Recombination in the human major histocompatibility complex (MHC) is thought to have played a role in generation of novel alleles at various HLA loci. It is also responsible for the diversity observed at the haplotype level, although the functional consequences of this activity are not clear. Historic and family studies of recombination in our laboratory have provided estimations of recombination fractions (q) across the MHC and identified potential hotspots for recombination in the class II region. Other characteristics of recombination in the human MHC such as haplotype-specificity in recombination frequency and localized sequence motifs involved in recombination have been considered, but have been difficult to address given the constraints of human population studies. Single-sperm typing holds promise in overcoming some of the limitations inherent in the study of recombination in human populations. We have used this technique to type two markers, D6S439 and MOGCA, which flank a region of about 7 Mb encompassing the human MHC. To date, about 26,000 sperm from twelve donors have been typed successfully for these markers and the range of recombination frequencies among donors is 1.72% to 6.5%. Haplotype specificity of recombination frequency and the influence of polymorphic genes outside of the MHC are being tested using the sperm typing technique on samples from two sets of identical twins, and brothers that share 0, 1, or 2 MHC haplotypes. 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 recently completed molecular typing of 30 markers within and flanking the MHC. Preliminary analysis of ld between pairs of these 30 markers has indicated that, in general, global disequilibrium (Wn) values decrease with increasing physical map distance. Further, the range of Wn values for pairs of loci separated by about 100 Kb is exceedingly wide range, as is clearly illustrated in the HLA class II region. 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 identified a ?hotspot? for recombination in the 21 Kb region separating TAP1 from TAP2 and a detailed analysis of linkage disequilibrium between eight sites of variation within this region is currently being investigated. Another notable feature of the data is that significant levels of ld exist between many pairs of markers that are separated by more than 1Mb. Further analyses of these data are ongoing. - linkage disequilibrium, Major histocompatibility Complex, recombination, single sperm typing, - Human Tissues, Fluids, Cells, etc.
|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|