Spontaneous H-2 mutants provide evidence that a copy mechanism analogous to gene conversion generates polymorphism in the major histocompatibility complex (protein sequence/restriction endonuclease analysis/genetic hypothesis)

The analysis of H-2K products from sponta- neously generated major histocompatibility complex (MHC) mu- tants 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 three partially characterized MHC mutants (bml, 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 two cases (bm3 and bm8) we successfully predicted the correct amino acid substitution at positions known to be altered but for which the specific nature of the substitution had not been determined. In two additional cases (bml and bm8) we predicted and found both new mutation sites and the specific amino acid substitutions. The positions 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 sub- stitutions 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 poly-