High-resolution HLA class I typing in the CEPH families: analysis of linkage disequilibrium among HLA loci.
The HLA region on the short arm of chromosome 6 (6p21.3) contains the most polymorphic coding sequences in the human genome. High-resolution DNA-based HLA typing of population samples of the polymorphic class I loci, HLA-A, -B, and -C has only recently become feasible. Here, we report molecular HLA typing on family-based samples of European origin (the CEPH repository), which demonstrated very high polymorphism, with 20 A alleles, 38 B alleles and 19 C alleles in the sample of 248 independent haplotypes. In general, allele frequency distributions are consistently more even (lower observed homozygosity statistic) than expected from a past of selective neutrality suggesting a history of balancing selection. This was also true for the class II loci, DRB1, DQA1 and DQB1 in these samples, but not for the DPA1 and DPB1 loci, whose allelic frequency distributions were more skewed (higher observed homozygosity statistic) than expected under a neutral model. Although linkage disequilibrium is a prominent feature across the HLA region, only 19% of the eight locus haplotypes were sampled more than once. The relative age of some of the B alleles could be inferred from the pattern of B-C haplotypic associations. We suggest that the observed patterns of linkage disequilibrium reflect the operation of selection on nearly all HLA alleles.
Bugawan
T L
TL
Roche Molecular Systems, Alameda, California 94501, USA.
Klitz
W
W
Blair
A
A
Erlich
H A
HA
D000483:Alleles; D005787:Gene Frequency; D006680:HLA Antigens / Q000145:classification / Q000235:genetics*; D015234:HLA-A Antigens / Q000145:classification / Q000235:genetics; D015235:HLA-B Antigens / Q000145:classification / Q000235:genetics; D015236:HLA-C Antigens / Q000145:classification / Q000235:genetics; D006682:HLA-DP Antigens / Q000145:classification / Q000235:genetics; D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; D006683:HLA-DQ Antigens / Q000145:classification / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006239:Haplotypes; D006650:Histocompatibility Testing / Q000379:methods; D006801:Humans; D015810:Linkage Disequilibrium; D044465:White People / Q000235:genetics
D006680:HLA Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D006682:HLA-DP Antigens; D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; C071172:HLA-DPA1 antigen; C071170:HLA-DPB1 antigen; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen