2/28/2024 0 Comments Modes of evolution gtrIndeed, 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. Although the molecular basis of the DNA-binding specificity of FoxO transcription factors is poorly understood, high-affinity DNA-binding studies have identified a consensus FoxO-recognized element (FRE) as (G/C) (T/A)AA(C/T)AA. In addition, both winged loops also make important interactions with DNA. ![]() The co-crystal structure of HNF-3γ 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. As transcription factors in the nucleus, the primary function of FoxO proteins is to bind to their cognate DNA targeting sequences as monomers. Since then, the discovery of mammalian FoxO genes has grown rapidly, now FoxO proteins have been identified in several different organisms, including zebrafish, mouse, rat and human. FOXO1 is the first identified member of the FoxO family of transcription factors and is involved in the transcriptional activity of alveolar rhabdomyosarcomas. Mammalian FoxO proteins (FoxO1, FoxO3a, FoxO4 and FoxO6) which are homologous to Caenorhabditis elegans protein DAF-16, belong to the O ('other') class of the Fox superfamily. Relaxed selection may play important roles in the process of functional differentiation evolved through gene duplications as well. We 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. The functional divergence in this family is best explained by either relaxed purifying selection or positive selection. Our results suggest that FoxO is constrained by strong purifying selection except four sites in FoxO6, which have undergone positive Darwinian selection. 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 d N/ d Sratio tests, site-specific d N/ d Sratio tests, branch-site d N/ d Sratio tests and clade level amino acid conservation/variation patterns analysis. Phylogenetic analysis was used to characterize the family evolutionary history by identifying two duplications early in vertebrate evolution. Sequence similarity searches have performed in genome and scaffold data to identify homologues of FoxO in vertebrates. As such, this study aims to address the evolutionary mode of FoxO, which may lead to the functional divergence. Whether the functional divergences are primarily due to adaptive selection pressure or relaxed selective constraint remains an open question. Yet, mouse FoxO knockouts have revealed that each FoxO gene has its unique role in the physiological process. The degree of homology between these four members is high, especially in the forkhead domain, which contains the DNA-binding interface. 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. ![]() 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.
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