Bridging Sequence-Structure Alignment in RNA Foundation Models

The alignment between RNA sequences and structures in foundation models (FMs) has yet to be thoroughly investigated. Existing FMs have struggled to establish sequence-structure alignment, hindering the seamless flow of genomic information between RNA sequences and structures. In this study, we introduce OmniGenome, an RNA FM trained to align RNA sequences with respect to secondary structures through structure-contextualized modelling. This alignment enables free and bidirectional mappings between sequences and structures by utilizing a flexible RNA modelling paradigm that supports versatile input and output modalities, i.e., sequence and/or structure as input/output. We implement RNA design and zero-shot secondary structure prediction as case studies to evaluate the Seq2Str and Str2Seq mapping capabilities of OmniGenome. Results on the EternaV2 benchmark show that OmniGenome solved 74% of puzzles, whereas existing FMs solved only up to 3% of the puzzles due to the lack of sequence-structure alignment. We leverage four comprehensive in-silico genome modelling benchmarks to evaluate performance across a diverse set of downstream genome tasks, where the results show that OmniGenome achieves state-of-the-art performance on RNA and DNA benchmarks, even without any training on DNA genomes.