Journal of Heredity Advance Access originally published online on January 19, 2006
Journal of Heredity 2006 97(2):100-106; doi:10.1093/jhered/esj011
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The Gene of Retroviral Origin Syncytin 1 is Specific to Hominoids and is Inactive in Old World Monkeys
From the Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322 (Cáceres and Thomas); and the Genome Technology Branch and NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 (NISC Comparative Sequencing Program)
Address correspondence to Mario Cáceres at the address above, or e-mail: mcaceres{at}genetics.emory.edu.
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Abstract |
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Syncytin 1 is one of the best known examples of recent acquisition of a new gene from an endogenous retrovirus (HERV) in the human genome and has been implicated in placental physiology. Within primates, Syncytin 1 is conserved in all hominoids but has not been characterized in Old World monkeys (OWMs). In this study, we investigated the status of Syncytin 1 in 14 hominoid and OWM species. We show that although the HERV-W provirus responsible for the origin of this gene was present in the genome of the most recent common ancestor of hominoids and OWMs, Syncytin 1 is inactive in OWMs. In addition, we were able to determine that the evolution of Syncytin 1 in hominoids involved an accumulation of amino acid changes and showed signatures of both positive and purifying selection. Our results indicate that Syncytin 1 is indeed a hominoid-specific gene and illustrate the complex and dynamic process associated with the origin of new genes.
Transposable elements (TEs) are genetic constituents that can have a significant effect in host genomes (Kidwell and Lisch 1997; McDonald 1993). One of the potential effects of TEs is the generation of new gene sequences (Britten 2004; Nekrutenko and Li 2001; Smit 1999), such as the envelope (env) genes of retroviral origin found in several mammals. In particular, the human genome contains full-length copies of four env open reading frames (ORFs) that are highly expressed in the placenta (Blaise et al. 2003, 2005; Blond et al. 1999; Cohen et al. 1985). There is still some controversy about the physiological role played by these genes. However, based on the normal functional properties of Env proteins, these genes have been related to the membrane fusion process involved in the formation of the syncytiotrophoblast, the syncitial cell layer that regulates maternal-fetal exchanges in the placenta, and to the suppression of the maternal immune response against the fetus (reviewed in Muir et al. 2004 and Rote et al. 2004).
The best known and most studied of the human env-derived genes is Syncytin 1 or ERVWE1, which was originated from a human endogenous retrovirus (HERV) of the HERV-W family inserted in human Chr.7q21 (Blond et al. 1999; Mi et al. 2000). Multiple inactivating mutations were found in the gag and pol coding sequences of the provirus. Conversely, the env gene maintained an ORF coding for a 538 amino acid polypeptide that has all characteristic features of Env proteins and mediates intercellular fusion in vitro (Blond et al. 2000; Frendo et al. 2003; Mi et al. 2000). Recently, a molecular evolution study of the HERV-W provirus in several ape species and in 24 humans showed that in all of them Syncytin 1 was conserved and retained its receptor-mediated fusogenic activity (Mallet et al. 2004). However, an analysis of the synonymous and nonsynonymous substitutions indicated a relatively high degree of amino acid changes in hominoids (Bonnaud et al. 2004), which could be consistent with a low degree of selective constraint. Although it has been documented that the HERV-W invasion of the primate genome occurred before the divergence of hominoids and Old World monkeys (OWMs) (Kim et al. 1999; Voisset et al. 1999), the Syncytin 1 locus in OWMs has not been described previously (Mallet et al. 2004). In this study, we have taken advantage of current sequencing efforts focused in targeted genomic regions of diverse species (Thomas et al. 2003) to analyze in detail the Syncytin 1 region in primates. In addition, by using the OWM Syncytin 1 sequence as the outgroup, we have been able to better characterize the amino acid changes related to the acquisition of this new gene in hominoids.
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DNA Samples
Genomic DNA samples from one individual each of the following species were used: human (Homo sapiens), chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla), orangutan (Pongo pygmaeus), siamang gibbon (Hylobates syndactylus), langur (Presbytis francoisi), colobus (Colobus guereza kikuyuensis), talapoin (Miopithecus talapoin), guenon (Cercopithecus hamlyni), rhesus monkey (Macaca mulatta), mangabey (Cercocebus atys atys), and hamadryas baboon (Papio hamadryas).
