Sequence variation and linkage disequilibrium in the human T-cell receptorbeta (TCRB) locus

The T-cell receptor (TCR) plays a central role in the immune system, and >9 0% of human T cells present a receptor that consists of the a TCR subunit ( TCRA) and the beta subunit (TCRB). Here we report an analysis of 63 variabl e genes (BV), spanning 553 kb of TCRB that yielded 279 single-nucleotide po lymorphisms (SNPs). Samples were drawn from 10 individuals and represent fo ur populations-African American, Chinese, Mexican, and Northern European. W e found nine variants that produce nonfunctional BV segments, removing thos e genes from the TCRB genomic repertoire. There was significant heterogenei ty among population samples in SNP frequency (including the BV-inactivating sites), indicating the need for multiple-population samples for adequate v ariant discovery. In addition, we observed considerable linkage disequilibr ium (LD) (r(2) > 0.1) over distances of similar to 30 kb in TCRB, and, in g eneral, the distribution of r(2) as a function of physical distance was in close agreement with neutral coalescent simulations. LD in TCRB showed cons iderable spatial variation across the locus, being concentrated in "blocks" of LD; however, coalescent simulations of the locus illustrated that the h eterogeneity of LD we observed in TCRB did not differ markedly from that ex pected from neutral processes. Finally, examination of the extended genotyp es for each subject demonstrated homozygous stretches of >100 kb in the loc us of several individuals. These results provide the basis for optimization of locuswide SNP typing in TCRB for studies of genotype-phenotype associat ion.