{"doi":"10.1101/2025.09.19.677370","title":"Maintaining transcriptome solubility constrains mRNA sequence composition","abstract":"Abstract RNA is built from a four-nucleotide alphabet. Complementary sequences inevitably arise, creating pervasive opportunities for promiscuous RNA–RNA interactions. Here, we show that this chemistry makes the transcriptome intrinsically prone to self-association. We simulated the simultaneous interactions of ~7,500 mRNAs representing the E. coli transcriptome at physiological concentrations. These large-scale simulations predict widespread, dynamic clustering driven by RNA alone and organized by long, multivalent transcripts. Purified mRNA recapitulates this behavior in vitro , with aggregate composition mirroring model predictions. Strikingly, native mRNA sequences are markedly less prone to self-association than matched randomized controls: they fold more stably, expose shorter single-stranded regions, and form weaker intermolecular contacts. Similar signatures are observed in abundant human mRNAs, suggesting that evolution has shaped coding sequences to minimize self-association. These findings identify transcriptome solubility as an unrecognized constraint on mRNA sequence evolution and provide a framework for understanding how cells keep their transcriptomes dispersed and functional.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":559109,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1459836,"name":"Ankur Jain","orcid":"0000-0002-8026-0819","position":1,"is_corresponding":false},{"id":1235017,"name":"Marco Todisco","orcid":"0000-0001-6627-5283","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:55:30.312295Z","pmid":"41000932","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}