Molecular and Genetic Mechanisms Involved in the Generation of Mhc Diversity
Class II genes in the major histocompatibility complex (Mhc) are extremely polymorphic, with many alleles differing in >10% of their nucleotide sequences. The mechanisms responsible for the generation of this diversity are controversial. We have analyzed the diversification pattern in the Mhc class II Ab gene by sequencing exon 2, exon 3 and a segment of intron 2 in alleles derived from 14 species of mice and rats. Our data indicate that the diversity of exon 2, which encodes the antigen binding site of the class II molecule, is localized to five highly polymorphic segments. This diversity was generated by the slow accumulation of point mutations over long evolutionary periods and has been amplified by repeated intra-exonic recombination. Sequence analysis of exon 3 and intron 2 indicates that these recombinational events occur specifically within exon 2, where a sequence highly homologous to a minisatellite common core sequence has been identified. This sequence may play a role in promoting recombination in Ab, DPb and DRb. The sequence data for Ab, together with other data, suggest that various molecular and genetic mechanisms are involved in the generation of Mhc diversity. The most important mechanism affecting the diversity of class II beta genes is the shuffling of highly conserved ancestral sequence segments.
KeywordsMajor Histocompatibility Complex Antigen Binding Site Ancestral Polymorphism Recombination Signal Sequence Allele Lineage
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