- In humans, 10 PSG genes encode closely related secreted. - In recent years, a role in modulation of the maternal immune system possibly to avoid rejection of the semiallogeneic fetus and to facilitate access of trophoblast cells to maternal resources via the blood system has been suggested. - Alternatively, they could serve as soluble pathogen decoy receptors like other members of the CEA family. - As these species share a hemochorial type of placentation and a seemingly convergent formation of PSG genes during evolution, we hypothesized that hemochorial placentae support the evolution of PSG gene families.. - Results: To strengthen this hypothesis, we have analyzed PSG genes in 57 primate species which exhibit hemochorial or epitheliochorial placentation. - Surprisingly, only 1 to 7 PSG genes could be identified in New World monkeys. - Interestingly, no PSG genes were found in more distantly related primates with epitheliochorial placentae like lemurs and lorises. - Conclusion: The distribution of trophoblast-specific PSGs in primates and their pattern of selection supports the hypothesis that PSG are still evolving to optimize fetal-maternal or putative pathogen interactions in mammals with intimate contact of fetal cells with the immune system of the mother like in hemochorial placentation.. - Full list of author information is available at the end of the article. - In placental mammals, the fetus develops in a protected environment inside the uterus of the mother. - The most intimate contact is found in mammals with hemochorial placentation where mater- nal blood is in direct contact with fetal trophoblast cells of the chorionic villi. - This facilitates efficient nutritional supply of the fetus but is more demanding to maintain gestational tolerance of the maternal immune system to- wards semiallogeneic fetal cells. - PSG belong to the CEA family which is a member of the immunoglobulin super- family. - These facts and the non-syntenic location of the human and murine PSG loci strongly suggest independent generation of these genes by con- vergent evolution [8].. - Some if not all of the tolerogenic and pro-angiogenic effects appear to be mediated through the transforming growth factor β1 (TGFβ1) signaling pathway [12–15]. - A region of the N domain of PSG1 around the lysine-tyrosine-histidine-tyrosine (LYHY) tetra-peptide motif appears to be responsible for the re- lease of activated TGFβ1 from macrophages and other immune cells while the C-terminal IgC-like B2 domain of human PSGs and the N domain of murine and equine PSGs are responsible for activation of so called latent TGFβ1 [16–18]. - endotheliochorial and epitheliochorial) like dogs and cattle were found to have no PSG genes. - To strengthen this hypothesis, we have analyzed 57 primate and four closely related species (1 flying lemur, 3 tree shrew species) with hemochorial or epitheliochorial placentae for the presence of PSG genes. - Indeed, all analyzed lemur and a loris species which exhibit epitheliochorial placentation lacked PSG genes. - On the other hand, the genomes of haplorhine apes, Old World monkeys (OWM) and New World monkeys (NWM) with hemochorial placentation con- tained highly variable numbers of PSG genes. - Only in tarsius a distantly related haplorhine primate with a hemochorial placenta no PSG genes could be identified.. - Differential expansion of PSG genes in primates at syntenic loci. - To this end we compared the CEA loci of three haplorhine primates human (Homo sapiens), rhesus mon- key (Macaca mulatta) and marmoset (Callithrix jacchus) representing great apes, Old World monkeys (OWM) and New world monkeys (NWM), respectively, as well as of the strepsirrhine primate species small-eared galago. - Despite a similar organization of the CEA gene locus and flanking non-CEACAM genes, no PSG-related genes were found in the galago and in the mouse lemur (Fig. - The PSG genes are shown in red, CEACAM1-related CEACAM genes in yellow, orthologous CEACAM genes in blue, selected flanking genes in black. - The nonsyntenic localization of the PSG cluster in rodents is indicated by a red line at the bottom. - The nucleotide numbering of the chromosomes starts at the telomere of the short arms which point to the right. - The place corresponding to the location of the PSG-like gene (not found in marmoset) in capucin (Cca) and Bolivian squirrel monkeys (Sbo) is indicated by a red arrow. - PSG genes are present in haplorhine but not in strepsirrhine primates. - In order to substantiate the correlation of the presence and absence of PSG in Haplorhini and Strepsirrhini pri- mates, respectively, we analyzed the PSG gene content in 39 haplorhine and 18 strepsirrhine primates (Supple- mentary Fig. - As a first step, N domain exons from human PSG genes were used to screen primate nucleo- tide databases. - In all analyzed haplorhine primates except for the NWM species, Cebus capuchinus and Saimiri boliviensis, and