Landscape of X chromosome inactivation across human tissues

GTEx Consortium

Research output: Contribution to journalArticle

79 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)244-248
Number of pages5
JournalNature
Volume550
Issue number7675
DOIs
StatePublished - Oct 11 2017
Externally publishedYes

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X Chromosome Inactivation
Genes
X Chromosome
Transcriptome
Sexism
Sex Characteristics

ASJC Scopus subject areas

  • General

Cite this

Landscape of X chromosome inactivation across human tissues. / GTEx Consortium.

In: Nature, Vol. 550, No. 7675, 11.10.2017, p. 244-248.

Research output: Contribution to journalArticle

GTEx Consortium. / Landscape of X chromosome inactivation across human tissues. In: Nature. 2017 ; Vol. 550, No. 7675. pp. 244-248.
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title = "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.",
author = "{GTEx Consortium} and Taru Tukiainen and Villani, {Alexandra Chlo{\'e}} and Angela Yen and Rivas, {Manuel A.} and Marshall, {Jamie L.} and Rahul Satija and Matt Aguirre and Laura Gauthier and Mark Fleharty and Andrew Kirby and Cummings, {Beryl B.} and Castel, {Stephane E.} and Karczewski, {Konrad J.} and Fran{\cc}ois Aguet and Andrea Byrnes and Gelfand, {Ellen T.} and Gad Getz and Kane Hadley and Handsaker, {Robert E.} and Huang, {Katherine H.} and Seva Kashin and Monkol Lek and Xiao Li and Nedzel, {Jared L.} and Nguyen, {Duyen T.} and Noble, {Michael S.} and Segr{\`e}, {Ayellet V.} and Trowbridge, {Casandra A.} and Abell, {Nathan S.} and Brunilda Balliu and Ruth Barshir and Omer Basha and Alexis Battle and Bogu, {Gireesh K.} and Andrew Brown and Brown, {Christopher D.} and Chen, {Lin S.} and Colby Chiang and Don Conrad and Cox, {Nancy J.} and Damani, {Farhan N.} and Davis, {Joe R.} and Olivier Delaneau and Dermitzakis, {Emmanouil T.} and Engelhardt, {Barbara E.} and Eleazar Eskin and Ferreira, {Pedro G.} and Laure Fr{\'e}sard and Gamazon, {Eric R.} and Diego Garrido-Mart{\'i}n",
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