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Sex chromosome evolution in non-mammalian vertebrates Manfred Schartl Birds, reptiles, amphibia and fish have an enormous variety of chromosomal sex determination mechanisms that apparently do not follow any phylogenetic or taxonomic scheme. A similar picture is now emerging at the molecular level. Most genes that function downstream of the mammalian master sexdetermining gene, Sry, have been found in non-mammalian vertebrates. Although the components of the machinery that determines sex seem to be conserved, their interaction and most importantly the initial trigger is not the same in all vertebrates. This variety is the consequence of the extremely dynamic process of the evolution of sex determination mechanisms and sex chromosomes, which is prone to create differences rather than uniformity. Addresses Physiologische Chemie I, Biozentrum der Universität Würzburg, Am Hubland, 97074 Würzburg, Germany e-mail: [email protected] follows SD — namely, the actual development of testes or ovaries — is called sex differentiation.) A similar picture has emerged for the genes that translate the chromosomal mechanism into molecular action. Sry is a gene on the Y chromosome that triggers male development in mammals. It has been found only in placental mammals and marsupials. However, genes that are known or thought to act downstream of Sry in the SD cascade have been detected in many vertebrate species. The finding that a Dmrt1 gene (encoding Doublesex and Mab-3related transcription factor 1) is Z-linked in birds and is also the male-sex-determining gene in a fish led to the hypothesis that Dmrt1 is the ‘Sry gene’ of non-mammalian vertebrates. Thus, the molecules also seemed to represent a common and stable developmental mechanism. This view has completely changed over the past few years, as it has become clear that we have to contend with a wide variety of SD mechanisms and master SD genes [1]. Current Opinion in Genetics & Development 2004, 14:634–641 This review comes from a themed issue on Genomes and evolution Edited by David Haig and Steve Henikoff Available online 3rd October 2004 0959-437X/$ – see front matter # 2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2004.09.005 Abbreviations AMH anti-Müllerian hormone Dmrt doublesex and Mab-3 related transcription factor FET female expressed transcript HIT histidine triad MHM male hypermethylated NRY non-combining region of the Y chromosome SD sex determination WPKCI similar to protein kinase C inhibitor (W-linked) ZPKCI similar to protein kinase C inhibitor (Z-linked) Introduction Whether a mammalian embryo develops into a male or a female is determined by its chromosomal complement: XX embryos become females and XY embryos become males. In birds it is the other way round: the homogametic sex (ZZ) is the male and the heterogametic sex (WZ) is the female. Without taking a deeper look into the field, this observation led many researchers to think that the chromosomal mechanism of sex determination (SD, the process that determines whether the bipotential gonad primordium will develop into testis or ovary) is a widespread and stable system. (Note that the process that Current Opinion in Genetics & Development 2004, 14:634–641 This review illustrates this variety and gives an update on some genes that are known, or believed, to play a role in SD of non-mammalian vertebrates. And — in quoting Dobshansky that ‘‘nothing in biology makes sense, except in the light of evolution’’ [2] — the phylogenetic and evolutionary context will be considered. A concept for sex chromosome evolution The gene at the top of the SD cascade, the ‘master sex regulator’, can have a marked effect on genome evolution, in particular on the very chromosome on which it is located. On the basis of many cytogenetic observations and theoretical considerations, a commonly accepted model of the process of sex chromosome evolution has been established [3]. The origin of a master SD gene is supposed to be an autosomal gene for which two different alleles developed and for which homozygosity leads to the development of one sex and heterozygosity to the other. Under this scheme, the evolution of an XY system occurs when suppression of recombination maintains one chromosome in a constant heterozygous state and the allele on this chromosome is dominant in determining male sex. Suppression of recombination would be most effectively achieved by a large inversion. Suppression of recombination is the first and crucial step in sex chromosome evolution: only through this process can the emerging heterogametic sex chromosome keep its identity. During subsequent evolution, suppression of recombination between the X and Y chromosomes spreads out from www.sciencedirect.com Sex chromosome evolution in non-mammalian vertebrates Schartl 