CHARACTERIZATION OF VARIATION OF RECOMBINATION IN THE HUMAN MHC

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Characterization of recombination in the human major histocompatibility complex (MHC) may lead to an understanding of the functional significance of haplotype diversification. Previously, we determined the distribution of crossover sites in 27 HLA class II recombinant families using 127 novel polymorphic markers located throughout the class II region. Recombination was shown to occur primarily in three regions: the 45 kilobase (kb)-interval between HLA-DNA and RING3, the 50-kb interval between DQB3 and DQB1, and an 8.8-kb segment of the TAP2 gene. We have now begun to identify HLA recombinant chromosomes using single sperm typing methods in order to measure variability of recombination frequency and location among individuals. Haploid DNA from single sperm is amplified using random oligonuclotide primers, and the products are typed at two microsatellite markers flanking the MHC. A preliminary screen has identified 49 recombinant chromosomes of 2,136 sperm typed (2.29%) from donor A and 20 of 1,705 (1.58%) from donor B. These two individuals differed significantly in the frequency at which recombination occurred in the class III (0.57% vs. 0.08%) and class I (0.77% vs. 0.31%) regions, as well as the entire 4 mebabase- pair region encompassing the MHC (2.97% vs. 1.58%). Further studies will be necessary to determine whether these differences are haplotype driven.