Abstract
In mammals, carcinoembryonic antigen cell adhesion molecules (CEACAMs) and pregnancy-specific glycoproteins (PSGs) play important roles in the regulation of pathogen transmission, tumorigenesis, insulin signaling turnover, and fetal–maternal interactions. However, how these genes evolved and to what extent they diverged in humans remain to be investigated specifically. Based on syntenic mapping of chordate genomes, we reveal that diverging homologs with a prototypic CEACAM architecture–including an extracellular domain with immunoglobulin variable and constant domain-like regions, and an intracellular domain containing ITAM motif–are present from cartilaginous fish to humans, but are absent in sea lamprey, cephalochordate or urochordate. Interestingly, the CEACAM/PSG gene inventory underwent radical divergence in various vertebrate lineages: from zero in avian species to dozens in therian mammals. In addition, analyses of genetic variations in human populations showed the presence of various types of copy number variations (CNVs) at the CEACAM/PSG locus. These copy number polymorphisms have 3–80% frequency in select populations, and encompass single to more than six PSG genes. Furthermore, we found that CEACAM/PSG genes contain a significantly higher density of nonsynonymous single nucleotide polymorphism (SNP) compared to the chromosome average, and many CEACAM/PSG SNPs exhibit high population differentiation. Taken together, our study suggested that CEACAM/PSG genes have had a more dynamic evolutionary history in vertebrates than previously thought. Given that CEACAM/PSGs play important roles in maternal–fetal interaction and pathogen recognition, these data have laid the groundwork for future analysis of adaptive CEACAM/PSG genotype-phenotypic relationships in normal and complicated pregnancies as well as other etiologies.
Highlights
Carcinoembryonic antigen cell adhesion molecules (CEACAMs) and pregnancy-specific glycoproteins (PSGs; known as Schwangerschafts Protein 1) are characterized by an N-terminal immunoglobulin variable domain-like region followed by a varied number of immunoglobulin constant domain-like structures
These earlier observations suggested that the duplication/retention of CEACAM/PSG genes could be susceptible to environmental selection, and the process could be similar to the birth, fixation, and loss of adaptive genes such as olfactory receptors and killer-cell immunoglobulin-like receptors (KIRs) in select vertebrates [24,25,26]
We found that human CEACAM/PSG locus is enriched with genetic variations, and the PSG gene inventory could range from 12 to 30 copies among individuals, indicating an ongoing selection of these genes in major, geographically separated human populations
Summary
Carcinoembryonic antigen cell adhesion molecules (CEACAMs) and pregnancy-specific glycoproteins (PSGs; known as Schwangerschafts Protein 1) are characterized by an N-terminal immunoglobulin variable domain-like region followed by a varied number of immunoglobulin constant domain-like structures. Earlier studies of nucleotide substitution and the dN/dS ratio in primates and rodents showed that select CEACAM/PSG genes underwent positive or purifying selection [22,23]. These earlier observations suggested that the duplication/retention of CEACAM/PSG genes could be susceptible to environmental selection, and the process could be similar to the birth, fixation, and loss of adaptive genes such as olfactory receptors and killer-cell immunoglobulin-like receptors (KIRs) in select vertebrates [24,25,26]. Because the analysis of nucleotide or amino acid selection across closely related species provides only a rough estimate of genetic variation within a narrow time frame, how unique the evolution of CEACAM/PSG genes in vertebrates remains to be investigated. Because PSGs and CEACAMs are important for normal pregnancy and immune responses, our study provides a framework for further exploration of adaptive genotype–phenotype relationships involving these fast-evolving genes in reproduction, pregnancy complications, and other patho-physiologies in humans
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