Cross-species modeling of plant genomes at single-nucleotide resolution using a pretrained DNA language model
Jingjing Zhai, Aaron Gokaslan, Yair Schiff, Ana Berthel, Zong-Yan Liu, Wei‐Yun Lai, Zachary Miller, Armin Scheben, Michelle C. Stitzer, M. Cinta Romay, Edward S. Buckler, Volodymyr Kuleshov
Abstract
Interpreting function and fitness effects in diverse plant genomes requires transferable models. Language models (LMs) pretrained on large-scale biological sequences can capture evolutionary conservation and offer cross-species prediction better than supervised models through fine-tuning limited labeled data. We introduce PlantCaduceus, a plant DNA LM that learns evolutionary conservation patterns in 16 angiosperm genomes by modeling both DNA strands simultaneously. When fine-tuned on a small set of labeled Arabidopsis data for tasks such as predicting translation initiation/termination sites and splice donor/acceptor sites, PlantCaduceus demonstrated remarkable transferability to maize, which diverged 160 Mya. The model outperformed the best existing DNA language model by 1.45-fold in maize splice donor prediction and 7.23-fold in maize translation initiation site prediction. In variant effect prediction, PlantCaduceus showed performance comparative to state-of-the-art protein LMs. Mutations predicted to be deleterious by PlantCaduceus showed threefold lower average minor allele frequencies compared to those identified by multiple sequence alignment-based methods. Additionally, PlantCaduceus successfully identifies well-known causal variants in both Arabidopsis and maize. Overall, PlantCaduceus is a versatile DNA LM that can accelerate plant genomics and crop breeding applications.