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Published online before print
February 14, 2005, 10.1101/gr.3266405 Genome Res. 15:343-351, 2005 ©2005 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/05 $5.00
Complex genomic rearrangements lead to novel primate gene function1 European Molecular Biology Laboratory, 69012 Heidelberg, Germany 2 Max-Delbrueck-Centrum, D-13092 Berlin, Germany
Orthologous genes that maintain a single-copy status in a broad range of species may indicate a selection against gene duplication. If this is the case, then duplicates of such genes that do survive may have escaped the dosage control by rapid and sizable changes in their function. To test this hypothesis and to develop a strategy for the identification of novel gene functions, we have analyzed 22 primate-specific intrachromosomal duplications of genes with a single-copy ortholog in all other completely sequenced metazoans. When comparing this set to genes not exposed to the single-copy status constraint, we observed a higher tendency of the former to modify their gene structure, often through complex genomic rearrangements. The analysis of the most dramatic of these duplications, affecting  10% of human Chromosome 2, enabled a detailed reconstruction of the events leading to the appearance of a novel gene family. The eight members of this family originated from the highly conserved nucleoporin RanBP2 by several genetic rearrangements such as segmental duplications, inversions, translocations, exon loss, and domain accretion. We have experimentally verified that at least one of the newly formed proteins has a cellular localization different from RanBP2's, and we show that positive selection did act on specific domains during evolution.
Gene duplication is known to play a leading role in evolution for the creation of novel gene function (Ohno 1970  ; Kimura 1983). The fate of duplicated genes is dependent on the selective advantage they bring to the organism, and the vast majority of them are deleted or degrade into pseudogenes (Nadeau and Sankoff 1997; Li et al. 2001). More rarely, the new copies acquire novel functions under the driving force of adaptive evolution, which exposes them to different selective constraints from those of the parental genes (Walsh 1995; Lynch and Conery 2000). Many gene functions have evolved through such a mechanism (Prince and Pickett 2002), and some of them involve primate-specific gene families (Courseaux and Nahon 2001; Johnson et al. 2001; Maston and Ruvolo 2002; Zhang et al. 2002; Paulding et al. 2003). Gene duplicability, defined as the tendency to retain duplicates, increases with organismal complexity, probably because of their increased adaptability (Yang et al. 2003). Yet, even in higher eukaryotes duplicability varies among gene families. There are classes of genes whose duplication is disadvantageous and consequently suppressed during evolution. Such a selection against duplication has been reported mostly for housekeeping genes (Hooper and Berg 2003) and for genes coding for complex subunits (Papp et al. 2003; Yang et al. 2003). The most likely explanation is that, as duplication directly affects gene dosage, it sometimes prevents the proper function of the gene product. Indeed, an inappropriate gene dosage balance is involved in the etiology of genetic disorders such as the Charcot-Marie-Tooth disease type 1A, which is caused by the duplication of the PMP22 gene (Lupski et al. 1992).
The maintenance of a single-copy status across diverse metazoans is likely to be an indicator for such a selection against duplication, considering the high frequency of duplications in eukaryotes (Lynch and Conery 2000 In order to apply this strategy to human, we searched for primate-specific intrachromosomal duplications of genes with single orthologs in all other metazoans. The detailed study of the most dramatic of such duplications revealed that the break from a well-conserved genetic stability is, indeed, linked to the birth of new gene function and is caused by complex genetic mechanisms. Using comparative genomics, we could reconstruct the genomic events leading to the emergence of a novel human gene function.
