MBE Advance Access originally published online on November 30, 2006
Molecular Biology and Evolution 2007 24(2):551-561; doi:10.1093/molbev/msl186
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Research Articles |
A New Evolutionary Paradigm for the Parkinson Disease Gene DJ-1
Departamento de Genética, Universidad de Valencia, Burjassot, Spain
E-mail: ignacio.marin{at}uv.es.
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Abstract |
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The DJ-1 gene is extensively studied because of its involvement in familial Parkinson disease. DJ-1 belongs to a complex superfamily of genes that includes both prokaryotic and eukaryotic representatives. We determine that many prokaryotic groups, such as proteobacteria, cyanobacteria, spirochaetes, firmicutes, or fusobacteria, have genes, often incorrectly called "Thij," that are very close relatives of DJ-1, to the point that they cannot be clearly separated from the eukaryotic DJ-1 genes by phylogenetic analyses of their sequences. In addition, and contrary to a previous study that suggested that DJ-1 genes were animal specific, we show that DJ-1 genes are found in at least 5 of the 6 main eukaryotic groups: opisthokonta (both animals and fungi), plantae, chromalveolata, excavata, and amoebozoa. Our results thus provide strong evidence for DJ-1 genes originating before the origin of eukaryotes. Interestingly, we found that some fungal species, among them the model yeast Schizosaccharomyces pombe, have DJ-1–like genes, most likely orthologous to the animal genes. This finding opens new ways for the analysis of the functions of this group of genes.
Key Words: comparative genomics • Parkinson disease • DJ-1 domain
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Introduction |
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The gene DJ-1 was originally described as an oncogene (Nagakubo et al. 1997
) and, in parallel, found to encode a protein involved in male fertility in rats and other mammals (Wagenfeld et al. 1998; Welch et al. 1998) and able to work as a regulatory subunit of an RNA-binding complex (Hod et al. 1999). However, interest in this gene largely increased when it was found to be involved in familial Parkinson disease (Bonifati et al. 2003). Several recessive mutations of DJ-1, both deletions and missense mutations, have been shown to cause early-onset Parkinson disease (reviewed in Bonifati et al. 2004). Homozygosis for the disease-associated missense mutations is thought to functionally impair or inactivate DJ-1. In particular, it has been shown that DJ-1 proteins form dimers, and the crystal structures of these dimers suggested that the first missense mutation described, L166P (Bonifati et al. 2003), would interfere with the dimerization process (Honbou et al. 2003; Huai et al. 2003; Lee et al. 2003, Tao and Tong 2003; Wilson et al. 2003). Several groups have since then obtained experimental evidence confirming that the L166P mutation indeed interferes with dimer formation, favoring rapid degradation of the monomers by the proteasome (Macedo et al. 2003; Miller et al. 2003; Moore et al. 2003; Olzmann et al. 2004; Takahashi-Niki et al. 2004). There is evidence that another missense mutation associated to familial Parkinson disease, M26I (Abou-Sleiman et al. 2003), may also cause rapid proteasomal degradation (Takahashi-Niki et al. 2004; Blackinton et al. 2005; Xu et al. 2005; for negative results, however, see Moore et al. 2003; Baulac et al. 2004). Increased protein instability may also explain the effect of a third missense mutation, E64D (Hering et al. 2004). Changes in cellular localization may also contribute to the effects of these mutations (Xu et al. 2005; but see Zhang et al. 2005). Recently, individuals with a combination of 2 DJ-1 mutations, a short duplication in its promoter plus another missense mutation, E163K, have been shown to suffer a complex syndrome with parkinsonism, dementia, and amyotrophic lateral sclerosis symptoms (Annesi et al. 2005). DJ-1 protein is also found in inclusion bodies together with Tau in patients of different tauopathies including Alzheimer disease (Neumann et al. 2004; Rizzu et al. 2004). These results suggest that DJ-1 may be involved in multiple neurodegenerative diseases.
