Characterization of recombination within the human major histocompatibility complex.

摘要

Recombination within the human Major Histocompatibility Complex (MHC) is thought to account for novel alleles at select HLA loci and the abundant HLA haplotype diversity observed across populations. Utilizing 173 novel polymorphic markers, patterns of recombination intensity within the MHC were mapped at the population and individual level using DNA from families selected for a crossover within the MHC class II region (860 kb) and sperm selected for a crossover within the entire MHC (3.3 Mb), respectively. Twenty-one of 31 class II recombinants were mapped within three hotspots 9, 45, and 61 kb in size, and the strength of linkage disequilibrium between alleles of markers flanking the hotspots were either lower than adjacent cold spots or absent. A survey of 20,031 sperm from twelve donors identified 325 crossovers within the MHC. Statistically significant variation in recombination (range 0.71% to 4.3%) was observed among donors, supporting heterogeneity in rates among individuals. Nevertheless, individuals sharing sequence identity within the MHC (three HLA identical sib pairs) exhibited similar rates of recombination within the MHC whereas a sib pair sharing only one parental HLA haplotype exhibited significantly different rates suggesting that individuals sharing a common genetic background exhibit similar rates of recombination. One hundred and ninety-five recombinants (60%) were fine-mapped between markers 225 kb apart. Additional 60 recombinants were mapped within intervals 395 kb (255 recombinants total). Subdividing the MHC into thirty genomic intervals, six hotspots (sizes 35 kb to 121 kb) exhibited levels of recombination 1.7 to 5.2 times greater than that expected assuming a uniform distribution of 325 crossovers (0.49 cM/Mb). Furthermore, three of the hotspots exhibited a statistically significant departure from the expected. The same three hotspots were identified individually in six of nine genetically distinct donors prompting a distinction between public hotspots (ubiquitously found within a population) and private hotspots (present only in select individuals). The frequency and distribution of twenty-five sequence motifs potentially involved in recombination were compared to patterns of recombination intensity within the MHC. The only notable significant correlation identified was between (CA) and (GT) repeat density and increased recombination intensity. No explanation for this association has been proposed.