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Though pluripotency is well characterized in mammals, many questions remain to be resolved regarding its evolutionary history. A necessary prerequisite for addressing this issue is to determine the phylogenetic distributions and orthology relationships of the transcription factor families sustaining or modulating this property. In mammals, the NANOG homeodomain transcription factor is one of the core players in the pluripotency network. However, its evolutionary history has not been thoroughly studied, hindering the interpretation of comparative studies. To date, the NANOG family was thought to be monogenic, with numerous pseudogenes described in mammals, including a tandem duplicate in Hominidae. By examining a wide-array of craniate genomes, we provide evidence that the NANOG family arose at the latest in the most recent common ancestor of osteichthyans and that NANOG genes are frequently found as tandem duplicates in sarcopterygians and as a single gene in actinopterygians. Their phylogenetic distribution is thus reminiscent of that recently shown for Class V POU paralogues, another key family of pluripotency-controlling factors. However, while a single ancestral duplication has been reported for the Class V POU family, we suggest that multiple independent duplication events took place during evolution of the NANOG family. These multiple duplications could have contributed to create a layer of complexity in the control of cell competence and pluripotency, which could explain the discrepancies relative to the functional evolution of this important gene family. Further, our analysis does not support the hypothesis that loss of NANOG and emergence of the preformation mode of primordial germ cell specification are causally linked. Our study therefore argues for the need of further functional comparisons between NANOG paralogues, notably regarding the novel duplicates identified in sauropsids and non-eutherian mammals.
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???displayArticle.pmcLink???PMC3894937 ???displayArticle.link???PLoS One
Figure 2. Simplified synteny of NANOG loci in osteichthyans.The synteny of the loci where NANOG orthologues are found in actinopterygians (TMSF9 - IPO4 region) and sarcopterygians (SLC2A3 - AICDA region) are shown on the left-hand and right-hand sides, respectively. The relevant chromosomes or gene scaffolds are given. The figure is not drawn to scale, âemptyâ spaces along the chromosomes (e.g. between TM9SF1 and IPO4 in sarcopterygians) do not reflect actual distances but are meant to facilitate comparisons. Double slashes (//) denote that intervening genes were omitted for simplicity (e.g. between FEN1 and IPO4 in Danio rerio). In species in which two NANOG paralogues were found, numbers indicate which paralogue was named âNANOG1â or âNANOG2â in this work (note that these names do not imply orthologous relationships). This region contains multiple paralogues of NANOG, AICDA and SLC2A3 in Guinea pig; and of both NANOG (NANOGP1, P1 on the figure) and SLC2A3 (named SLC2A14, A14 on the figure) in Hominidae. More detailed information regarding these two regions is listed in File S2, including coordinates for the genes presented on this figure.
Figure 1. Phylogenetic analysis of NANOG paralogues in osteichthyans.Translated sequences of exons 2 and 3 were analyzed by Maximum Likelihood and Bayesian inference. Here we show a strict consensus tree, using the scaffold of the ML tree. Branch support was assessed and is given next to the relevant branches (top number: aLRT for the ML analysis and bottom number PP for the Bayesian analysis). The actinopterygian sequences form a monophyletic group that was used to root the tree. Duplicates are highlighted in red. Note that two paralogues are found in coelacanth (Latimeria chalumnae), Archosaurs (Alligator mississipiensis; Gallus gallus; Meleagris gallopavo; Taeniopygia guttata; Melopsittacus undulates; Anas platyrhynchos; Geospiza fortis; Ficedula albicollis), Testudines (Pelodiscus sinensis, Chrysemys picta belli), platypus (Ornithorhynchus anatinus), Tasmanian devil (Sarcophilus harrisii), Guinea pig (Cavia porcellus), Hominidae (Pan troglodytes; Homo sapiens) and spotted gar (Lepisosteus oculatus). The topology suggests that independent duplication events occurred in the three latter clades.
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