With functions in the male germ line, the brain, and probably many other tissues (Nagakubo et al. 1997), the biological roles of DJ-1 are expected to be diverse (see reviews by Bonifati et al. 2004; Abou-Sleiman et al. 2006). In the context of Parkinson disease, DJ-1 has been implicated in response to oxidative stress. Loss of function of DJ-1 leads to increased stress levels in cellular models (e.g., Yokota et al. 2003; Canet-Aviles et al. 2004; Martinat et al. 2004; Xu et al. 2005). DJ-1 null mutants in mice and Drosophila also show exacerbated sensitivity to agents that increase oxidative stress (Goldberg et al. 2005; Kim, Smith, et al. 2005; Menzies et al. 2005; Meulener et al. 2005; Park et al. 2005), and the same is true for Caenorhabditis worms in which DJ-1 is downregulated using RNA interference (Ved et al. 2005). Diverse functions in stress response have been already described for DJ-1. First, it has been reported to be a redox-dependent chaperone (Shendelman et al. 2004). Its chaperone action may contribute to inhibit the aggregation of 
-synuclein (Shendelman et al. 2004; Zhou et al. 2006). This functional link may be very significant because -synuclein and ubiquitin are the most abundant proteins in Lewy bodies, the characteristic cytoplasmic inclusions found in Parkinson disease. Moreover, some mutations in the -synuclein gene such as duplications, triplications, and missense mutations that may contribute to increased aggregation are known to cause familiar Parkinson disease (reviewed in Abou-Sleiman et al. 2006). DJ-1 may act also as a redox-sensitive negative regulator of apoptosis. Apoptosis inhibition is probably mediated by diverse independent actions. Thus, DJ-1 has been characterized as contributing to the activation of the PI3K/Akt survival signaling pathway (Kim, Peters, et al. 2005; Yang et al. 2005) and downregulates the DAXX-ASK1 proapoptotic pathway (Junn et al. 2005). Additional protective actions have been also reported (Xu et al. 2005; Zhou and Freed 2005).
Animal models have so far failed to recapitulate the effects of DJ-1 mutations in humans. Null DJ-1 mutant mice show anomalies in dopaminergic function and, as already indicated, increased sensitivity to oxidative stress but not lack of dopaminergic neurons (Goldberg et al. 2005; Kim, Smith, et al. 2005). Similarly, Drosophila has 2 recently duplicated DJ-1 genes, and lack of both of them has no apparent effect on dopaminergic neurons (Meulener et al. 2005). The search for other possible models in which to analyze DJ-1 genes function depends on the detection of orthologs of those genes. This is quite a complex task in this case because genes with sequences obviously related to that of DJ-1 exist in many organisms, and to determine their precise relationships of orthology and paralogy, that is, whether they are true orthologs or just related paralogous genes, requires careful consideration of their similarities in a phylogenetic framework. Interestingly, Welch et al. (1998) determined long ago that some of the genes most similar to DJ-1 are prokaryotic. In particular, they detected an Escherichia coli gene called "ThiJ," supposedly involved in thiamine synthesis (Backstrom 1996), which was very similar to mammalian DJ-1 genes. The puzzling idea that mammalian DJ-1 genes would derive from prokaryotic thiamine synthesis genes has pervaded the literature until very recently, in spite of the fact that Mueller et al. (1998) already cited that the putative relationship of the E. coli gene similar to DJ-1 to thiamine synthesis was indeed due to an experimental artifact, a fact detailed by many gene and protein databases (e.g., UniProt, EcoGene, EchoBase, EcoCyc, etc.). Even so, only recently a study has been published in which this fact has been finally fully taken into account (Wilson et al. 2005). The DJ-1–related gene of E. coli formerly called Thij is currently named YajL.
As part of an ongoing project to trace the evolutionary history of Parkinson disease genes in order to provide novel hints about their cellular functions (Marín and Ferrús 2002; Marín et al. 2004; Lucas et al. 2006; Marín 2006), we describe in this study our novel analyses of this significant group of genes. Our goals were to provide Parkinson disease researchers with a correct conceptual framework about the origin and evolutionary history of DJ-1 genes and to suggest novel organisms in which to study their functions. As we will detail, our conclusions are in substantial disagreement with a superficial analysis of this family of genes published before.
