The Evolution of Pepsinogen C Genes in Vertebrates: Duplication, Loss and Functional Diversification

<div><h3>Background</h3><p>Aspartic proteases comprise a large group of enzymes involved in peptide proteolysis. This collection includes prominent enzymes globally categorized as pepsins, which are derived from pepsinogen precursors. Pepsins are involved in gastric digestion, a hallmark of vertebrate physiology. An important member among the pepsinogens is pepsinogen C (<em>Pgc</em>). A particular aspect of <em>Pgc</em> is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (<em>Pga</em>). Although gene sequences with similarity to <em>Pgc</em> have been described in some vertebrate groups, no exhaustive evolutionary framework has been considered so far.</p> <h3>Methodology/Principal Findings</h3><p>By combining phylogenetics and genomic analysis, we find an unexpected <em>Pgc</em> diversity in the vertebrate sub-phylum. We were able to reconstruct gene duplication timings relative to the divergence of major vertebrate clades. Before tetrapod divergence, a single <em>Pgc</em> gene tandemly expanded to produce two gene lineages (<em>Pgbc</em> and <em>Pgc2</em>). These have been differentially retained in various classes. Accordingly, we find <em>Pgc2</em> in sauropsids, amphibians and marsupials, but not in eutherian mammals. <em>Pgbc</em> was retained in amphibians, but duplicated in the ancestor of amniotes giving rise to <em>Pgb</em> and <em>Pgc1</em>. The latter was retained in mammals and probably in reptiles and marsupials but not in birds. <em>Pgb</em> was kept in all of the amniote clade with independent episodes of loss in some mammalian species. Lineage specific expansions of <em>Pgc2</em> and <em>Pgbc</em> have also occurred in marsupials and amphibians respectively. We find that teleost and tetrapod <em>Pgc</em> genes reside in distinct genomic regions hinting at a possible translocation.</p> <h3>Conclusions</h3><p>We conclude that the repertoire of <em>Pgc</em> genes is larger than previously reported, and that tandem duplications have modelled the history of <em>Pgc</em> genes. We hypothesize that gene expansion lead to functional divergence in tetrapods, coincident with the invasion of terrestrial habitats.</p> </div