Sequence diversity, natural selection and linkage disequilibrium in the human T cell receptor alpha/delta locus

Abstract

T cell receptors (TR), through their interaction with the major histocompatibility complex, play a central role in immune responsiveness and potentially immune-related disorders. We resequenced all 57 variable (V) genes in the human T cell receptor alpha and delta (TRA/TRD) locus in 40 individuals of Northern European, Mexican, African-American and Chinese descent. Two hundred and eighty-four single nucleotide polymorphisms (SNPs) were identified. The distribution of SNPs between V genes was heterogeneous, with an average of five SNPs per gene and a range of zero to 15. We describe the patterns of linkage disequilibrium for these newly discovered SNPs and compare these patterns with other emerging large-scale datasets (e.g. Perlegen and HapMap projects) to place our findings into a framework for future analysis of genotype-phenotype associations across this locus. Furthermore, we explore signatures of natural selection across V genes. We find evidence of strong directional selection at this locus as evidenced by unusually high values of Fst.

Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis

“…In addition to intralocus variation, the presence of two or more alleles has been noted for many of the alpha V and J gene segments. 51,55 To further investigate TCR alpha/ delta nucleotide diversity, Mackelprang et al 58 utilized a V gene-based genomic sequencing approach in 40 individuals from four ethnic backgrounds (Chinese, African-American, Northern European, Mexican), generating sequence in V gene exons, introns, and 5 0 and 3 0 flanking regions. From this 284 SNPs were identified, 51 of which were nonsynonomous, coding for amino acid changes.…”

“…They also showed that nucleotide diversity, in general, was higher in CDRs than framework regions, although, heterozygosity within the CDRs was not higher than that found within neutral sequence, suggestive of purifying selection. 58 Nine SNPs were also identified in recombination signal sequences, which, given that recombination signal sequences are essential to the process of V(D)J rearrangement, suggests that these polymorphisms could contribute to biased gene usage. 58 Initial analyses of linkage disequilibrium (LD) within the TCR alpha locus using 24 V region SNP markers and two microsatellite markers revealed the occurrence of LD at distances ranging from 0 to 150 Kb, the most significant LD localizing to three concentrated regions.…”

“…58 Nine SNPs were also identified in recombination signal sequences, which, given that recombination signal sequences are essential to the process of V(D)J rearrangement, suggests that these polymorphisms could contribute to biased gene usage. 58 Initial analyses of linkage disequilibrium (LD) within the TCR alpha locus using 24 V region SNP markers and two microsatellite markers revealed the occurrence of LD at distances ranging from 0 to 150 Kb, the most significant LD localizing to three concentrated regions. 59 Strikingly, although Mackelprang et al 58 observed similar patterns from analyses of three separate SNP-based data sets, in that particular regions within the locus exhibited high LD, they also observed that in 64% of V genes where at least two common SNPs were found, these SNPs were not in LD.…”

“…58 Initial analyses of linkage disequilibrium (LD) within the TCR alpha locus using 24 V region SNP markers and two microsatellite markers revealed the occurrence of LD at distances ranging from 0 to 150 Kb, the most significant LD localizing to three concentrated regions. 59 Strikingly, although Mackelprang et al 58 observed similar patterns from analyses of three separate SNP-based data sets, in that particular regions within the locus exhibited high LD, they also observed that in 64% of V genes where at least two common SNPs were found, these SNPs were not in LD. These findings have important implications for disease-association studies within the TCR alpha/delta locus, and imply that rather dense panels of markers may be required to reveal or exclude associations between these genes and disease.…”

“…These findings have important implications for disease-association studies within the TCR alpha/delta locus, and imply that rather dense panels of markers may be required to reveal or exclude associations between these genes and disease. 58,59 Reviewing the TCR alpha/delta locus and MS…”