*Laboratoire de Biologie Moléculaire de la Cellule, Ecole Normale Supérieure de Lyon, Lyon, France
Correspondence: E-mail: vincent.laudet{at}ens-lyon.fr.
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Abstract |
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Key Words: bilaterian development endocrinology gene duplication gene loss phylogeny
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Introduction |
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Nuclear receptors share a common organization in structural domains, which notably includes a very conserved DNA binding domain (DBD) and a moderately conserved ligand-binding domain (LBD). These domains allow relatively easy identification of nuclear receptors in genomic sequences (Robinson-Rechavi et al. 2001a) and also robust phylogenetic reconstruction at the scale of the superfamily (Laudet et al. 1992; Escriva, Laudet, and Robinson-Rechavi 2003). This phylogenetic reconstruction shows that receptors for similar ligands do not group in the tree, but are interspersed with receptors for totally different ligands, while orphans are widely distributed in the tree. This led to the hypothesis that the superfamily evolved from an orphan receptor that acquired several times independently the capacity to bind ligands (Escriva et al. 1997; Laudet 1997; Escriva, Delaunay, and Laudet 2000). Thus, the capacity to bind, for example, retinoic acids, would have been acquired several times by mutation of an orphan nuclear receptor in some ancestor of vertebrates, allowing the establishment of nuclear retinoic acid signaling pathways (RARs, RXRs). The recent identification of fatty acids that play a structural role inside the 3-D structure of some orphan receptors suggests that bona fide nuclear receptor ligands may have evolved from such structural ligands (review in Auwerx, Drouin, and Laudet 2003). The isolation of an ortholog of the vertebrate estrogen receptor (ER) from a mollusk has shown the interest of phylogenetic analysis of nuclear receptors from distant organisms in defining ancestral endocrinology signaling pathways (Thornton, Need, and Crews 2003).
The evolution of nuclear receptors (or other genes) can only be understood on the background of a reference phylogeny of the species analyzed. One could hope that dealing with two nematode worms, two insects, and five chordates, we would not encounter any problems defining this reference. But the phylogeny of animals has been the object of molecular studies that have resulted in contradictory results concerning the relative positions of these three lineages. Studies of ribosomal RNA suggest that nematodes and insects form a clade, "Ecdysozoa" (Aguinaldo et al. 1997; Mallatt and Winchell 2002), which is also consistent with information from developmental genes (Adoutte et al. 2000). But recent studies, using more genes and less species, have given renewed support to the traditional view of a clade grouping insects and chordates, "Coelomata" (Blair et al. 2002; Dopazo, Santoyo, and Dopazo 2004; Wolf, Rogozin, and Koonin 2004). In this work, we have chosen to consider all results in light of both possibilities, the "ecdysozoan hypothesis" and the "coelomate hypothesis." Thus, we hope our results to be robust to the outcome of this interesting debate.
In this work we take advantage of the wealth of data provided by complete genome projects, spanning several degrees of divergence among animals, to redefine relationships inside the superfamily and to characterize nuclear receptor evolution since the divergence of major bilaterian lineages. We are also in the process of characterizing experimentally all nuclear receptors from the zebrafish Danio rerio (unpublished data), and we took these sequences into account in our interpretations. Using a phylogenetic approach, and thanks to the completeness of the information available, we can for the first time define overall nuclear receptor evolution in terms of gene gain and loss and show which mechanisms were instrumental in establishing modern endocrine systems.
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Materials and Methods |
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All new nuclear receptor protein sequences were aligned by eye using Seaview (Galtier, Gouy, and Gautier 1996) on the reviewed alignment of Nurebase. The alignments used for phylogenetic analysis included all available sequences and were not limited to the species discussed in the text. Sequences with less than 200 amino acids including the DBD were excluded, and only complete sites (no gap, no X) were used for phylogenetic reconstruction. Phylogenetic trees were built using (1) Neighbor-Joining (Saitou and Nei 1987) with distances corrected for rate heterogeneity between sites, with a gamma law of parameter alpha estimated in Tree-Puzzle (Schmidt et al. 2002) with eight categories, and using (2) PHYML (Guindon and Gascuel 2003), a fast and accurate maximum likelihood heuristic, under the JTT substitution model (Jones, Taylor, and Thornton 1992), with a gamma distribution of rates between sites (eight categories, parameter alpha estimated by PHYML). Trees were built for the whole superfamily, for each subfamily, and for each group. In case of conflict, trees built using groups were considered more reliable because they use more complete sites and less divergent sequences. All phylogenetic relations that are discussed were tested by a comparison of likelihoods between alternative topologies, using the SH test (Shimodaira and Hasegawa 1999) as implemented in Tree-Puzzle, correcting for rate heterogeneity between sites with a gamma law.
