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

Abstract

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.

A complex major histocompatibility complexDlocus variant generated by an unusual recombination mechanism in mice

“…This model implies the interaction of at least three genes in the gene conversion event. We previously have discussed one model that could give rise to type III substitutions, and we proposed that an interaction between two donor genes occurs during an intermediate step before the actual conversion of the acceptor locus (11). This is currently our favored hypothesis, because it explains all the observations of the spontaneous mutations.…”

“…Therefore, on the basis of the unusual recombination activity of this region of the K b gene, one might consider the possibility that the type III mutations arise as a result of sequential type I gene conversion events. We have argued that this is probably not the case, because even at the inflated frequencies observed for the K b gene, and allowing for the possibility that silent substitutions occurred in generations preceding and following the generation of a functional variant, it is highly improbable that two independent type III variants would have been observed among the 30 characterized class I variants (11).…”

“…The structure of these variants resembles the type I and type II categories; all of the substituted nucleotides can be found in other class I genes of the parental haplotype. However, a single putative-donor gene containing all of the clustered substitutions cannot be found in the genome of the parental strain (11).…”

“…We previously have characterized two type III variants, K bm3 and K bm23 (11). Both contain a cluster of five nucleotide substitutions in and adjacent to the 3Ј end of exon 2 of the K b gene.…”

Discrimination of MHC-derived odors by untrained mice is consistent with divergence in peptide-binding region residues

“…Thus, we determined minimum detectable odor changes arising from single, naturally occurring mutations. Sequence analyses indicate that the vast majority of spontaneous H2 mutations detected through transplant rejection carry multiple amino acid substitutions resulting from microrecombinational events involving nonreciprocal exchange of DNA sequence from related MHC coding and noncoding loci (49)(50)(51)(52)(53)(54)(55). Such events are more likely to surpass a physiochemical threshold for odor detection than are single point mutations.…”