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Characterization of a de novo conversion in human complement C4 gene producing a C4B5-like protein
Taina Jaatinen1, Miia Eholuoto, Tarja Laitinen
1Department of Tissue Typing, Finnish Red Cross Blood Transfusion Service, Helsinki, Finland. Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Insights
A novel hybrid complement C4 (C4) protein was identified, arising from gene conversion between maternal C4A and C4B genes. This discovery supports gene conversion as a mechanism driving C4 diversity.
Area of Science:
- Immunogenetics
- Molecular Biology
- Human Genetics
Background:
- Complement C4 (C4) is a polymorphic protein crucial for the classical complement pathway.
- Allelic variation in C4, particularly in the C4d region, influences its function and antigenic properties.
- Rare C4 allotypes are hypothesized to result from recombination events, such as gene conversions, between homologous C4 genes.
Purpose of the Study:
- To investigate the origin and characteristics of a de novo C4 hybrid protein.
- To explore the role of nonhomologous recombination and gene conversion in generating C4 diversity.
Main Methods:
- Analysis of C4 gene sequences and protein allotypes.
- Identification of recombination events between maternal C4A and C4B genes.
- Electrophoretic and antigenic characterization of the resulting hybrid C4 protein.
Main Results:
- A functional de novo C4 hybrid gene was identified, resulting from gene conversion between maternal C4A3a and C4B1b genes.
- The hybrid gene exhibited C4B isotype codons but C4A3a polymorphic sites in exon and intron 28.
- The produced protein was electrophoretically similar to C4B5 and possessed reversed Rodgers and Chido antigenicity.
Conclusions:
- This case demonstrates the formation of a rare bimodular C4B-C4B haplotype with a de novo C4 hybrid gene.
- The findings support gene conversion as an active process contributing to the allelic diversity of the human C4 locus.
Abstract:
Complement C4 is a highly polymorphic protein essential for the activation of the classical complement pathway. Most of the allelic variation of C4 resides in the C4d region. Four polymorphic amino acid residues specify the isotype and an additional four specify the Rodgers and Chido determinants of the protein. Rare C4 allotypes have been postulated to originate from recombination between highly homologous C4 genes through gene conversions. Here we describe the development of a de novo C4 hybrid protein with allotypic and antigenic diversity resulting from nonhomologous intra or interchromosomal recombination of the maternal chromosomes. A conversion was observed between maternal C4A3a and C4B1b genes producing a functional hybrid gene in one of the children. The codons determining the isotype, Asp(1054), Leu(1101), Ser(1102), Ile(1105) and His(1106), were characteristic of C4B gene, whereas the polymorphic sites in exon and intron 28 were indicative of C4A3a sequence. The protein produced by this hybrid gene was electrophoretically similar to C4B5 allotype. It also possesses reversed antigenicity being Rodgers 1, 2, 3 and Chido-1, -2, -3, 4, -5, and -6. Our case describes the development of a rare bimodular C4B-C4B haplotype containing a functional de novo C4 hybrid gene arisen through gene conversion from C4A to C4B. Overall the data supports the hypothesis of gene conversions as an ongoing process increasing allelic diversity in the C4 locus.