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*
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190;
American Red Cross, National Histocompatibility Laboratory, Baltimore, MD 21201; and
National Marrow Donor Program, Minneapolis, MN 55413
Although extensive HLA-A and HLA-B polymorphism is evident, the
true diversity of HLA-C has remained hidden due to poor resolution of
HLA-C Ags. To better understand the polymorphic nature of HLA-C
molecules, 1823 samples from the National Marrow Donor Program research
repository in North America have been typed by DNA sequencing and
interpreted in terms of HLA-C diversification. Results show that
HLA-Cw*0701 was the most common allele with a frequency of 16%,
whereas 28% of the alleles typed as Cw12-18 (serologic blanks). The
frequency of homozygotes was 9.8% as compared with previous studies of
18% for sequence-specific primers and 50% for serology. Most
startling was the frequency at which new alleles were detected; 19 new
HLA-C alleles were detected, representing a rate of 
1 in 100 samples
typed. These new HLA-C alleles result from 29 nucleotide substitutions
of which 4 are silent, such that coding substitutions concentrated
about the Ag-binding groove predominate. Polymorphism at the HLA-C
locus therefore resembles that at the HLA-A and HLA-B loci more than
previously believed, indicating that antigenic stress is driving HLA-C
evolution. However, sequence conservation in the 
-helix of the first
domain and a clustering of unique amino acids around the B pocket
indicate that HLA-C alleles respond to antigenic pressures differently
than HLA-A and HLA-B. Finally, because the samples characterized were
predominantly from Caucasians, we hypothesize that HLA-C polymorphism
will equal or exceed that of the HLA-A and -B loci as DNA
sequence-based typing is extended to include more non-Caucasian
individuals.
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