{"doi":"10.1101/2025.08.01.668097","title":"Escape from X inactivation drives sex differences in gene expression","abstract":"X chromosome inactivation (XCI) partially balances gene dosage between sexes, yet expression from the inactive X (Xi) is variable across genes. In this study, we investigate whether gene-level Xi expression predicts transcriptional and phenotypic consequences of X-linked variation. We find that Xi expression levels are a strong linear predictor of female-male expression differences, suggesting that other compensatory or regulatory mechanisms play a more minor role in sex differences in X-linked gene expression. Among females, we identify three traits-lymphocyte percentage, HbA1c, and schizophrenia-for which higher Xi expression correlates with the strength of evidence for dominance effects. We hypothesize that an underappreciated mechanism could generate dominance effects of X-linked variants on a trait-specifically when the variant influences skew in X inactivation. This work establishes Xi expression as essential for understanding sex differences and the female-specific genetic basis of disease.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":571547,"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":0.954,"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":1477265,"name":"Liaoyi Xu","orcid":"0000-0002-7198-3353","position":1,"is_corresponding":false},{"id":65300,"name":"Arbel Harpak","orcid":"0000-0002-3655-748X","position":2,"is_corresponding":false},{"id":1020559,"name":"Carrie Zhu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:57:15.755535Z","pmid":"40766617","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":[]}