635 the SD gene and encompasses larger and larger portions of the Y. Again, large inversions are thought to be the most effective means for enlarging the non-recombining region of the Y chromosome (NRY). Mutations that destroy genes can accumulate in the NRY, and deletions, insertions, accumulations of transposable elements and expansions of repetitive sequences are the hallmarks of this process, which has been termed ‘asexual decay’ [3]. Such molecular changes accumulate to a threshold, at which point they become visible on the cytological level as two distinct changes in chromosome morphology: one is an accumulation of heterochromatin, the other is shrinkage owing to loss of genetic material. This explains Ohno’s postulate [4] that the young sex chromosomes — being at an earlier stage of the decay process — are homomorphic, whereas the more derived, older sex chromosomes show clearly visible, morphological differences. Owing to asexual decay, the recombining (or pseudoautosomal) part of the Y chromosome will become smaller and even vanish. At some point the SD gene will be the only gene left on the Y, and at this stage it will also be the only factor that guarantees persistence of the chromosome. Eventually the Y will be lost, and either a new Y chromosome can emerge from an autosome or the mode of SD may change. There are, however, processes that can stabilize the Y chromosome. Genes that are male-specific, for example genes associated with spermatogenesis, can accumulate on the Y. Sexually antagonistic genes are those that are beneficial to one sex but harmful to the other. For example, in species where female mate choice operates, genes associated with colour make a male attractive (although they are also harmful because they enhance predation), but increase predation in females without enhancing attractiveness. The larger the number of ‘male-specific’ genes on the Y is, the more reasons to keep it. Suppression of recombination has a severe consequence — namely, that mutations will accumulate in the NRY [5]. On the one hand, this is the driving force of asexual decay. On the other hand, the male-specific genes need to escape from the acquisition of deleterious mutations. A single mutation in a spermatogenesis-associated gene can exclude the respective Y chromosome from transmission to the next generation. If the effective population size is small, as it is in most mammalian and many avian species, this exclusion can become a considerable problem. An efficient solution to how the Y-linked genes can be kept in shape has been detected through sequencing of the male-specific region of the human Y chromosome [6]. Most of the genes that have a function in testis are encoded as near identical gene pairs in inverted repeats; thus, gene conversion can occur between the inverted sequence pairs and will purge deleterious mutations. www.sciencedirect.com Of course, all of the above issues concerning the evolution of the Y chromosome apply in the same way to the other type of heterogametic sex chromosome — that is, the W chromosome. Sex determination in non-mammalian vertebrates Birds The ratitae birds (e.g. ostrich, emu and cassowary), which are considered to be ‘primitive’ birds, have karyologically indistinguishable or only slightly differentiated Z and W chromosomes, whereas all other (carinatae) birds have generally well distinguishable sex chromosomes, in which the W is usually small and heterochromatic. This observation seems to defy Ohno’s law [4] because the most basal group, the ratitae, has the least differentiated sex chromosomes even though it is evolutionarily ‘older’ than the carinatae. Another unexpected finding is that the Z chromosome of chicken contains the orthologs of genes that are located on human chromosome 9 [7,8]. This indicates that the ZW chromosomes of birds and the XY chromosomes of mammals have evolved from different autosomal pairs. As yet, it is unclear whether the W chromosome carries a dominant female-determining gene or the Z chromosome carries a dosage-dependant male determinant, or whether both features may apply. Definitive evidence from sex chromosome aneuploidy (e.g. the sexual development of ZO or ZZW birds) is lacking [9]. There are two candidate genes on the W, whose expression patterns are consistent with a female-determining function. The first candidate is WPKCI (also known as HINTW or ASW for avian, sex-specific, W-linked), which encodes a protein with similarity to the protein kinase C inhibitor. There are roughly 40 copies of the WPKCI gene on the W of carinatae (but not ratitae) birds [10]. The Z carries a single copy of this gene (ZPKCI). WPKCI is strongly expressed in female chicken embryos, specifically in the gonad, whereas ZPKCI is expressed at similarly low levels in both sexes. There is a major structural difference in the