ReviewThe X factor: X chromosome dosage compensation in the evolutionarily divergent monotremes and marsupials
Introduction
In mammals, sex is determined by heteromorphic sex chromosomes with male heterogamety (XY male, XX female). The sex chromosomes evolved from ancestral autosomes, and in the common therian ancestor of both the placental mammals (eutherians) and marsupials (metatherians), it is estimated that the X and Y chromosomes emerged approximately 181 million years ago, just prior to the divergence of the two lineages [1] (Fig. 1). In contrast, monotremes (prototherians) possess multiple X and Y chromosomes that appear to have arisen independently of, and yet concomitantly with, the therian sex chromosomes around 175 million years ago [1] and which display partial homology to the sex chromosomes of birds [2], [3] (Fig. 1). Given that monotremes and ancestral therians evolved their sex chromosomes independently of each other, between 175 and 181 million years ago, the mechanism by which their common mammalian ancestor determined sex, around 200 million years ago, is a fascinating enigma.
A defining feature of the evolution of the sex-determining Y chromosome is its progressive degradation, such that in humans it contains less than 3% of its original gene content [4], in contrast to the X chromosome which has recruited and retained large numbers of genes [5]. A consequence of Y chromosome decay is an imbalance between the expression of X-linked genes in the male (equivalent to a monosomy) and those in the female. Hence, in 1967, Ohno [6] proposed a mechanism whereby a two-fold increase in the expression of X-linked genes in both sexes, followed by an inactivation of one of the X chromosomes in females, would both balance the expression of X-linked genes between males and females in addition to restoring the level of expression of genes on the X chromosome relative to those on the autosomes. While in eutherians the phenomenon of X chromosome inactivation (XCI) has been extensively characterised, studies into Ohno's premise of X chromosome upregulation have yielded data that are conflicting and the results inconclusive [7], [8], [9], [10], [11], [12], [13], [14]. Given their evolutionary divergence from eutherians, monotremes and marsupials are well placed to provide insight into the evolution of X chromosome dosage compensation.
Section snippets
Monotremes
Monotremes are egg-laying mammals whose extant representatives include two genera of echidna (the Australian species Tachyglossus aculeatus and several species of Zaglossus that are endemic to Papua New Guinea) and the Australian platypus (Ornithorhynchus anatinus). Monotremes diverged from the therian lineage approximately 200 million years ago [1] (Fig. 1) and sequencing of the platypus genome [15] provided genetic evidence in support of the observational suspicion that they are indeed an
Marsupials
In contrast to the monotremes, marsupials share orthologous sex chromosomes with eutherian mammals. Thus, our X and Y chromosomes originated in the therian (marsupial and eutherian) ancestor around 180 million years ago and around 20 million years after the divergence of monotremes [1]. The sex chromosomes started life as an autosomal pair. However, the separate evolution of the marsupials and eutherians has seen diversification of the X and Y chromosome content in each lineage. Similarly,
Conclusions
The sex chromosomes of therians evolved after the divergence of therians and monotremes, but before the eutherian-marsupial split [1], and so they share orthologous sex chromosomes. Intriguingly, both have independently evolved an effective XCI mechanism that is dependent upon a lncRNA, and while eutherians display random XCI in the embryo, with paternal XCI restricted to the trophectoderm of some species, marsupials show strict paternal XCI throughout the embryo. Thus, it is possible that
Acknowledgement
We thank Dr Dmitry Ovchinnikov for his critical reading of the manuscript.
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