Marsupial Genetics Reveals Insights into Evolution of Mammalian X Chromosome Inactivation

X chromosome inactivation (X-inactivation; XCI) in mammals equalizes X gene dosage between XX females and XY males. It is the prime example of epigenetic repression on a grand scale. This regulatory process differentially treats homologous chromosomes within the same nucleus to ensure that only a single X chromosome remains active in a diploid female cell. The best-studied models of X-inactivation, humans and mice, represent only one of four clades of placental (eutherian) mammals. Comparisons of dosage compensation mechanisms in distantly related eutherian mammals, marsupial and monotreme mammals, and even birds, will offer entirely new insights to the mechanisms and evolution of dosage compensation. In order to reconstruct what dosage compensation mechanisms might have been functioning in the mammalian ancestor, we highlight the molecular similarities and differences between X-inactivation in marsupials and eutherians, and compare them with the partial dosage compensation system observed in monotreme mammals, which appears more similar to bird dosage compensation. We draw parallels between these mechanisms, which may well have evolved independently by drawing from a common epigenetic “toolbox”, and therefore utilize similar molecular mechanisms to down-regulate gene expression.