Complement genetics

Abstract With the advent of recombinant DNA methodology about 20 years ago, tremendous progress has been made in the definition of the genetic basis of the complement system. Most genes coding for complement components and related proteins have been cloned, partially or completely sequenced, their chromosomal location determined, and a variety of mutations leading to partial or complete genetic deficiency described. Nevertheless, genetic typing of complement polymorphisms is still being carried out routinely for almost all components at the protein level. Protein typing technology using electrophoretic as well as serological methods has been proven to be a reliable tool for the definition of polymorphic variants. The analysis of complement polymorphisms has been applied to a wide range of problems, such as association with diseases, structure–function relationship, phylogenetic as well as ethnological studies, and paternity testing. The analysis of complement polymorphisms at the DNA level has provided an even more complex picture by revealing further variants, which subdivide alleles defined at the protein level. DNA sequence analysis of protein allotypes of a number of complement components has demonstrated that most sequence variations are not confined to short stretches of genomic DNA, but are rather scattered throughout the entire gene. Therefore it appears to be technically difficult to replace protein typing methods completely by direct DNA typing using PCR methodology. In contrast, PCR typing has been established successfully for the direct genetic typing of HLA class II genes. A combination of typing methods both at the protein and DNA level has to be applied to obtain complete genetic typing results for complex polymorphic complement components as well as for the detection of complement deficiency.