A basic understanding of meiotic recombination patterns in humans is necessary for the effective use of haplotypic blocks in complex disease gene mapping. Given the complexities associated with studying recombination in humans (e.g., random mating, large genome, and limited number of offspring), targeting large-scale recombination studies initially to gene-rich regions that likely influence a broad and diverse group of diseases is pragmatic and useful. The Major Histocompatibility Complex (MHC) contains over 100 genes and has been associated with most autoimmune diseases, as well as a number of infectious diseases and tumors. Recombination within the MHC accounts for novel alleles at certain human leukocyte antigens (HLA) loci and the abundant HLA haplotypic diversity, thereby serving as an excellent model for studying meiotic recombination in humans. A total of 20,031 sperm from 12 donors were successfully genotyped for two short tandem repeats (STRs) flanking the MHC and 576 recombinant sperm were identified, of which 325 carried a crossover within the MHC (3.3 Mb), and 310 were further localized within the MHC class I, II, and III regions. Microsatellite markers were used to fine-map 255 of the MHC recombinants within intervals as small as 8 kb and no larger than 395 kb. An average genetic distance of 0.49 cM/Mb was observed, although the rate of recombination varied significantly among unrelated (but not MHC identical) donors. The distribution of recombination sites among 30 segments (average size = 110 kb) comprising the entire MHC indicated the presence of six segments (accounting for 13% of the MHC) that showed levels of recombination that were 1.7-5.2 times the expected. Three of these were highly significant (p < 10-5) hot spots of recombination. Nevertheless, at least one recombination event occurred in nearly all of the 30 segments, suggesting the presence of fairly evenly distributed warm spots of recombination. Genetic variation appears to dictate to some extent where and how frequently recombination occurs based on two observations: 1) the rates and distribution of recombination did not differ significantly between members of any MHC identical sib pairs, but significant differences were observed between unrelated individuals, and 2) the presence of specific sequence motifs (i.e., [GT]>12) were significantly associated with recombination hot spots. These data provide a profile of recombination characteristics that serve as a model for the human genome and they will contribute substantially to an accurate interpretation of MHC evolutionary and disease association data. Studies that take into account both recombination fractions and linkage disequilibrium (LD) may provide insight into MHC haplotype evolution and the conservation of linkage groups. LD is the nonrandom association of alleles at two linked loci. Strong LD across the MHC exists, particularly among alleles of specific multi-locus haplotypes and between particular genes within the complex. LD is a measurement of historical events that may reflect selective pressures in some cases, whereas studies of recombinant chromosomes essentially measure real-time events, which are unlikely to reflect the protracted process of selection. For example, a reasonable conclusion drawn from the observation of a hotspot for recombination in the region between a pair of genes that are in strong LD is that there has been selection for haplotypes composed of alleles at those or neighboring genes. Thus, analysis of LD statistics in the context of recombination data (i.e., genetic distance) could be a powerful tool for identification of potential selective pressures resulting in retention of certain haplotypes. Our previous efforts to elucidate the relationship between LD and recombination were carried out in the MHC class II region through a comparison of CEPH genotyping data of eight class II loci flanking hot and cold spots of recombination (based on family data). By and large, levels of linkage disequilibrium were reduced across the hotspots compared to the cold spots of recombination. Recently, we have initiated an analysis of LD between eight pairs of microsatellite markers in the MHC located near the boundaries of two hot spots and two cold spots (based on the sperm data discussed above). These markers are currently being typed in the 59 CEPH families using the ABI 3100 DNA sequencer. We hypothesize that the strength of linkage disequilibrium across these small genomic intervals and recombination intensity for the same intervals should be negatively correlated.
| Gao, Xiaojiang; Single, Richard M; Karacki, Peter et al. (2006) Diversity of MICA and linkage disequilibrium with HLA-B in two North American populations. Hum Immunol 67:152-8 |
| Traherne, James A; Horton, Roger; Roberts, Anne N et al. (2006) Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history. PLoS Genet 2:e9 |
| Malkki, M; Single, R; Carrington, M et al. (2005) MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies. Tissue Antigens 66:114-24 |
| Carrington, Mary; Cullen, Michael (2004) Justified chauvinism: advances in defining meiotic recombination through sperm typing. Trends Genet 20:196-205 |
| Gourraud, P A; Mano, S; Barnetche, T et al. (2004) Integration of microsatellite characteristics in the MHC region: a literature and sequence based analysis. Tissue Antigens 64:543-55 |
