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Molecular Cloning of C4 Gene and Identification of the Class III Complement Region in the Shark MHC ¹

Tokio Terado^*, Kazuhiko Okamura, Yuko Ohta, Dong-Ho Shin, Sylvia L. Smith, Keiichiro Hashimoto, Tadashi Takemoto^*, Mayumi I. Nonaka^¶, Hiroshi Kimura^*, Martin F. Flajnik and Masaru Nonaka^2,¶

^* Department of Experimental Radiology, Shiga University of Medical Science, Ohtsu-shi, Shiga, Japan; Institute for Comprehensive Medical Science, Fujita Health University, Toyooka, Aichi, Japan; Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201; Department of Biological Sciences, Florida International University, Miami, FL 33199; and ^¶ Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan

	Abstract

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To clarify the evolutionary origin of the linkage of the MHC class III complement genes with the MHC class I and II genes, we isolated C4 cDNA from the banded hound shark (Triakis scyllium). Upon phylogenetic tree analysis, shark C4 formed a well-supported cluster with C4 of higher vertebrates, indicating that the C3/C4 gene duplication predated the divergence of cartilaginous fish from the main line of vertebrate evolution. The deduced amino acid sequence predicted the typical C4 three-subunits chain structure, but without the histidine residue catalytic for the thioester bond, suggesting the human C4A-like specificity. The linkage analysis of the complement genes, one C4 and two factor B (Bf) genes, to the shark MHC was performed using 56 siblings from two typing panels of T. scyllium and Ginglymostoma cirratum. The C4 and one of two Bf genes showed a perfect cosegregation with the class I and II genes, whereas two recombinants were identified for the other Bf gene. These results indicate that the linkage between the complement C4 and Bf genes, as well as the linkage between these complement genes and the MHC class I and II genes were established before the emergence of cartilaginous fish >460 million years ago.

	Introduction

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Evolutionary studies of the complement genes have suggested that deuterostome invertebrates and cyclostomes have a simple complement system with a limited number of components. By contrast, jawed vertebrates have a more complex system with the addition of the classical and lytic pathways to the ancient lectin and alternative pathways (1). It is believed, therefore, that marked development of the complement system occurred in the jawed vertebrate lineage by gene duplications and following structural and functional differentiation. Although the exact timing of the gene duplications among the central component C3 gene and its homologous genes C4 and C5 is still not clearly defined, bony fish has all three genes (2, 3), indicating that these gene duplications predated the divergence of bony fish from tetrapods. In contrast, only a single gene with the closest similarity to higher vertebrate C3 has been identified from amphioxus (cephalochordate) (4) and sea urchin (echinoderm) (5). Although two C3-like genes have been identified from asidian (urochordate) (6), they are considered to be recent gene duplication products in the ascidian lineage. These results suggested that the C3/C4/C5 gene duplication occurred in the vertebrate lineage. It is still to be clarified whether the C3/C4/C5 gene duplication predated the emergence of cartilaginous fish or not. The situation is less clear with the Bf/C2 gene duplication. Most bony fish Bf/C2-like sequences analyzed to date form a third cluster independent from the Bf or C2 clusters of higher vertebrates (7, 8, 9, 10), making the assignment of them as Bf or C2 difficult. Thus, it is not clear the Bf/C2 gene duplication predated the divergence of bony fish from tetrapods or not. Again, deuterostome invertebrate (11) and cyclostome (12) Bf/C2-like sequences are considered to be derived directly from a common ancestor of jawed vertebrate Bf and C2. The phylogenetic position of shark Bf isolated from Triakis scyllium also has not been clearly defined (13).