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Methods |
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All genes of the DJ-1 superfamily are characterized by having a common protein domain that in the structural Pfam database has been named "DJ-1_PfpI" and that we will call here, in abbreviated form, DJ-1 domain. We found that this highly conserved domain extends from amino acids 5–172 in the 189 amino acids-long human DJ-1 protein. To obtain a representative sample of genes of the DJ-1 superfamily, we first performed extensive BLASTP and TBlastN searches against the National Center for Biotechnology Information databases (http://www.ncbi.nlm.nih.gov/) and those compiled in the GOLD database (http://www.genomesonline.org/) using the DJ-1 domains of several DJ-1 and YajL sequences as queries. Additional specific searches were performed to obtain a representative sample of genes distantly related to DJ-1. These genes included those belonging to the PfpI class, genes that contain both a DJ-1 and a DNA-binding AraC domain (that we will call DJ-1/AraC from now on), genes encoding DJ-1–related catalases, and genes encoding Hsp31-related and YDR533c-related proteins (see descriptions in Gallegos et al. 1997
; Du et al. 2000; Horvath and Grishin 2001; Quigley et al. 2003; Graille et al. 2004; Wilson et al. 2004). Results obtained from all those searches were merged and the protein sequences aligned using ClustalX version 1.83 (Thompson et al. 1997). We then generated a preliminary phylogenetic tree using the Neighbor-Joining (NJ, Saitou and Nei 1987) routine available in ClustalX 1.83. That tree was used to detect duplicates and partial sequences, which were eliminated. After these corrections, our final database of DJ-1–like genes contained 686 sequences.
We then used this database to generate a final multiple protein alignment using again ClustalX 1.83, which was manually corrected with GeneDoc version 2.6 (Nicholas et al. 1997). Phylogenetic trees were obtained from this alignment both by the NJ and the maximum-parsimony (MP) methods, using the routines available in MEGA 3.1 (Kumar et al. 2004) and PAUP*, beta 10 version (Swofford 2003), respectively. For NJ, sites with gaps were included and Kimura's (also known as Poisson) correction was used, whereas for MP, the parameters were as follows: 1) all sites included, 2) randomly generated trees used as seeds, 3) maximum number of tied trees saved equal to 20, and 4) heuristic search using the subtree pruning–regrafting algorithm. Support for the topologies obtained with those 2 methods was determined using the bootstrap routines also available in MEGA 3.1 and PAUP*. One thousand replicates were performed for both NJ and MP bootstrap analyses. For the more limited analyses that include only part of the DJ-1 superfamily sequences (see Results and figs. 2 and 3 below), we used a third method of phylogenetic inference, namely, maximum likelihood (ML), as implemented in the PHYML program (Guindon and Gascuel 2003). We took the BIONJ tree as starting point for the iterative ML searches, and calculations were performed using the Blosum62 matrix of amino acidic similarity. This method is computer intensive, so only 200 bootstrap replicates were performed to check for the reliability of the topologies obtained. The figures that show the phylogenetic trees were generated using the tree editor of MEGA 3.1. Three-dimensional structures were predicted with Swiss-Model (Peitsch 1996; http://swissmodel.expasy.org/) using different crystal models of human DJ-1 protein as templates (Protein Data Bank codes 1PE0
[PDB]
, 1UCF, 1Q2U, and 1PS4). Swiss-Pdb viewer version 3.7 (Guex and Peitsch 1997) was used to generate the 3-dimensional image shown below.
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Genes Closely Related to DJ-1 Are Found in Both Prokaryotes and Eukaryotes
Figure 1 shows the results for the phylogenetic analyses based on our complete protein sequence database. NJ and MP results were congruent enough as to be shown in a single tree. Several likely monophyletic groups that contain well-known prokaryotic proteins, such as DJ-1/AraC, DJ-1 domain–containing catalases, and Hsp31-related proteins, were detected. In addition, 3 groups containing both prokaryotic and eukaryotic sequences were also found. One of them contains both eubacterial and fungal sequences related to the protein encoded by the Saccharomyces cerevisiae YDR533c gene. The second one mostly contains eubacterial PfpI-related proteins but also includes a few archaeal and eukaryotic proteins. Finally, the third one, that is shown in full in figure 1, is a poorly supported ensemble that contains the animal DJ-1 genes together with a mixture of prokaryotic and eukaryotic genes. We found that CHG (or, occasionally, CHA) putative catalytic triads, which suggest a hydrolytic function, were restricted to 3 of these groups—Hsp31-related proteins, YDR533c-related proteins, and PfpI proteins—in agreement with the results presented by other authors (Du et al. 2000
; Quigley et al. 2003; Graille et al. 2004; Wilson et al. 2004).
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We detected that the sequences of the DJ-1 domains of several of those groups, in spite of their obvious similarity, cannot be fully reliably aligned along their whole sequences. This is due either to the fact that sequences contain long stretches of group-specific amino acids (e.g., the protein encoded by the genes most related to S. cerevisiae YDR533C contains 2 extra regions in the middle of the DJ-1 domain) or to low similarity in particular regions (e.g., the C-terminal part of the DJ-1 domain of the catalases cannot be unambiguously aligned to DJ-1 genes). Thus, to avoid serious distortions in our phylogenetic trees that might obscure the true evolutionary relationships with DJ-1 genes, we decided to select only those sequences similar enough as to be aligned without ambiguity with animal DJ-1 genes along the whole DJ-1 domain. This eliminated from the analysis the catalase, Hsp31, and YDR533c-like monophyletic groups detected before. We thus aligned all DJ-1–related sequences plus representatives of the DJ-1/AraC and PfpI classes. This final selection included 288 sequences. However, after repeating our analyses, and even including a third method of phylogenetic reconstruction, ML, we determined that leaving only the sequences with the most similar, fully alignable DJ-1 domains did not significantly improve the resolution of the topology (fig. 2). All 3 methods generated very similar trees, but the bootstrap support for the inner branches of those trees was always very low. We conclude that the information contained in the alignment of DJ-1–related genes is insufficient to completely determine the true topology of the tree. Therefore, the relationships among these DJ-1–related sequences are uncertain, and, considering our large sample size, probably they will remain so no matter the number or variety of sequences of DJ-1–related genes analyzed.
If we center our attention in the group in which animal DJ-1 genes are included and that therefore must contain the most likely candidates to be considered true orthologs of the human DJ-1, some significant features are detected. First, regarding the prokaryotic sequences, we can see that they belong to taxa that cover essentially all the eubacterial phylogenetic range, such as proteobacteria, spirochaetes, chloroflexi, firmicutes, fusobacteria, cyanobacteria, etc. (details in figs. 1 and 2, black branches). This result strongly suggests an ancient origin for this type of genes in eubacteria. Second, there are many eukaryotic groups in which we found species that contain sequences closely related to DJ-1 (figs. 1 and 2; shown in red). We concluded that DJ-1–like genes are present in 5 of the 6 main eukaryotic groups (see Simpson and Roger 2004): Opisthokonta, including both animals and fungi, Plantae, Chromoalveolata, Excavata, and Amoebozoa. Within these eukaryotic groups, the range of species is normally very wide. For example, animals ranging from cnidarians to vertebrates, including all model organisms with completely sequenced genomes, contain DJ-1 genes. Similarly, in plants, both angiosperms and gymnosperms are found to contain DJ-1–related genes. Only in fungi, we found that independent losses of DJ-1 genes must have occurred. Although they are present in both ascomycetes (Schizosaccharomyces, Alternaria) and basidiomycetes (Ustilago, Coprinopsis), most fully or almost fully sequenced fungi (e.g., Saccharomyces, Candida, Aspergillus, etc.) lack DJ-1–related genes. As it can be noticed from examining figures 1 and 2, we cannot exclude that DJ-1–like genes may also be present in some archaea. A few archaeal sequences with ambiguous positions in the trees were found that cannot be clearly included in any known group (green branches in figs. 1 and 2).
With these results, we may ask which would be the simplest hypothesis to explain such a close relationship among prokaryotic and eukaryotic sequences as to be intermingled in our trees. A first option would be similarity due to common descent. Alternatively, we can envisage similarity due to horizontal transmission. In our opinion, our results, taken as a whole, clearly favor the hypothesis that prokaryotic and eukaryotic DJ-1–like genes are orthologous and that the high similarity of some eukaryotic and prokaryotic sequences is due to parallel or convergent evolution. The reason why we favor this hypothesis is the broad phylogenetic range of these genes in both prokaryotes and eukaryotes. This broad range means that, although we cannot discard horizontal transfer events, they are unnecessary to explain our results. We therefore suggest that eukaryotic DJ-1–like genes may have derived from prokaryotic genes and were already present when eukaryotes arose. If this hypothesis is correct, the group including all the eukaryotic DJ-1–like genes shown in figure 1 should be monophyletic, and therefore, they should have related functions.
