Identification and physical mapping of a polymorphic human T cell receptor Vβ gene with a frequent null allele

Abstract

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 Vβ18 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 Vβ18 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 Vβ18 allele in their peripheral blood lymphocytes. Two other DNA polymorphisms were identified in Vβ18, one of which would result in an amino acid substitution in an expressed Vβ18 gene. Genotypes for all three of these Vβ18 DNA polymorphisms were determined in a group of unrelated individuals. Statistical analyses of the associations between alleles of the Vβ18 polymorphisms and those of other DNA polymorphisms in the TCR β locus suggested a close physical proximity between the Vβ18 gene and the 3′ end of the Cβ2 region. This localization of human Vβ18 had been previously predicted by the sequence homology between human Vβ18 and mouse Vβ14, a V gene segment previously mapped to 3′ of the mouse Cβ genes. We confirmed this localization of the human Vβ18 gene by isolating a cosmid clone that contains both the Vβ18 and Cβ2 gene segments. Mapping by restriction enzyme digestion and by the polymerase chain reaction indicated that the Vβ18 gene segment is approximately 9 kb 3′ of the Cβ2 gene, making this the only known human Vβ gene 3′ of the Cβ region.