Evolution of dosage compensation and x chromosome inactivation in therian mammals

Abstract

The sex chromosomes in therian mammals (eutherian mammals and marsupials) evolved from an identical autosomal pair. One of the two chromosomes in the original pair degraded in males due to suppression of recombination, resulting in monosomy of the X chromosome in males. It has been accepted for years that the differences in gene dosage that resulted from monosomy of the X chromosome in males were restored in a two-step way, firstly by upregulating the single X chromosome in males, then by transcriptionally silencing one X chromosome in females, in a process known as X chromosome inactivation (XCI). Though XCI has been extensively studied at the mechanistic and evolutionary level, upregulation of the X chromosome (which presumably preceded XCI) was assumed as a fact for decades, and has only been recently investigated and questioned. To gain insights into how the dosage compensation system evolved upon emergence of the sex chromosomes in therians, I tested upregulation of the X in marsupials and eutherian mammals distantly related to human and mouse. I observed that global upregulation of the X occurred in the marsupial lineage but not in the eutherian lineage. The eutherian X chromosome was augmented by the addition of an autosomal region (XAR), and I show that, similar to the marsupial X, this region has been upregulated in eutherians. Underlying differences in the XCI system between marsupials and eutherians have been previously described. I confirmed that paternally imprinted XCI is common to somatic tissues in the marsupial clade, in contrast to the conserved random XCI observed in eutherian embryonic tissues. I observed that as opposed to eutherians, escapee genes are not confined to the recent evolutionary strata on the X. A similarity with the eutherian clade is that the proportion of genes that escape XCI differs between species of the same clade; I observed that a greater proportion of genes (̃30%) escape XCI in tammar wallaby, in contrast to the 14% escape reported for opossum. I proposed a model for evolution of dosage compensation, where upregulation of the X chromosome started for a few dosage sensitive genes in the therian ancestor, and evolved into a global system in marsupials but not in eutherians. In addition, I discuss the relationship between upregulation of the X chromosome and evolution of XCI.