CORRELATING SEQUENCE VARIATION WITH HLA-A ALLELIC FAMILIES - IMPLICATIONS FOR T-CELL RECEPTOR-BINDING SPECIFICITIES

Six families of HLA-A alleles have been previously proposed on the bas is of nucleotide sequence and phylogenetic analysis. Here, sequence po lymorphism has been examined at both the protein and DNA levels in a f amily specific manner and new minimal signatures for each of the famil ies have been delineated. The DNA and protein sites that constitute th ese signatures are distributed throughout the length of the sequence a nd generally do not appear to act to promote structural or functional features of the molecules. This is explained by the fact that traditio nal signatures suffer biases where, for example, recombination product s of low frequency can obscure one family's trend by introducing 'impu rities' intrinsic to another family. In the absence of complete freque ncy data, a closer approximation of family signatures can be defined b y sites that show strong correlation with the family groups. Using thi s description, the amino acid positions 62, 97 and 114, localized in t he antigen-binding cleft are, in combination, sufficient to discrimina te between the six families. Thus, while the composition of the whole cleft defines the details of antigen specificity, these sites in parti cular, play a key role in modulating supertype peptide specificity and T cell recognition.