Scenarios for dosage compensation after sex chromosome differentiation. (A) Sex chromosomes stem from ordinary pairs of ancestral autosomes, also known as proto-sex chromosomes. (B) Following sex chromosome differentiation and extensive Y gene loss, females retain two active X Chromosomes while males are left with a single active X and a Y Chromosome with only very few remaining ancestral genes (i.e., males effectively retain only one of the ancestral copies for most genes). Several scenarios for how this dosage reduction was compensated have been proposed and/or described; three prominent scenarios are outlined in panels C–E. (C) A twofold up-regulation of all X-linked genes in both sexes is secondarily compensated by the inactivation (black symbols) of one X Chromosome in females (Ohno's hypothesis) (Ohno 1967). This scenario applies to at least several tissues of marsupials (imprinted XCI is present in marsupials) (Fig. 3A; Grant et al. 2012). (D) The expression output of the X Chromosome remains unchanged in both sexes, and one of the female X Chromosomes is secondarily inactivated. This scenario is observed—at least globally and at the transcriptional level—in placentals (Fig. 3A; Julien et al. 2012; Lin et al. 2012; Mank 2013). Note that it is not clear in this scenario how a dosage reduction without expression increase could be tolerated and why random X inactivation evolved in these mammals; i.e., this scenario is shown because it illustrates the currently known placental pattern. Alternative mechanisms (e.g., down-regulation of autosomal partner genes, translational up-regulation) likely contributed to dosage compensation of haploinsufficient genes in this scenario (see main text). (E) Females retained two active X Chromosomes and a male-specific epigenetic mechanism prompted a twofold up-regulation of the X Chromosome in males. This scenario is observed in both Drosophila (Conrad and Akhtar 2012) and Anolis (this study; Conrad and Akhtar 2012).
