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Polymorphism of the human complement component C4
R D Campbell1, I Dunham, E Kendall
1MRC Immunochemistry Unit, Department of Biochemistry, Oxford, UK.
Insights
The study details the structural polymorphism of complement C4A and C4B genes within the human major histocompatibility complex. It highlights the high frequency of null alleles and variations in gene size and number, impacting C4 function.
Area of Science:
- Immunogenetics
- Molecular genetics
- Human leukocyte antigen (HLA) complex
Background:
- The complement system plays a crucial role in innate and adaptive immunity.
- Complement component 4 (C4) exists as two isotypes, C4A and C4B, encoded within the human major histocompatibility complex (MHC) class III region.
- These isotypes exhibit significant structural polymorphism, influencing their function and serological detection.
Purpose of the Study:
- To characterize the structural polymorphism of C4A and C4B genes.
- To provide a structural basis for observed functional and serological differences between C4 isotypes.
- To investigate genetic variations including null alleles, gene duplication, and gene size differences.
Main Methods:
- Detailed characterization of numerous C4A and C4B alleles.
- Analysis of gene structure, including polymorphism patterns.
- Pulsed field gel electrophoresis (PFGE) to assess gene size and copy number variations.
Main Results:
- Established the pattern of structural polymorphism in C4 genes.
- Identified an unusually high frequency of null alleles, leading to C4A and C4B null haplotypes.
- Documented variations in gene size due to the presence or absence of a large intron.
- Observed gene duplication events affecting C4 loci.
- Demonstrated direct visualization of gene size and number differences on haplotypes using PFGE.
Conclusions:
- The extensive structural polymorphism in C4 genes provides a foundation for their functional and serological diversity.
- The high prevalence of null alleles and variations in gene copy number represent significant features of C4 genetics.
- These genetic variations can be directly assessed, offering insights into C4's role in immune responses and disease susceptibility.
Abstract:
The genes encoding the two C4 isotypes, C4A and C4B, lie 10 kb apart in the class III region of the human major histocompatibility complex. The two isotypes exhibit extensive structural polymorphism. Characterisation of a number of C4A and C4B alleles has established the pattern of polymorphism in C4 and this has provided a structural basis for the observed functional and serological differences between the C4 isotypes. An intriguing feature in the genetics of C4 is the unusually high frequency of null alleles forming half null C4A and C4B haplotypes. Duplication of one of the loci has also been recognised. In addition the genes can differ in size due to the presence or absence of a large intron near the 5' end of the genes. These differences in gene size and gene number can be observed directly on different haplotypes using pulsed field gel electrophoresis.