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The Journal of Immunology, 1998, 161: 3438-3443.
Copyright © 1998 by The American Association of Immunologists

C4d DNA Sequences of Two Infrequent Human Allotypes (C4A13 AND C4B12) and the Presence of Signal Sequences Enhancing Recombination1 ,2

Narcisa Martínez-Quiles3, Estela Paz-Artal3, Miguel A. Moreno-Pelayo, Javier Longás, Sergio Ferre-López, Manuel Rosal and Antonio Arnaiz-Villena4

Department of Immunology, Hospital "12 de Octubre," Universidad Complutense, Carretera de Andalucía, 28041 Madrid, Spain


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The DNA sequences of the polymorphic region (C4d) that belong to the infrequent complement C4 allotypes C4A13 and C4B12 have been obtained. In addition, C4A4 and C4B2 C4d sequences have been completed. C4A13 shows a new combination of amino acids at the following polymorphic positions: Asp1054, Pro1101, Cys1102, Leu1105, Asp1106, Asn1157, Ala1188, and Arg1191. These amino acids conform to the antigenic determinants Chido 1 and Rodgers 3; thus C4A13 is the only allele described thus far that carries both Ags. C4A13 and C4A4 carry the motif "ggctc*" (* means "deletion") at positions 14 to 19 in their intron 28; this motif had previously been reported only in C4B alleles. The C4B12 nucleotide sequence is analogous to C4B1b and C4B3 sequences, except for codon 1076, which is GCC in C4B1b and C4B3 and GGA in C4B12, which is coding for glycine in both cases. A recombination model for the generation of C4 alleles is formulated based on the analysis of these new sequences. One recombination would take place between positions 1157 and 1186 and would give rise to C4A13 and C4B5 or C4A3 (or C4A6) and C4B2; another one would occur between positions 1054 and 1076 and would generate C4A3 (or C4A6) and C4B12 or C4A2 and C4Bnew. Analysis of 1157 to 1186 and 1054 to 1076 fragments reveals the presence of putative sequence signals for recombination (similar to Escherichia coli {chi} recombination signal); the accumulation of such signals in fragments 1054 to 1076 supports the notion that a recombination hot spot for the C4 gene may exist and it also enhances new allele generation and intraspecies C4 gene homogenization.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The protein C4 plays a role in activating the complement system through the classical pathway. In humans, C4 is usually encoded by two different genes per chromosome, and each gene codifies for one of the two different C4 isotypes: C4A and C4B. The isotypes differ at the functional level in that C4A preferentially binds to protein Ags while C4B does so with carbohydrates (1). C4A and C4B proteins show a variety of allelic forms (allotypes) determined by different electrophoretic migration patterns and different hemolytic activity. Also, the two isotypes bear several antigenic determinants, called Rodgers (Rg,5 generally associated with C4A allotypes) and Chido (Ch, generally associated with C4B allotypes). Ch and Rg typing is usually determined with immune human antisera by hemagglutination inhibition assay (2).

The C4 polymorphic residues that define isotypes, allotypes, and antigenic Ch and Rg determinants cluster between amino acids 1054 and 1191 within an area of the C4 protein named C4d (3). An analysis of the C4d allotypes (4) demonstrates that four amino acids (1101, 1102, 1105, and 1106) coded at exon 26 are responsible for the isotypic variability; these positions, together with 1054, 1157, 1188, and 1191, are responsible for allotypic and Ch/Rg diversity (Table IGo).


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  		Table I. C4d polymorphism in human C4A and C4B genes1

 
C4A and C4B genes show high homology at the DNA sequence level; this similarity may be the cause of the observed relatively frequent occurrence of unequal crossing-over events between nonhomologous genes (i.e., C4A and C4B) (5). The unequal crossing-over would be responsible for 1) the existence of haplotypes with more or less than two C4 genes, and 2) the observed "mixed" patterns of amino acid residues at the polymorphic sites (Table IGo).

This paper describes the DNA sequences of the C4d fragment from two C4 infrequent variants, C4A13 and C4B12,6 and their comparison with the rest of available C4 human sequences (Fig. 1Go). The growing number of sequenced alleles makes it possible to suggest different models of crossing-over events as the possible mechanisms for the generation of the C4 gene allelic diversity.




