Evolution of the ferritin family in vertebrates

Ferritins are ubiquitous, highly-conserved proteins that constitute one of the most important components of the cellular machinery devoted to the management of iron levels. Various ferritins have been described in vertebrates, though their exact functions and phylogenetic relationships remain to be established. Our attempts to properly annotate two ferritin subunits isolated from the Asian sea bass Lates calcarifer, prompted us to investigate the evolutionary relationships among vertebrate ferritins and their relationships with non-vertebrate homologs. We carried out a detailed screening of mined ferritin sequences by examining the regulatory elements and gene structures. Subsequently, we performed comprehensive phylogenetic analyses involving the various metazoan and vertebrate ferritin chain types, respectively. Our analyses suggest that a single ferritin chain duplicated in the early vertebrates and that the various ferritin chain types in vertebrate and non-vertebrate species evolved independently through lineage-specific duplications. Notably, this includes the mitochondrial ferritin found only in insects and mammals that we show to result from two parallel lineage-specific duplications followed by convergent events of mitochondrial targeting. Regarding the various cytosolic ferritin chains in vertebrates, our results suggest a scenario of a duplication at the base of vertebrates followed by more recent duplications in teleosts and amphibians. This scenario implies that the light chain in mammals is orthologous to the middle chain in teleosts, in contrast to previous claims of a paralogous relationship coupled with differential gene loss. We hypothesise that the extensive differences in sequence and function between these two orthologous chains may have been driven by the adaptation of tetrapods to terrestrial environments, which involved changes in the dynamics of iron uptake and storage. Altogether, our analyses clarify the evolutionary relationships among vertebrate ferritins and pave the way for the interpretation of functional adaptations within an evolutionary framework.