Polymerase Chain Reaction Amplification and DNA Sequencing
Polymerase chain reaction (PCR) amplification of the Syncytin 1 coding sequence was carried out with primer Sync-1 in combination with primer Sync-3 in hominoids or primer Sync-4 in OWMs (Figure 1), using approximately 50–100 ng of genomic DNA of each species. After amplification, DNA fragments were gel purified, and both the DNA strands were sequenced using a total of 19 different primers separated by approximately 500 bp. Analysis of the 5'-deletion of the HERV-W provirus in OWMs was done with primers Sync-21 and Sync-24 (Figure 1). Primers sequence is available on request.
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DNA Sequence Analysis
Syncytin 1 sequences for each species were assembled using the PHRED/PHRAP/CONSED program (Gordon et al. 1998) and have been deposited in GenBank (accession numbers DQ256474–DQ256483). High-quality ordered and oriented bacterial artificial chromosome (BAC) sequences (Blakesley et al. 2004) generated at the NIH Intramural Sequencing Center from olive baboon (Papio anubis; AC092510 [GenBank] ), marmoset (Callithryx jacchus; AC148269 [GenBank] ), and galago (Otolemur garnettii; AC148249 [GenBank] ) and a finished chimpanzee BAC clone sequence (AC145964 [GenBank] ) generated at the Washington University Genome Sequencing Center were also used in this study. Note that all these sequences were contiguous across the Syncytin 1 provirus integration site. Genomic sequences were aligned with MultiPipMaker (Schwartz et al. 2003), and repetitive elements were identified with RepeatMasker (www.repeatmasker.org). Multiple species alignments of shorter sequences were generated with Clustal W (Thompson et al. 1994) and are deposited at the EMBL-ALIGN database (ALIGN_000952 and ALIGN_000953).
For phylogenetic and molecular evolution analysis of Syncytin 1, the sequences generated in this study were combined with the available genomic sequences and the hominoid sequences from previous studies (Mallet et al. 2004). When intraspecific nucleotide polymorphisms were found, the ancestral sequence was inferred based on that of the other species and was used for the subsequent analysis. For simplicity, HERV17, which represents the consensus sequence of the HERV-W family (Repbase Update database; Jurka 2000), was used as the outgroup. The same results were also observed when we used as outgroups six different sequences representing ancestral HERV-W insertions in the catarrhine lineage, based on the full-length env copies of this retrovirus available in the human, chimpanzee, and rhesus genomes. Phylogenetic trees of Syncytin 1 were obtained by neighbor-joining from 1,000 bootstrap replicates using the PHYLIP software package (Felsenstein 2004). Distances between species were calculated by the Kimura two-parameter model (Kimura 1980). Synonymous (Ks) and nonsynonymous (Ka) substitution rates along different branches were calculated by maximum likelihood under the codon substitution model implemented in the PAML program (Yang 1997). In this analysis, codons including alignment gaps or stop signals were removed from all the sequences. To compare the Ka/Ks ratios of different parts of the tree, a likelihood ratio test was performed as described previously (Yang 1998).
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Comparative Genomic Analysis of the Syncytin 1 Region
To characterize the Syncytin 1 locus in primates, a 56-kb segment of human Chr.7q21 centered on Syncytin 1 was compared with high-quality BAC-based sequence assemblies of the orthologous segments from the chimpanzee, baboon, marmoset, and galago genomes. The genomic alignment revealed homologous sequences for this gene in chimpanzee and baboon but not in marmoset and galago (Figure 1). This is consistent with the proposed invasion of the primate genome by elements of the HERV-W family less than 40 Ma, after the divergence of catarrhines and New World monkeys (Kim et al. 1999; Voisset et al. 1999). The integration of the HERV-W element responsible for the origin of Syncytin 1 can therefore be definitively mapped between 40 Ma and the divergence of hominoids and OWMs, around 25 Ma (Goodman et al. 1998).
