From reference-genome prediction to causal generalization: sequence-to-function models for plant regulatory genomics

Abstract

Sequence-to-function (seq2func) models predict molecular regulatory outputs from DNA sequence and can prioritize non-coding variants, annotate cis-regulatory elements (CREs), and design regulatory sequences. Although accuracy has improved, most models are trained and evaluated on observational data from one or a few reference genomes. Their performance may therefore not translate to natural haplotypes, structural variants, tissues, developmental stages, environments, or species. These limitations are especially important in plants, where pan-genomic diversity, transposable elements, polyploidy, long-range regulation, and genotype-by-environment interactions shape regulatory landscapes. This Mini Review summarizes seq2func modelling in plant regulatory genomics, discusses plant-specific challenges and the complementary value of observational and perturbation assays, and proposes evaluation frameworks based on biologically meaningful distribution shifts. We further outline how pan-genomes, multi-omics, genome editing, reporter assays, active learning, and continual learning could support closed-loop experimental–computational systems. Progress should be judged not only by reference-genome accuracy, but by calibrated and experimentally validated generalization across plant diversity.