Landscape of X chromosome inactivation across human tissues.

Nature. 2017 Oct 11;550(7675):244-248. doi: 10.1038/nature24265.


X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals. The extent to which XCI is shared between cells and tissues remains poorly characterized, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression and phenotypic traits. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.


Tukiainen T1,2, Villani AC2,3, Yen A2,4, Rivas MA1,2,5, Marshall JL1,2, Satija R2,6,7, Aguirre M1,2, Gauthier L1,2, Fleharty M2, Kirby A1,2, Cummings BB1,2, Castel SE6,8, Karczewski KJ1,2, Aguet F2, Byrnes A1,2; GTEx Consortium; Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group; Statistical Methods groups—Analysis Working Group; Enhancing GTEx (eGTEx) groups; NIH Common Fund; NIH/NCI; NIH/NHGRI; NIH/NIMH; NIH/NIDA; Biospecimen Collection Source Site—NDRI; Biospecimen Collection Source Site—RPCI; Biospecimen Core Resource—VARI; Brain Bank Repository—University of Miami Brain Endowment Bank; Leidos Biomedical—Project Management; ELSI Study; Genome Browser Data Integration &Visualization—EBI; Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz, Lappalainen T6,8, Regev A2,9, Ardlie KG2, Hacohen N2,3, MacArthur DG1,2. Collaborators (248)

Institute Authors

Ira M. Hall, Ph.D.