The region flanking the HERV-W provirus in humans and chimpanzees is almost identical, with short, unique sequences separated by many, mostly incomplete, TEs, including short interspersed repetitive elements (SINEs) and HERVs of various families (Figure 1). A similar array of repetitive elements is present in baboon. However, in baboon, the 5'-end of the Syncytin 1 locus and the adjacent sequences are absent, including the first exon and the promoter (Figure 1), likely as a result of one or more large deletions. We also found a small deletion in baboon that eliminated the last 306 bp of the 3' long terminal repeat. In marmoset and galago, there is conservation of the basal promoter sequences immediately flanking the HERV-W insertion, which are involved in Syncytin 1 transcription (Cheng and Handwerger 2005; Prudhomme et al. 2004) (Figure 1). In marmoset, the conservation extends to a putative 0.5-kb enhancer region that is included within a preexisting HERV-H element and is required for maximal expression in normal trophoblast cells (Cheng et al. 2004). This suggests that the integration site was important for the current transcriptional regulation of Syncytin 1 and that its regulatory elements predated the HERV-W insertion. In addition, TEs were involved in the origin not only of the coding sequence of Syncytin 1 but also of its upstream regulatory regions.
Sequence Analysis of Syncytin 1 in Different Primate Species
A detailed analysis of the HERV-W provirus coding sequences detected multiple inactivating mutations in the gag and pol genes of humans and chimpanzees, as already noted (Mallet et al. 2004). Similarly, in baboons, the whole gag coding sequence is deleted and that of pol contains a 5-bp deletion and five nonsense mutations, one of which is also present in hominoids. For the env gene, corresponding to Syncytin 1, a complete ORF coding for 538 amino acids was present in both hominoid species (Mallet et al. 2004). However, we detected three stop codons and three frameshift mutations in the baboon locus, which render the ORF completely nonfunctional.
To investigate the status of Syncytin 1 in other species and to determine the time points at which the baboon mutations occurred, we amplified by PCR and sequenced the env-coding region in 10 additional hominoid and OWM species. Primers for the amplification were located in the pol sequence, 0.2-kb upstream of the Syncytin 1 start codon, and in a region of single-copy sequence located 0.9 and 0.5-kb downstream of the stop codon in humans and baboons, respectively (Figure 1). In all cases, PCR fragments of the expected size, 2.8 kb in hominoids and 2.4 kb in OWMs, were obtained, and their sequence was consistent with their origin from the region of interest. When combined with the previously published Syncytin 1 sequences (Mallet et al. 2004), phylogenetic analysis of the entire HERV-W sequenced region produced the expected phylogenetic tree between the species (Figure 2), strongly supporting that the orthologous genomic segments had been amplified by our PCR assays.
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Comparison of the Syncytin 1 coding sequence revealed an intact ORF in all hominoids, as recently reported (Mallet et al. 2004). In contrast, six nonsense and seven frameshift mutations (two insertions and five deletions) were detected in OWMs, with the longest ORF being 43 amino acids shorter compared with its hominoid counterpart (Figure 2). Two additional in-frame 3-bp deletions occurred, one before the divergence of langur and colobus and another in the olive baboon branch. Furthermore, the signature 12-bp deletion in the 3'-region of the gene with respect to the HERV-W consensus described in hominoids (Bonnaud et al. 2004) was also found in OWMs and thus preceded the divergence of the two groups (Figure 2). Interestingly, according to the most parsimonious scenario, one of the nonsense mutations detected in the OWM lineage, which eliminates the last 30 amino acids of the protein, occurred in the catarrhine ancestor and was later changed to arginine in hominoids by a compensatory nucleotide substitution (Figure 2). Alternatively, the nonsense mutation could have appeared only in the OWM lineage, but that would require two independent mutations in the same codon in the hominoid lineage, one of which is identical to that in the OWM lineage. Another stop codon was generated in the OWM lineage by an insertion of a T nucleotide between positions 1485 and 1486, shortening the encoded protein by an extra 13 amino acids. Therefore, the large genomic alterations in baboon and multiple truncating mutations in the coding region of the OWM Syncytin 1 orthologs suggest that this gene is functional only in hominoids.
Molecular Evolution of Syncytin 1 in Hominoids and OWMs
By using the maximum likelihood analysis program PAML (Yang 1997), we have estimated the rate of synonymous (Ks) and nonsynonymous (Ka) substitutions in Syncytin 1 in different branches of the primate phylogenetic tree (Figure 2). In general, the Ka/Ks ratio for this gene is considerably high, with an average of 0.88 over the whole tree, very similar to that of 0.91 obtained for the HERV-W env pseudogene inserted in human Chr.Xq22 (Table 1). However, as expected, when comparing inactivated and functional genes, OWMs accumulated twice as many nucleotide substitutions as hominoids and there are differences in the Ka/Ks ratio between them.
