XY and ZW: Is Meiotic Sex Chromosome Inactivation the Rule in Evolution?

The sex chromosomes are among the most rapidly evolving and most diverse genetic systems in all of biology. Students of model organisms may, however, have the false impression that there is only one chromosomal mechanism of specifying sex. Among the best-studied metazoans, the XY system is indeed the rule, with inheritance of two X’s determining the female sex (XX), and inheritance of an X and a Y specifying the male sex (XY) [1]. In this system, females produce only one type of oocyte (X), whereas males produce two types of sperm (X and Y). However, sex is not always determined this way. Throughout evolution, the XY system has co-existed alongside the lesser known ZW system, a scheme exemplified by members of the avian clade who diverged from Mammalia 300 million years ago (Figure 1) [2,3]. In birds, females are the heterogametic sex, as females have one Z and one W chromosome (ZW) and can therefore produce two types of gametes (Z or W oocytes). By contrast, males are ZZ and can produce only one type of gamete (homogametic)—the Z-bearing sperm. In XY and ZW systems, the homologous sex chromosomes are genetically unequal due to suppression of homologous recombination and accumulation of deleterious mutations on one chromosome of the heterogametic sex [1]. In the XY system, it is the Y that genetically degenerates; in the ZW system, it is the W. Today, the mammalian X carries over three times more genes than the Y does, whereas the chicken Z carries over ten times more than the W. There are two intriguing consequences of having unequal sex chromosomes. The first relates to dosage imbalance or Xor Z-borne genes between males and females. A need to correct for this imbalance has led to co-evolution of ‘‘dosage compensation’’ in many organisms that use the XY system, such as mammals, fruit flies, and worms [4,5]. In mammals, dosage compensation involves transcriptional inactivation of one X chromosome in the female. The second consequence of unequal sex chromosomes is the absence of a full pairing partner during meiosis in the heterogametic sex [6]. During meiosis, homologous chromosomes pair (align), synapse (held by the synaptonemal complex), and exchange genetic material via homologous recombination. But for sex chromosomes, pairing occurs either partially or not at all. The X and Y of eutherian mammals pair through their pseudoautosomal regions, but the X and Y of marsupial mammals lack significant homology and come together without synapsis [7,8]. Lack of pairing triggers meiotic silencing of unsynapsed chromatin (or unpaired DNA) (MSUC or MSUD) [9–11], which is an ancient genome defense mechanism that silences sequences without pairing partners [12]. Mammalian MSUC/MSUD results in meiotic sex chromosome inactivation (MSCI), by which the X and Y alone become transcriptionally inactivated during the first meiotic prophase [6,13–15]. MSCI is not confined to mammals, as metazoans as diverse as the fruit fly [16], grasshopper [17], and the nematode worm [18] also demonstrate MSCI (grasshopper and worm males are XO, with the Y having completely degenerated). How universal are dosage compensation and MSCI? Analyses in chickens have reached the consensus that Z genes may only be partially equalized between ZZ and ZW individuals, although the mechanism of dosage compensation remains unclear [2,3]. Until now, no evidence of MSCI had been found in birds [19,20]. In this issue of PLoS Genetics, Schoenmakers et al. have re-examined bird oogenesis and found that MSCI actually occurs in chickens [21]. This discovery has a number of implications for the evolution and developmental behavior of sex chromosomes. Chicken MSCI is both similar and different from MSCI in XY animals [21]. Like mammal and worm MSCI, chicken MSCI occurs during the first meiotic prophase (divided into leptotene, zygotene, pachytene, and diplotene) and is marked by chromatin changes. Schoenmakers and colleagues observed heterochromatic marks and exclusion of Pol-II on both Z and W and verified, by quantitative reverse-transcriptase (RT)PCR analysis of a handful of Z and W genes, that the genes are expressed at lower levels during pachytene than in zygotene and diplotene, as is observed for murine X and Y genes [13,14]. Although how much of Z and W is silenced remains to be investigated, these similarities imply a conserved mechanism based in part on MSUC/MSUD. There are intriguing differences as well, one of which is in the timing relative to chromosome synapsis. In eutherian mammals, MSCI coincides with the failure of synapsis during pachytene [9,10]. On the other hand, chicken MSCI precedes synapsis of Z and W. Thus, chicken MSCI may be based as much on ‘‘unpairing’’ as on ‘‘asynapsis.’’ Interestingly, this feature of ZW MSCI is similar to opossum MSCI, which occurs in early pachytene before X and Y colocalization [7]. Therefore, in chickens and opossum, a homology search mechanism—rather than asynapsis itself— might be the trigger for MSCI. MSCI in birds and mammals also differs in terms of what chromatin changes occur. In the mouse and the opossum,