X-chromosome inactivation (XCI) in eutherian mammals is the epigenetic inactivation of one of the two X chromosomes in XX females in order to compensate for dosage differences with XY males. Not all genes are inactivated, and the proportion escaping from inactivation varies between human and mouse (the two species that have been extensively studied). We used DNA methylation to predict the XCI status of X-linked genes with CpG islands across 12 different species: human, chimp, bonobo, gorilla, orangutan, mouse, cow, sheep, goat, pig, horse and dog. We determined the XCI status of 342 CpG islands on average per species, with most species having 80–90% of genes subject to XCI. Mouse was an outlier, with a higher proportion of genes subject to XCI than found in other species. Sixteen genes were found to have discordant X-chromosome inactivation statuses across multiple species, with five of these showing primate-specific escape from XCI. These discordant genes tended to cluster together within the X chromosome, along with genes with similar patterns of escape from XCI. CTCF-binding, ATAC-seq signal and LTR repeats were enriched at genes escaping XCI when compared to genes subject to XCI; however, enrichment was only observed in three or four of the species tested. LINE and DNA repeats showed enrichment around subject genes, but again not in a consistent subset of species. In this study, we determined XCI status across 12 species, showing mouse to be an outlier with few genes that escape inactivation. Inactivation status is largely conserved across species. The clustering of genes that change XCI status across species implicates a domain-level control. In contrast, the relatively consistent, but not universal correlation of inactivation status with enrichment of repetitive elements or CTCF binding at promoters demonstrates gene-based influences on inactivation state. This study broadens enrichment analysis of regulatory elements to species beyond human and mouse.

中文翻译：

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X染色体失活的跨物种检查突出了逃避沉默的领域

eutherian 哺乳动物中的 X 染色体失活 (XCI) 是 XX 雌性中两条 X 染色体之一的表观遗传失活，以补偿与 XY 雄性的剂量差异。并非所有基因都失活，并且从失活中逃脱的比例因人和小鼠（已被广泛研究的两个物种）而异。我们使用 DNA 甲基化来预测 12 个不同物种的 X 连锁基因与 CpG 岛的 XCI 状态：人类、黑猩猩、倭黑猩猩、大猩猩、猩猩、小鼠、牛、绵羊、山羊、猪、马和狗。我们确定了每个物种平均 342 个 CpG 岛的 XCI 状态，大多数物种有 80-90% 的基因受 XCI 影响。小鼠是一个异常值，与其他物种相比，受 XCI 影响的基因比例更高。发现 16 个基因在多个物种中具有不一致的 X 染色体失活状态，其中 5 个显示出灵长类动物特异性逃离 XCI。这些不一致的基因倾向于聚集在 X 染色体内，以及具有相似从 XCI 逃逸模式的基因。与受 XCI 影响的基因相比，CTCF 结合、ATAC-seq 信号和 LTR 重复序列在逃逸 XCI 的基因上富集；然而，仅在三个或四个测试物种中观察到富集。LINE 和 DNA 重复显示围绕主题基因的富集，但同样不是在一致的物种子集中。在这项研究中，我们确定了 12 个物种的 XCI 状态，表明小鼠是一个异常值，很少有基因可以逃脱失活。失活状态在物种间很大程度上是保守的。跨物种改变 XCI 状态的基因聚类暗示了域级控制。相比之下，失活状态与重复元件的富集或启动子处的 CTCF 结合的相对一致但不普遍的相关性证明了基于基因的对失活状态的影响。这项研究将调节元件的富集分析扩大到人类和小鼠以外的物种。