{"doi":"10.1101/gr.275677.121","title":"Inferring genes that escape X-Chromosome inactivation reveals important contribution of variable escape genes to sex-biased diseases","abstract":"The X Chromosome plays an important role in human development and disease. However, functional genomic and disease association studies of X genes greatly lag behind autosomal gene studies, in part owing to the unique biology of X-Chromosome inactivation (XCI). Because of XCI, most genes are only expressed from one allele. Yet, ∼30% of X genes \"escape\" XCI and are transcribed from both alleles, many only in a proportion of the population. Such interindividual differences are likely to be disease relevant, particularly for sex-biased disorders. To understand the functional biology for X-linked genes, we developed X-Chromosome inactivation for RNA-seq (XCIR), a novel approach to identify escape genes using bulk RNA-seq data. Our method, available as an R package, is more powerful than alternative approaches and is computationally efficient to handle large population-scale data sets. Using annotated XCI states, we examined the contribution of X-linked genes to the disease heritability in the United Kingdom Biobank data set. We show that escape and variable escape genes explain the largest proportion of X heritability, which is in large part attributable to X genes with Y homology. Finally, we investigated the role of each XCI state in sex-biased diseases and found that although XY homologous gene pairs have a larger overall effect size, enrichment for variable escape genes is significantly increased in female-biased diseases. Our results, for the first time, quantitate the importance of variable escape genes for the etiology of sex-biased disease, and our pipeline allows analysis of larger data sets for a broad range of phenotypes.","journal":"Genome Research","year":2021,"id":213049,"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":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9559,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":804911,"name":"Jill M. Stahl","orcid":null,"position":1,"is_corresponding":false},{"id":804912,"name":"J. Chen James","orcid":null,"position":2,"is_corresponding":false},{"id":804913,"name":"Marisa Englebright","orcid":null,"position":3,"is_corresponding":false},{"id":804285,"name":"Fang Chen","orcid":"0009-0000-2050-8950","position":4,"is_corresponding":false},{"id":14650,"name":"Xiaowei Zhan","orcid":"0000-0002-6249-7193","position":5,"is_corresponding":false},{"id":51331,"name":"Laura Carrel","orcid":"0000-0002-5868-4228","position":6,"is_corresponding":false},{"id":804286,"name":"Dajiang J. Liu","orcid":"0000-0003-2909-7646","position":7,"is_corresponding":false},{"id":804284,"name":"Renan Sauteraud","orcid":"0000-0002-3485-6849","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-18T23:52:31.378994Z","pmid":"34426515","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":[]}