Molecular phylogeny of the antiangiogenic and neurotrophic serpin, pigment epithelium derived factor in vertebrates.
BACKGROUND
Pigment epithelium derived factor (PEDF), a member of the serpin family, regulates cell proliferation, promotes survival of neurons, and blocks growth of new blood vessels in mammals. Defining the molecular phylogeny of PEDF by bioinformatic analysis is one approach to understanding the link between its gene structure and its function in these biological processes.


RESULTS
From a comprehensive search of available DNA databases we identified a single PEDF gene in all vertebrate species examined. These included four mammalian and six non-mammalian vertebrate species in which PEDF had not previously been described. A five gene cluster around PEDF was found in an approximate 100 kb region in mammals, birds, and amphibians. In ray-finned fish these genes are scattered over three chromosomes although only one PEDF gene was consistently found. The PEDF gene is absent in invertebrates including Drosophila melanogaster (D. melanogaster), Caenorhabditis elegans (C. elegans), and sea squirt (C. intestinalis). The PEDF gene is transcribed in all vertebrate phyla, suggesting it is biologically active throughout vertebrate evolution. The multiple actions of PEDF are likely conserved in evolution since it has the same gene structure across phyla, although the size of the gene ranges from 48.3 kb in X. tropicalis to 2.9 kb in fugu, with human PEDF at a size of 15.6 kb. A strong similarity in the proximal 200 bp of the PEDF promoter in mammals suggests the existence of a possible regulatory region across phyla. Using a non-synonymous/synonymous substitution rate ratio we show that mammalian and fish PEDFs have similar ratios of <0.13, reflecting a strong purifying selection of PEDF gene. A large number of repetitive transposable elements of the SINE and LINE class were found with random distribution in both the promoter and introns of mammalian PEDF.


CONCLUSIONS
The PEDF gene first appears in vertebrates and our studies suggest that the regulation and biological actions of this gene are preserved across vertebrates. This comprehensive analysis of the PEDF gene across phyla provides new information that will aid further characterization of common functional motifs of this serpin in biological processes.
Xu
Xuming
X
Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06520, USA. xuming.xu@yale.edu
Zhang
Samuel Shao-Min
SS
Barnstable
Colin J
CJ
Tombran-Tink
Joyce
J
D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005399:Fishes / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007438:Introns / Q000235:genetics; D008322:Mammals / Q000235:genetics; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009414:Nerve Growth Factors / Q000235:genetics*; D010802:Phylogeny; D011401:Promoter Regions, Genetic / Q000235:genetics; D016415:Sequence Alignment / Q000379:methods; D012689:Sequence Homology, Nucleic Acid; D015843:Serpins / Q000235:genetics*; D014714:Vertebrates / Q000145:classification / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
D004251:DNA Transposable Elements; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor