The X factor: X chromosome dosage compensation in the evolutionarily divergent monotremes and marsupials

Marsupials and monotremes represent evolutionarily divergent lineages from the majority of extant mammals which are eutherian, or placental, mammals. Monotremes possess multiple X and Y chromosomes that appear to have arisen independently of eutherian and marsupial sex chromosomes. Dosage compensation of X-linked genes occurs in monotremes on a gene-by-gene basis, rather than through chromosome-wide silencing, as is the case in eutherians and marsupials. Specifically, studies in the platypus have shown that for any given X-linked gene, a specific proportion of nuclei within a cell population will silence one locus, with the percentage of cells undergoing inactivation at that locus being highly gene-specific. Hence, it is perhaps not surprising that the expression level of X-linked genes in female platypus is almost double that in males. This is in contrast to the situation in marsupials where one of the two X chromosomes is inactivated in females by the long non-coding RNA RSX, a functional analogue of the eutherian XIST. However, marsupial X chromosome inactivation differs from that seen in eutherians in that it is exclusively the paternal X chromosome that is silenced. In addition, marsupials appear to have globally upregulated X-linked gene expression in both sexes, thus balancing their expression levels with those of the autosomes, a process initially proposed by Ohno in 1967 as being a fundamental component of the X chromosome dosage compensation mechanism but which may not have evolved in eutherians.