Use of taxonomic and common names: We use the word "fish" for Actinopterygii, or ray-finned fishes; this usage does not include cartilaginous fishes (sharks and rays) or flesh-finned fishes (lungfishes and coelacanths). We use the word "pufferfish" for Tetraodontiformes, which include Takifugu rubripes and Tetraodon nigroviridis. We use the word "nematode worm" for the two Caenorhabditis species studied. We use the word "trematode" for Schistosoma mansoni.
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Results |
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The insect and nematode lineages (ecdysozoans) notably lost genes that code for major liganded receptors in vertebrates. The lethal or sterile phenotypes of knockout mice for these genes (for a review, see Laudet and Gronemeyer 2002) and their conservation among vertebrates suggest that the ancestral organism(s) lost genes which did not yet have their present function. Contradictory to this, a reconstructed ancestor of steroid receptors (ERs and SRs) appears to be regulated by estrogen (Thornton, Need, and Crews 2003). However, the mollusk ER is not regulated by estrogen, which implies that either the result on the ancestral receptor is an artifact or that it had insufficient functional importance in the urbilaterian to prevent loss of the gene (nematodes, insects) or of the function (mollusk). These essential hormone binding functions were probably either acquired or integrated into signaling pathways secondarily, together with the development of the vertebrate endocrine system; thyroid hormone signaling is thought to be specific to chordates (see Dehal et al. 2002), as is nuclear retinoic acid signaling, although other forms of retinoid signaling may exist in insects (Mansfield et al. 1998; Adam, Perrimon, and Noselli 2003). Concerning steroid signaling, the only subfamily 3 receptor in insects is the orphan ERR (Adams et al. 2000; Ostberg et al. 2003), whereas the only steroid hormone known in insects, ecdysone, is mediated by EcR, a subfamily 1 nuclear receptor closely related to other vertebrate steroid receptors (FXRs and LXRs; fig. 4) but not to subfamily 3. The functional study of more orthologs of liganded nuclear receptors from diverse lineages, such as trematode TR (fig. 5), is needed to clarify this issue.
It should be emphasized that the data unambiguously support the hypothesis that these nuclear receptors were lost in nematodes and insects, as opposed to vertebrate "innovations." This result is consistently found across the different nuclear receptors cited in this paragraph and across phylogenetic methods, with strong support, notably from maximum likelihood. For example, if subfamily 3 steroid receptors were a chordate or vertebrate invention, both insect ERR and mollusk ER should branch at the base of the subfamily 3 gene tree, a possibility strongly rejected by a likelihood ratio test (SH test: P = 0.0030). This view contradicts our previous conclusion that most liganded nuclear receptors are chordate-specific (Escriva et al. 1997; Laudet 1997).
In a similar manner, the chordate lineage lost four genes that mediate insect-specific responses (fig. 2). Unlike genes lost in insects and nematodes, all are orphan receptors. FAX1 and DSF are both members of the TLL/PNR group, which bind DNA as strict homodimers (for a review Laudet and Gronemeyer 2002), which may have favored their loss in chordates (see Krylov et al. 2003). Two other genes lost in chordates, Drosophila HR39 and E78 are both active in ecdysone signaling, which is absent in chordates. It should be noted that an alternative scenario, with E78 as the result of an arthropod-specific duplication of E75, cannot be significantly excluded (likelihood SH test: P = 0.069). Data from more diverse arthropods would probably help us reach a significant conclusion. Finally, if the coelomate tree of animals is correct (fig. 2B), chordates also lost the ancestor of Knirps, KNRL, and Eagle, a monophyletic group of proteins with a typical nuclear receptor DNA-binding domain but without any detectable similarity to a ligand-binding domain. These unusual members of the superfamily were previously only known in dipteran insects, which made them appear to be a dipteran innovation. However, we have found clear representatives of this group in trematode EST data, which pushes back significantly their appearance by domain recombination. In dipterans, they are active in the regulation of early developmental genes.
