The RAF oncogenes of vertebrates are ohnologs that derive from the two rounds of whole-genome duplications early in vertebrate evolution

Abstract

The Rapidly Accelerated Fibrosarcoma (RAF) kinases are part of large group of serine/threonine-specific protein kinases that play important roles in cell differentiation and organism development. Animal RAF kinases are key connectors in the signaling cascade that links the small G protein RAS and the Mitogen-activated protein kinase phosphorylation pathway. Mutations in the RAF genes have been linked to a number of cancers including melanoma, lung cancer, colorectal cancer, thyroid cancer, and ovarian cancer. Most animals possess a single RAF gene, but vertebrates have three RAF genes in their genomes, named as A-, B-, and C-RAF, the latter also known as RAF-1. The emergence of the multiple copies of vertebrate RAFs is not well resolved, on the one hand, because of sequence and functional similarities, some authors speculate that vertebrate B-Raf is most closely related to the RAF genes of the fruit fly and Caenorhabditis elegans, whereas a competing hypothesis is that the A-, B- and C-RAF paralogs emerged from the two rounds of whole genome duplications that occurred early in the evolution of vertebrates. We applied a comparative approach grounded in synteny and phylogenetic analyses to evaluate these two scenarios. Our results are consistent with the hypothesis that the RAF genes of vertebrates are paralogs generated by whole genome duplications. Thus, the functional similarities between vertebrate B-RAF and invertebrate RAF probably reflect the retention of ancestral characters. Interestingly, data from the literature indicate that B-RAF is the paralog that associated with cancer more strongly, and also yields the most severe phenotypes when knocked out.