gene products of the W- and Z-encoded genes: WPKCI lacks the histidine triad (HIT) motif, which is essential for the protein’s function as a protein kinase C inhibitor. The HIT motif is present in ZPCKI; thus, the Z encodes a bona fide enzyme. Enzymes with HIT motifs function as homodimers, which has led to the hypothesis that WPKCI functions as a dominant-negative factor in avian SD by inhibiting ZPKCI activity in heterodimers [11]. The second candidate is FET1 (female-expressed transcript 1), which has no homolog on the Z chromosome. FET1 is expressed almost exclusively in the female urogenital system, and its expression is especially strong Current Opinion in Genetics & Development 2004, 14:634–641 636 Genomes and evolution in the developing gonads before differentiation. Interestingly, expression is higher in the left gonad, which in female chicken develops to ovary as the right anlage regresses. The predicted amino acid sequence of FET1 does not correspond to any known domain that would be informative to infer a function and, similar to WPKCI, no ortholog has been found outside birds [12]. The high degree of conservation of synteny between human chromosome 9 and chicken Z immediately has put the spotlight on Dmrt1 as a Z-linked candidate male SD gene [7,8]. The human gene is located at the tip of chromosome 9 (9p24.3). Haploinsufficency for this region is connected to a male-to-female sex reversal with normal XY chromosomes. Thus, Dmrt1 seems to be a dosagesensitive SD gene in birds. There is no copy of Dmrt1 on the W chromosome, and thus males have a double gene dosage. Whether there is a dosage compensation mechanism for Z-linked genes in birds as there is for X-linked in mammals is the subject of ongoing debate. Quantitative RT–PCR data have indicated that six Z-linked genes are expressed at similar levels in both males and females [13], whereas fluorescent in situ hybridization studies on nascent mRNAs have demonstrated the transcription of five genes from both Z chromosomes in males [14]. Regardless of whether one or two copies of Dmrt1 are expressed in male chicken, an interesting observation seems to indicate that Dmrt1 is downregulated in females. Dmrt1 is located close to a region of roughly 460 kb on the Z chromosome, termed the MHM (male hypermethylated) locus, which is hypermethylated in males starting from day 1 of embryonic development [15]. In females, this region is hypomethylated and the MHM locus is transcribed into a non-coding RNA. This RNA, being produced only in female cells, stays in the nucleus around the MHM locus and the Dmrt1 locus [16]. Mizuno et al. [16] have speculated that this accumulation of MHM RNA, similar to the role of Xist RNA in X-chromosome inactivation in female mammals, may silence the Dmrt1 gene in female chicken. Such a silencing would explain the observed expression pattern of Dmrt1: it is expressed exclusively in the gonad of both sexes, but is more highly expressed in males than in females before (in the medullary cord cells, where a testis-determining gene is expected to be expressed) and during gonadal sex differentiation [17,18]. The repression is probably only partial, because in WZ sex-reversed chicken Dmrt1 is upregulated in the gonad, although it is expressed later and at lower levels than in ordinary males [19]. Direct evidence to suggest a possible role for these genes, which could come from one of three lines of investigation, is still lacking. None of the candidate genes has been reported to generate, following gene transfer, the expected effect of sex reversal in genetically altered Current Opinion in Genetics & Development 2004, 14:634–641 chicken. Similarly, mutations in these genes — either naturally occurring or artificially induced — should cause a sex reversal and yet also have not been observed. The second functional test would be a knock-down experiment that affects gonad development, for example, by injecting antisense oligonucleotides or morpholinos into chicken embryos. Such experiments have not been reported. Reptiles The incubation temperature of the eggs regulates the development of the embryonic gonad towards testis or ovary in all crocodilians and marine turtles examined so far, and is common in terrestrial turtles and some lizards. In crocodiles the higher temperature is male-determining, whereas in turtles a higher temperature promotes female development. By contrast, snakes have a firm genetic SD of the WZ type. Some lizards are also WZ, but others have an XY system. The expression of the reptile homologs of several mammalian SD genes has been studied during temperaturedependent SD. In the American alligator, expression of Sox9 (a transcription factor of HMG Box family), AMH (anti-Müllerian hormone) and Dmrt1 is testis-specific. Expression of Sox9 in the developing Sertoli cells of the male gonad