Toward understanding MHC disease associations: Partial resequencing of 46 distinct HLA haplotypes

• Published in: Genomics (San Diego, Calif.) Calif.), 2006-05, Vol.87 (5), p.561-571
• Main Authors: Smith, Wade P., Vu, Quyen, Li, Shuying Sue, Hansen, John A., Zhao, Lue Ping, Geraghty, Daniel E.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Line, Transformed; Conserved Sequence; Evolution, Molecular; Fundamental and applied biological sciences. Psychology; Genes; Genes. Genome; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Haplotypes; Haplotypes - genetics; HLA Antigens - genetics; HLA-A1 Antigen - genetics; HLA-B8 Antigen - genetics; HLA-DR3 Antigen - genetics; Humans; Immune System Diseases - genetics; Linkage Disequilibrium; Major histocompatibility complex; Major Histocompatibility Complex - genetics; MHC classes I and II; Molecular and cellular biology; Molecular genetics; Polymorphism, Single Nucleotide; Sequence Analysis, DNA
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1016/j.ygeno.2005.11.020

We carried out a resequencing project that examined 552 kb of sequence from each of 46 individual HLA haplotypes representing a diversity of HLA allele types, generating nearly 27 Mb of fully phased genomic sequence. Haplotype blocks were defined extending from telomeric of HLA-F to centromeric of HLA-DP including in total 5186 MHC SNPs. To investigate basic questions about the evolutionary origin of common HLA haplotypes, and to obtain an estimate of rare variation in the MHC, we similarly examined two additional sets of samples. In 19 independent HLA-A1, B8, DR3 chromosomes, the most common HLA haplotype in Northern European Caucasians, variation was found at 11 SNP positions in the 3600-kb region from HLA-A to DR. Partial resequencing of 282 individuals in the gene-dense class III region identified significant variability beyond what could have been detected by linkage to common SNPs.