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Comparative Study
. 2003 Jul 17;4(1):29.
doi: 10.1186/1471-2164-4-29.

Comparative Genomic Analysis Reveals Independent Expansion of a Lineage-Specific Gene Family in Vertebrates: The Class II Cytokine Receptors and Their Ligands in Mammals and Fish

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Free PMC article
Comparative Study

Comparative Genomic Analysis Reveals Independent Expansion of a Lineage-Specific Gene Family in Vertebrates: The Class II Cytokine Receptors and Their Ligands in Mammals and Fish

Georges Lutfalla et al. BMC Genomics. .
Free PMC article

Abstract

Background: The high degree of sequence conservation between coding regions in fish and mammals can be exploited to identify genes in mammalian genomes by comparison with the sequence of similar genes in fish. Conversely, experimentally characterized mammalian genes may be used to annotate fish genomes. However, gene families that escape this principle include the rapidly diverging cytokines that regulate the immune system, and their receptors. A classic example is the class II helical cytokines (HCII) including type I, type II and lambda interferons, IL10 related cytokines (IL10, IL19, IL20, IL22, IL24 and IL26) and their receptors (HCRII). Despite the report of a near complete pufferfish (Takifugu rubripes) genome sequence, these genes remain undescribed in fish.

Results: We have used an original strategy based both on conserved amino acid sequence and gene structure to identify HCII and HCRII in the genome of another pufferfish, Tetraodon nigroviridis that is amenable to laboratory experiments. The 15 genes that were identified are highly divergent and include a single interferon molecule, three IL10 related cytokines and their potential receptors together with two Tissue Factor (TF). Some of these genes form tandem clusters on the Tetraodon genome. Their expression pattern was determined in different tissues. Most importantly, Tetraodon interferon was identified and we show that the recombinant protein can induce antiviral MX gene expression in Tetraodon primary kidney cells. Similar results were obtained in Zebrafish which has 7 MX genes.

Conclusion: We propose a scheme for the evolution of HCII and their receptors during the radiation of bony vertebrates and suggest that the diversification that played an important role in the fine-tuning of the ancestral mechanism for host defense against infections probably followed different pathways in amniotes and fish.

Figures

Figure 1
Figure 1
Strategy for the characterization of the T. nigroviridis HCR genes
Figure 2
Figure 2
Expression pattern for the classII helical cytokine receptor genes. RNA samples were prepared from tissues, reverse transcribed and abundance of each cDNA was measured by QPCR using oligonucleotides listed in supplementary material. All data were normalized to the level of hnRNPA2 cDNA. 5% confidence in a student T test is shown. Orf4 stands for the T nigroviridis homologue of the human C21orf4 gene.
Figure 3
Figure 3
Comparative genomic mapping of the HCR genes in human and T. nigroviridis All genes are represented by an arrow that indicates the orientation of transcription. A) Clusters of HCR in the human genome. Orientation of transcription is relative to the centromere indicated on the left of the figure. MT stands for the human homolog of the S cerevisiae YDR140w gene. All genes are around 30 kb long. The MT gene is approximately 4 Mb centromeric to the IFNAR2 gene. B) The unique T. nigroviridis HCR cluster. TnC21orf4 is for the T. nigroviridis homolog of the human C21orf4 gene. TnMT is for the T. nigroviridis homolog of the S cerevisiae YDR140w gene. All genes are around 3 kb long.
Figure 4
Figure 4
Phylogenetic tree (NJ) derived from the alignment of the Tn HCR D200 domains together with the human D200s Domains from other species have been included to allow better grouping. T. nigroviridis D200s are written in red italic in order to highlight them. Branching points with bootstrap values over 80% are shown in bold. h, human; Tn, T. nigroviridis; m, mouse; r, rat; b, bovine; o, ovine and c, chicken. Alignment in Additional file: 2.
Figure 5
Figure 5
Phylogenetic tree (NJ) derived from the alignment of the fish interferons with human IFN lambda and some typeI IFNs Number and phase of introns in the corresponding genes are indicated. Symbols same as in figure 4 plus: sh, sheep; ce, Cervus elaphus (red deer); f, Fugu; gc, Giraffa camelopardalis (giraffe) and z: Danio rerio (zebrafish). Alignment in Additional file: 3.
Figure 6
Figure 6
Expression pattern of the TnIFN and TnIL10 genes and accumulation of the TnMX mRNA after IFN treatment. Results are amounts of mRNA relative to the hnRNPA2 mRNA. 5% confidence in a student T test is shown. A) TnIL10 in different tissues. B) TnIFN in different tissues in animals injected by PolyI/PolyC or PBS(basal). C) TnMX in primary kidney cells treated either with PolyI/PolyC, recombinant GFP (Green Fluorescent Protein) or recombinant TnIFN with either Nterm or Cterm 6His tag.
Figure 7
Figure 7
Schematic drawing for the diversification of the helical cytokines and their receptors during the evolution of the osteichthians. Open boxes are for coding exons, black parts for 3' and 5' non coding regions. Broken lines are for introns; their phase is indicated. For the receptors, broken boxes indicate that all D200 part of larger proteins. Exons are numbered A1 (for the first exon coding the SD100A) to B2 (second exon coding the SD100B). Conserved cysteines are indicated as vertical bars over the exon boxes. The retroposition event leading to typeI IFNs has only been observed in amniotes and is therefore labeled "amniote specific". Data from other sarcopterygians could lead to a revision.

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