begins up to 10 days after the first signs of testis differentiation are visible. Expression of AMH starts some days earlier in the same type of cells, but again does not precede testis formation [20]. Thus, at least one temperature-dependent mediator of SD functions upstream of AMH and Sox9. Notably, Sox9 upregulates AMH expression in mammals [21]. In reptiles, however, it looks as though the sequence of events is turned around. Although Dmrt1 is initially expressed in both the developing ovary and the testis, expression becomes higher in testis as development proceeds [18]. In the red-eared slider turtle, Dmrt1 mRNA is more abundant in the genital ridge and mesonephros complex at the maledetermining temperature [22,23]. Dmrt1 is still the only gene that shows temperature-dependent expression before or around the stage when sexual differentiation starts. It is reasonable to assume that Dmrt1 has a key role in sexual development; however, how temperature — either directly or indirectly — regulates its expression is unknown. Amphibians All amphibians that have been tested so far possess a genetic mechanism of SD. Male or female heterogamety has been repeatedly found in anurans and urodeles. Most species have homomorphic sex chromosomes, but there are also some species with heteromorphic gonosomes [24]. The chromosomal mechanisms in action do not apparently follow any systematic scheme. In the Japanese frog Rana rugosa, populations with heteromorphic XY, www.sciencedirect.com Sex chromosome evolution in non-mammalian vertebrates Schartl 637 homomorphic XY and heteromorphic WZ sex chromosomes have been identified even in the same species [25]. Sex can be reverted by hormone or temperature treatment or even occurs spontaneously. Heat and cold treatment can be either masculinizing or feminizing in XY or WZ systems, depending on the species. There is no indication, however, that the temperature during embryo and larval development under natural conditions has a SD effect as it does in some reptiles [24]. Not much is known about candidate SD genes. Dmrt1 has been studied in Rana rugosa and found to be an autosomal gene. During development, Dmrt1 is expressed in interstitial and Sertoli cells in the testis of tadpoles just before metamorphosis. In young tadpoles, in which the testis is already differentiated, no expression has been found. In adult frogs, the gene is expressed in interstitial, Sertoli and germ cells of the testis. When XX tadpoles were masculinized by testosterone injection, Dmrt1 expression started in the sex-reverted gonad. The rather late expression assigns a role to Dmrt1 in testis differentiation, but not necessarily in testis determination [26,27]. Fish With roughly 25 000 species, fishes are by far the largest group of vertebrates. They show the widest variety of adaptation responses to a universe of aquatic habitats and ecological constraints. With respect to SD, fishes also have the most variety. Unlike the situation in higher vertebrates, where the male and female sexes are always represented by two different individuals (gonochorism), several hundred species of fish are known to be hermaphrodites [28], most of them from the order Perciformes. Either they are males first and become females subsequently (protandric), or vice versa (protogynic). The sex change can be triggered by age, social factors or temperature. The most extreme situation known so far is found in a single species, the cyprinodont Rivulus marmoratus, which is a self-fertilizing simultaneous hermaphrodite. chromosomes exist in a population. One of the best studied species is the platyfish (Xiphophorus maculatus), in which three types of sex chromosomes, X, W and Y, coexist in a population. Depending on their chromosomal complement WX, XX and WY fish become females, whereas XY and YY fish become males. The different ‘strength’ of the X and the W in inducing female development may indicate that different genes or at least copies of SD genes are involved, although complex regulatory networks or dosage models for a single gene have been also proposed to be involved in sex determination [30,31]. Most orthologs of the common set of downstream sex determinators have been found in fish. Analysis of Sox9 and Dmrt1 in several species has shown differential expression in testis, consistent with an important role in SD and/or testis differentiation [32–35]. In a protandrous hermaphroditic fish, expression of Dmrt1 parallels the development and regression of the testes [36]. So far, there is no report of a fish gene that could be the ortholog of the AMH hormone. If it exists, then it may have a different function, because in fish the genital ducts are not derived from the renal duct system, but from the somatic cells of the gonad and/or the coelomic epithelium [37,38]. The medaka case The medaka is a