More generally, the only members of the superfamily known to lack the typical DBD-hinge-LBD structure are always different between insects and vertebrates, forming another source of divergence. The common functional point of these atypical nuclear receptors in dipterans and vertebrates seems to be their role in the regulation of the derived developmental features of dipterans and vertebrates (Laudet 1997). It may be noted that the diversity of nuclear receptors in nematodes also includes several proteins lacking the LBD or the DBD (Sluder et al. 1999), notably Odr-7 (Sengupta, Colbert, and Bargmann 1994), and that these genes may also regulate derived features of nematodes. As a side note, there is an ortholog of fly Trithorax in the mosquito; it is not considered a nuclear receptor, although it includes a highly divergent nuclear receptor like DBD (Stassen et al. 1995).
As opposed to gene loss, gain by gene duplication is frequent in vertebrates, but almost absent in insects, and absent in early evolution of bilaterian lineages (fig. 2). While there are ten nuclear receptors with one ortholog in insects versus two or more in vertebrates, there is only one receptor with one ortholog in vertebrates versus two in a dipteran insect, and it is a recent duplication of TLL specifically in the mosquito. This abundance of vertebrate specific duplications is not restricted to nuclear receptors (Escriva, Laudet, and Robinson-Rechavi 2003), which reflect a general pattern of abundant gene (or genome) duplication at the origin of vertebrates that is discussed elsewhere (Holland et al. 1994; Dehal et al. 2002; McLysaght, Hokamp, and Wolfe 2002; Panopoulou et al. 2003; Robinson-Rechavi, Boussau, and Laudet 2004).
Derived Nuclear Receptor Complements for Derived Anatomies: Nematodes and the Sea Squirt
The highest rates of loss of nuclear receptor groups are found in two very distant groups of organisms: eight in nematodes and five in the sea squirt (fig. 2). Both are characterized by comparatively simple anatomy, brought to the extreme in C. elegans adult morphology, which has fewer than 1,000 cells. The apparent contradiction between this description of nematodes as having lost nuclear receptors and the abundance of more than 250 nuclear receptor genes in C. elegans (Sluder et al. 1999) comes from our phylogenetic reasoning. There are eight independent events of loss of genes, which most probably already had an established functional role at that point in evolution. On the other hand, the supplementary nuclear receptor genes in nematodes come from a unique burst of lineage-specific duplications (unpublished data), concerning only one group of the superfamily (HNF4). Thus, we obtain the apparent paradox that an evolutionary history dominated by loss of genes of known function also produced a huge diversity of novel nuclear receptors, whose function remains unclear.
Given the importance of nuclear receptors in development and gene regulation, it is tempting to establish a relationship between loss of regulatory genes and derived, simple anatomies and developmental pathways, especially because there are several cases of parallel gene loss. All nuclear receptors lost in the sea squirt except TLL were also lost in parallel in the nematode lineage (fig. 2). Concerning TLL, phylogenetic resolution is not significant, but nematode NHR67 seems to be the nematode ortholog of TLL. The parallel losses with nematodes (or ecdysozoans) notably include estrogen and "classical" steroid hormone receptors. Similarly, at least HR39 was lost in parallel in nematodes and in the ancestor of chordates; DSF was probably also lost in nematodes and chordates, although phylogenetic support is not significant. Both these genes are instrumental in the development of insect specialized structures, which nematodes lack. This suggests that both sea squirt and nematode lineages went through a process of anatomical simplification, losing the corresponding regulatory genes. It is consistent with data that suggest that the anatomy both of nematodes (Aboobaker and Blaxter 2003) and sea squirt (Holland and Gibson-Brown 2003) are derived, and not ancestral. Notably, it would be interesting to investigate whether regulation cascades downstream of nuclear receptors have also been simplified in these organisms (Gissendanner et al. 2004).
Recent Evolution of Nuclear Receptor Subfamilies
The only functional difference between the two mammalian genomes is that the mouse (and rat, Zhang et al. 2004) genome contains FXRb, a paralog of FXR, which was lost in primates. Similarly, four genes (DAX1-2, SHP2, RARb, and ERRd) found in the fugu were lost specifically in tetraodon. When compared to Drosophila, the mosquito genome includes a specific duplication of TLL, but has lost Knirps. TLL is a key gene in the establishment of nonmetameric units of the embryo as well as in nervous system development in Drosophila, while Knirps is a transcription repressor also involved in the regulation of developmental genes during early development, some of them the same as TLL (i.e., Ftz). It is thus possible that this loss and this gain represent a divergence in developmental regulation pathways between flies and mosquitoes.