Detection of primate-specific gene duplications We systematically searched for single-copy orthologs in all completely sequenced metazoan genomes except human, and then identified their multicopy orthologs located in the same human chromosome (inparalogs) (Table 1). We restricted the analysis to intrachromosomal duplications because these events are expected to be more recent when compared to interchromosomal translocations (D. Torrents, M. Suyama, and P. Bork, unpubl.), and hence more likely to have occurred after the rodent-primate split. Furthermore, the inclusion of orthologs located in different chromosomes would have affected the specificity of our analysis, owing to the possible inclusion of processed pseudogenes. In total we detected 22 metazoan single-copy orthologs with at least one additional paralog in human. Of those we excluded four identical copies that might represent copy number polymorphisms (Sebat et al. 2004 ). Of the duplicates, 55% are localized in the subtelomeric and pericentromeric regions of the human chromosomes, highlighting the genetic dynamism of those regions (Guy et al. 2003; She et al. 2004). At least 82% of the detected duplications are clearly part of larger segments that have undergone recent duplication (Bailey et al. 2002). This confirms the primary role of large segmental duplications particularly in the appearance of primate-specific traits (Eichler 2001; Samonte and Eichler 2002).
In order to refine the duplication events and to predict the putative functional role of the duplicated genes, we reconstructed the functional relationships between the human copies and their orthologs in the other species. We thus compared the score of the global alignment within the human paralogs and between them and the corresponding mouse ortholog. Higher scores between one of the human copies and the mouse ortholog than within the human paralogs should reveal divergent paralogs in terms of rearrangements in the gene structure. Thus, depending on this score, we defined two categories for the classification of the observed duplications. When the pairwise alignment score is higher within the human paralogs, it is likely that the duplications occurred recently and were not affected by genomic rearrangements. These gene copies might not have been subjected to functional selection, might differ only in their expression patterns (Gu et al. 2004 ), or might have other relatively small functional differences that are difficult to measure. Of the 18 human paralogous families recorded here, six (33%) fall into this group, while in the remaining 12 duplications (67%) one of the human genes aligns globally better with the mouse ortholog than with the other paralogs. To test whether our data set is, indeed, enriched in genes with a modified structure, we performed a comparable analysis on a reference set obtained by relaxing the constraint of a single-copy status across metazoa. For this purpose, we required a single ortholog in rodents but allowed complete freedom elsewhere, meaning gene absence or presence of multiple paralogs in other metazoans. In this case we detected 215 duplications, and in 55% of them the human copies align better with the mouse ortholog than with the other paralogs. It should be noted that the reference set is likely to include ancient duplications that either underwent rodent-specific loss or whose rodent paralogs were overlooked in the database. This might inflate the final count by increasing the number of human paralogs more similar to the mouse orthologs than to the other copies. Despite this possible bias, we found an enrichment in divergent human paralogs in the data set of genes that have originated from metazoan single-copy orthologs. This supports our hypothesis that there are considerable functional differences among this specific set of novel genes. The duplicated human genes with a modified structure are all candidates for the rapid evolution of new functions through rapid genomic rearrangements. As a case study to test the validity of our strategy, we analyzed in detail the most dramatic of these duplications, interspersed in more than 10% of human Chromosome 2.
A novel gene family descended from RanBP2 and with a domain contribution from GCC2 Single-copy orthologs of RanBP2 are unambiguously detectable in all fully sequenced animal genomes, but not in other eukaryotes such as plants and fungi (Fig. 1A). Although there are slight differences in the domain architectures among the species, the overall domain organization of the protein is well conserved (Fig. 1A). The N-terminal leucine-rich region is followed by RanGTP-binding domains (RanBP1 homologous domains or RBD) related to the one present in RanBP1, a variable number of zinc-finger motifs, and a C terminus with homology to cyclophilin A (Fig. 1A).
