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Landscape of X chromosome inactivation across human tissues

View ORCID ProfileTaru Tukiainen, Alexandra-Chloé Villani, Angela Yen, Manuel A. Rivas, Jamie L. Marshall, Rahul Satija, Matt Aguirre, Laura Gauthier, Mark Fleharty, Andrew Kirby, Beryl B. Cummings, Stephane E. Castel, Konrad J. Karczewski, François Aguet, Andrea Byrnes, Consortium GTEx, Tuuli Lappalainen, Aviv Regev, Kristin G. Ardlie, Nir Hacohen, Daniel G. MacArthur
doi: https://doi.org/10.1101/073957
Taru Tukiainen
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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  • ORCID record for Taru Tukiainen
  • For correspondence: ttuk@broadinstitute.org danmac@broadinstitute.org
Alexandra-Chloé Villani
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
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Angela Yen
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
4Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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Manuel A. Rivas
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
5Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
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Jamie L. Marshall
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Rahul Satija
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
6New York Genome Center, New York, NY 10013, USA.
7Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY 10003, USA.
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Matt Aguirre
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Laura Gauthier
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Mark Fleharty
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Andrew Kirby
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Beryl B. Cummings
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Stephane E. Castel
6New York Genome Center, New York, NY 10013, USA.
8Department of Systems Biology, Columbia University, New York, NY 10032, USA.
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Konrad J. Karczewski
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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François Aguet
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Andrea Byrnes
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Tuuli Lappalainen
6New York Genome Center, New York, NY 10013, USA.
8Department of Systems Biology, Columbia University, New York, NY 10032, USA.
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Aviv Regev
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
9Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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Kristin G. Ardlie
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Nir Hacohen
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA.
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Daniel G. MacArthur
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
2Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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  • For correspondence: ttuk@broadinstitute.org danmac@broadinstitute.org
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Abstract

X chromosome inactivation (XCI) silences the transcription from one of the two X chromosomes in mammalian female cells to balance expression dosage between XX females and XY males. XCI is, however, characteristically 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 (Fig. 1). However, 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 report a systematic survey of XCI using a combination of over 5,500 transcriptomes from 449 individuals spanning 29 tissues, and 940 single-cell transcriptomes, integrated with genomic sequence data (Fig. 1). By combining information across these data types we show that XCI at the 683 X-chromosomal genes assessed 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 new escape genes supported by multiple lines of evidence, and demonstrate that escape from XCI results in sex biases in gene expression, thus establishing incomplete XCI as a likely mechanism introducing phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues informs our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

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Posted September 19, 2016.
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Landscape of X chromosome inactivation across human tissues
Taru Tukiainen, Alexandra-Chloé Villani, Angela Yen, Manuel A. Rivas, Jamie L. Marshall, Rahul Satija, Matt Aguirre, Laura Gauthier, Mark Fleharty, Andrew Kirby, Beryl B. Cummings, Stephane E. Castel, Konrad J. Karczewski, François Aguet, Andrea Byrnes, Consortium GTEx, Tuuli Lappalainen, Aviv Regev, Kristin G. Ardlie, Nir Hacohen, Daniel G. MacArthur
bioRxiv 073957; doi: https://doi.org/10.1101/073957
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Landscape of X chromosome inactivation across human tissues
Taru Tukiainen, Alexandra-Chloé Villani, Angela Yen, Manuel A. Rivas, Jamie L. Marshall, Rahul Satija, Matt Aguirre, Laura Gauthier, Mark Fleharty, Andrew Kirby, Beryl B. Cummings, Stephane E. Castel, Konrad J. Karczewski, François Aguet, Andrea Byrnes, Consortium GTEx, Tuuli Lappalainen, Aviv Regev, Kristin G. Ardlie, Nir Hacohen, Daniel G. MacArthur
bioRxiv 073957; doi: https://doi.org/10.1101/073957

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