Scaling a context-aware genomic model for condition-specific edit design in plants

Abstract

Engineering agronomically relevant traits in crops often requires changing a gene's activity in a specific tissue, developmental stage or environmental condition while preserving its roles in other contexts. Designing such selective changes requires predicting how cis-regulatory sequences are interpreted in different biological states, as the same edit can have different effects across contexts. Genomic models have made substantial progress in predicting gene expression from DNA sequence, yet sequence-only predictors do not receive an explicit description of biological states. We introduce CROP-1 (Context-aware Regulatory Output Prediction model), which combines DNA sequence with transcription factor binding motifs and measured expression to predict gene activity as a function of both sequence and regulatory state. On a held-out test set spanning six plant species, CROP-1 achieves a median per-gene Pearson correlation across contexts of 0.831, compared with 0.486 for its parameter-matched sequence-only counterpart, and 57-246% higher median correlations than three genomic foundation models fully fine-tuned on the same task. Prediction accuracy also improves with scale: increasing model capacity reduces validation error by 48%, while expanding training data to include more diverse biological contexts reduces it by 58%. We then use gradient-based sequence optimisation to translate a desired gene expression pattern into candidate edits of its cis-regulatory sequence, targeting up- or down-regulation in one context while preserving expression in others. In soybean and tomato, edit designs with 1-20 nucleotide substitutions produce strong predicted target responses and much smaller average changes across non-target contexts. By connecting scalable learning of sequence-state relationships to selective edit design, CROP-1 provides a computational foundation for controlling where, when and under which conditions endogenous crop genes are active.