Dröge J et al. (2012), Comparative genomics of neuroglobin reveals its...

ECB-ART-42638

PLoS One 2012 Jan 01;710:e47972. doi: 10.1371/journal.pone.0047972.

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Comparative genomics of neuroglobin reveals its early origins.

Dröge J , Pande A , Englander EW , Makałowski W .

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BACKGROUND: Neuroglobin (Ngb) is a hexacoordinated globin expressed mainly in the central and peripheral nervous system of vertebrates. Although several hypotheses have been put forward regarding the role of neuroglobin, its definite function remains uncertain. Ngb appears to have a neuro-protective role enhancing cell viability under hypoxia and other types of oxidative stress. Ngb is phylogenetically ancient and has a substitution rate nearly four times lower than that of other vertebrate globins, e.g. hemoglobin. Despite its high sequence conservation among vertebrates Ngb seems to be elusive in invertebrates. PRINCIPAL FINDINGS: We determined candidate orthologs in invertebrates and identified a globin of the placozoan Trichoplax adhaerens that is most likely orthologous to vertebrate Ngb and confirmed the orthologous relationship of the polymeric globin of the sea urchin Strongylocentrotus purpuratus to Ngb. The putative orthologous globin genes are located next to genes orthologous to vertebrate POMT2 similarly to localization of vertebrate Ngb. The shared syntenic position of the globins from Trichoplax, the sea urchin and of vertebrate Ngb strongly suggests that they are orthologous. A search for conserved transcription factor binding sites (TFBSs) in the promoter regions of the Ngb genes of different vertebrates via phylogenetic footprinting revealed several TFBSs, which may contribute to the specific expression of Ngb, whereas a comparative analysis with myoglobin revealed several common TFBSs, suggestive of regulatory mechanisms common to globin genes. SIGNIFICANCE: Identification of the placozoan and echinoderm genes orthologous to vertebrate neuroglobin strongly supports the hypothesis of the early evolutionary origin of this globin, as it shows that neuroglobin was already present in the placozoan-bilaterian last common ancestor. Computational determination of the transcription factor binding sites repertoire provides on the one hand a set of transcriptional factors that are responsible for the specific expression of the Ngb genes and on the other hand a set of factors potentially controlling expression of a couple of different globin genes.

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Genes referenced: LOC100887844 LOC100893907 LOC115919910 LOC583082 LOC763287 pomt2 srpl unpgl

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	Figure 1. Bayesian tree of Ngb, GbX, Cygb, GbY and several invertebrate globins.Posterior probability values are shown below branches while bootstrap support values were superimposed above the branches. Values above 50% are shown. A globin form the choanoflagellate Monosiga brevicollis was used to root the tree. For a description of used abbreviations please see Table S1.
	Figure 2. Maximum likelihood tree of several globins from D. rerio, Trichoplax and the sea urchin.Globins from D. rerio, Trichoplax and the sea urchin are highlighted in blue, red and green, respectively. Only one globin domain of the polymeric globin from the sea urchin was used for tree reconstruction. Two globins from Trichoplax (TadGb4, TadGb5) were excluded from this analysis due to doubtful annotation. The RAxML rapid bootstrapping algorithm was used applying 1000 bootstrap replicates. Bayesian posterior probability values are superimposed (bootstrap support/posterior probability). Only support values above 50% are shown. The clades of α/β-Hb were collapsed. SpuGb and TadGb1, that are located in similar gene neighborhoods as vertebrate Ngb, position next to Ngb and between Ngb and GbX, respectively. For an explanation of abbreviations please see Table S1.
	Figure 3. Gene neighborhood of vertebrate Ngb compared to the genomic localization of the putative invertebrate orthologs.Shown is the gene neighborhood of Ngb from human, mouse and chicken compared to scaffold 12 of the Trichoplax genome and scaffold 79420 of the sea urchin genome. Arrows indicate the location of the genes (right handed arrow = plus strand, left handed arrow = minus strand). Genes drawn in the same color are orthologous. Dots indicate that shown genes are separated by more than one gene. The shared syntenic position of the globin of Trichoplax, the polymeric globin from the sea urchin and of vertebrate Ngb indicates that they are orthologous.
	Figure 4. Schematic representation of the coding exon structure of selected vertebrate Ngbs and several invertebrate globins.The coding exons and the corresponding protein alignments are printed in red and blue, respectively. Black lines indicate introns. Vertebrate Ngb genes consist of four highly conserved coding exons and three introns at positions B12.2, E11.0 and G7.0. The globins from Ciona intestinalis also possess a central intron at position E10.2. However, this intron is not orthologous to the central intron in Ngb genes. Abbreviations are explained in Table S1.
	Figure 5. Ka/Ks ratios of several vertebrate Ngb proteins.Shown is a neighbor joining tree with Ka/Ks ratios indicated above the branches. Expect for branches leading to S. galili and S. judaei, no values above one were observed indicating strong purifying selection.
	Figure 6. Distribution of missense mutations over the coding sequences of Teleostei fishes.The ancestral sequence of Tetrapoda and Teleostei was used as a reference. The sum of nonsynonymous substitutions was calculated for each 30 nucleotides.
	Figure 7. Graphical overview of the results from the CONREAL search.The TFBSs are represented as blocks with different colors. The blue lines indicate the genomic sequence. The scale on the x-axis describes the position of the motifs relative to the translation initiation site. The predicted TFBSs are positionally conserved among the different analyzed vertebrates.
	Figure 8. Results of the FootPrinter motif search.Sequence logos of found motifs in Mb and Ngb genes are shown. The found motifs are G-rich and highly conserved. According to the comparison against the JASPAR database the motifs show the highest similarity to binding sites of TFs highlighted above the logos. The results of the complete phylogenetic footprinting analyses are summarized in Table1.

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