DNA methylation and the origin of complement factor B polymorphism.

BF is a polymorphic complement component encoded in the MHC. In each of two frequent alleles of BF, BFFA and BFFB, the difference in relation to the major allele BFS has been shown to consist in the nonsynonymous substitution of only one base of the coding sequence. Both substitutions occur within the same codon and affect contiguous positions, corresponding to the dinucleotide CpG in BFS. We propose here that BFFA and BFFB arose independently from BF*S by the frequently described transition mutations associated with cytosine methylation at CpG sites. By probing sperm DNA with methylation-sensitive restriction enzymes, we obtained experimental evidence of germ line methylation of the CpG site considered. The dinucleotide of the BF gene probably constitutes a site for recurrent mutation, and this is of relevance for the use of BF as a genetic marker, and the origin of forms of the protein with altered functional properties.