Current Biology 16, R736–R743, September 5, 2006 ª2006 Elsevier Ltd All rights reserved DOI 10.1016/j.cub.2006.08.021 Relationships between Vertebrate ZW Review and XY Sex Chromosome Systems Tariq Ezaz, Rami Stiglec, Frederic Veyrunes, and Jennifer A. Marshall Graves with sex determination, whereas the Y- and W-chro- mosomes are smaller, highly heterochromatic and re- tain few active genes. The mammalian Y-chromosome specializes in male sex and spermatogenesis. The peculiar cytology and unique evolution of sex Early speculations on the origin of the Drosophila chromosomes raise many fundamental questions. melanogaster X- and Y-chromosomes proposed that Why and how sex chromosomes evolved has been sex chromosomes started out as an ordinary autoso- debated over a century since H.J. Muller suggested mal pair. Then, one member acquired a sex determin- that sex chromosome pairs evolved ultimately from ing allele and accumulated male-advantage genes in a pair of autosomes. This theory was adapted to ex- a non-recombining region that progressively degraded plain variations in the snake ZW chromosome pair [1]. The same process is proposed to account for the and later the mammal XY. S. Ohno pointed out simi- large X and small, gene-poor Y in mammals [2,3]. larities between the mammal X and the bird/reptile What causes Y or W degradation has been debated Z chromosomes forty years ago, but his speculation over decades. Two main mechanisms have been iden- that they had a common evolutionary origin, or at tified in mammalian Y-chromosome degradation: a least evolved from similar regions of the genome, higher mutation rate and inefficiency of selection on has been undermined by comparative gene map- a non-recombining chromosome [3,4]. ping, and it is accepted that mammal XY and reptile The opposite process, i.e. accumulation of female- ZW systems evolved independently from a common advantage genes and degradation of the W-chromo- ancestor. Here we review evidence for the alterna- some, was predicted for ZW species. Ohno [5] ob- tive theory, that ZW5XY transitions occurred during served that the Z- and W-chromosomes of different evolution, citing examples from fish and amphibians, snake families appeared to represent intermediates and probably reptiles. We discuss new work from in such a W-degradation process. Bird sex chromo- comparative genomics and cytogenetics that leads somes, too, offer a range of degree of differentiation, to a reconsideration of Ohno’s idea and advance a and there is now molecular evidence for degradation new hypothesis that the mammal XY system may of the W-chromosome in avian lineages [6,7]. Ohno have arisen directly from an ancient reptile ZW [5] also observed that the Z-chromosome appeared system. to be similar in all snakes, as did the Z in all birds; in fact, there were similarities that suggested a highly conserved ZW-system in birds and reptiles. He went Introduction further to speculate, based largely on the absolute Nearly all vertebrates have separate males and fe- size and similarities of some sex-linked phenotypes, males, but sex is determined in different ways. Many that the bird Z and mammal X shared genes and fish and reptile species use an environmental cue, evolved via parallel pathways or even descended commonly temperature, to trigger male-determination from a common ancestor. (environmental sex determination or temperature sex Forty years later, Ohno’s bold theory is all but forgot- determination). In other fish and reptile species, as ten. Gene mapping and chromosome painting confirm well as in all amphibians, birds, snakes and mammals, his hypotheses that the mammalian X is highly con- sex is genetically determined (genetic sex determina- served — at least in placental mammals [8] — and tion). Amongst species using genetic sex determina- that the avian Z is also highly conserved [9]. However, tion, some are male heterogametic — that is, the male gene mapping has decisively shown that the avian Z- is heterozygous at a sex determining locus — while chromosome has no homology to the human X [10]. others are female heterogametic. Many such species Therefore, the accepted theory is that the bird ZW- have reinforced this allelic difference by differentiating and the mammalian XY-systems originated inde- sex chromosomes, some to a remarkable extent. Male pendently from two different autosomal regions in a heterogametic species have XX females and XY males, common ancestor, which probably had temperature- whereas female heterogametic species have ZW fe- dependent sex determination [11]. Moreover, gene males and ZZ males (Figure 1). mapping shows that the Z of at least one snake spe- The best studied vertebrate sex chromosomes are cies is not homologous to the bird Z-chromosome [12]. the XY system of mammals, and the ZW systems of However, new molecular cytogenetic and compara- birds and snakes. These systems show superficial tive gene mapping methods greatly expand our view of similarity in that the X and Z are large chromosomes how far and how fast sex chromosome systems can bearing many genes that seem to have little to do