Spontaneous H-2 mutants provide evidence that a copy mechanism analogous to gene conversion generates polymorphism in the major histocompatibility complex.

Abstract

The analysis of H-2K products from spontaneously generated major histocompatibility complex (MHC) mutants and of the primary structure of other class I antigens suggests the genetic hypothesis that diversity in the MHC results from a copy mechanism analogous to gene conversion. The hypothesis was tested by making precise structural predictions about 3 partially characterized MHC mutants (bm1, bm3 and bm8). The predictions were based on consensus sequences among class I genes that differ from H-2Kb in the same region of the molecule as do the Kb mutants. In 2 cases (bm3 and bm8) the correct amino acid substitution was predicted at positions known to be altered but for which the specific nature of the substitution had not been determined. In 2 additional cases (bm1 and bm8) both new mutation sites and the specific amino acid substitutions were predicted and found. The postions and identifications of the variant amino acids were determined by radiolabeled amino acid sequence analysis and DNA restriction endonuclease analysis. The interaction of MHC genes through a copy mechanism to generate diversity permits the introduction of multiple nucleotide base substitutions into class I sequences by a single genetic event. Such a mechanism may account, in part, for the large structural divergence among alleles of MHC loci and the high degree of MHC polymorphism among wild mice.