Dosage sensitivity of X-linked genes in human embryonic single cells
Dosage sensitivity of X-linked genes in human embryonic single cells
复制标题
人胚胎单细胞中X连锁基因的剂量敏感性
DOI：
10.1186/s12864-019-5432-8
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发表时间：
2019-01-14
期刊：
影响因子：
4.4
通讯作者：
Chen, Xiaoshu
中科院分区：
文献类型：
--
作者：
Yang, Jian-Rong;Chen, Xiaoshu
背景在哺乳动物性染色体的进化过程中，Y连锁同源基因的退化导致X连锁基因和常染色体基因之间的剂量不平衡。正如 Susumu Ohno 五十年前所假设的那样，这种剂量不平衡的进化解决方案应该是 X 连锁基因的表达加倍。然而，最近的研究表明，在单倍体人类孤雌胚胎干 (pES) 细胞中，X 与常染色体的表达比等于 ~ 1，在二倍体 pES 细胞中等于 ~ 0.5，这表明 X 连锁基因没有双表达，并驳斥了 Ohno 的假设。结果在这里，通过重新分析人类胚胎的基于 RNA-seq 的单细胞转录组数据集，我们发现从 8 细胞阶段到之前的时间点到着床时，X连锁基因的表达水平在雄性细胞中并未上调两倍，并且在雌性细胞中从两倍逐渐下降。对基因表达噪声的额外分析进一步表明，X连锁基因的剂量敏感性弱于分化雌性细胞中的常染色体基因，这与Ohno假设中的一个关键假设相矛盾，即大多数X连锁基因对剂量敏感。此外，剂量敏感的管家基因优先位于常染色体上，这意味着对剂量敏感基因的X连锁选择。结论我们观察到X连锁基因和常染色体基因之间的剂量不平衡，以及X连锁基因的相对较高的表达噪声。这些结果共同表明，X 连锁基因的剂量敏感性低于常染色体基因，这使得大野假说的一个主要假设受到质疑。
BackgroundDuring the evolution of mammalian sex chromosomes, the degeneration of Y-linked homologs has led to a dosage imbalance between X-linked and autosomal genes. The evolutionary resolution to such dosage imbalance, as hypothesized by Susumu Ohno fifty years ago, should be doubling the expression of X-linked genes. Recent studies have nevertheless shown that the X to autosome expression ratio equals ~ 1 in haploid human parthenogenetic embryonic stem (pES) cells and ~ 0.5 in diploid pES cells, suggesting no doubled expression for X-linked genes and refuting Ohno’s hypothesis.ResultsHere, by reanalyzing an RNA-seq-based single-cell transcriptome dataset of human embryos, we found that from the 8-cell stage until the time-point just prior to implantation, the expression levels of X-linked genes are not two-fold upregulated in male cells and gradually decrease from two-fold in female cells. Additional analyses of gene expression noise further suggest that the dosage sensitivity of X-linked genes is weaker than that of autosomal genes in differentiated female cells, which contradicts a key assumption in Ohno’s hypothesis, that most X-linked genes are dosage sensitive. Moreover, the dosage-sensitive housekeeping genes are preferentially located on autosomes, implying selection against X-linkage for dosage-sensitive genes.ConclusionsWe observed dosage imbalance between X-linked and autosomal genes, as well as relatively high expression noise from X-linked genes. These results collectively suggest that X-linked genes are less dosage sensitive than autosomal genes, putting one primary assumption of Ohno’s hypothesis in question.