Dosage sensitivity of X-linked genes in human embryonic single cells

Fifty years ago, Susumu Ohno proposed that the expression levels of X-linked genes have doubled as dosage compensation for autosomal genes due to degeneration of Y-linked homologs during evolution of mammalian sex chromosomes. 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, thus refuting Ohnos hypothesis. Here, by reanalyzing a RNA-seq-based single-cell transcriptome dataset of human embryos (Petropoulos, et al. 2016), 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. This observation suggests that the expression levels of X-linked genes are imbalanced, with autosomal genes starting from the early 8-cell stage, and that the dosage conversion is fast, such that the X:AA expression ratio reaches ~0.5 in no more than a week. 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 of Ohnos hypothesis. Moreover, the dosage-sensitive housekeeping genes are preferentially located on autosomes, implying selection against X-linkage for dosage-sensitive genes. Our results collectively suggest an alternative to Ohnos hypothesis that X-linked genes are less likely to be dosage sensitive than autosomal genes.