Identification and Physical Mapping of A Polymorphic Human T Cell Receptor V3 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 VB18 gene, resulting from a nucleotide substitution that creates a stop codon (CGA~ 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 V318 mKNA in peripheral blood lymphocytes from an individual homozygous for this null allele. In addition, all heterozygous individuals expressed detectable levels of only the functional V/318 allele in their peripheral blood lymphocytes. Two other DNA polymorphisms were identified in VB18, one of which would result in an amino acid substitution in an expressed V~18 gene. Genotypes for all three of these V/318 DNA polymorphisms were determined in a group of unrelated individuals. Statistical analyses of the associations between alleles of the V318 polymorphisms and those of other DNA polymorphisms in the TCR 3 locus suggested a close physical proximity between the VB18 gene and the 3' end of the C~2 region. This localization of human V318 had been previously predicted by the sequence homology between human V~18 and mouse VB14, a V gene segment previously mapped to 3' of the mouse C3 genes. We confirmed this localization of the human V318 gene by isolating a cosmid done that contains both the V318 and C~2 gene segments. Mapping by restriction enzyme digestion and by the polymerase chain reaction indicated that the V318 gene segment is approximately 9 kb 3' of the C32 gene, making this the only known human V3 gene 3' of the C3 region.