Meiotic recombination serves to diversify the human genome, and this mechanism of generating novel haplotypes in the major histocompatibility complex (MHC) is likely to have significant consequences on the immune response to foreign material such as infectious pathogens and tumors. Efforts toward characterizing recombination within the MHC using sperm as a source of recombinant chromosomes have now been completed and are being formalized for publication. 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. Hotspots for recombination within the MHC were identified, which we term """"""""public"""""""" or """"""""private"""""""" depending on the number of individuals who contributed recombinants to that segment and the number of recombinants contributed. Three highly significant public hotspots for recombination were identified (p<0.00001), two of which were located in class II and one of which was located in class III. Several private hotspots were identified, based on increased recombination (2X that expected) in only one or two individuals. Identification of these hotspots will now allow us to select appropriate markers across the MHC when studying disease association within this genomic region (i.e. at least one marker between each hotspot for complete coverage of the MHC in an association study). Studies that take into account both recombination fractions and linkage disequilibrium (ld) may provide meaning to conservation of the MHC linkage group, whether selected or coincidental. 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 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. We have completed molecular typing of 30 markers within and flanking the MHC. Analysis of ld between pairs of these 30 markers has indicated that, in general, global disequilibrium (Wn) values decrease with increasing physical map distance, but the average distance over which significant ld occurs in the MHC is much greater than that reported for the genome as a whole (several hundred kb vs. 60 kb, respectively). In some cases, significant levels of ld occur between markers separated by more than 1 Mb. The range of Wn values for pairs of loci separated by about 100 Kb is exceedingly wide, however, and this is most clearly illustrated in the HLA class II region between TAP1 and TAP2. The data conform to the concept that a monotonic relationship between disequilibrium and distance does not necessarily occur in small genomic segments where factors such as drift, mutation, and admixture may overcome the effect of recombination. We have previously suggested that a """"""""hotspot"""""""" for recombination exists in the 21 Kb region separating TAP1 from TAP2 based on ld and family-based recombination studies. However, the sperm typing data does not support this data, suggesting that some combination of mutation or gene conversion may be operating in this short segment. A detailed analysis of ld between eight sites of variation within this region has now been investigated, indicating a complicated pattern of ld between pairs of markers and the absence of one specific site where recombination has occurred repeatedly. Further genotyping is required for a direct comparison of the recombination data with the ld data and this phase of the project will begin within the next fiscal year.
| 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 |
