biostudies-literatureSan Roman AKNICHD NIH HHSNCATS NIH HHSNHGRI NIH HHS100259https://www.ebi.ac.uk/biostudies/studies/S-EPMC9932992biostudies-literatureUnknown3(2)The "inactive" X chromosome (Xi) has been assumed to have little impact, in <i>trans</i>, on the "active" X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in <i>cis</i>, through Xi-Cell genomicsThe human inactive X chromosome modulates expression of the active X chromosome.PMC9932992F32 HD091966K23 HD092588U01 HG007587UL1 TR002535Blanton LVPhou SPage DCGodfrey AKSkaletsky HBanks NHughes JFSamango-Sprouse CKruszka PTartaglia NRPak EGroff AFDavis SMBrown LDutra ALasutschinkow PCMuenke MSan Roman AKBellott DWBuscetta AKeen CHarris HLfalseThe human inactive X chromosome modulates expression of the active X chromosome.The "inactive" X chromosome (Xi) has been assumed to have little impact, in <i>trans</i>, on the "active" X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in <i>cis</i>, through Xi-2023-01-01T00:00:00Z2023 Feb2026-05-29T08:26:56.271Z2025-04-05T00:16:31.63ZS-EPMC99329923681966310.1016/j.xgen.2023.100259