Most differences between pufferfish and mammal genomes are due to gene duplications in the ray-finned fish lineage (as already observed by Maglich et al. 2003), consistent with the general pattern of abundant gene/genome duplication in fishes (Robinson-Rechavi et al. 2001b; Christoffels et al. 2004; Vandepoele et al. 2004). Differences between the two lineages are also due to differential gene loss: four genes were lost in the mammalian (or tetrapode) lineage, and three were lost in pufferfishes (figs. 2, 3, and 4). Of note, we found duplications for two pufferfish NR genes which were not reported previously (Maglich et al. 2003): TRa1/2 and RARg1/2. It is also worth mentioning that RARb had never been isolated in a fish and was thought to be amniote-specific, but it is found in the pufferfish genomes, as well as in Paralichthys olivaceus (accession numbers BAB71757, BAB71755). Out of a total of 53 NR genes that can be estimated to have existed in the ancestor of vertebrates (48 in human + FXRb + 4 lost in mammals), 20 are secondarily duplicated in fishes (38%). Due to their number, we will not detail these 20 duplications here; most are described in Maglich et al. (2003).
A special case of gene loss is HNF4b, which appears to have been lost in parallel in both the pufferfish and mammalian lineages. We were also unable to clone it from zebrafish (unpublished data). Thus, HNF4b is absent from all the completed vertebrate genomes. The only previously known HNF4b was cloned in Xenopus (Holewa et al. 1997). A search on the prerelease of the chicken genome shows three HNF4 genes, clear orthologs of human HNF4a and HNF4g plus a clear ortholog of Xenopus HNF4b (fig. 6). This sequence clearly establishes that HNF4b is indeed a vertebrate-specific duplicate, lost independently in fishes and mammals.
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Discussion |
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Branches dominated by gene duplication include the two originally identified (Laudet et al. 1992), plus the branch leading to fishes. At the origin of bilaterians, duplications can be divided into at least two "subperiods" (fig. 2). The first subperiod leads from an ancestral nuclear receptor gene to six paralogs, which represent the ancestors of the currently defined six subfamilies of nuclear receptors (Nuclear Receptors Nomenclature Committee 1999). The second leads to further diversification of each subfamily, in a very nonequilibrated manner: while subfamilies 1 and 2 gave rise to approximately nine paralogs each, subfamilies 4 and 6 did not preserve any duplicates from this period (or did not experience any duplications). This diversification at the origin of bilaterians does not seem to have been linked to events in genome evolution, but these may be difficult to detect at such evolutionary distances. A similar trend has been observed for other gene families involved in regulation and development (Miyata and Suga 2001). On the other hand, the periods of nuclear receptor gene duplication at the origin of vertebrates and of teleost fishes are clearly part of more general patterns of genome evolution (Escriva, Laudet, and Robinson-Rechavi 2003); in both cases many gene families experienced gene duplication. This observation has given rise to widely discussed genome duplication hypotheses (Holland et al. 1994; Meyer and Schartl 1999; Postlethwait et al. 2000; Hughes, da Silva, and Friedman 2001; Robinson-Rechavi et al. 2001b, 2001c; Dehal et al. 2002; McLysaght, Hokamp, and Wolfe 2002; Hughes and Friedman 2003; Panopoulou et al. 2003; Christoffels et al. 2004; Robinson-Rechavi, Boussau, and Laudet 2004; Vandepoele et al. 2004). It seems that when nuclear receptor gene duplication was frequent, gene loss in the superfamily was rare; LXRb, Rev-erba, and CAR in the teleost fish lineage are exceptions, although gene loss in the ancestor of bilaterians would be harder to establish. Also, there is the special case of nematodes, with both high loss rate over the superfamily and explosive duplication specific to HNF4. There may be a link between low rates of gene loss and conservation of duplicate genes over long periods of evolutionary time. Such a link may be selection for gene diversity or neutral change in genome dynamics (as in Lynch and Conery 2003).
