Tukiainen Taru, Villani Alexandra-Chloé, Yen Angela, Rivas Manuel A, Marshall Jamie L, Satija Rahul, Aguirre Matt, Gauthier Laura, Fleharty Mark, Kirby Andrew, Cummings Beryl B, Castel Stephane E, Karczewski Konrad J, Aguet François, Byrnes Andrea, Lappalainen Tuuli, Regev Aviv, Ardlie Kristin G, Hacohen Nir, MacArthur Daniel G
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
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.
X染色体失活（XCI）可使雌性哺乳动物细胞中两条X染色体之一的转录沉默，以平衡XX雌性和XY雄性之间的表达剂量。然而，XCI在人类中并不完全：在雌性细胞中，高达三分之一的X染色体基因在活跃和失活的X染色体（分别为Xa和Xi）上均有表达，不同基因和个体的“逃逸”失活程度有所不同。XCI在细胞和组织之间的共享程度以及不完全XCI在基因表达和表型特征中表现为可检测到的性别差异的程度，目前仍知之甚少。在此，我们描述了一项对XCI的系统调查，整合了来自GTEx（v6p版本）的29种组织的449个个体的5500多个转录组和940个单细胞转录组，并结合了基因组序列数据。我们发现，683个X染色体基因的XCI在人体组织中通常是一致的，但也发现了组织、个体和细胞之间存在异质性的例子。我们表明，不完全XCI影响至少23%的X染色体基因，通过多条证据支持鉴定出7个逃逸XCI的基因，并证明从XCI逃逸会导致基因表达的性别偏差，确立不完全XCI是一种可能引入表型多样性的机制。总体而言，这份更新后的人类组织XCI目录有助于增进我们对XCI维持过程中不完全性的程度和影响的理解。