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To compare the Syncytin 1 Ka/Ks within the catarrhine phylogeny, we tested the fit of the data to several models that allow these ratios to vary among evolutionary groups (Yang 1998). The analysis yielded two main conclusions. First, the average Ka/Ks ratio before the divergence of hominoids and OWMs and in the OWM lineage (0.47) is significantly lower than the theoretical neutral expectation of 1 (2
l = 4.08, df = 1, P = .044). Accordingly, the gene was under certain degree of functional constraint before the divergence of OWM species and, probably coinciding with its complete inactivation, has been evolving neutrally ever since, with an average Ka/Ks ratio of 1.07 in OWMs (Table 1). Second, there appears to be an acceleration of the rate of amino acid substitutions in the branch leading to all hominoid species, and its Ka/Ks ratio (1.35) is around three times larger than that of the catarrhine and OWM lineages (Table 1), although this difference is not significant. As previously observed (Bonnaud et al. 2004), most of the remaining hominoid branches have Ka/Ks values below 1, with an average of 0.77 for hominoid species (Table 1). The main exception is the human branch, where there are six nonsynonymous substitutions and no synonymous substitution, resulting in a Ka/Ks ratio that is significantly higher than 1 (2l = 4.03, df = 1, P = .045). The reason for this elevated rate of amino acid change in the human lineage is not clear, but a predominance of nonsynonymous polymorphisms (4) compared with synonymous polymorphisms (1) was also seen in the 48 human alleles sequenced by Mallet et al. (2004). Additional studies are needed to determine whether there could be other selective pressures in humans.
The potential positive and negative selection acting on Syncytin 1 was examined further by analyzing the distribution of synonymous and nonsynonymous substitutions across the coding sequence. Previously, a sliding window analysis observed a consistently higher Ka/Ks ratio in the 5'-region of the gene than in the 3'-region in hominoids (Bonnaud et al. 2004). A similar analysis in OWMs showed that the Ka/Ks ratios are relatively uniform throughout the gene and oscillate around 1 (data not shown). We carried out a more accurate partition of the gene according to which amino acid positions are more important for Env function by aligning the protein sequence of the ancestral HERV-W env gene (HERV17) with that of the 10 retroviruses most closely related to it. Based on this alignment, the 542 amino acid HERV17 Env protein was divided into 202 conserved positions, with identical or similar amino acids in at least eight of the other retrovirus, and 340 nonconserved positions. Table 1 summarizes the Syncytin 1 Ka/Ks ratios for the conserved and nonconserved positions. Conserved positions show significant differences between evolutionary groups (2l = 11.16, df = 4, P = .025), with Ka/Ks values significantly higher in OWMs than in the rest of the tree (2l = 5.48, df = 1, P = .019) and significantly lower than 1 in hominoid species (2l = 8.20, df = 1, P = .004). Conversely, nonconserved positions tend to have Ka/Ks values slightly higher than 1, especially in the catarrhine lineage, hominoids, and OWMs, but no significant differences between groups were found (2l = 2.81, df = 4, P = .589). Therefore, conserved and nonconserved positions in OWMs evolve at similar rates, whereas in hominoids the conserved positions are clearly under functional constraint, providing further support that in this case Syncytin 1 is truly a protein-coding gene subjected to some degree of purifying selection.
Inactivation and Evolution of Syncytin 1
Two possible scenarios emerge for the evolution of Syncytin 1 in primates. First, the gene could have originated before the divergence of hominoids and OWMs and was later inactivated in the OWM lineage. Second, the gene could have been recruited only in the hominoid lineage and degenerated in OWMs because of the lack of selective pressure, as most other endogenous retrovirus coding sequences. The accumulation of amino acid changes in the hominoid lineage, together with the putative reversion of a nonsense mutation, would be more consistent with the second scenario. On the other hand, the Ka/Ks ratio below 1 in the catarrhine and OWM lineages is consistent with the action of purifying selection, as expected for a functional protein. Most of the amino acid changes in Syncytin 1 evolution were located in positions that are variable across Env proteins, either in the surface domain, typically involved in receptor recognition and binding, or the intracytoplasmatic tail, related to the regulation of the fusogenic activity, and could represent gradual adjustments to its cellular role. As a result, it is not clear when the HERV-W env gene acquired its new physiological function, and detailed functional analyses would be necessary to determine the effect of these amino acid changes in Syncytin 1 activity and to discern between the above possibilities.
