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The evolution of pepsinogen C genes in vertebrates: duplication, loss and functional diversification.

Castro LF, Lopes-Marques M, Gonçalves O, Wilson JM - PLoS ONE (2012)

Bottom Line: A particular aspect of Pgc is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (Pga).We find that teleost and tetrapod Pgc genes reside in distinct genomic regions hinting at a possible translocation.We conclude that the repertoire of Pgc genes is larger than previously reported, and that tandem duplications have modelled the history of Pgc genes.

View Article: PubMed Central - PubMed

Affiliation: CIMAR Associate Laboratory, CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, UPorto-University of Porto, Porto, Portugal. filipe.castro@ciimar.up.pt

ABSTRACT

Background: 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 (Pgc). A particular aspect of Pgc is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (Pga). Although gene sequences with similarity to Pgc have been described in some vertebrate groups, no exhaustive evolutionary framework has been considered so far.

Methodology/principal findings: By combining phylogenetics and genomic analysis, we find an unexpected Pgc 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 Pgc gene tandemly expanded to produce two gene lineages (Pgbc and Pgc2). These have been differentially retained in various classes. Accordingly, we find Pgc2 in sauropsids, amphibians and marsupials, but not in eutherian mammals. Pgbc was retained in amphibians, but duplicated in the ancestor of amniotes giving rise to Pgb and Pgc1. The latter was retained in mammals and probably in reptiles and marsupials but not in birds. Pgb was kept in all of the amniote clade with independent episodes of loss in some mammalian species. Lineage specific expansions of Pgc2 and Pgbc have also occurred in marsupials and amphibians respectively. We find that teleost and tetrapod Pgc genes reside in distinct genomic regions hinting at a possible translocation.

Conclusions: We conclude that the repertoire of Pgc genes is larger than previously reported, and that tandem duplications have modelled the history of Pgc genes. We hypothesize that gene expansion lead to functional divergence in tetrapods, coincident with the invasion of terrestrial habitats.

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Multiple sequence alignment of vertebrate Pgc-like sequences performed in Geneious V5.5.6 using Clustal plugin with Gonnet scoring matrix and the following parameters: Gap opening = 10, Gap extension = 0.2.The red bar indicates signal peptide, blue bar activation segment or propeptide, yellow boxes highly conserved residues of the propeptide [3], light green boxes residues (pLys37 pTyr38 and Tyr9) involved in interactions that block access to the catalytic aspartates at neutral pH [1] black boxes “+” conserved catalytic aspartates (Asp32 and Asp217), orange bridges six conserved cysteines involved in the formation of disulphide linkages (Cys45, Cys50, Cys208, Cys212, Cys251, Cys284), grey boxes residues reported to be involved in pepsinogen B substrate specifity [13] and underlining black boxes sequence features specific to fish pepsinogens (All coordinates are relative to human PGC).
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pone-0032852-g001: Multiple sequence alignment of vertebrate Pgc-like sequences performed in Geneious V5.5.6 using Clustal plugin with Gonnet scoring matrix and the following parameters: Gap opening = 10, Gap extension = 0.2.The red bar indicates signal peptide, blue bar activation segment or propeptide, yellow boxes highly conserved residues of the propeptide [3], light green boxes residues (pLys37 pTyr38 and Tyr9) involved in interactions that block access to the catalytic aspartates at neutral pH [1] black boxes “+” conserved catalytic aspartates (Asp32 and Asp217), orange bridges six conserved cysteines involved in the formation of disulphide linkages (Cys45, Cys50, Cys208, Cys212, Cys251, Cys284), grey boxes residues reported to be involved in pepsinogen B substrate specifity [13] and underlining black boxes sequence features specific to fish pepsinogens (All coordinates are relative to human PGC).

Mentions: Pgc sequences were identified in the Ensembl and GenBank databases for the following species with genome sequences available: Homo sapiens (human), Pan troglodytes (common chimpanzee), Gorilla gorilla (Gorilla), Loxodonta fricana (African savanna elephant), Sus scrofa (pig), Mus musculus (mouse), Rattus norvegicus (brown rat), Monodelphis domestica (opossum), Xenopus tropicalis (western clawed frog), Anolis carolinensis (anolis), Gallus gallus (chicken), Meleagris gallopavo (turkey), Tetraodon nigroviridis (green spotted puffer), Takifugu rubripes (pufferfish), Danio rerio (zebrafish), Oryzias latipes (medaka) and Gasterosteus aculeatus (stickleback). To identify non-annotated genes Blastp searches were performed using the human PGC protein sequence. Blast searches to EST databases (when available) were also implemented. Sequences previously described in organisms (teleosts) without genome sequences were also incorporated in the phylogenetic analysis. Accession numbers for the sequences are listed in Table 1. The alignment provided in Fig. 1 was performed in Geneious V5.4.6 [12] with the Clustal plugin (settings below).


The evolution of pepsinogen C genes in vertebrates: duplication, loss and functional diversification.

