Linkage Disequilibrium and Age of HLA Region SNPs in Relation to Classic HLA Gene Alleles within Europe
Résumé
The HLA region on chromosome 6 is gene-rich and under selective pressure due to the high proportion of immunity-related genes. Linkage disequilibrium (LD) patterns and allele frequencies in this region are highly differentiated across broad geographical populations, making it a region of interest for population genetics and immunity-related disease studies. We examined LD in this important region of the genome among 6 European populations using 166 putatively neutral SNPs and the classical HLA-A, -B and -C gene alleles. We found the pattern of association between the classical HLA gene alleles and SNPs implied that most of the SNPs predated the origin of the classic HLA gene alleles. The SNPs most strongly associated with HLA gene alleles were in some cases highly predictive of HLA allele carrier status (misclassification rates ranged from less than 1% to 27%) in independent populations using 5 or fewer SNPs, a much smaller number than tagSNP panels previously proposed and often with similar accuracy, showing our approach may be a viable solution to designing novel HLA prediction panels. To describe the LD within this region, we developed a novel haplotype clustering method/software based on r2, which may be more appropriate for use within regions of strong LD. Haplotype blocks created using this proposed method, classic HLA gene alleles and SNPs were predictive of northern versus southern European population membership (misclassification error rates ranged from 0-23% depending on which independent population was used for prediction), indicating this region may be a rich source of ancestry informative markers.
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