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  		FIGURE 1. DNA sequence of the human C4d fragments from C4A13 and C4B12 alleles (boxes) compared with the rest of available human C4d sequences: C4A3 (3, 12, 13, 29); C4A4 (12, 29); C4A91, C4A2, C4A6, C4BNew (9); C4B3 and C4B5 (13); C4B1b and C4B1a (12, 13, 29); and C4B2 (12, 29).

 

   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cell lines

Five EBV cell lines obtained from the European Collection for Biomedical Research (Essen, Germany) were used for sequencing. Allotyping of C4 gene products was performed by high-voltage agarose electrophoresis followed by immunoblotting with a polyclonal anti-human C4 Ab (Atlantic Antibodies, Still Water, Maine) or monoclonal anti-human C4A and C4B Abs (6, 7).

Amplification and sequencing

C4d fragments from DNA belonging to the above-mentioned cell lines were amplified by PCR by using the the following primers: L3, 5'-TGCGGATCCAGCAGTTTCGGAAG-3' (exon 25), and L4, 5'-ATAGGATCCTAAGGTCCCCTGGGCCTC-3' (intron 28) (8). The PCR products were purified by using the Qiaquick Gel Extraction Kit (Qiagen, Hilden, Germany) and inserted into the pGEM-T vector (Promega, Madison, WI) following the manufacturer’s protocol. Only recombinant clones bearing the DNA sequence of the required isotype were selected for sequencing. This selection was done by PCR amplification using C4A and C4B primers specifically designed from the genetic region that defines isotypes (1101–1106). Primer C4A (5'-CCCCTGTCCAGTGTTAGAC-3'; exon 26) combined with the two plasmidic vector primers (see below) amplified only C4A alleles and not C4B ones, whereas primer C4B (5'-CCTCTCTCCAGTGATACATAGG-3'; exon 26) combined with the two plasmidic vector primers amplified only C4B alleles and not C4A ones. This methodology made it possible to scan the target sequences in a shorter time by avoiding full C4B sequencing from the cells carrying the C4A13 allele and also full C4A sequencing from the cells carrying the C4B12 allele. DNA templates were sequenced with the Sanger’s dideoxy terminator method using dye-labeled dideoxy terminators (Applied Biosystems PRISM dye terminator cycle sequencing ready kit; Perkin-Elmer, Foster City, CA) and oligonucleotides M13 direct (5'-TGTAAAACGACGGCCAG-3') and M13 inverse (5'-CAGGAAACAGCTATGACC-3'), which anneal to complementary sequences in the plasmidic vector, and also an internal primer L5 (5'-AGCAGCAGGCTGACGGCTCG-3'; exon 26) (9). The samples were run and analyzed on a model 373A automated DNA sequencer (Applied Biosystems, Foster City, CA). Five C4B12 clones from three different individuals and four C4A13 clones from two different individuals were obtained, which made it possible to discard artifact sequences from erroneous polymerase reactions.


   Results and Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Description of C4A13 and C4B12 DNA C4d sequences

Three cell lines bearing the allotype C4B12 were used for sequencing. They correspond to three members (father and two siblings) from family 228 (10). The two individuals bearing the allotype C4A13 are siblings from family 558 (10). Other amplified C4 allotypes from the five cell lines correspond to previously sequenced alleles: C4A3, C4B1, C4B2, and C4B3 (see compiled C4 sequences in 4 ; this allows the direct identification of the new sequences and their respective assignation to the newly sequenced allotype.

Figure 1Go shows the human C4 sequences available at present. C4A13 has the specific amino acids that determine the "A" isotype at the corresponding positions: Pro1101, Cys1102, Leu1105, and Asp1106, as expected. The remaining amino acids at polymorphic positions are Asp1054, Asn1157, Ala1188, and Arg1191; this is a new combination of amino acids at the polymorphic positions (Asp1054, Pro1101, Cys1102, Leu1105, Asp1106, Asn1157, Ala1188, Arg1191) that has not been observed in any of the alleles sequenced up to now (Table IGo). On the other hand, C4d fragment intron 28 also contains a polymorphic signal or motif which consists of the presence of two cytosines (c----c) in C4A alleles or, alternatively, both the presence of a guanine at the first position and the deletion of the second cytosine (g----*) in C4B alleles. Surprisingly, C4A13 presents g----* at intron 28. Ch and Rg antigenicity is determined by a particular amino acid combination at the polymorphic sites (11); thus it may be deduced that C4A13 would present Ch1 (Ala1188 and Arg1191) and Rg3 (Asn1157) Ags. The presence of only both Ch1 and Rg3 determinants in a human C4 molecule (C4A13) is described here for the first time. Several pigmy and common chimpanzee, gorilla, orangutan, and cotton top tamarin C4 predicted proteins would also present Ch1 and Rg3 antigenic determinants; human C4B1a would also carry Ch1 and Rg3, but would be associated with Ch2, -4, and -5 (4).

