Landscape of X chromosome inactivation across human tissues

Abstract

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 individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. 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 diversity6,7. 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.

Genetic effects on gene expression across human tissues

“…Additional papers from the GTEx consortium for the v6p data describe the impact of rare genetic variation on gene expression 62 , methods for analysis of transcriptome data 27 , the discovery and characterization of regulatory networks across tissues 63 , and analyses of diverse regulatory processes such as RNA editing 64 and X-inactivation 65 . To enable ongoing use of the GTEx data, summary-level expression data and eQTLs across all tissues are available from the GTEx Portal (www.gtexportal.org), while all individual-level raw data have been deposited in dbGaP (accession phs000424.v6.p1).…”

Cracking the regulatory code

“…In the third and fourth papers (pages 244 and 249, respectively), the consortium combined its GTEx data with other data sets to investigate how variants associated with altered gene expression can regulate two phenomena -RNA-editing processes 3 and X-chromosome inactivation 4 . In addition to the results presented, the GTEx project has provided a valuable resource for the community, making its raw data available in the dbGaP database (www.ncbi.nlm.nih.…”

“…This technique allows the researchers to generate a comprehensive catalogue of associations between genetic variation and gene expression across many tissues in many individuals. In four papers [1][2][3][4] in this issue, the consortium presents the second phase of their project, and the largest survey of this type so far.…”

Gene-expression study raises thorny ethical issues

“…It routinely releases new data, which are freely available to qualified researchers. And in this week's Nature, GTEx is publishing its latest and biggest analysis, based on tissue from 449 donors (see pages 204, 239, 244 and 249) [1][2][3][4] . In assembling so much information from such a large number of deceased donors, the project has raised some thorny ethical issues concerning informed consent and scientists' moral obligations to families who donate the tissues of their loved ones for nothing in return.…”