In addition to the human RanBP2 ortholog, we detected eight partial copies located in regions that have arisen from intrachromosomal segmental duplications (Figs. 1B, 2A). Despite the fact that human Chromosome 2 appears to be relatively poor in segmental duplications (Bailey et al. 2002 ), the eight segments containing the RanBP2-related genes added up to 1.5 Mb of DNA interspersed in 26 Mb of the chromosome sequence. Two of the gene copies are located in the pericentromeric region of the short arm (band 2p11.2) and the other seven on the long arm (bands 2q12.3 and 2q13) (Fig. 2A). The entire region of duplication is proximal to the site of fusion between the two ancestral ape chromosomes that originated the human Chromosome 2 (Yunis and Prakash 1982). This area is known to be prone to rearrangements occurring before and after the fusion (Fan et al. 2002a,b). It is worth noting that only five of the eight RanBP2-related genes were identified by automated gene prediction pipelines (Table 1). Only a manual analysis of this large, complex chromosomal region uncovered the entire duplication event. Although all of the eight additional copies maintain more than 95% local sequence similarity to RanBP2, the overall gene structure is significantly modified. The new gene copies lack part of RanBP2 exons 20 and 21 and all of exons 22-29. As a consequence, the predicted encoded proteins lack the whole zinc-finger region, the first and the last RBD, and the cyclophilin A homologous domain (Fig. 1B). In addition, they acquire the 3'-terminal exons p-r from the GCC2 gene, coding for a GRIP (Golgin-97, RanBP2 , Imh1p, and p230/golgin-245) domain (Munro and Nichols 1999), which has been reported to be implicated in Golgi localization (McConville et al. 2002; see the legend to Fig. 1 for the exon nomenclature). Because of its novel domain architecture, we named the gene family RGP (RanBP2-like, GRIP domain containing proteins). The predicted length for each of the eight encoded proteins exceeds 1700 amino acids. Several lines of evidence suggest that all eight gene copies are expressed. Firstly, a full-length copy aligning with 99.6% sequence identity both to RGP5 and RGP6 has been reported as a testis-specific protein BS-63 (RANBP2L1 isoform 1, RefSeq accession no. NP_005045
[GenBank]
) (Cai et al. 2002). Secondly, ubiquitous expression has been assessed for a short variant encoding the first 18 exons of RGP5, 6, or 7 (they are 100% identical in this part of their sequence; RANBP2L1 isoform 2, RefSeq accession no. NP_115636
[GenBank]
) (Nothwang et al. 1998). Thirdly, ESTs unambiguously matching all of the copies are detectable. These ESTs derive from different human tissues, including fetal, adult, normal, and tumoral cells. Finally, by RT-PCR we could amplify DNA fragments specifically corresponding to RGP1, 3, 4, 7, 8 and to RGP1 or 2 and to RGP5 or 6 from both testis and HeLa cell cDNA libraries (Fig. 3).
Genomic rearrangements led to the formation of the new gene Although the current coverage and quality of the chimp genome do not allow a final assessment, we were able to detect at least four partial genes of the RGP family in addition to the complete RanBP2 ortholog. This is an indication that at least some of the RGP duplications occurred before the human-chimp split. A further confirmation derives from the recent publication of hominoid-specific gene duplications detected by cDNA-array-based comparative genomic hybridization, in which the cDNA corresponding to RanBP2L1 isoform 2 cohybridizes with the genomic DNA of several hominoids (Fortna et al. 2004 ). The conservation in synteny of the RanBP2 and GCC2 surrounding regions between mouse and human allowed us to unambiguously identify the starting segment (ancestor locus) for the following duplications. Through the analysis of gene order and the detection of significant sequence similarity in the noncoding regions, we were able to extend the borders of the duplicated segment and reconstruct the most parsimonious evolutionary scenario leading to the progenitor locus (Fig. 2B). This region of 200 kb already contains the gene structure of the newly formed RGP family, which evolved from RanBP2 and GCC2 by successive rearrangements. Although it is not possible to assess the temporal order of the events, the ancestor locus underwent duplication, inversion, partial deletion of the long RanBP2 exon 20, and acquisition of the 3'-end of the GCC2 gene coding for the GRIP domain (see Fig. 2B legend for more details). The resulting progenitor locus contains the core coding and noncoding regions common to all the duplicated copies. We performed a similar comparative analysis using the surrounding genomic regions of the eight RGP copies to reconstruct the entire duplication scenario and to assess the parental relationships between them (Fig. 2B). The reliability of this reconstruction is confirmed by the agreement in topology between the trees obtained by using both the gene order approach (Fig. 2B) and the cDNA sequences of RanBP2 and RGPs (Fig. 1B).