small aquarium model fish species that is comparable to the more widely known zebrafish. Tools similar to those used for zebrafish have been developed to make it a complementary system for studying developmental biological issues or for generating disease models for biomedical research [39]. In addition, medaka is a classical system for genetic studies of sexual development [40]. In fact, in 1921 it was the first vertebrate to be found to show crossing over between the sex chromosomes [41]. In several gonochoristic species, environmental factors can influence the sex ratio even if the species has a genetic SD system. The most prominent factor is the incubation temperature of the embryos and larvae. It should be noted, however, that all studies have been performed under laboratory conditions. Only for a few fish species can circumstantial evidence be presented that these fish might use this mechanism for SD under natural conditions [28,29]. Medaka has an XX–XY SD system. In independent studies using candidate gene [42] and positional cloning [43] approaches, a gene with high similarity to Dmrt1 was found to be an excellent candidate for the master male SD gene. It was shown that a region on the autosomal linkage group 9, which contains Dmrt1, was duplicated and the whole fragment was inserted into another chromosome. That chromosome became the proto-Y, whereas its wildtype homolog (the progenitor chromosome without the insertion) became the proto-X. This is in perfect agreement with Ohno’s hypothesis that sex chromosomes are derived from a pair of autosomes [4]. The chromosomal mechanisms of SD show an amazing variety. XY and WZ systems are most common, but there are several examples of polygenic SD (i.e. the SD factors are distributed over several chromosomes). In addition, XO, ZO, X1X2Y, XY1Y2 and Y–autosome fusion have been described [28], and systems in which multiple sex According to the nomenclature for duplicated genes, the autosomal copy is dmrt1a and the Y-chromosomal copy is dmrt1bY (the suffix Y indicates its sex chromosomal location; the gene is also called dmY by some authors). dmrt1bY is expressed before gonad differentiation. Naturally occurring mutations in the gene lead to www.sciencedirect.com Current Opinion in Genetics & Development 2004, 14:634–641 638 Genomes and evolution male-to-female sex reversal. Both features are expected for a master SD gene. Simliar to its autosomal counterpart [44], dmrt1bY is expressed exclusively in the Sertoli cells in adults [42,43]. In the Y-specific insertion, all co-duplicated genes except dmrt1bY are corrupted by frameshift mutations and deletions. The region also contains an unusual high density of transposable elements and repetitive DNA. Notably, the male-specific region is only 260 kb, which constitutes less than 1% of the sex chromosome [45]. It is flanked by a direct repeat of 20 kb, which is present only once on the X chromosome. The Y repeat is obviously a tandem duplication generated during the process of insertion of the fragment derived from linkage group 9. Outside the tandem duplication, the X and the Y chromosomes are homologous. The age of the medaka Y chromosome has been determined by a comparative analysis of several species of the same genus. A sister species of medaka contains a homologous Y chromosome with a male-determining dmrt1bY gene, but other more distantly related species have only the autosomal dmrt1 gene. Calculations based on the timing of the divergence of Oryzias species with or without dmrt1bY and on nucleotide substitution rates have shown that the medaka Y is about 10 million years old [46]. This makes it the youngest vertebrate male-determining chromosome known so far. Studies on the genomic organization of the male-specific region will aid our understanding of the initial processes that occurred during the early evolution of heterogametic sex chromosomes, which will be impossible to infer from almost terminally differentiated and genetically highly degenerated ‘old’ sex chromosomes such as the mammalian Y. is not known, but environmental factors are not likely to be involved: obviously, other genes can substitute for the function of dmrt1bY. Because dmrt1bY originated during evolution of the genus Oryzias, it may not be surprising that this gene has not been found to be the master SD gene of other fish species [48–50]. It is possible, however, that a gene duplication event involving dmrt1 might have also occurred independently in another lineage, leading to the convergent evolution of a SD system similar to that observed in medaka. Conclusions The evolution of the gene cascade that regulates SD has been explained to happen from the bottom to the top, and new SD systems arise through the addition of each new component [51]. Thus, the downstream genes should be more highly conserved. This