There are several branches of the species tree characterized by abundant gene loss. As previously mentioned, two of these events may be related to anatomical simplification: the sea squirt and nematode lineages. In the case of the nematodes, this loss is paralleled by duplications of two genes, proto-DAF12 and HNF4, the latter giving rise to a greater diversity of nuclear receptors than in any other animal. Thus, lineage-specific expansion (Lespinet et al. 2002) of one gene can more than compensate for an overall trend to gene loss. Another period of gene loss is at the origin of chordates (e.g., E78, DSF, FAX1, HR39). A third group of gene loss is more difficult to place, because of its dependence on the reference animal phylogeny used: if the cdysozoan hypothesis (Aguinaldo et al. 1997) is correct, then ecdysozoans paralleled chordates in important nuclear receptor gene losses at the origin of the group; if the coelomate hypothesis is correct (Blair et al. 2002; Wolf, Rogozin, and Koonin 2004), then these genes were lost in parallel in nematodes and in insects. In either case, gene loss apparently played the major role in differentiating the different nuclear receptor complements of nematodes, insects, and chordates, not duplication. Finally, there is a minor period of gene loss apparent in our data, which is most unexpected in the lineage leading to mammals (e.g., COUP-TFg, ERRd, NR5A5, and probably Rev-erbg). The Xenopus and chicken genomes should be instrumental in determining whether these are mammal-specific or general to tetrapodes. None of these four genes is found in the prerelease of the chicken genome, but a more complete sequence should be analyzed before we can draw final conclusions. These losses concern genes which had been "recently" duplicated at the origin of vertebrates and which can be supposed to have been relatively redundant at the time of loss. In a similar manner, Hox genes appear to have been prone to loss after duplication in fishes (Amores et al. 2004).
It may be noted that the coelomate hypothesis of animal phylogeny necessitates six additional parallel gene losses in the dipteran and nematode lineages (fig. 2B), which in the ecdysozoan hypothesis would be lost in the common ancestor of ecdysozoans (fig. 2A). Probably due to the fast evolution of nematode nuclear receptors (unpublished data), phylogenetic signal for the relative position of nematodes and insects is low in the phylogeny based on nuclear receptor sequences (fig. 1), but the gene loss pattern of nuclear receptor genes supports the ecdysozoan hypothesis.
Nuclear Receptor Genes, the Evolution of Endocrine Systems, and the "Cambrian Explosion"
Previous studies have noted that patterns of the presence/absence of nuclear receptor genes correspond to the evolution of major developmental and endocrine pathways, such as thyroid hormone regulation or "classical" steroid hormones (testosterone, glucocorticoids, mineralocorticoids, progesterone, and estrogen) in vertebrates (Dehal et al. 2002; Baker 2003). The phylogenetic approach we have adopted allows us to delineate and correct this notion. The most notable observation is that the presence of steroid hormone receptor or thyroid hormone receptor genes cannot be properly called a "chordate innovation," as confirmed by the recent cloning of an ER in a mollusk (Thornton, Need, and Crews 2003) and our finding of a TR in a trematode (fig. 5). Rather, these genes are absent in other lineages because they were secondarily lost, but they were present in the ancestral Urbilaterian genome. In that case, the proper innovation is the function, not the presence of the gene, and this will not be understood by counting genes but by functional experiments in species chosen for their key phylogenetic position, such as sea squirt, amphioxus (e.g., Escriva et al. 2002), lamprey, or hagfish. Indeed, the precise status of the mollusk ER and the trematode TR remain to be established by detailed functional characterization, notably in terms of ligand binding and transcriptional activation.
To get the full picture of the evolution of steroid hormone signaling we should consider other nuclear receptors that bind steroids; it is most parsimonious to assume that the ancestor of LXRs, FXRs, and EcR (NR1H) was regulated by steroids, because all genes in this monophyletic group are steroid receptors (discussed in Escriva, Delaunay, and Laudet 2000). This implies that steroid binding was lost secondarily in nematodes. Considering this, it is probable that other animal lineages than insects and chordates have steroid receptors from the NR1H group. Moreover, since proto-SR and proto-ER genes were present in the ancestor of bilaterians (fig. 4), it is possible that there are other invertebrate lineages than those sampled now in which they were not secondarily lost. It should be noted that since steroids are also found in plants (for a review, Clouse 2002), they might have been used in signaling through membrane receptors before the divergence of plants and animals. It should also be noted that orthology does not always imply conservation of function, and orthologs of SRs or ERs may or may not be regulated by steroid hormones in divergent lineages. Indeed, the mollusk ER is not regulated by estrogen (Thornton, Need, and Crews 2003), and the expression of the fly E75 gene is regulated by ecdysone, a steroid hormone, whereas the expression of its vertebrate orthologs, Rev-erbs, is regulated by circadian rhythm (although cross-regulation between these pathways may exist). In any case, the results on NR1H as well as NR3 receptors imply that steroid hormone regulation is widespread, probably in all bilaterian animals.