One of the most intriguing features of mammalian complement genes is the close linkage of the Bf, C2, and C4 genes in the class III region of the mammalian MHC (14). Although Bf and C2 are homologous genes and the linkage between them is considered to be a result of tandem gene duplication, C4 is structurally distinct from Bf and C2. However, the C4 protein has an intimate functional link with C2, because these two proteins assemble to form the C3 convertase of the complement classical pathway (15). Phylogenetic studies indicate that the classical pathway was generated by gene duplications from the more ancient lectin and alternative pathways in which the C3 convertase is composed of C3 itself and Bf. One tempting hypothesis, therefore, is that the genetic linkage between C4 and C2 may have been important in establishing the classical pathway by facilitating the coevolution of these two disparate genes (1). This process is considered to be complex, because C4 and C2 must have been modified simultaneously from their ancestral genes, C3 and Bf, respectively, but also maintained the ability to interact to each other. Thus, it is important to determine when the linkage between the C4 and Bf/C2 genes was established during the vertebrate evolution. They are linked in Xenopus (16), but not in medaka, a bony fish (17). These results suggest that the genetic linkage was established after the emergence of bony fish, but before the emergence of amphibians. However, phylogenetic studies of MHC genomic organization have indicated that the linkage between MHC class I and II genes is conserved throughout the jawed vertebrate evolution from cartilaginous fish to mammals, except for all bony fish examined in which class I and II genes map to different chromosomes (18). Even in bony fish, the MHC class I gene and several genes directly involved in class I Ag processing and presentation are linking to each other, defining the teleost MHC class I region (19, 20, 21). However, mammalian MHC-encoded genes are dispersed to several teleost chromosomes, indicating that extensive chromosomal rearrangement occurred in the teleost lineage. Thus, the absence of linkage between C4 and Bf/C2 genes in bony fish could be a derived character rather than an ancestral situation. It is critical to analyze the possible linkage between these complement genes and MHC class I and II genes in the phylogenetically older cartilaginous fish for our understanding of the evolution of the complement system as well as the MHC.

	Materials and Methods

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Degenerate RT-PCR

A young adult banded hound shark, T. scyllium, caught in Mie prefecture, was used. RNA was isolated from liver, and was converted into cDNA using the SMART PCR cDNA Library Construction Kit (Clontech, Palo Alto, CA). Original degenerate PCR using C3/C4-A, GGNTGYGGNGARCARAC and C3/C4-C, ACRWAIGCIGTIARCCAIGT generated an expected 220-bp band (Fig. 1). After cloning into pT7Blue TA cloning vector (Novagen, Madison, WI), 20 clones were sequenced, and 2 of them contained the same sequence to be identified as T. scyllium C4 (TrscC4). ³ The 3' and 5' RACE, performed using the Smart cDNA as template and primers C4-R1, C4-R2, and C4-R3 (Fig. 1), resulted in isolation of 2.2- and 2.5-kb fragments, respectively. Sequence analysis of these RACE products indicated that the 5' terminal region was still missing, whereas the 3' terminus was covered. The additional 800-bp 5' terminal region was isolated by the second round of 5' RACE using C4-top-R1 and C4-top-R2 (Fig. 1). The entire primary structure of TrscC4 was composed from these four cDNA fragments. To confirm that these fragments actually represent the different parts of a single mRNA species, PCR amplification of the entire length was performed using primers C4F and C4R (Fig. 1).

View larger version (88K): [in this window] [in a new window]   FIGURE 1. Nucleotide and deduced amino acid sequence of TrscC4. The nucleotide sequence was composed of two 5' RACE, one degenerate RT-PCR, and one 3' RACE sequences, and was confirmed by the full-length PCR using the C4F and C4R primers. The intiation methionine codon and leader peptide were assigned from alignment with other C3/C4/C5 sequences. The nucleotide and amino acid numbers of the rightmost residues are shown for each lane. The - processing site (651654), the thioester site (980984), the aspartic acid residue crucial for reactivity of thioester (1096), and the - processing site (13991402) are shown in bold. The leader peptide and the poly(A) addition signals are underlined. PCR primers are enclosed by rectangles or shaded.

Nucleotide sequence analysis was performed from both strands by the BigDye Terminal Cycle Sequencing FS Ready Reaction Kit and PRISM 310 Genetic Analyzer. Nucleotide sequences of the 5' and 3' RACE products were determined using GPS-1 Genome Priming System Kit (New England Biolabs, Beverly, MA) by the transposon insertion method.

Phylogenetic tree analysis

The entire amino acid sequence of TrscC4 was aligned with those of C3, C4, and C5 of representative vertebrate and invertebrate species and human ₂-macroglobulin using the ClustalW software (22). Based on this alignment, a phylogenetic tree was constructed using the neighbor-joining method (23).

Northern blotting analysis

Total RNA from various tissues of a banded hound shark was denatured by the addition of 40% glyoxal, separated on a 1% agarose gel, and blotted onto a nylon membrane (Hybond-N; Amersham, Arlington Heights, IL). Hybridization with radiolabeled probes prepared using the Rediprime kit (Amersham) was performed in 10x Denhardt’s solution, 1 M sodium chloride, 50 mM Tris, 10 mM EDTA, 0.1% SDS, and 0.1 mg/ml denatured salmon sperm DNA at 65°C for 16–20 h. Membranes were washed twice for 30 min at 65°C in 0.1x SSC and 0.1% SDS.

