THE DIVERSITY AND EVOLUTIONARY RELATIONSHIPS OF THE PREGNANCY-ASSOCIATED GLYCOPROTEINS, AN ASPARTIC PROTEINASE SUBFAMILY CONSISTING OF MANYTROPHOBLAST-EXPRESSED GENES

The pregnancy-associated glycoproteins (PAGs) are structurally related to the pepsins, thought to be restricted to the hooved (ungulate) mam mals and characterized by being expressed specifically in the outer ep ithelial cell layer (chorion/trophectoderm) of the placenta, At least some PAGs are catalytically inactive as proteinases, although each app ears to possess a cleft capable of binding peptides, By cloning expres sed genes from ovine and bovine placental cDNA libraries, by Southern genomic blotting, by screening genomic libraries, and by using PCR to amplify portions of PAG genes from genomic DNA, we estimate that cattl e, sheep, and most probably all ruminant Artiodactyla possess many, po ssibly 100 or more, PAG genes, many of which are placentally expressed , The PAGs are highly diverse in sequence, with regions of hypervariab ility confined largely to surface-exposed loops, Nonsynonymous (replac ement) mutations in the regions of the genes coding for these hypervar iable loop segments have accumulated at a higher rate than synonymous (silent) mutations, Construction of distance phylograms, based on comp arisons of PAG and related aspartic proteinase amino acid sequences, s uggests that much diversification of the PAG genes occurred after the divergence of the Artiodactyla and Perissodactyla, but that at least o ne gene is represented outside the hooved species, The results also su ggest that positive selection of duplicated genes has acted to provide considerable functional diversity among the PAGs, whose presence at t he interface between the placenta and endometrium and in the maternal circulation indicates involvement in fetal-maternal interactions.