change over time. We now have complete genome sequences for three fish, a toad, a bird, and many mammals from all three major groups. We have dense Research School of Biological Sciences, The Australian gene maps of many diverse species and cytological National University, Canberra, ACT 2601, Australia. methods for detecting sexually heteromorphic regions Email: [email protected] and identifying molecular homology between species. Current Biology R737 Figure 1. Vertebrate sex determination systems. Phylogeny of major vertebrate clades XX/XY Eutherians showing the sex determining systems XX/XY multiple 180mya found in members of the respective clade. Marsupials ZZ/ZW ‘Mulitple’ indicates involvement of more 210mya than one pair of chromosomes in sex de- ZZ/ZW multiple Monotremes termination. Dates of divergence are taken TSD Snakes from [42,82,83]. TSD: temperature-depen- dent sex determination. 310mya 220mya Lizards 230mya Tuatara 285mya Birds 450mya 354mya 245mya Crocodilians 272mya Turtles Amphibians Fish Current Biology Some observations directly challenge the accepted sex determination. There is also polygenic sex deter- view that sex chromosomes have evolved indepen- mination and sex determination by genotype-environ- dently in different vertebrate groups. ment interaction. Temperature sex determination has There is a fundamental difference between male and been unequivocally established in at least one species, female heterogametic systems; yet, transitions be- the silverside, Menidia menidia [14]. tween ZW and XY systems have happened many times Morphologically differentiated sex chromosomes during the course of evolution in fish, amphibians and have been identified only in about 10% (176 species reptiles, although we do not understand how. It has out of 1700 species) of fish studied karyologically often been assumed that transition requires a spell of [15]. These include ZW and XY systems with eight dif- temperature-induced sex determination as an inter- ferent variants [16], among which male heterogamety mediate stage, but there are also direct mechanisms is twice as common as female heterogamety. Within for transition. It is generally considered that homomor- XY or ZW systems, variation in sex chromosome mor- phic sex chromosomes are a necessary prerequisite phology is readily explained by addition/deletion of for transition between sex-determining systems. heterochromatin [17], or chromosomal fission or rear- Highly differentiated sex chromosomes are likely to rangement by Robertsonian or tandem fusion to pro- pose a barrier to the subsequent transition, as WW- duce a multiple system. More interestingly, some com- or YY-genotypes are likely to be lethal, if the W or Y pletely novel sex determining systems have evolved by is highly degraded [13]. Heteromorphic sex chromo- gene duplication or retrotransposition, or by variation some systems are thought to evolve from an initial and deletion of sequences. Did fish ZW and XY sys- state of sex chromosome homomorphy through in- tems evolve independently from an ancestral system, creasing — and presumably irreversible — stages of or have there been recent ZW5XY transitions? It differentiation, until a point of cytologically distinguish- was proposed that single gene sex determination is able sex chromosome heteromorphy is attained ancestral to both male and female heterogamety in [1,2,13]. Here we examine some of the evidence for teleost fish [5,18]. XY and ZW systems could, there- the relationship and transition between ZW and XY fore, have evolved independently following fixation of sex chromosomes in vertebrates from fish to mam- dominant male or female sex determiners, rather mals. We reconsider Ohno’s hypothesis that vertebrate than requiring transition from one to another system. sex chromosomes were fashioned from the same A few fish sex chromosome systems are very old ancestral material and that transition between these and conserved, as might be expected from indepen- two heterogametic systems happened frequently dur- dent evolution of male and female heterogamety. For ing the course of evolution. instance, a ZW sex chromosomal system has been conserved in several species of the fish families Aulo- Sex Chromosomes and ZW5XY Transitions in Fish pidae and Synodontidae for at least 60 million years One of the most interesting vertebrate groups in which [19,20]. Similar modes of sex chromosomal systems to examine sex chromosome evolution are fish. This are often conserved within the species in the same ge- large vertebrate group displays the widest variety of nus or family [15,21]. However, many fish sex deter- sex determination and sex chromosomal systems, in- mining systems appear to have evolved recently, judg- cluding gonochorism (separate sexes), hermaphrodit- ing by the minimal sequence difference between the ism (individuals displaying both sexes) and unisexual- sex chromosomes, and observations that sequences ity (all female-species). In gonochoristic species, the that are sex specific in one species are autosomal in two sexes may be determined genetically — ranging sister species (e.g.