Segregation analysis

Two shark families, a hound shark family of 17 sharks and a nurse shark family of 39 sharks, previously analyzed for the class I and II genes, were used (24, 25). C4 typing probe was a SalI(4342)-PvuII(5061) fragment of TrscC4 (Fig. 1). This probe cross-hybridized well with the nurse shark DNA under the low stringent hybridization/washing condition. The Bf probe for the hound shark was the same 248-bp fragment as described previously (13). Both hound shark and nurse shark have two Bf genes, termed Bf-A and Bf-B, considered to be generated by a gene duplication that occurred in the shark lineage before the separation of these two species (D. H. Shin, B. M. Webb, M. Nakao, T. Terado, H. Kimura, M. Nonaka, and S. L. Smith, unpublished data). This hound shark Bf probe was Bf-A. The Bf probe for nurse shark was a full-length Bf-B cDNA.

	Results

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Cloning and phylogenetic analysis of hound shark C4

A part of the TrscC4 cDNA was amplified using the degenarate primers corresponding to the thioester site and 100 residues downstream of it, a region that is highly conserved among the thioester-containing proteins. Two clones with the same insert were clearly identified as TrscC4 based on the result of Blast homology search using the translated amino acid sequences. The 5' and 3' RACE were performed to isolate the entire protein-encoding region. By connecting the RT-PCR and 5' and 3' RACE product sequences, the entire primary structure of TrscC4 was deduced (Fig. 1). The possible open reading frame of 1693 aa residues is organized from the N terminus, the leader sequence of 17 residues, the -chain of 633 residues, the RQRR - processing site, the -chain of 744 residues, the RRKR - processing site, and the -chain of 291 residues. A putative poly(A) addition signal was found (Fig. 1, underline), although no poly(A) sequence was recognized. The thioester site was found at the expected position (980–984); however, the histidine residue catalytic for the thioester was replaced by aspartic acid (1096). In this respect, shark C4 is human C4A like. Because all nonmammalian C4 sequences reported to date, besides one of two carp C4 genes, have the human C4B-like sequence with the catalytic His (2, 26), shark C4 is exceptional and suggests the presence of the second C4 gene in hound shark still to be identified. Using the entire protein sequence, the phylogenetic analysis of TrscC4 with representative C3, C4, and C5 sequences was performed. Amino acid sequences were aligned using the ClustalW program, and a phylogenetic tree was constructed by the neighbor-joining method. TrscC4 formed a monophyletic cluster with the mammalian, amphibian, and teleost C4 sequences, and this clustering was supported by a maximal bootstrap percentage of 100 (Fig. 2). Although the branching order of OrlaC4 and TrscC4 seems to be inverted, this result strongly suggests that the C3/C4/C5 gene duplication predated the emergence of cartilaginous fish. Recently, we isolated T. scyllium C3 and C5 cDNA, confirming this conclusion (T. Terado, M. Nonaka, and H. Kimura, unpublished data).

View larger version (45K): [in this window] [in a new window]   FIGURE 2. Phylogenetic tree of TrscC4 and C3, C4, and C5 of representative species. The species names and accession numbers of each sequence are as follows: Hosa2M (human, NP000005), StpuC3 (sea urchin, AAC14396), BrbeC3 (amphioxus, BAB47146), HaroC3 (Halocynthia ascdian, BAA75069), CiinC3-1 and C3-2 (Ciona ascidian, CAC85958 and CAC85959), HosaC5 (human, AAA51925), MumuC5 (mouse AAA37349), OrlaC4 (medaka, BAA92287), XelaC4 (Xenopus, AAA11188), MumuSlp and C4 (mouse, AAA39685 and AAC05279), HosaC4A and C4B (human P01028 and AAB67980), LajaC3 (lamprey, BAA00983), EpbuC3 (hagfish, CAA77677), XelaC3 (Xenopus, AAB60608), NanaC3 (cobra, AAA49385), GagaC3 (chicken, AAA64694), MumuC3 (mouse, AAA37336), HosaC3 (human, AAA85332), OrlaC3-1 and C3-2 (medaka, BAA92285 and BAA92286), CycaC3-H2, C3-H1 and C3-S (carp, BAA36620, BAA36619, and BAA36621). Numbers on branches are bootstrap percentages supporting a given partitioning. Filled circles indicate the C5/(C3, C4) and C3/C4 divergences.