Castro LF, Lopes-Marques M, Gonçalves O, Wilson JM - PLoS ONE (2012)

Multiple sequence alignment of vertebrate Pgc-like sequences performed in Geneious V5.5.6 using Clustal plugin with Gonnet scoring matrix and the following parameters: Gap opening = 10, Gap extension = 0.2.The red bar indicates signal peptide, blue bar activation segment or propeptide, yellow boxes highly conserved residues of the propeptide [3], light green boxes residues (pLys37 pTyr38 and Tyr9) involved in interactions that block access to the catalytic aspartates at neutral pH [1] black boxes “+” conserved catalytic aspartates (Asp32 and Asp217), orange bridges six conserved cysteines involved in the formation of disulphide linkages (Cys45, Cys50, Cys208, Cys212, Cys251, Cys284), grey boxes residues reported to be involved in pepsinogen B substrate specifity [13] and underlining black boxes sequence features specific to fish pepsinogens (All coordinates are relative to human PGC).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3298455&req=5

pone-0032852-g001: Multiple sequence alignment of vertebrate Pgc-like sequences performed in Geneious V5.5.6 using Clustal plugin with Gonnet scoring matrix and the following parameters: Gap opening = 10, Gap extension = 0.2.The red bar indicates signal peptide, blue bar activation segment or propeptide, yellow boxes highly conserved residues of the propeptide [3], light green boxes residues (pLys37 pTyr38 and Tyr9) involved in interactions that block access to the catalytic aspartates at neutral pH [1] black boxes “+” conserved catalytic aspartates (Asp32 and Asp217), orange bridges six conserved cysteines involved in the formation of disulphide linkages (Cys45, Cys50, Cys208, Cys212, Cys251, Cys284), grey boxes residues reported to be involved in pepsinogen B substrate specifity [13] and underlining black boxes sequence features specific to fish pepsinogens (All coordinates are relative to human PGC).
Mentions: Pgc sequences were identified in the Ensembl and GenBank databases for the following species with genome sequences available: Homo sapiens (human), Pan troglodytes (common chimpanzee), Gorilla gorilla (Gorilla), Loxodonta fricana (African savanna elephant), Sus scrofa (pig), Mus musculus (mouse), Rattus norvegicus (brown rat), Monodelphis domestica (opossum), Xenopus tropicalis (western clawed frog), Anolis carolinensis (anolis), Gallus gallus (chicken), Meleagris gallopavo (turkey), Tetraodon nigroviridis (green spotted puffer), Takifugu rubripes (pufferfish), Danio rerio (zebrafish), Oryzias latipes (medaka) and Gasterosteus aculeatus (stickleback). To identify non-annotated genes Blastp searches were performed using the human PGC protein sequence. Blast searches to EST databases (when available) were also implemented. Sequences previously described in organisms (teleosts) without genome sequences were also incorporated in the phylogenetic analysis. Accession numbers for the sequences are listed in Table 1. The alignment provided in Fig. 1 was performed in Geneious V5.4.6 [12] with the Clustal plugin (settings below).

Bottom Line: A particular aspect of Pgc is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (Pga).We find that teleost and tetrapod Pgc genes reside in distinct genomic regions hinting at a possible translocation.We conclude that the repertoire of Pgc genes is larger than previously reported, and that tandem duplications have modelled the history of Pgc genes.

View Article: PubMed Central - PubMed

Affiliation: CIMAR Associate Laboratory, CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, UPorto-University of Porto, Porto, Portugal. filipe.castro@ciimar.up.pt

ABSTRACT

Background: 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 (Pgc). A particular aspect of Pgc is its apparent single copy status, which contrasts with the numerous gene copies found for example in pepsinogen A (Pga). Although gene sequences with similarity to Pgc have been described in some vertebrate groups, no exhaustive evolutionary framework has been considered so far.

Methodology/principal findings: By combining phylogenetics and genomic analysis, we find an unexpected Pgc 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 Pgc gene tandemly expanded to produce two gene lineages (Pgbc and Pgc2). These have been differentially retained in various classes. Accordingly, we find Pgc2 in sauropsids, amphibians and marsupials, but not in eutherian mammals. Pgbc was retained in amphibians, but duplicated in the ancestor of amniotes giving rise to Pgb and Pgc1. The latter was retained in mammals and probably in reptiles and marsupials but not in birds. Pgb was kept in all of the amniote clade with independent episodes of loss in some mammalian species. Lineage specific expansions of Pgc2 and Pgbc have also occurred in marsupials and amphibians respectively. We find that teleost and tetrapod Pgc genes reside in distinct genomic regions hinting at a possible translocation.

Conclusions: We conclude that the repertoire of Pgc genes is larger than previously reported, and that tandem duplications have modelled the history of Pgc genes. We hypothesize that gene expansion lead to functional divergence in tetrapods, coincident with the invasion of terrestrial habitats.

Show MeSH