prediction is confirmed by the facts that Dmrt1 is a conserved SD gene from flies and worms [52], Sox9, WT1 and SF1 are conserved from fish to mammals and AMH is conserved from reptiles to mammals. The large variety of SD mechanisms that exist even in closely related species of lower vertebrates could suggest that there are permanently new top SD genes emerging. The idea that SD cascades grow constantly from the bottom upwards immediately raises the issue of whether this will continue ad infinitum or whether there are mechanisms that limit the process or even trim the cascade. Below, I put forward a hypothesis on the basis of the situation in medaka that may provide answers and that also underscores the importance of gene duplication in the evolution of SD genes. Some features of the medaka Y do not coincide with common expectations. The medaka male-determining gene did not arise from a stepwise allelic diversification at one locus but from a chromosomal segment duplication that also included other genes. The new copy (dmrt1bY) was free from selective pressure and could acquire a new or altered function, whereas the original copy (dmrt1a) on linkage group 9 continued to fulfill its physiological function. The insertion of the duplicated fragment into another chromosome per se and ab initio excluded pairing in meiosis. This situation was fixed by enlarging the insert through the expansion of repetitive DNAs, the accumulation of transposable elements and the insertion of duplicated pieces from elsewhere in the genome [42] and not by a chromosomal inversion. We can consider the SD cascade as a gene hierarchy in which, at certain points, genes will be upregulated above a threshold by their controlling gene so that they can transmit a signal, for example, for male development (Figure 1). If one gene becomes duplicated, the additional copy will add its basal expression to the basal levels of the pre-existing copies. This increase in expression might shift the amount of transcripts of this gene above the threshold that would be normally reached only after the upstream controller transcriptionally had activated it. Thus, the duplicated copy will make all upstream components unnecessary and become the new ‘master SD gene’. The upstream genes will then loose their SD function, and — if they have no other function — will decay and eventually will be lost completely. The SD system of medaka seems not to be totally stable. In several laboratory strains there is a considerable proportion of XX males (up to 20%) [47]. Their uncompromised fertility shows that dmrt1bY is not always necessary for SD. What triggers male development in these XX fish Mutations in regulatory regions, which could occur either concomitantly with or after the duplication event, could confer constitutive activity to the duplicated copy in the cells of the primordial gonad. This would strengthen its function as the dominant SD gene or would make it the Current Opinion in Genetics & Development 2004, 14:634–641 www.sciencedirect.com Sex chromosome evolution in non-mammalian vertebrates Schartl 639 Figure 1 A A A B B B C C C D D E E E E F F F F F (a) ( b) (c) (d) (e) D D X Mutation D D D′ D′ E Current Opinion in Genetics & Development Evolution of the sex-determining gene cascade by gene duplication. (a) A sex-determining gene cascade, in which each component transcriptionally activates a downstream gene above a threshold so that it can activate the next downstream gene. (b) Gene duplication generates a second copy of gene D with a basal level of gene expression. (c) The basal transcript levels of both copies of D are sufficient to activate E without the necessity of C activating D. The upstream components of the cascade become obsolete. (d) One of the copies of D becomes mutated, D0 , so that its expression alone is sufficient to activate E. (e) A new gene is added to the cascade and becomes the new master regulator. Arrows indicate transcriptional activation of a downstream gene; the size of the arrow represents the degree of activation. master SD gene in those cases where there is no basal level of gene expression. Such an hypothesis might help to explain how a gene that starts out at a downstream position of the SD cascade can become the master regulator at the top, as has happened with the dmrt1bY gene in medaka. Acknowledgements I thank Monika Niklaus-Ruiz for help in preparing the manuscript, and Jean-Nicolas Volff and Indrajit Nanda for critical comments on the review. This work was funded by the European Commission and the Deutsche Forschungsgemeinschaft. References and recommended reading 5. 6. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T et al.: The malespecific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 2003, 423:825-837. This paper presents an analysis of the non-recombining region of the human Y. A DNA-sequence-based description of a heterogametic sex chromosome at an advanced stage of evolution is presented. It describes a mechanism for keeping male-specific genes in shape in the absence of crossover. 7. Nanda I, Shan Z, Schartl M, Burt DW, Koehler M, Nothwang H, Grutzner F, Paton IR, Windsor D, Dunn I et al.: 300 million years of conserved synteny between chicken Z and human chromosome 9. Nat Genet 1999, 21:258-259. 8. Nanda I, Zend-Ajusch E, Shan Z, Grutzner F, Schartl M, Burt DW, Koehler M, Fowler VM, Goodwin G, Schneider WJ et al.: Conserved synteny between the chicken Z sex chromosome and human chromosome 9 includes the male regulatory gene DMRT1: a comparative (re)view on avian sex determination. Cytogenet Cell Genet 2000, 89:67-78. 9. Smith CA, Sinclair AH: Sex determination: insights from the chicken. BioEssays 2004, 26:120-132. Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Koopman P, Loffler KA: Sex determination: the fishy tale of Dmrt1. Curr Biol 2003, 13:R177-R179. 2. Dobzhansky T: Nothing in biology makes sense except in the light of evolution. The American Biology Teacher 1973:125-129. 3. Vallender EJ, Lahn BT: How mammalian sex chromosomes acquired their peculiar gene content. BioEssays 2004, 26:159-169. 4. Ohno S: Sex Chromosomes and Sex-Linked Genes. . Berlin: Springer; 1967. www.sciencedirect.com Charlesworth B: The evolution of sex chromosomes. Science 1991, 251:1030-1033. 10. O’Neill M, Binder M, Smith C, Andrews J, Reed K, Smith M, Millar C, Lambert D, Sinclair A: ASW: a gene with conserved avian W-linkage and female specific expression in chick embryonic gonad. Dev Genes Evol 2000, 210:243-249. 11. Pace HC, Brenner C: Feminizing chicks: a model for avian sex determination based on titration of Hint enzyme activity and the predicted structure of an Asw–Hint heterodimer. Genome Biol 2003, 4:R18. This paper proposes a model of how a W-linked female-determining gene may function through a dominant-negative effect. Current Opinion in Genetics & Development 2004, 14:634–641 640 Genomes and evolution 12. Reed KJ, Sinclair AH: FET-1: a novel W-linked, female specific gene up-regulated in the embryonic chicken ovary. Gene Expr Patterns 2002, 2:83-86. 13. McQueen HA, McBride D, Miele G, Bird AP, Clinton M: Dosage compensation in birds. Curr Biol 2001, 11:253-257. 14. Kuroda Y, Arai N, Arita M, Teranishi M, Hori T, Harata M, Mizuno S: Absence of Z-chromosome inactivation for five genes in male chickens. Chromosome Res 2001, 9:457-468. 15. Teranishi M, Shimada Y, Hori T, Nakabayashi O, Kikuchi T, Macleod T, Pym R, Sheldon B, Solovei I, Macgregor H et al.: Transcripts of the MHM region on the chicken Z chromosome accumulate as non-coding RNA in the nucleus of female cells adjacent to the DMRT1 locus. Chromosome Res 2001, 9:147-165. 16. Mizuno S, Kunita R, Nakabayashi O, Kuroda Y, Arai N, Harata M, Ogawa A, Itoh Y, Teranishi M, Hori T: Z and W chromosomes of chickens: studies on their gene functions in sex determination and sex differentiation. Cytogenet Genome Res 2002, 99:236-244. 17. Raymond CS, Kettlewell JR, Hirsch B, Bardwell VJ, Zarkower D: Expression of Dmrt1 in the genital ridge of mouse and chicken embryos suggests a role in vertebrate sexual development. Dev Biol 1999, 215:208-220. 18. Smith CA, McClive PJ, Western PS, Reed KJ, Sinclair AH: Conservation of a sex-determining gene. Nature 1999, 402:601-602. 19. Smith CA, Katz M, Sinclair AH: DMRT1 is upregulated in the gonads during female-to-male sex reversal in ZW chicken embryos. Biol Reprod 2003, 68:560-570. 20. Western PS, Sinclair AH: Sex, genes, and heat: triggers of diversity. J Exp Zool 2001, 290:624-631. 21. De Santa Barbara P, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck P, Scherer G, Poulat F, Berta P: Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol Cell Biol 1998, 18:6653-6665. 22. Kettlewell JR, Raymond CS, Zarkower D: Temperaturedependent expression of turtle Dmrt1 prior to sexual differentiation. Genesis 2000, 26:174-178. 23. Murdock C, Wibbels T: Expression of Dmrt1 in a turtle with temperature-dependent sex determination. Cytogenet Genome Res 2003, 101:302-308. 24. Schmid M, Steinlein C: Sex chromosomes, sex-linked genes, and sex determination in the vertebrate class amphibia. EXS 2001, 91:143-176. 25. Miura I, Ohtani H, Nakamura M, Ichikawa Y, Saitoh K: The origin and differentiation of the heteromorphic sex chromosomes Z, W, X, and Y in the frog Rana rugosa, inferred from the sequences of a sex-linked gene, ADP/ATP translocase. Mol Biol Evol 1998, 15:1612-1619. 26. Aoyama S, Shibata K, Tokunaga S, Takase M, Matsui K, Nakamura M: Expression of Dmrt1 protein in developing and in sex-reversed gonads of amphibians. Cytogenet Genome Res 2003, 101:295-301. 27. Shibata K, Takase M, Nakamura M: The Dmrt1 expression in sex-reversed gonads of amphibians. Gen Comp Endocrinol 2002, 127:232-241. 