Five micrograms of total RNA isolated from various tissues of banded hound shark were analyzed for TrscC4 expression by Northern hybridization (Fig. 3). A 5.4-kb band was detected only in the liver lane, indicating that TrscC4 expression is liver specific. Because an 5.3-kb sequence of TrscC4 has been determined (Fig. 1), only an 100-bp 5' untraslated region seems still to be cloned.

View larger version (70K): [in this window] [in a new window]   FIGURE 3. Northern blotting analysis. Five micrograms of total RNA isolated from liver, pancreas, heart, gonad, gill, spleen, brain, stomach, and intestine of banded hound shark were analyzed for TrscC4 expression. The probe was an 875-bp BamHI fragment at the 5' end of the TrscC4 cDNA.

To test a possible linkage of TrscC4 to the MHC, the same hound shark family with 17 offspring used for typing of MHC class I and II genes (24) was typed by genomic Southern hybridization using the TrscC4 cDNA fragment as a probe. A diagnostic C4 band was detected in offspring numbers 7, 8, 11, 12, 13, and 17, showing a precise concordance with the distribution of the MHC d haplotype (Fig. 4a). This result demonstrates linkage of the TrscC4 gene to the T. scyllium MHC. A ² test was applied to this result, and the linkage of the TrscC4 gene to the T. scyllium MHC was revealed to be statistically significant (p < 0.05). When the same offspring were typed for Bf-A (Fig. 4b), a diagnostic band also cosegregating with the d haplotype was observed, indicating that TrscBf-A is linked to the MHC (² test, p < 0.01). We could not map the TrscBf-B gene, because no polymorphism was detected with the TrscBf-B probe. To confirm the conclusion that the shark C4 and Bf genes are linked with the MHC, another typing panel of nurse shark, Ginglymostoma cirratum, was used. This panel was also previously used for mapping of the MHC class I and II genes (24, 25), and contains 39 siblings with at least 6 fathers. For clarity, only 23 siblings of this family are shown. The TrscC4 probe detected two diagnostic bands that cosegregate perfectly with the m1 (maternal haplotype 1) and p3 (paternal haplotype 3) haplotypes, respectively, confirming the linkage of the C4 gene with the shark MHC (² test, p < 0.05) (Fig. 5). For the typing of the Bf genes in the same nurse shark siblings, RFLP was searched with both GiciBf-A and GiciBf-B probes. In this species, the only Bf-B probe detected polymorphism available for gene mapping. Three paternal haplotypes generated two bands; p1 and p3 showed a unique band, and p2 showed a band identical with one of the maternal band, making the relative density of that band higher. However, sibling numbers 14 and 38, both with the p2 MHC haplotype, showed the p1/p3-type Bf-B band, indicating that these two siblings are recombinants. We think p1 and p2 came from one father from other genes we analyzed, and thus these recombinations were between the p1 and p2 haplotypes. Because p1 and p2 are not polymorphic bands with the C4 gene, it is not definitive to draw the conclusion that Bf is distantly linked to MHCI/II/C4. However, lower recombination frequency with C4 suggests that C4 is more proximal than Bf to the MHC class I and II genes.

View larger version (54K): [in this window] [in a new window]   FIGURE 4. Linkage analysis of the banded hound shark C4 and Bf genes with the MHC. S, M, and P, Represent sibling number, maternal haplotype, and paternal haplotype, respectively. The sibling numbers are the same as described (24 ), and M represents mother. The maternal and paternal MHC class I and II haplotypes assigned by the previous study are shown. Arrowheads indicate the polymorphic bands used for typing. A, C4 gene. EcoRI-digested DNA was hybridized with a SalI (4342)-PvuII (5061) fragment of TrscC4 (Fig. 1). B, Bf-A gene. EcoRI-digested DNA was hybridized with the same 248-bp Bf-A cDNA fragment, as described previously (7 ).

View larger version (77K): [in this window] [in a new window]   FIGURE 5. Linkage analysis of the nurse shark C4 and Bf genes with the MHC. Twenty-three of thirty-nine siblings already typed for the MHC genes were used. They were grouped based on their maternal and paternal MHC haplotypes noted above the blot. Arrows indicate the polymorphic bands used for typing. A, C4 gene. BamHI-digested DNA was hybridized with the TrscC4 cDNA probe, as described above. B, Bf-B gene. PstI-digested DNA was hybridized with the nurse shark Bf-B probe.

