV host prediction tool with domain adaptation and uncertainlty awareness. GiantHost employs a dual-tower neural network to integrate dense genome traits and sparse GVOG profiles, allowing better integration of heterogeneous features. To overcome label scarcity and domain shift, we leverage 1400 environmental viral genomes (GVMAGs) via semi-supervised multi-task learning and Domain Adversarial Neural Networks (DANN), effectively bridging the distributional gap between RefSeq and environmental data. Additionally, GiantHost incorporates Conformal Prediction (CP) to output statistically guaranteed prediction sets rather than overconfident single labels. Evaluated under rigorous genome-level cross-validation, GiantHost demonstrates robust predictive power. Applied to the Tara Ocean dataset, GiantHost successfully captured the vertical stratification of NCLDV hosts-revealing a depth-dependent decline of phytoplankton-infecting viruses and a relative enrichment of Amoebozoa-infecting viruses in the mesopelagic zone. AVAILABILITY: The source code of GiantHost is available via: https://github.com/FuchuanQu/GiantHost.