C4B12 has the amino acids that determine the "B" isotype at the corresponding positions: Leu1101, Ser1102, Ile1105, and His1106, as expected. Other amino acids at the polymorphic positions are Gly1054, Ser1157, Ala1188, and Arg1191; this combination of amino acids at polymorphic positions (Gly1054, Leu1101, Ser1102, Ile1105, His1106, Ser1157, Ala1188, and Arg1191) conforms the antigenic determinants Ch1, -2, -3, -4, -5, and -6 and is also observed in C4B1b and C4B3 alleles. These alleles (C4B1b and C4B3) differ from C4B12 at codon 1076, which is GGC in the former alleles and GGA in the latter, with coding for glycine in both cases.

C4B12 presents g----* at its intron 28; the motif g----* had only been found in alleles from the human C4B isotype (C4B1b, C4B1a, and C4BNew) and three chimpanzee C4A sequences (Patr-C4-1*03, Papa-C4-1*01, and Papa-C4-1*02) (4). This report shows that the g----* signal is present also in human C4A alleles: C4A13 and C4A4 (33 bases of C4A4 intron 28 have also been obtained; only the C4A4 cDNA sequence is available from a previous publication; Ref. 12, Fig. 1Go).

Mechanisms for the generation of new C4 alleles

Point mutations, intragenic crossing-over, and gene conversion-like events have been postulated as mechanisms responsible for the generation of new C4 alleles in humans and other primates (4, 5, 9, 13). We propose two hypothetical ancient crossing-over events (i.e., among a C4A and a C4B gene) that would give rise to the new C4A13 and C4B12 alleles (Fig. 2Go). Figure 2Go (upper) depicts a putative crossing-over event among C4A3 or C4A6 (both bearing the same C4d DNA sequence) and C4B2, giving rise to C4A13 and C4B5 (note that the mechanism might occur also in the reverse direction: C4A13 and C4B5 would be the parental sequences and C4A3 or C4A6 and C4B2 the emerging ones). This recombination might take place between codons 1157 and 1186; this is the first report of a theoretical recombination mechanism occurring in that particular region of the C4 gene.



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  		FIGURE 2. Hypothetical crossing-over events proposed to explain the generation of the C4A13 and C4B12 sequences (the crossed arrows do not represent an exact recombination point). Deduced amino acids (instead of codons) are represented in single-letter code. Lowercase letters represent nucleotides (third position at codons 1076 and 1186). Intronic sequences for C4A4 and C4B2 have also been obtained in this work.

 
Figure 2Go (lower) shows that a putative ancient crossing-over event among positions 1054 and 1076 of C4A2 and C4BNew could have generated C4A3 and C4B12 alleles (otherwise, the reverse may have occurred). As only one nucleotide difference (at residue 1054) identifies the border of the putative cross-over event, the case for C4B12 arising by cross-over is weaker than the one for C4A13. Another stronger candidate for crossing-over is C4A91, which possibly arose from a double cross-over event. The region placed between codons 1054 and 1076 has been previously involved in the generation of other C4 polymorphisms (C4A3 and C4B3 or C4A2 and C4B2) (4). The sequencing of more C4 variants could test whether the C4d region between codons 1054 and 1076 may be a hot spot for C4 genes recombination.