	Discussion

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It was unexpected that TrscC4 would lack the His catalytic to the thioester. Although the human C4A has a similar structure, the second C4 protein, C4B, does have the catalytic His (31). C4B-type C4 is found in all vertebrate species analyzed to date and thus is the prototype. The C4A type has been identified from only some mammals and carp that possess multiple C4 genes (32). Similarly, all vertebrate and invertebrate C3s analyzed to date also have the catalytic His, except for teleost species that have multiple C3 genes, a predominantly expressed one with the catalytic histidine and the others with various residues (1). Thus, the catalytic His is a common feature in most thioester-containing complement components in all vertebrates. If extra C3 or C4 copies have been gained by gene duplication, the His residue of some copies can be replaced by other amino acids. In mammalian C4 and teleost C3, this substitution changes the reactivity of the thioester bond and thus binding specificity to various activating surfaces (33, 34, 35). Variation in binding specificity may therefore expand the recognition repertory of the thioester-containing proteins (36). The T. scyllium situation with only the C4A-type gene is unique, and T. scyllium may also have the C4B-type gene, still to be identified. Even if there is the second, C4B-type C4 gene in T. scyllium, TrscC4 identified in this study seems to be the mainly expressed C4 gene, because only the TrscC4 sequence was obtained by the original RT-PCR amplification using the degenerate primers universal for all thioester-containing genes. Moreover, liver-specific expression of TrscC4 supports the idea that TrscC4 is an authentic C4 gene, if not exclusive, of this shark species.

Linkage of the shark counterparts of the mammalian MHC class III complement C4 and Bf genes with the MHC class I, II, proteasome subunit, and TAP genes indicates that the cartilaginous fish MHC is equipped with all three subregions. Because cartilaginous fish is the most primitive extant vertebrate group to have the MHC (18), MHC seems to have started as a complex genomic region from its inception early in vertebrate evolution. Although the physiological or evolutionary significance of linkage between complement genes and the class I and II genes is speculative, the significance of the linkage between the C4 and Bf/C2 genes could be to support the coevolution of these genes to establish the classical pathway. From the structural or phylogenetic criteria, the assignment of the shark Bf gene to Bf or C2 is difficult (13) (unpublished data). However, from a functional viewpoint, the presence of the classical pathway in cartilaginous fish is well established (27), supporting this hypothesis. Thus, the physiological role of the MHC could be an evolutionary one to allow coevolution of functionally linked genes. Another, more prominent example is the linkage within the MHC among the genes directly involved in class I Ag processing and presentation, class Ia, proteasome subunit, TAP, and tapasin. Even in teleosts, in which the counterparts of the mammalian MHC-encoded genes are dispersed over several chromosomes, these class I processing and presentation genes are found in a tight cluster, suggesting the presence of strong selective pressure to keep them together. Thus, for the class I Ag presentation system, tight linkage among these genes could be important not only for establishing the system, but also for combating with new pathogens.

The identification of two possible recombinants in this study indicated that the cartilaginous fish Bf-B gene is genetically separated from the other shark MHC genes. Because only one of two Bf/C2-like genes (37) (unpublished data), TrscBf-A and GiciBf-B, has been mapped in each shark species, there is no direct linkage data between Bf-A and Bf-B. However, it is most likely that they are arranged in tandem like the mammalian Bf and C2 genes. Compared with the Bf-B gene, the recombination frequency seems to be lower with the C4 gene because all RFLP bands matched to MHC haplotypes perfectly. If the shark C4 and Bf-B genes are closely linked, these results suggest that the C4 gene is more proximal to the MHC class I and II genes and the Bf-B gene locates more distal. The same relative organization was assumed for the chicken and Xenopus MHC genes (16 , 38), suggesting a possible phylogenetic conservation of this organization. This could reflect the conservation of an ancient organization, although we need further analyses to clarify this point.

	Footnotes

 
¹ This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports, and Culture, Japan 11236205 (to M.N.) and National Institutes of Health Grants A127877 (to M.F.F.) and GM08205 (to S.L.S.). The sequence reported in this paper has been deposited in the DDBJ/EMBL/GenBank databases under Accession AB091397.

² Address correspondence and reprint requests to Dr. Masaru Nonaka, Biological Sciences, Graduate School of Science, University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-0033, Japan. E-mail address: mnonaka{at}biol.s.u-tokyo.ac.jp

³ Abbreviation used in this paper: TrscC4, T. scyllium C4.

Received for publication February 21, 2003. Accepted for publication June 19, 2003.

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