Tarsius syrichta (see below) PSG genes could be identified using this strategy. - The number of non-pseudogene PSG genes (for definition see Method section) varied widely between primate families: in apes from 5 PSG (gorilla) to 11 (Northern white cheeked gibbon), in OWM from 6 (mandrill) to 24 (red guenon) and 1–7 in NWM (Supplementary Table 1. - On average 3- and 6-fold more PSG genes were found in ape (mean ± standard error of the mean (SEM and OWM subgroups respectively in comparison to NWM . - Four of the CEACAM1-like genes contain a nonsense mutation in their N exons. - No PSG genes could be detected in 16 lemurs and 1 loris (Fig. - In summary, PSG genes were detected in 38 out of 39 Haplorhini primates (with Tarsius syrichta being the sin- gle exception) but not in 17 Strepsirrhini primates.. - Primate PSG genes con- tain a duplicated set of IgC-related A and B domain exons named A1, B1 and A2, B2. - In humans, the B1 exon splice acceptor is corrupted in most PSG genes except for PSG11 (Supplementary Fig. - OWM PSG genes exhibit the same exon organization as human PSG genes, but their B1 exon splice acceptor sites appear to be functional. - Phylogenetic analyses of PSG genes in great apes re- vealed rapid divergence of N domain exon sequences as. - demonstrated by the lack of an orthologous relationship of the majority of orangutan and all gibbon PSG genes with ape PSG genes evident from intraspecies clusters (Supplementary Fig. - Two of the orangutan PSG N domain sequences, however, cluster with the corre- sponding sequences of human, bonobo, chimpanzee and. - In addition, no orthologs could be identified in NWM (with the exception of the single PSG gene found in the closely related capucin species) and between PSG genes of the. - This indicates that although all primates inherited probably the same number of PSG genes from a common ancestor, rapid divergence led to an extended expansion or contraction of the PSG family as well as loss of an orthologous relationship. - Assuming that the paralogous PSG genes were derived from a single PSG by repeated tandem duplication [21]. - in a common primate ancestor, determination of the ra- tio of the number of nonsynonymous substitutions per non-synonymous site (dN) and the number of synonym- ous substitutions per synonymous site (dS) in the N do- main exons of paralogous PSG genes allows estimation whether overall pressure for conservation (dN/dS <. - Gene conversion events which are com- mon within families of closely related genes like the PSG genes [22] and might influence the dN/dS ratios were not considered. - 3 PSG genes exist only in primates with hemochorial placentation. - account that some of the amino acids of the IgV-like do- main have to be invariant in order to maintain the β- sheet structure. - For the bush baby the domain organization could not be delineated for all CEACAM1-like proteins due to low quality of the genome assembly. - N exons of CEACAM1 genes of the same ape and OWM species exhibited similar or lar- ger dN/dS ratios SEM and SEM, respectively) (Fig. - Amino acids positions which are needed for the generation of the im- munoglobulin fold are anticipated to be under purifying selection while regions involved in ligand binding might exhibit selection for diversification. - Indeed, the regions known in other CEACAM members such as CEACAM1 (but not CEACAM19) to interact with ligands and bac- terial adhesins, the CC’C″FG face of the immunoglobu- lin fold, with the exception of the LYHY and RGD motifs, apparently accumulate nonsynonymous substitu- tions with a high rate (black stippled lines) while other regions e.g. - In addition, we used the MEME software to confirm that individual sites of the N domains are under positive selection. - We hypothesized that direct exposure of fetal tropho- blast cells to maternal immune cells is a requirement for the presence of PSG genes. - 5 The most highly expressed human and OWM PSG genes lack the disintegrin-like RGD motif. - The relative expression frequencies of PSG were estimated by counting the clones matching N exon nucleotide sequences of the different PSG genes present in human, baboon and rhesus monkey placental EST libraries. - The presence of the LYHY motif needed for latent TGF β 1 secretion and the disintegrin-like RGD motif are shown as red and blue filled-in circles, respectively. - Of note: The PSG genes were numbered arbitrarily. - Interestingly, PSG-like genes are only found in bats of the suborder Yangochiroptera with hemochorial placen- tation but not in the Yinpterochiroptera suborder des- pite the presence of species with hemochorial placentae in the latter [4]. - Thus it appears that the presence of highly invasive trophoblast cells like in hemochorial pla- centae or in equine endometrial cups is necessary but not sufficient for the presence of PSG genes.. - During evolution of the Catarrhini (apes and OWM) and Platyrrhini parvor- ders (NWM) the PSG loci expanded or contracted quite differently or stayed the same leading to a single copy in capucin and Bolivian squirrel monkeys and a total of 27 copies (including PSG pseudogenes) in the De Brazza’s OWM. - The average PSG family sizes (excluding pseudo- genes) vary vastly: 3 PSG genes in NWM, 9 in apes and 17 in OWM. - a Nucleotide sequences of N domain exons of PSG paralogs from ape and NWM species with ≥ 3 PSG as well as a subset of OWM species were compared pair-wise in all combinations for each indicated species and the ratio of the rate of nonsynonymous (dN) and synonymous mutations (dS) was calculated and the mean ratios. - Hmo, Nle) and OWM species (Cat, Mfa, Mle, Mml, Mne, Pan) but not for NWM by phylogenetic analyses and for comparison for CEACAM1 orthologs of the same species or all NWM species. - Thus some paralogs may be optimized for one of the functions of the ances- tral gene. - As pointed out before, strong selection for diversi- fication as indicated by an excess of nonsynonymous substitutions in PSG genes [25] and an dN/dS ratio of greater than 1 in N exons of PSG in a number of pri- mates has been shown here. - Interaction of PSGs with pathogens is also sug- gested by the rapid accumulation of nonsynonymous substitutions encoding the CC’C″FG β-sheet of the N domain which is targeted by pathogen adhesins in CEACAM pathogen receptors [39]. - For identification of PSG genes regions syntenic to human PSG loci were analyzed for the presence of CEACAM Ig domain-encoding exons.. - Primate genomes were reprobed with exon sequences from newly identified PSG genes. - Although most of the genomes had been sequenced in great depth (see gen- ome coverage in Supplementary Table 1) the number of PSG genes might increase with further genome refine- ment. - PSG genes were numbered arbitrarily except for ape PSG genes for which assignment to orthologous hu- man genes was possible. - The same strategy was employed to identify other genes of the CEACAM families. - The relative expression frequencies of PSG were esti- mated by counting the clones matching N exon nucleo- tide sequences of the different PSG genes present in human, baboon (Pan anubis) and rhesus monkey (Macaca mulatta) placental EST libraries using the NCBI BLAST program as above. - In order to determine the selective pressure on the maintenance of the nucleo- tide sequences, the number of nonsynonymous nu- cleotide substitution per nonsynonymous site (dN) and the number of synonymous nucleotide substitu- tions per synonymous site (dS) were determined for PSG and CEACAM N domain and IgC-like exons.. - Evolutionary relationship of the primate species of this study. - The number of PSG genes with N exon open reading frames is indicated in red. - For the long form of the abbreviated Latin species names see Supplementary Table 1. - (A) a schematic exon organization of human, rhesus monkey and howler monkey PSG genes is shown. - Two pairs of exons encoding IgC-like A- and B-type do- mains are present in primate PSG genes. - Most of A1 and B2 exons con- tain intact consensus splice sites and open reading frames in transcribed human and rhesus monkey PSG genes. - Due to the lack of PSG transcrip- tion information in howler monkey all exons of the Apa_PSG genes were analyzed. - For howler monkey the domain organization of the expected largest PSG is shown. - Phylogenetic trees were constructed based on N domain exons nucleotide sequences of PSG genes from great ape (A), OWM (B) and NWM (C) species using the Maximum Likelihood method (MEGA6 software). - Part of orangutan and most gibbon PSG genes cluster in a paralogous manner.. - white-fronted capuchin, Cebus albifrons) NWM PSG genes form paralogous clusters. - Contains nucleotide sequences of N domain exons and accession numbers of PSG genes of all primates analyzed. - SEM: Standard error of the mean. - This funding source had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. - Recent expansion and adaptive evolution of the carcinoembryonic antigen family in bats of the Yangochiroptera subgroup.. - Structure and evolution of the mouse pregnancy-specific glycoprotein (Psg) gene locus. - Conservation of pregnancy-specific glycoprotein (PSG) N domains following independent expansions of the gene families in rodents and primates. - Widespread divergence of the CEACAM/. - PSG genes in vertebrates and humans suggests sensitivity to selection. - Direct binding of the ligand PSG17 to CD9 requires a CD9 site essential for sperm-egg fusion.. - Identification of allelic variants of the bovine immune regulatory molecule CEACAM1 implies a pathogen-driven evolution. - coli Exploit CEA to Promote Colonization of the Urogenital Tract Mucosa. - The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA. - Evolution of the rodent eosinophil- associated RNase gene family by rapid gene sorting and positive selection.
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