Unusual mutation clusters provide insight into class I gene conversion mechanisms.

Genetic diversity among the K and D alleles of the mouse major histocompatibility complex is generated by gene conversion among members of the class I multigene family. The majority of known class I mutants contain clusters of nucleotide changes that can be traced to linked family members. However, the details of the gene conversion mechanism are not known. The bm3 and bm23 mutations represent exceptions to the usual pattern and provide insight into intermediates generated during the gene conversion process. Both of these variants contain clusters of five nucleotide substitutions, but they differ from the classic conversion mutants in the important respect that no donor gene for either mutation could be identified in the parental genome. Nevertheless, both mutation clusters are composed of individual mutations that do exist within the parent. Therefore, they are not random and appear to be templated. Significantly, the bm3 and bm23 mutation clusters are divided into overlapping regions that match class I genes which have functioned as donor genes in other characterized gene conversion events. The unusual structure of the mutation clusters indicates an underlying gene conversion mechanism that can generate mutation clusters as a result of the interaction of three genes in a single genetic event. The unusual mutation clusters are consistent with a hypothetical gene conversion model involving extrachromosomal intermediates.