The region surrounding the junction site of each of the duplicated segments is enriched in DNA repeats (55%) when compared to a random control (39%) (Supplemental Fig. S1a; Supplemental Table S1; see the legend to the figure for the procedure used to detect the content in DNA repeats). The repeats that mainly contribute to the enrichment are the Alu elements with a peak localized at the junction site (Supplemental Fig. S1b). These results are in agreement with the proposed mechanism for segmental duplications involving Alu-mediated recombinations (Babcock et al. 2003
Alternative splicing of the RGP genes
Positive selection drives the evolution of the RGP family
Five of the seven residues of exon 20 that are potentially under positive selection belong to the RBD domains of the RGP proteins (underlined in Table 2). Four of them correspond to residues directly involved in the binding of RanBP2 to Ran (Vetter et al. 1999 ; Supplemental Fig. S3a). In particular, the two mutations R2039G and K2338E modify the two RBD domains in a similar way, both affecting the same region of contact to the C terminus of Ran (Supplemental Fig. S3b,c).
Distinct cellular localization of the RGP proteins
In this study we report primate-specific duplications of genes that have maintained a single-copy status in all other metazoans sequenced so far. Our hypothesis is that the escape from an evolutionarily conserved single-copy status in one specific lineage is connected to the acquisition of novel molecular functions. In addition, we expect that this functional divergence is acquired through massive genetic rearrangements over a relatively short period of time so as to avoid negative dosage effects. Indeed, in the set of 22 recent duplications with a single-copy ortholog in all other metazoans, we observe an enrichment of genes with a modified structure, compared to human duplications not exposed to the same evolutionary constraints. Further confirming the validity of our strategy, we were also able to detect previously reported acquisitions of primate-specific functions by gene duplication. An example is the TRE2 gene (Table 1), which derived from the chimeric fusion of the duplicates of two parental genes (USP32 and TBC1D3) and was recently described as a novel hominoid-specific gene (Paulding et al. 2003 ). Other duplications within the set of 22 recently duplicated human genes have been reported as parts of bigger segments that underwent primate-specific segmental duplications (Samonte and Eichler 2002). Examples are the genes EIF3S8 and PM5, which are contained in the 12-Mb duplicated region of human Chromosome 16 (Loftus et al. 1999). Lineage-specific duplications with novel gene structures not only hint at new function, but also allow the tracing of the evolutionary events leading to the actual genomic arrangements. This is particularly true for primate-specific duplications as they are recent and more likely to be still contained in larger segments. Thus, the comparison of the paralogous and orthologous regions permits the identification of the ancestor locus and allows a detailed reconstruction of the evolutionary mechanism.
Both the discovery of new gene function and the reconstruction of the underlying mechanism were applicable to the most dramatic of the primate-specific duplications reported here, which involves the nucleoporin RanBP2. Diverse genetic events were apparently required over a short time period to allow the emergence of the RGP gene family (Figs. 1, 2). Moreover, within the duplicated segments, RGPs represent the vast majority of the surviving coding regions, indicating that they drive the evolution of the entire region. Finally, the cytoplasmic localization of one of the RGP variants, originally termed RanBP2L1 isoform 2 (Nothwang et al. 1998 Why did RGP appear in primates and nowhere else? There are two possible answers to this question depending on the evolutionary scenario considered. Under the more neutral one, the high number of complex rearrangements required to escape the dosage imbalance renders this event so unlikely that it would only happen in a single lineage. The alternative, and more selective scenario, requires that the positive contribution of the newly formed genes to lineage-specific traits outweighs the negative impact of the dosage imbalance. In this case, the new genes that we detected are likely to have evolved in primates because of their specific genomic and functional context. As is usual in evolutionary biology, it is difficult to determine which one of these scenarios is correct; however, if the selective one is true, a thorough functional characterization of the new genes reported here would reveal the functionally most relevant areas for primate evolution.
