Expansion and collapse of VEGF diversity in major clades of the animal kingdom

Together with the platelet-derived growth factors (PDGFs), the vascular endothelial growth factors (VEGFs) form the PDGF/VEGF subgroup among cystine knot growth factors. The evolutionary relationships within this subgroup have not been examined thoroughly to date. Here, we comprehensively analyze the PDGF/VEGF growth factors throughout all animal phyla and propose a phylogenetic tree. Vertebrate whole-genome duplications play a role in expanding PDGF/VEGF diversity, but several limited duplications are necessary to account for the temporal pattern of emergence. The phylogenetically oldest PDGF/VEGF-like growth factor likely featured a C-terminus with a BR3P signature, a hallmark of the modern-day lymphangiogenic growth factors VEGF-C and VEGF-D. Some younger VEGF genes, such as VEGFB and PGF, appeared completely absent in important vertebrate clades such as birds and amphibia, respectively. In contrast, individual PDGF/VEGF gene duplications frequently occurred in fish on top of the known fish-specific whole-genome duplications. The lack of precise counterparts for human genes poses limitations but also offers opportunities for research using organisms that diverge considerably from humans.

Automated summary

This study comprehensively analyzed the evolutionary relationships of PDGF/VEGF growth factors and proposed a phylogenetic tree. Whole-genome duplications in vertebrates contribute to the diversity of PDGF/VEGF, but limited duplications are necessary to explain the emergence pattern. The oldest phylogenetically PDGF/VEGF-like growth factor likely had a BR3P signature in the C-terminus, similar to modern lymphangiogenic growth factors. Some younger VEGF genes are absent in specific vertebrate clades, while PDGF/VEGF gene duplications frequently occur in fish on top of fish-specific whole-genome duplications.