Novel Model Organisms in Which to Study DJ-1 Function
One of the main goals of our study was to determine whether novel eukaryotic model species could be found in which significant functional analyses of DJ-1 genes may be performed. When we detected that DJ-1–like genes were present in some fungi, and especially in Schizosaccharomyces pombe, a species that is broadly used in genetic, cell biology, and biochemical studies, we decided to perform additional analyses to confirm whether these genes are true DJ-1 orthologs. We thus selected from our database all eukaryotic sequences and performed new phylogenetic analyses to avoid any potential distortion due to the presence of homoplastic prokaryotic sequences. Results are shown in figure 3. All 3 methods generated very similar topologies. However, the ML analysis showed a few anomalies: 2 plant II sequences appeared as abnormally long branches inside the plant I group and one fungal sequence, from Alternaria brassicicola, again appeared as a very long branch, this time inside the plant II group (data not shown). These obvious misplacements, which are in contradiction with all the previous results (including the ML results obtained with the larger data set that we showed before; fig. 2), must have been caused by this particular analysis being trapped in a local likelihood maximum (Chor et al. 2000). In any case, either 3 (ML) or 4 (NJ, MP) fungal sequences, among them the S. pombe gene (called SPAC22E12.03c), are found as the closest relatives of animal DJ-1 genes, in good agreement with the classification of animals and fungi as sister groups within the Opisthokonta. The fungal gene most similar to animal DJ-1 genes was found to be the one in the basidiomycete Coprinopsis cinerea (identity with the human gene along the DJ-1 domain: 35%, similarity: 56%). This similarity is high enough as to allow the modeling of the 3-dimensional structure of the fungal protein using the available crystallographic data for animal DJ-1 genes. The model is shown in figure 4. Fungal sequences have a characteristic short extra loop of 2–12 amino acids located close to the N-terminus of the DJ-1 domain. However, this loop is in a position that would not interfere with the formation of the characteristic DJ-1 domain fold (asterisk in fig. 4). It is also opposite to the dimerization surface, and therefore, it would not affect the dimer formation that is characteristic of DJ-1 gene products. Amino acids known to be critical for DJ-1 redox sensitivity (e.g., a cysteine residue that in human DJ-1 protein is located at position 106; Canet-Aviles et al. 2004; Zhou et al. 2006) are also conserved in the fungal sequences. The alignment in figure 5 shows additional evidence for all genes that we have hypothesized to be orthologous to human DJ-1 actually being true orthologs and for the products of all of them being able to dimerize in the way described for human DJ-1 and E. coli YajL proteins. In that figure, we have included a canonical member of each of the main type of DJ-1–related sequences detected in our analyses plus canonical examples of human, fungal, and plant DJ-1 sequences (in this last case, the 2 DJ-1 domains characteristic of those proteins are included). Two results are noteworthy. First, as it could be predicted from our phylogenetic trees and is obvious observing the alignment, eukaryotic DJ-1 proteins are more similar among them and with prokaryotic YajL proteins (identity in the DJ-1 domain: 27–38%, similarity: 48–56%) than with the rest of DJ-1–related sequences (identity: 12–20%, similarity: 24–38%). Second, and very important, all eukaryotic DJ-1 proteins (both DJ-1 domains in plant sequences) and prokaryotic YajL proteins have an additional alpha helix at the C-terminus of their DJ-1 domain (see fig. 5). This helix is known to be part of the dimerization surface of human DJ-1 and Escherichia YajL proteins (Honbou et al. 2003; Tao and Tong 2003; Wilson et al. 2003, 2005). It is absent from other proteins, such as PfpI, Hsp31, or YDR533c, that use different modes of dimer and/or multimer formation (Du et al. 2000; Quigley et al. 2003; Tao and Tong 2003; Graille et al. 2004; Wilson et al. 2004, 2005). The presence of this additional helix in the DJ-1–like plant and fungal sequences is an independent confirmation that of all of them are closely related to the animal DJ-1 proteins. Significantly, the only other type of DJ-1–related proteins that may contain this additional helix are those in the DJ-1/AraC group, which are characterized by having an additional AraC domain that can bind DNA (reviewed in Gallegos et al. 1997). In figure 5, the sequence of one of these proteins (from Pseudomonas aeruginosa) is shown after eliminating the AraC domain. Notice the similarity in the region that would correspond to DJ-1 helix 8.
