Dataset Information

Origin and diversification of the plasminogen activation system among chordates.

ABSTRACT:

Background

The plasminogen (PLG) activation system is composed by a series of serine proteases, inhibitors and several binding proteins, which together control the temporal and spatial generation of the active serine protease plasmin. As this proteolytic system plays a central role in human physiology and pathophysiology it has been extensively studied in mammals. The serine proteases of this system are believed to originate from an ancestral gene by gene duplications followed by domain gains and deletions. However, the identification of ancestral forms in primitive chordates supporting these theories remains elusive. In addition, evolutionary studies of the non-proteolytic members of this system are scarce.

Results

Our phylogenetic analyses place lamprey PLG at the root of the vertebrate PLG-group, while lamprey PLG-related growth factors represent the ancestral forms of the jawed-vertebrate orthologues. Furthermore, we find that the earliest putative orthologue of the PLG activator group is the hyaluronan binding protein 2 (HABP2) gene found in lampreys. The prime plasminogen activators (tissue- and urokinase-type plasminogen activator, tPA and uPA) first occur in cartilaginous fish and phylogenetic analyses confirm that all orthologues identified compose monophyletic groups to their mammalian counterparts. Cartilaginous fishes exhibit the most ancient vitronectin of all vertebrates, while plasminogen activator inhibitor 1 (PAI-1) appears for the first time in cartilaginous fishes and is conserved in the rest of jawed vertebrate clades. PAI-2 appears for the first time in the common ancestor of reptiles and mammals, and represents the latest appearing plasminogen activator inhibitor. Finally, we noted that the urokinase-type plasminogen activator receptor (uPAR)-and three-LU domain containing genes in general-occurred later in evolution and was first detectable after coelacanths.

Conclusions

This study identifies several primitive orthologues of the mammalian plasminogen activation system. These ancestral forms provide clues to the origin and diversification of this enzyme system. Further, the discovery of several members-hitherto unknown in mammals-provide new perspectives on the evolution of this important enzyme system.

SUBMITTER: Chana-Munoz A

PROVIDER: S-EPMC6337849 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Understanding the origins of genome content has long been a goal of molecular evolution and comparative genomics. By examining genome evolution through the guise of lineage-specific evolution, it is possible to make inferences about the evolutionary events that have given rise to species-specific diversification. Here we characterize the evolutionary trends found in chordate species using The Adaptive Evolution Database (TAED). TAED is a database of phylogenetically indexed gene families designed to detect episodes of directional or diversifying selection across chordates. Gene families within the database have been assessed for lineage-specific estimates of dN/dS and have been reconciled to the chordate species to identify retained duplicates. Gene families have also been mapped to the functional pathways and amino acid changes which occurred on high dN/dS lineages have been mapped to protein structures. RESULTS:An analysis of this exhaustive database has enabled a characterization of the processes of lineage-specific diversification in chordates. A pathway level enrichment analysis of TAED determined that pathways most commonly found to have elevated rates of evolution included those involved in metabolism, immunity, and cell signaling. An analysis of protein fold presence on proteins, after normalizing for frequency in the database, found common folds such as Rossmann folds, Jelly Roll folds, and TIM barrels were overrepresented on proteins most likely to undergo directional selection. A set of gene families which experience increased numbers of duplications within short evolutionary times are associated with pathways involved in metabolism, olfactory reception, and signaling. An analysis of protein secondary structure indicated more relaxed constraint in β-sheets and stronger constraint on alpha Helices, amidst a general preference for substitutions at exposed sites. Lastly a detailed analysis of the ornithine decarboxylase gene family, a key enzyme in the pathway for polyamine synthesis, revealed lineage-specific evolution along the lineage leading to Cetacea through rapid sequence evolution in a duplicate gene with amino acid substitutions causing active site rearrangement. CONCLUSION:Episodes of lineage-specific evolution are frequent throughout chordate species. Both duplication and directional selection have played large roles in the evolution of the phylum. TAED is a powerful tool for facilitating this understanding of lineage-specific evolution.