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Chemokines, relatively small secreted proteins, are involved in cell migration and function in various biological events, including immunity, morphogenesis, and disease. Due to their nature, chemokines tend to be a target of hijacking of immunity by virus and therefore show an exceptionally high mutation rate. Xenopus laevis is considered an excellent model to investigate the effect of whole-genome duplication for gene family evolution. Because its allotetraploidization occurred around 17-18 million years ago, ancestral subgenomes L and S were well conserved. Based on the gene model of human and diploid frog Xenopus tropicalis, we identified 52 chemokine genes and 26 chemokine receptors in X. laevis. The retention rate of the gene in the X. laevis L and S subgenomes was 96% (45/47) and 68% (32/47), respectively. We conducted molecular phylogenetic analysis and found clear orthologies in all receptor genes but not in the ligand genes, suggesting rapid divergences of the ligand. dN/dS calculation demonstrated that dN/dS ratio greater than one was observed in the four ligand genes, cxcl8b.1.S, cxcl18.S, ccl21.S, and xcl1.L, but nothing in receptor genes. These results revealed that the whole-genome duplication promotes diversification of chemokine ligands in X. laevis while conserving the genes necessary for homeostasis, suggesting that selective pressure also supports a rapid divergence of the chemokines in amphibians.
FIGURE 1. Genomic organization of Xenopus chemokines. Positions of chemokine genes (open triangles) and flanking genes (closed triangles) with direction are indicated in the order of Xenopus chromosome numbers. Chromosomes Abbreviations. HSA: H. sapiens (black lines); XTR: X. tropicalis (green lines); XLA_L and XLA_S: X. laevis L and S subgenome (red and blue lines), respectively. Sc is a scaffold number that is unbuilt in the chromosome assembly. The homologous relationship presented by connected lines was analyzed phylogenetically. The dotted line with N represents the genes unidentified with N-gap. Triangles drawn with dotted line show fossil genes (f).
FIGURE 2. Genomic organization of Xenopus chemokine receptors. Representation is the same as Figure 1.
FIGURE 3. Phylogenetic tree of chemokine ligands. The tree indicates 154 chemokine proteins, including 52 of X. laevis, 30 of X. tropicalis, 24 of G. Gallus, and 48 of H. sapiens genes. Chemokine names related to Xenopus represented on the arcs. Bootstrap values greater than 50% were indicated, and asterisks show values greater than 90%. The alignment of chemokine proteins was prepared using CLUSTAL omega. Maximum likelihood methods using full-length were performed with 1,000 bootstraps using JTT with Gamma-distributed model, and inference option was a nearest-neighbor interchange method on NJ tree.
FIGURE 4. Phylogenetic tree of chemokine receptors. The tree indicates 82 chemokine receptor proteins, including 26 of X. laevis, 17 of X. tropicalis, 17 of G. Gallus, and 22 of H. sapiens genes. Receptor names represented on the arcs. Bootstrap values greater than 50% were indicated, and asterisks show values greater than 90%. The alignment of the receptor proteins was prepared using clustal omega and trimmed manually as 297 peptides with gaps. Maximum likelihood methods were performed with 1,000 bootstraps using the JTT model with Gamma distribution and invariant sites and complete deletion of gaps/missing data and inference option was a nearest-neighbor interchange method on NJ tree.
FIGURE 5. Expression profiles during oogenesis and embryogenesis. Genes with a max TMP value of 5 or higher during oogenesis and embryogenesis are presented. Expression profiles for X. tropicalis were obtained from Tan et al. (2013). Unfortunately, cxcl8, cxcl13a, and ccl42c have no expression profile of X. tropicalis. The vertical axis shows the expression level (TPM), and the horizontal axis is the developmental stages of X. laevis, X. tropicalis indicated within parentheses. All TPM values are shown in Supplementary Table S1. Orthologous family names and results of transcriptome correlation analysis are indicated on the upper left of each graph. Symbols. Square: X. tropicalis (green); circle,: X. laevis L-clutch T (red); diamond: X. laevis L-clutch U (magenta); triangle: X. laevis S-clutch T (blue); reverse triangle: X. laevis S-clutch U (cyan). Note that the TPM value of X. tropicalis in cxcl12 was indicated one-fifth scale to increase the resolution (x5).
FIGURE 6. Expression profiles in adult tissues. log2 transformed TPM values in Clutch T and Clutch U [log2 (TPM+1)] of all chemokine ligand and receptor genes of brain, eye, lung, stomach, intestine, liver, pancreas, kidney, testis, ovary, heart, muscle, skin, and spleen are presented with heat maps. For each homeologous pair, transcriptome correlation groups are indicated on the right side of panels. In cases of the “inc.” group, their details are described with parentheses. If results from two clutches showed half-consistency, their common results are indicated (HC or SE). Singletons were presented in the separated panels. All TPM values are shown in Supplementary Table S1.
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