The one gene group that presents a true innovation in vertebrates is the DAX1/SHP group, which results from a domain recombination that occurred after the divergence between vertebrates and sea squirt. This echoes a similar innovation leading to the Knirps/KNRL/Eagle group earlier in animal evolution. In both cases these genetic innovations seem to have been used to regulate specialized developmental features, although the role of the Knirps homolog in trematode remains to be determined.
The most important episode in nuclear receptor evolution occurred before the diversification of bilaterian animals, in their common ancestral lineage. Understanding of these events will come with further characterization of sponge or cnidarian nuclear receptors (see Grasso et al. 2001; Wiens et al. 2003). This period was dominated by gene duplication, also observed in other gene families (Ono et al. 1999; Suga et al. 1999; Miyata and Suga 2001). In contrast, the divergence of the major bilaterian lineages (nematodes/arthropods/chordates) is characterized by little or no detectable gene duplication but a lot of gene loss. Miyata and Suga (2001) already noted the paradox that there was very little gene duplication during the diversification of animal lineages (the "Cambrian explosion"). Our results, although limited to one gene family, suggest that the diversification of these lineages may have been fueled by differential loss of genes acquired during a previous period of duplication.
Consequences of Genome Sequencing for Nuclear Receptor Research
The most obvious consequence of genome sequencing on nuclear receptor research is that we now know the complete set of nuclear receptor genes for nine animals, which include major model organisms: the mouse M. musculus, the fly D. melanogaster, and the worm C. elegans, as well as human. To these we should add the draft rat genome (Zhang et al. 2004). For each of these we also know the genomic structure of the genes (intron positions) and have access to the promoter sequence, although this is of limited utility without further experimental work (discussed in Robinson-Rechavi and Laudet 2003). We have tried in this study to go beyond the simple enumeration of parts and specify the relations between nuclear receptors of these different animals. This allows us to precisely pinpoint the differences between them and to specify which experimental results can be generalized and which cannot.
Thus, we have observed very conserved sets of nuclear receptor genes over the last 250 MYA, whereas more divergent species have very different NR complements. From this observation we can predict similar nuclear receptor contents in other closely related animals (other dipterans, other mammals, etc.), but we should expect surprises in nuclear receptor characterization from more divergent species. For example, the genome sequencing projects of a sea urchin (an echinoderm) or a bee (an hymenopteran insect) may well yield new NR genes or new patterns of loss. Moreover, we should be very careful in extrapolating nuclear receptor results among such large groups as vertebrates or insects, while we can more safely extrapolate among mammals or among dipterans (although differences do exist). This is notably important for more distant models of human physiology and development, such as fishes. Indeed, more than a third of the genes present in the common ancestor of fishes and mammals were duplicated in the pufferfish lineage. Adding the genes lost in either lineage, 86% of NR genes were touched by events of gain or loss separating these two NR complements. Our preliminary data on RT-PCR in the zebrafish Danio rerio (unpublished data) indicate that in many cases the duplication predates the divergence with pufferfishes, as has already been reported for some nuclear receptors (Marchand et al. 2001; Robinson-Rechavi et al. 2001b; Bardet et al. 2002; Bury et al. 2003), predicting a similar complement of nuclear receptors in this major model of vertebrate development. This observation is consistent with other reports of duplicated development genes in zebrafish, which probably derives from a genome duplication event (Amores et al. 1998; Postlethwait et al. 2000; Robinson-Rechavi et al. 2001c; Christoffels et al. 2004; Vandepoele et al. 2004).
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Conclusion |
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Acknowledgements |
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Footnotes |
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William Jeffery, Associate Editor
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References |
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