28. Devlin RH, Nagahama Y: Sex determination and sex differentiation in fish: an overview of genetic, physiological, and environmental influences. Aquaculture 2002, 208:191-364. 29. Baroiller JF, Guiguen Y: Endocrine and environmental aspects of sex differentiation in gonochoristic fish. Exs 2001:177-201. 30. Kallman KD: A new look at sex determination in poeciliid fishes. In Evolutionary Genetics of Fishes. Edited by Turner BJ. Plenum Publishing Corporation; 1984:95-171. Current Opinion in Genetics & Development 2004, 14:634–641 31. Volff JN, Schartl M: Variability of genetic sex determination in poeciliid fishes. Genetica 2001, 111:101-110. 32. Guan G, Kobayashi T, Nagahama Y: Sexually dimorphic expression of two types of DM (Doublesex/Mab-3)-domain genes in a teleost fish, the Tilapia (Oreochromis niloticus). Biochem Biophys Res Commun 2000, 272:662-666. 33. Brunner B, Hornung U, Shan Z, Nanda I, Kondo M, Zend-Ajusch E, Haaf T, Ropers HH, Shima A, Schmid M et al.: Genomic organization and expression of the doublesex-related gene cluster in vertebrates and detection of putative regulatory regions for DMRT1. Genomics 2001, 77:8-17. 34. Marchand O, Govoroun M, D’Cotta H, McMeel O, Lareyre J, Bernot A, Laudet V, Guiguen Y: DMRT1 expression during gonadal differentiation and spermatogenesis in the rainbow trout, Oncorhynchus mykiss. Biochim Biophys Acta 2000, 1493:180-187. 35. Chiang EF, Pai CI, Wyatt M, Yan YL, Postlethwait J, Chung B: Two sox9 genes on duplicated zebrafish chromosomes: expression of similar transcription activators in distinct sites. Dev Biol 2001, 231:149-163. 36. He CL, Du JL, Wu GC, Lee YH, Sun LT, Chang CF: Differential Dmrt1 transcripts in gonads of the protandrous black porgy. Acanthopagrus schlegeli. Cytogenet Genome Res 2003, 101:309-313. 37. Nagahama Y: The functional morphology of teleost gonads. In Fish Physiology, Vol 9, pt A. Edited by Hoar WS, Randall DJ, Donaldson EM. Academic Press; 1983:223-264. 38. Suzuki A, Shibata N: Developmental process of genital ducts in the medaka, Oryzias latipes. Zoolog Sci 2004, 21:397-406. 39. Wittbrodt J, Shima A, Schartl M: Medaka — a model organism from the Far East. Nat Rev Genet 2002, 3:53-64. 40. Yamamoto T: Medaka (killifish): Biology and Strains. Edited by Yamamoto T. Tokyo: Keigaku; 1975. 41. Aida T: On the inheritance of color in a freshwater fish, Aplocheilus latipes Temminck and Schlegel, with special reference to sex-linked inheritance. Genetics 1921, 6:554-573. 42. Nanda I, Kondo M, Hornung U, Asakawa S, Winkler C, Shimizu A, Shan Z, Haaf T, Shimizu N, Shima A et al.: A duplicated copy of DMRT1 in the sex-determining region of the Y chromosome of the medaka, Oryzias latipes. Proc Natl Acad Sci USA 2002, 99:11778-11783. 43. Matsuda M, Nagahama Y, Shinomiya A, Sato T, Matsuda C, Kobayashi T, Morrey CE, Shibata N, Asakawa S, Shimizu N et al.: DMY is a Y-specific DM-domain gene required for male development in the medaka fish. Nature 2002, 417:559-563. 44. Winkler C, Hornung U, Kondo M, Neuner C, Duschl J, Shima A, Schartl M: Developmentally regulated and non-sex-specific expression of autosomal dmrt genes in embryos of the Medaka fish (Oryzias latipes). Mech Dev 2004, 121:997-1005. 45. Naruse K, Tanaka M, Mita K, Shima A, Postlethwait J, Mitani H: A medaka gene map: the trace of ancestral vertebrate proto-chromosomes revealed by comparative gene mapping. Genome Res 2004, 14:820-828. 46. Kondo M, Nanda I, Hornung U, Schmid M, Schartl M: Evolutionary origin of the medaka Y-chromosome. Curr Biol 2004, in press. 47. Nanda I, Hornung U, Kondo M, Schmid M, Schartl M: Common spontaneous sex-reversed XX males of the medaka Oryzias latipes. Genetics 2003, 163:245-251. 48. Lutfalla G, Roest Crollius H, Brunet FG, Laudet V, RobinsonRechavi M: Inventing a sex-specific gene: a conserved role of DMRT1 in teleost fishes plus a recent duplication in the medaka Oryzias latipes resulted in DMY. J Mol Evol 2003, 57 (Suppl 1):S148-S153. www.sciencedirect.com Sex chromosome evolution in non-mammalian vertebrates Schartl 641 49. Kondo M, Nanda I, Hornung U, Asakawa S, Shimizu N, Mitani H, Schmid M, Shima A, Schartl M: Absence of the candidate male sex-determining gene dmrt1b(Y) of medaka from other fish species. Curr Biol 2003, 13:416-420. 50. Veith AM, Froschauer A, Korting C, Nanda I, Hanel R, Schmid M, Schartl M, Volff JN: Cloning of the dmrt1 gene of Xiphophorus maculatus: dmY/dmrt1Y is not the master www.sciencedirect.com sex-determining gene in the platyfish. Gene 2003, 317:59-66. 51. Wilkins AS: Moving up the hierarchy: a hypothesis on the evolution of a genetic sex determination pathway. Bioessays 1995, 17:71-77. 52. Zarkower D: Establishing sexual dimorphism: conservation amidst diversity? Nat Rev Genet 2001, 2:175-185. Current Opinion in Genetics & Development 2004, 14:634–641