A linkage disequilibrium map of the MHC region based on the analysis of 14 loci haplotypes in 50 French families

Abstract

A sample of 100 individuals from 50 French families of known pedigrees were typed for 14 loci of the HLA region (DPB1, DQB1, DQA1, DRB1, DRB3, 4, 5, C4B, C4A, Bf, C2, TNFa, TNFb, B, Cw, A). Linkage disequilibrium in each pair of loci was investigated by an exact test using a Markov chain algorithm. The results indicate no disequilibrium between DPB1 and the other loci, whereas the other class II genes are all significantly linked to each other. Linkage disequilibrium is also detected between some pairs of class I and class II-class I loci despite the long physical distance separating the loci (eg A-B, Cw-DRB1). On the other hand, some contiguous loci of the class III region are found to be in equilibrium with each other. Several hypotheses including selection, but also unequal allelic diversity at different MHC loci are discussed to explain this complex pattern of linkage disequilibrium.

How selection shapes variation of the human major histocompatibility complex: a review

“…In a recent survey of haplotypes from loci in the HLA region in 100 French individuals, Sanchez-Mazas et al (2000) found that all loci within the class II region (except for DPB1) are in ld with each other, as are all loci of the class I region. The finding that DPB1 was not in linkage disequilibrium with DQ/DR loci differs from the results of Klitz et al (1995), even though both studies involved samples from the CEPH (Centre des Etudes de Polymorphismes Humaines) database.…”

“…Several human populations have HLA allele frequencies which are more even than expected under neutrality (Hedrick & Thomson, 1983;Markow et al 1993;Valdes et al 1999;Salamon et al 1999;Sanchez-Mazas et al 2000). Valdes et al (1999), in a survey of 22 (mainly European) populations from the 12th International Histocompatibility Workshop (Charron, 1997), found that at the DQB1 locus the observed homozygosity of populations was on average 68.9 % of that expected under neutrality and that almost half of these populations deviated significantly from neutral expectations and implicated balancing selection (Table 2).…”

Short tandem repeat (STR) haplotypes in HLA: an integrated 50-kb STR/linkage disequilibrium/gene map between the RING3 and HLA-B genes and identification of STR haplotype diversification in the class III region

“…The course of LD appears to correspond well to published pair-wise data, with a peak LD across the HLA-DQ-DR region and marked drop in global LD just centromeric. 35,36 The absence of significant LD, previously observed for several pairs of class III loci such as Bf-C4 or C2-C4, 36 was in a region of low LD measures in our study (Figure 1). A recent report showed little correspondence of D' with crossover frequency in a small area of the TAP2 recombination hot spot using sperm typing, 46 suggesting that LD measures are a poor predictor of recombination frequencies in regions influenced by selection.…”

“…This proportion seems to be higher than that observed in Sardinian populations, but lower than in the UK population, 35,36 which may be due to different haplotypes analysed in these studies. It will be interesting to study the role of population-or haplotype-specific factors in the STR variability, but our results and results of others 35,36 suggest that both factors probably account for only smaller differences in the proportion of variant STR alleles and that most of the observed STR variability is inherent to a particular tandem repeat. The D3A locus also showed a higher pair-wise LD measures with the TNF STRs (Figure 1).…”

“…A recent study described variability at the D3A and 9N1 loci on HLA-B18-DR3 haplotypes, while the STR stability was generally higher in the telomeric region. 35,36 In our study, the 15-D3A STR, which is also located in the region of high GC content about 90 kb centromeric of D6S2670 (Figure 1), had a higher than average allelic variability as well, with three out of 40 variants in homozygous donors and 12% variants Allelic frequencies were estimated in founders and married-ins of families with immunoglobulin A deficiency and common variable immunodeficiency using the GAS programme; n, number of tandem tetra-and pentanucleotide repeats.…”