Journal Article

Landscape of X chromosome inactivation across human tissues

Villani, Alexandra-Chloé, Hacohen, Nir, Aguirre, Matt, Cummings, Beryl B., Gauthier, Laura, Karczewski, Konrad J., Regev, Aviv, Aguet, François, Fleharty, Mark, Castel, Stephane E., Lappalainen, Tuuli, Satija, Rahul, Marshall, Jamie L., Rivas, Manuel A., Tukiainen, Taru, Byrnes, Andrea, MacArthur, Daniel G., Kirby, Andrew, Ardlie, Kristin G., Yen, Angela

2017

Overview

Multiple transcriptome approaches, including single-cell sequencing, demonstrate that escape from X chromosome inactivation is widespread and occasionally variable between cells, chromosomes, and tissues, resulting in sex-biased expression of at least 60 genes and potentially contributing to sex-specific differences in health and disease. Genetic effects on gene expression across human tissues The GTEx (Genotype-Tissue Expression) Consortium has established a reference catalogue and associated tissue biobank for gene-expression levels across individuals for diverse tissues of the human body, with a broad sampling of normal, non-diseased human tissues from postmortem donors. The consortium now presents the deepest survey of gene expression across multiple tissues and individuals to date, encompassing 7,051 samples from 449 donors across 44 human tissues. Barbara Engelhardt and colleagues characterize the relationship between genetic variation and gene expression, and find that most genes are regulated by genetic variation near to the affected gene. In accompanying GTEx studies, Alexis Battle, Stephen Montgomery and colleagues examine the effect of rare genetic variation on gene expression across human tissues, Daniel MacArthur and colleagues systematically survey the landscape of X chromosome inactivation in human tissues, and Jin Billy Li and colleagues provide a comprehensive cross-species analysis of adenosine-to-inosine RNA editing in mammals. In an accompanying News & Views, Michelle Ward and Yoav Gilad put the latest results in context and discuss how these findings are helping to crack the regulatory code of the human genome. 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 1 , 2 . The extent to which XCI is shared between cells and tissues remains poorly characterized 3 , 4 , as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression 5 and phenotypic traits 6 . 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 6 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/23 / 38/91 / 631/208/176/1433 / 692/308/2056 / 692/700/478/174 / Chromosomes / Chromosomes, Human, X - genetics / Deactivation / Dosage compensation / Epidemiology / Epigenetics / Female / Gender aspects / Gene expression / Genes / Genes, X-Linked - genetics / Genetics research / Genome, Human - genetics / Genomes / Genomics / Heterogeneity / Human tissues / Humanities and Social Sciences / Humans / Inactivation / letter / Male / Males / Mammalian cells / multidisciplinary / Organ Specificity - genetics / Phenotype / Physiological aspects / Principal components analysis / Science / Sequence Analysis, RNA / Sex / Sex differences / Single-Cell Analysis / Tissues / Transcription / Transcriptome - genetics / X Chromosome Inactivation - genetics / X chromosomes / X-chromosome inactivation