The existence of highly differentiated X and Y chromosomes in mammals raises the issue of X-linked gene dosage compensation between XX females and XY males to avoid what would be similar to a monosomy X in males (Veitia et al., 2015). Inactivation of one copy of the X chromosomes in females provides a dosage-compensation mechanism equalizing the expression of X-linked genes in males and females (Ohno et al., 1959; Lyon, 1961). However, a simple X-chromosome inactivation (XCI) would not ensure a balanced expression between X-linked and autosomal genes (Figure 1). This can be achieved if genes on the active X undergo a two-fold upregulation (Ohno, 1967). Some evidence supports this idea (Veitia et al., 2015 and references therein).