Abstract
BackgroundForkhead box, class O (FoxO) belongs to the large family of forkhead transcription factors that are characterized by a conserved forkhead box DNA-binding domain. To date, the FoxO group has four mammalian members: FoxO1, FoxO3a, FoxO4 and FoxO6, which are orthologs of DAF16, an insulin-responsive transcription factor involved in regulating longevity of worms and flies. The degree of homology between these four members is high, especially in the forkhead domain, which contains the DNA-binding interface. Yet, mouse FoxO knockouts have revealed that each FoxO gene has its unique role in the physiological process. Whether the functional divergences are primarily due to adaptive selection pressure or relaxed selective constraint remains an open question. As such, this study aims to address the evolutionary mode of FoxO, which may lead to the functional divergence.ResultsSequence similarity searches have performed in genome and scaffold data to identify homologues of FoxO in vertebrates. Phylogenetic analysis was used to characterize the family evolutionary history by identifying two duplications early in vertebrate evolution. To determine the mode of evolution in vertebrates, we performed a rigorous statistical analysis with FoxO gene sequences, including relative rate ratio tests, branch-specific dN/dS ratio tests, site-specific dN/dS ratio tests, branch-site dN/dS ratio tests and clade level amino acid conservation/variation patterns analysis. Our results suggest that FoxO is constrained by strong purifying selection except four sites in FoxO6, which have undergone positive Darwinian selection. The functional divergence in this family is best explained by either relaxed purifying selection or positive selection.ConclusionWe present a phylogeny describing the evolutionary history of the FoxO gene family and show that the genes have evolved through duplications followed by purifying selection except for four sites in FoxO6 fixed by positive selection lie mostly within the non-conserved optimal PKB motif in the C-terminal part. Relaxed selection may play important roles in the process of functional differentiation evolved through gene duplications as well.
Highlights
Forkhead box, class O (FoxO) belongs to the large family of forkhead transcription factors that are characterized by a conserved forkhead box DNA-binding domain
Inclusion of these did not improve the reliability of the phylogeny, and as the aim of this study was to determine the evolutionary history of the FoxO gene family, only representatives from the major vertebrate clades were included
Phylogenetic analyses of FoxO gene lineages To study the molecular evolution of vertebrate FoxO genes, we carried out phylogenetic inference analyses based on codon alignment and inferred their evolutionary history using Bayesian methods
Summary
Class O (FoxO) belongs to the large family of forkhead transcription factors that are characterized by a conserved forkhead box DNA-binding domain. As transcription factors in the nucleus, the primary function of FoxO proteins is to bind to their cognate DNA targeting sequences as monomers. The co-crystal structure of HNF3γ with DNA shows that there are 14 protein-DNA contacts distributing throughout the forkhead domain, but the third α-helix (H3) plays the most important role in a winged helix/forkhead protein's DNA-binding specificity [4] Both winged loops make important interactions with DNA [4,5]. Functional FRE sites that match this consensus sequence have been identified in the promoters of many genes, such as Fas ligand (FasL), insulin-like growth factor binding protein 1 (IGFBP1) and the apoptotic regulator BIM[9,10]. FoxO6 is the latest member of the FoxO family to be cloned and shares significant sequence similarity with the other members of the family [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
