ANCESTRAL MAJOR HISTOCOMPATIBILITY COMPLEX DRB GENES BEGET CONSERVED PATTERNS OF LOCALIZED POLYMORPHISMS

Genes within the major histocompatibility complex (MHC) are characteri zed by extensive polymorphism within species and also by a remarkable conservation of contemporary human allelic sequences in evolutionarily distant primates. Mechanisms proposed to account for strict nucleotid e conservation in the context of highly variable genes include the sug gestion that intergenic exchange generates repeated sets of MHC DRB po lymorphisms [Gyllensten, U. B., Sundvall, M. & Erlich, H. A. (1991) Pr oc. Natl. Acad. Sci. USA 88, 3686-3690; Lundberg, A. S. & McDevitt, H. O. (1992) Proc. Natl. Acad. Sci. USA 89, 6545-6549]. We analyzed over 50 primate MHC DRB sequences, and identified nucleotide elements with in macaque and baboon DRB6-like sequences with deletions corresponding to specific exon 2 hypervariable regions, which encode a discrete alp ha helical segment of the MHC antigen combining site. This precisely l ocalized deletion provides direct evidence implicating segmental excha nge of MHC-encoded DRB gene fragments as one of the evolutionary mecha nisms both generating and maintaining MHC diversity. Intergenic exchan ge at this site may be fundamental to the diversification of immune pr otection in populations by permitting alteration in the specificity of the MHC that determines the repertoire of antigens bound.