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Discussion |
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A precise knowledge of the origin and evolution of a complex family of genes may provide useful functional perspectives. As we have shown in previous works, a detailed consideration of the phylogenetic framework and structural characteristics of the products of genes involved in human diseases may often unearth significant findings (e.g., Marín and Ferrús 2002
; Marco et al. 2004; Lucas et al. 2006; Marín 2006). In this study, we have performed detailed analyses in order to establish the origin and evolutionary history of the DJ-1 genes, known to be involved in Parkinson disease. The main conclusions of our study are as follows: 1) the existence of a group of prokaryotic and eukaryotic DJ-1–like genes that are so similar that they cannot be separated by sequence analyses of their protein products. At least 5 of the 6 main eukaryotic groups posses this type of genes and the phylogenetic range in prokaryotes is also very wide. These results suggest that they have an ancient origin. 2) The presence in all these sequences of a particular structural feature an additional helix at the end of the DJ-1 domain, which supports their close evolutionary relationship. Notable is the fact that plant proteins, which have 2 DJ-1 domains, conserve this feature in both of them, suggesting that these domains may interact in the same way as the monomers of human DJ-1 interact in composing the homodimer that has been observed in crystal structures of the protein. This plant-specific domain duplication must be quite recent, after the plant/red alga split, because the DJ-1–like gene found in the red alga Cyanidioschyzon lacks it (see fig. 3). The finding of a similar helix in DJ-1/AraC proteins is interesting, especially considering that this helix is involved in dimerization in other types of AraC-containing proteins (Soisson et al. 1997a, 1997b). A possible, although highly speculative, explanation would be that current DJ-1 genes evolved from a DJ-1/AraC gene, by a fission in which the AraC domain was almost completely eliminated, but left behind a single alpha helix. 3) The finding of DJ-1–like genes in fungi, and most especially in Schizosaccharomyces, suggests new ways of examining the function of DJ-1 genes. We think that the characterization of the endogenous roles of the fungal DJ-1 genes by both biochemical analyses of S. pombe DJ-1 functions and genetic screenings for suppressors or enhancers of DJ-1 mutations in the yeast may provide many significant insights of the in vivo roles of this interesting class of genes. Such experiments have already been successfully performed in a different yeast, S. cerevisiae, for determining the potential cellular roles of another Parkinson-related protein, -synuclein (Outeiro and Lindquist 2003; Cooper et al. 2006), although this protein is not even found in yeasts.
Bandyopadhyay and Cookson (2004) examined these same genes, arriving to qualitatively different conclusions. The most important difference is that their analyses concluded that DJ-1 genes were animal specific and that a few prokaryotic YajL-like genes (that they still called Thij and considered related to thiamine biosynthesis) were their only close relatives. Part of the discrepancies may be due to them considering just a small sample of DJ-1–related sequences. However, it must also be pointed out that their study is technically deficient (superficial phylogenetic analyses, ML is confused with MP, it is stated that bootstrap is used as a measure of branch length, etc.) and contains several factual mistakes, the most striking being that they explicitly depicted 2 independent times Plasmodium falciparum, Plasmodium yoelii, and Giardia lamblia as prokaryotes (see their figs. 2 and 3). In summary, their conclusion of a close proximity of eubacterial and animal genes, with DJ-1 genes being absent in all the other eukaryotes, is an artifact. We hope that our study will contribute to debunk this mistaken paradigm and thus to open new venues of research.
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Our group is supported by grants SAF2003-09506 and SAF2006-08977 (Ministerio de Educación y Ciencia, Spain). J.I.L. is supported by Generalitat Valenciana.
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Claudia Schmidt-Dannert, Associate Editor
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References |
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