IDENTIFICATION AND PHYSICAL MAPPING OF A POLYMORPHIC HUMAN T-CELL RECEPTOR V-BETA GENE WITH A FREQUENT NULL ALLELE

Germline variation in genes that encode the human T cell receptors (TCRs) may have an important influence in shaping the immune T cell repertoire. In this report we describe a frequent null allele of the human Vbeta18 gene, resulting from a nucleotide substitution that creates a stop codon (CGA<->TGA). Approximately 11% of the population tested was homozygous for this null allele, indicating that this is a frequent ''hole in the repertoire.'' We confirmed that there is a greatly reduced (undetectable) level of Vbeta18 mRNA in peripheral blood lymphocytes from an individual homozygous for this null allele. In addition, all heterozygous individuals expressed detectable levels of only the functional Vbeta18 allele in their peripheral blood lymphocytes. Two other DNA polymorphisms were identified in Vbeta18, one of which would result in an amino acid substitution in an expressed Vbeta18 gene. Genotypes for all three of these Vbeta18 DNA polymorphisms were determined in a group of unrelated individuals. Statistical analyses of the associations between alleles of the Vbeta18 polymorphisms and those of other DNA polymorphisms in the TCR beta locus suggested a close physical proximity between the Vbeta18 gene and the 3' end of the Cbeta2 region. This localization of human Vbeta18 had been previously predicted by the sequence homology between human Vbeta18 and mouse Vbeta14, a V gene segment previously mapped to 3' of the mouse Cbeta genes. We confirmed this localization of the human Vbeta18 gene by isolating a cosmid clone that contains both the Vbeta18 and Cbeta2 gene segments. Mapping by restriction enzyme digestion and by the polymerase chain reaction indicated that the Vbeta18 gene segment is approximately 9 kb 3' of the Cbeta2 gene, making this the only known human Vbeta gene 3' of the Cbeta region.