Analysis of putative recombination signal sequences

Several reports suggest the existence of signal sequences that promote the recombination in particular regions of the genome. Many of these sequences resemble the canonical {chi} signal for recombination described in Escherichia coli (14). Although the precise function of {chi} is unknown, {chi} is suggested to bind endonuclease V, which unwinds locally and nicks DNA to produce a ssDNA projection. DNA repair from the nicking site and ligation to the DNA projection could generate a short tandem duplication of the {chi} sequence that would promote, by unequal exchange, the amplification of the {chi} sequence, thus producing a minisatellite (15). This result would explain the fact that {chi}-like sequences may conform the core region of many minisatellites, which may be recombination hot spots (16). {chi}-like sequences have also been found in MHC class I and class II regions (17, 18, 19, 20, 21, 22). For instance, in the primate DRB1 locus, a {chi}-like putative recombination signal is located between sequences encoding the ß-pleated sheet and the {alpha}-helix of the first domain and could represent a breakpoint for the observed exchange among alleles (18). In four human DR ß cDNA, a {chi}-like sequence is found 36 bp upstream from a recombinant segment in exon 2 (21). The {chi}-like sequences are frequently included within the region of recombination or seem to enhance recombination of closely placed regions and their effects decrease with distance (16). We have searched for the possible presence of 31 such signals reported in the literature (15, 17, 18, 19, 20, 21, 23, 24, 25, 26) in the DNA fragments hypothetically related to C4 recombination events: from codon 1054 to 1076 (223 bases) and from codon 1157 to 1186 (84 bases) (see above and Fig. 2Go). To decrease the possibility that the presence of recombination signals in the analyzed fragments would be due to chance, the search was also performed along the C4 fragment from codon 1080 to the end of intron 26 (188 bases), which comprises the isotypic residues. This fragment was chosen as a negative control for cross-over events because recombinant C4 sequences involving the "1080 end of the intron 26 region" have not been found up to now (4). The search was also done in a randomly selected genome sequence belonging to a 10-kb fragment of the ataxia-telangiectasia gene, from position 30,000 to 40,000 (ATM4) (27). This region was also used as a negative control for the presence of recombination signals to improve the statistical significance of the results obtained (Table IIGo). The screening was conducted with the QGSEARCH program included in the PC/GENE software (IntelliGenetics, Mountain View, CA). The number of accepted mismatches always corresponded to a homology >=80% among sequences (22).


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  		Table II. Postulated recombination signal sequences related to C4 DNA recombination mechanisms1

 
Results from this analysis are shown in Table IIGo. It may be observed that two fragments probably related to crossing-over events (1054–1076 and 1157–1186, see Fig. 2Go) are found; they contain signal sequences that are not present in the DNA fragments used as negative controls. These signal sequences could play a role in promoting the recombination mechanism proposed in 1054 to 1076 and 1157 to 1186 fragments. Fragments 1054 to 1076 contains 7 such signals. Six of them are {chi}-like sequences related to the generation of hypervariable "minisatellite" regions (15), to the BCL2 oncogene translocation in human genome (25), or to recombination in mouse and primate MHC class II ß-chains genes (17, 18). The remaining one is a telomeric sequence related to chromosome size polymorphism in Plasmodium berghei (23, 24). Two similar recombination signals, related to the {chi}-like regions of the human minisatellite 33.15 and of primate DRB1 gene, are absent from the 10-kb negative control fragment ATM4 (Table IIGo). This result strengthens a possible role of a GGAGG/CTGGGG/CC/AGG sequence on the recombination mechanisms postulated for the generation of C4 polymorphism. The spatial relationship between this signal and the exact point of recombination and the mechanisms of recombination initiation themselves remain to be elucidated.

Gene conversion-like mechanisms promoting the shuffling of discrete C4d regions that originate the observed mixed polymorphism pattern in C4 genes cannot be discarded. However, the presence of putative recombination signal sequences supports the finding that certain C4 alleles may have been generated by ancient crossing-over events in fragments 1054 to 1076 (Ref. 4 and this work) and also that this region could be a hot spot for recombination in C4 genes; it may also enhance the postulated intraspecies homogenization recorded for C4d alleles from primates (4) which is in contrast with the trans-species evolution found for neighboring MHC genes (28).


   Footnotes
 
1 This work was supported by grants from the Ministerio de Educación (PM-95-57 and PM-96-28) and from Ramón Areces Fundation. Back

2 The nucleotide sequence data reported in this paper have been submitted to the GenBank database (accession nos. U77886 (C4A13) and U77887 (C4B12)). Back

3 N.M.-Q. and E.P.-A. contributed equally to the work, and the order of authorship is arbitrary. Back

4 Address correspondence and reprint requests to Dr. Antonio Arnaiz-Villena, Inmunología, Hospital "12 de Octubre," Universidad Complutense, Carretera de Andalucía, 28041 Madrid, Spain. E-mail address: Back

5 Abbreviations used in this paper: Rg, Rodgers; Ch, Chido. Back

6 Local names, unregistered by the Complement Nomenclature Committee. Back

Received for publication February 17, 1998. Accepted for publication May 27, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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