Haplotype Linkage Disequilibrium Research Articles

Linkage disequilibrium in HLA cannot be explained by selective recombination.

Some combinations of HLA-A, -B and -DR antigens occur more frequently than would be expected from their gene frequencies in the population. This phenomenon, referred to as Linkage Disequilibrium (LD) has been the origin of many speculations. One hypothesis to explain LD is that some haplotypes are protected from recombination. A second hypothesis is that these HLA antigens preferentially recombine after cross-over to create an LD haplotype. We tested these 2 hypotheses: from a pool of over 10,000 families typed in our department, we analyzed 126 families in which HLA-A:B or B:DR recombinant offspring was documented. To overcome a possible bias in our material, we used the non-recombined haplotypes from the same 126 families as a control group. Our results show that the number of cross-overs through LD haplotypes is not significantly lower then would be expected if recombination occurred randomly. Also the number of LD haplotypes created upon recombination was not significantly increased.

Linkage map of the chromosomal region surrounding the infantile neuronal ceroid lipofuscinosis on 1p.

The neuronal ceroid lipofuscinoses (NCLs) of childhood are divided into 3 main types according to age-of-onset, clinical course, and neurophysiological and neuropathological findings: infantile, late infantile, and juvenile. All forms are inherited as an autosomal recessive trait, and their biochemical background is still unknown. The infantile type (INCL) with the earliest age-of-onset and the most severe clinical course, occurs in Finland with an incidence of 1:20,000, i.e., 116 patients have been found in our country up to now, whereas only about 50 cases have been reported from other parts of the world. Earlier we reported the linkage of INCL to the short arm of chromosome 1. Here we describe a more precise linkage map of this area. Our current map places the INCL mutation between D1S57 and D1S79; D1S7 has so far shown no recombination events between the marker and the disease (lod score 4.55 at theta = 0.00). Our material includes 64% of all living patients in Finland, and no linkage disequilibrium of haplotypes is seen, using the 2 physically close markers D1S57 and D1S79. This finding as well as our LINKMAP analyses suggest that the distance between the disease locus and the flanking markers is about 3-4 cm.

Polymorphism, recombination, and linkage disequilibrium within the HLA class II region.

Thirty-nine CEPH (Centre d'Etude du Polymorphisme Humain) families, comprised of 502 individuals, have been typed for the HLA class II genes DRB1, DQA1, DQB1, and DPB1 using nonradioactive sequence-specific oligonucleotide probes to analyze polymerase chain reaction amplified DNA. This population, which consists of 266 independent chromosomes, contains 27 DRB1, 7 DQA1, 12 DQB1, and 17 DPB1 alleles. Analysis of the distribution of allele frequencies using the homozygosity statistic, which gives an indication of past selection pressures, suggests that balancing selection has acted on the DRB1, DQA1, and DQB1 loci. The distribution of DPB1 alleles, however, suggests a different evolutionary past. Family data permits the estimation of recombination rates and the unambiguous assignment of haplotypes. No recombinants were found between DRB1, DQA1, and DQB1; however, recombinants were detected between DQB1 and DPB1, resulting in an estimated recombination fraction of greater than or equal to 0.008 +/- 0.004. Only 33 distinct DRB1-DQA1-DQB1 haplotypes were found in this population which illustrates the extreme nonrandom haplotypic association of alleles at these loci. A few of these haplotypes are unusual (previously unreported) for a Caucasian population and most likely result from past recombination events between the DR and DQ subregions. Examination of disequilibrium across the HLA region using these data and the available serologic HLA-A and HLA-B types of these samples shows that global disequilibrium between these loci declines with the recombination fraction, approaching statistic nonsignificance at the most distant interval, HLA-A to HLA-DP.DR-DQ haplotypes in linkage disequilibrium with DPB1 and B are noted and, finally, the evolutionary origin of certain class II haplotypes is addressed.

Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in type 1 (insulin-dependent) diabetes.

Heterogeneity between two haplotypes in linkage disequilibrium with DR3: B8, C4AQOB1,BfS,DR3 and B18,C4A3BQO,BfF1,DR3, with regard to age at onset of Type 1 (insulin-dependent) diabetes mellitus, was investigated in 325 unrelated French patients (146 males and 179 females, age at onset 1 month to 29 years) who were genotyped for HLA-A, B, C, DR and Bf and 225 of whom were typed for the C4A, B complement components. A subgroup of 82 patients and 75 control subjects were tested for DR beta and DQ beta DNA restriction fragment length polymorphism. The distribution according to age at onset and the mean ages at onset were compared between patients bearing B8, DR3 (n = 58), B18,DR3 (n = 62) or other DR3 haplotypes (Bx, DR3, n = 70), the haplotype segments C4AQOB1,DR3 (n = 41) or C4A3BQO,DR3 (n = 52) and the C4 null alleles C4AQO (N = 48) or C4BQO (n = 112) alone. The B8,DR3 haplotype, its smaller segment C4AQOB1,DR3 or C4AQO alone were associated with age at onset after 6 years (p less than 0.01, less than 0.08 and less than 0.02 respectively); on the other hand, the B18,DR3 haplotype, its segment C4A3BQO,DR3 or C4BQO alone were significantly more frequent in patients aged less than 6 years at onset (p less than 0.02, less than 0.01 and less than 0.01 respectively). Accordingly, the mean age of onset was significantly lower in the latter compared with the former patients (p less than 0.02, less than 0.02 and less than 0.01 respectively). No age-related variation was observed in BX,DR3 patients and their mean age of onset was intermediate.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA DQα and DQβ restriction fragment length polymorphisms associated with Felty's syndrome and DR4-positive rheumatoid arthritis

HLA DQα and DQβ cDNA probes were used to study TaqI generated restriction fragment length polymorphisms (RFLPs) in DR4-positive patients with Fetly's syndrome (FS), seropositive rheumatoid arthritis (RA), and in HLA-DR4 positive controls. The results of this analysis revealed two DQβ RFLP patterns (DQβ3a and DQβ3b) associated with DR4, of which DQβ3b was found at significantly higher frequency in patients with FS (73%) or with RA (52%) than in DR4 controls (29%). Hind III generated RFLPs provide evidence that DQβ3b is in strong linkage disequilibrium with the gene encoding the serologically recognized epitope TA10. Results obtained using a DQα chain probe revealed polymorphic difference between DQα chain genes associated with different DR types, thereby providing a possible explanation for the lack of association between RA and other DR haplotypes in linkage disequilibrium with TA10. We conclude that both DQα and DQβ genes may be important in determining HLA-linked susceptibility to serve forms of RA.