Detection of primate-specific gene duplications of single-copy genes The complete protein sets of Anopheles gambiae (BDGP build 2a), Caenorhabditis briggsae (Cb25.agp8), Caenorhabditis elegans (Wormbase build 102), Drosophila melanogaster (BDGP build 3a), Fugu rubripes (Fugu build 2.0), Homo sapiens (NCBI build 34), Mus musculus (NCBI build 30), and Rattus norvegicus (BGDP build 3.1) were downloaded from the Ensembl Web site (http://www.ensembl.org, Dec 20th 2003), and reduced to one translation at each locus (longest transcript). All-against-all Smith-Waterman searches and a previously described algorithm (Tatusov et al. 1997 ; Zdobnov et al. 2002) were then used to search for orthologous groups containing at least one protein from each of the analyzed species. Only the groups that had a single representative in each of the nonhuman species, but at least two representatives in human, were extracted. The resulting list was extended by searching for additional cases possibly overlooked because of artifacts in the gene-prediction procedure (partial/fragmentary prediction or accidental fusion with surrounding genes). All orthologous groups were searched for the presence of additional paralogs in all the genomes (with reduced stringency). Only those human paralogs which resided on the same chromosome and with markedly better similarity scores than paralogs in any of the other genomes were included to the list (the similarity of paralogs was expressed in bit scores normalized by self-hit bit scores; this value had to be above 0.4 for putative paralogs in the human lineage to be included, all other paralogs occurring elsewhere had to be below 0.3). In order to exclude processed pseudogenes and events predating the human/mouse split, only the intrachromosomal duplications were kept. To avoid unprocessed pseudogenes, ESTs from dbEST (Feb. 5th 2004) were aligned against the DNA region corresponding to each of the human proteins using stand-alone BLAT (Kent 2002). Of the resulting alignments, only the best alignment with a percent identity higher than 96% and a length greater than 100 bases was kept. In cases where the best alignment could not be unambiguously assigned, the EST was discarded. For comparison, a background set of unrestricted gene duplications in the human lineage was derived. This set included all detectable duplications in the human lineage located on the same chromosome and with single-copy orthologs in rodents. In all other metazoans duplications as well as absences/losses were allowed.
Calculation of the global alignment score and analysis of the primate-specific duplications
RanBP2 orthology assignment, sequence analysis, and gene structure definition
Analysis of the genomic DNA sequence and detection of the duplicated fragments
Evolutionary analysis
The Ka/Ks ratios were measured using the ML method implemented in PAML (http://abacus.gene.ucl.ac.uk/software/paml.html/; Yang 1997
Amplification of cDNAs corresponding to the RGP gene family
Localization of RGP proteins HeLa cells were grown on coverslips in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 µg/mL streptomycin. Transfections were performed in six-well plates with Lipofectamine Plus reagent (Invitrogen), according to the manufacturer's instructions. Then, 24 h after transfection, cells were washed in PBS, fixed for 10 min in 3.7% paraformaldehyde in PBS, washed again in PBS, and stained with a polyclonal anti-calnexin antibody (Santa Cruz). Cells were then mounted in Fluoromount G (Southern Biotechnology). Images were acquired using a Zeiss LSM510 FCS confocal microscope.
We thank Elena Conti for the RBD structure analysis, Sean Hooper for his help with the Ka/Ks calculations, and David Torrents for helpful discussions.
3 Corresponding author. E-mail peer.bork{at}embl.de; fax 49 6221 387 517.  [Supplemental material is available online at www.genome.org. and at http://www.bork.embl.de/~ciccarel/RGP_add_data.html.] Article and publication are at http://www.genome.org/cgi/doi/10.1101/gr.3266405. Article published online ahead of print in February 2005.
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Received September 20, 2004; accepted in revised format December 15, 2004.  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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