The inactivation of Syncytin 1 in OWMs is supported by the presence of multiple nonsense and frameshift mutations in phylogenetically diverse species and the observed Ka/Ks ratios around 1. However, the exact causes of the pseudogenization of the gene are not clear. There are two mutations in the coding sequence common to all OWM species that together shorten the protein by 43 amino acids (Figure 2): a nonsense mutation that probably occurred before the divergence of hominoids and OWMs and a frameshift specific to the OWM lineage. The relatively low Ka/Ks ratio along the OWM lineage branch suggests that the protein could still have been functional after the first mutation. Furthermore, deletion mutants lacking as many as 58 amino acids from the C-terminal end of the protein maintain their fusogenic activity (Chang et al. 2004; Cheynet et al. 2005). Alternatively, a large deletion that removed the regulatory sequences and the first exon of the gene was found in baboon (Figure 1) but not in any of the hominoid species (Mallet et al. 2004). A preliminary PCR study with primers flanking the deleted region showed that the same deletion was present in rhesus macaque and mangabey, and possibly also in talapoin, although the repetitive nature of the region complicated the amplification in other species (data not shown). The presence of this deletion explains why Syncytin 1 was not detected in baboon or rhesus in a previous study (Mallet et al. 2004), and we suggest that it could also be responsible of the initial inactivation of the gene in OWM species.
The resulting picture of the env-derived genes in the genome of primates is quite complex. So far, four different env genes are known to be expressed in placenta in humans: ERV3, ERVWE1 (Syncytin 1), HERV-FRD (Syncytin 2), and envV (Blaise et al. 2005). Of those, ERV3 is conserved in hominoids and OWMs, but it is deleted in gorilla and contains an inactivating mutation in 1% of humans (de Parseval and Heidmann 1998; Herve et al. 2004). Syncytin 2 appears to be the oldest of the four genes and is conserved over a span of 40 Ma, from New World monkeys to hominoids (Blaise et al. 2003). This gene shows an average Ka/Ks ratio of only 0.30 in hominoids and OWMs and it may be under intense functional constraint. In this study, we found that Syncytin 1 is functional only in hominoids. The variation in the number of acquired env genes between primates does not seem to correlate with significant changes in placenta structure (Carter and Enders 2004). It is thus possible that acquired retroviral genes have redundant, accessory roles that are not essential for placental function. For example, Syncytin 1 inhibition reduced intercellular fusion by only 40%–50% in vitro (Mi et al. 2000). Recently, a similar situation was discovered in rodents, with two fusogenic placenta-specific env genes, named Syncytin-A and -B, conserved in the Muridae family (Dupressoir et al. 2005). Therefore, analogous multigenic systems have likely been developed independently several times in different clades of placental mammals by convergent evolution. Future studies dissecting the function and regulation of these and other env-derived genes will provide further insights into the evolution of placenta and the acquisition of new genes.
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Acknowledgments |
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We would like to thank Leona Chemnick and Oliver Ryder (Frozen Zoo of the Zoological Society of San Diego), David Ledbetter and Andrew Wang (Department of Human Genetics, Emory University), and Thomas Vanderford (Yerkes National Primate Research Center) for kindly providing the primate DNA samples used in this study, and Eric Green and the other members of the NISC Comparative Sequencing Program for the BAC clone sequencing. We would also like to thank Antonio Barbadilla, Arcadi Navarro, Marta Puig, and Soojin Yi for helpful comments and discussion. Work was supported by NIH grant MH068185 awarded to J.W.T. M.C. was supported by a James S. McDonnell Foundation grant awarded to Todd Preuss.
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Footnotes |
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Corresponding Editor: Shozo Yokoyama
Received August 25, 2005
Accepted November 2, 2005
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