{"doi":"10.1101/2023.02.14.528376","title":"Human gene regulatory evolution is driven by the divergence of regulatory element function in both <i>cis</i> and <i>trans</i>","abstract":"SUMMARY Gene regulatory divergence between species can result from cis -acting local changes to regulatory element DNA sequences or global trans -acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying trans -acting changes. We present a comprehensive approach to directly identify cis- and trans- divergent regulatory elements between human and rhesus macaque lymphoblastoid cells using ATAC-STARR-seq. In addition to thousands of cis changes, we discover an unexpected number (~10,000) of trans changes and show that cis and trans elements exhibit distinct patterns of sequence divergence and function. We further identify differentially expressed transcription factors that underlie &gt;50% of trans differences and trace how cis changes can produce cascades of trans changes. Overall, we find that most divergent elements (67%) experienced changes in both cis and trans , revealing a substantial role for trans divergence—alone and together with cis changes—to regulatory differences between species.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":403121,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.948,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":413521,"name":"Sarah Fong","orcid":"0000-0003-0900-5505","position":1,"is_corresponding":false},{"id":258343,"name":"John A. Capra","orcid":"0000-0001-9743-1795","position":2,"is_corresponding":false},{"id":17369,"name":"Emily Hodges","orcid":"0000-0001-6513-610X","position":3,"is_corresponding":false},{"id":278197,"name":"Tyler Hansen","orcid":"0000-0003-3328-783X","position":0,"is_corresponding":true}],"reference_count":103,"raw_metadata":null,"created_at":"2026-07-19T01:20:32.588152Z","pmid":"36824965","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":[]}