High Frequency of the TCRBV20S1 Null Allele in the Sardinian Population Silvana Bonfigli, Claudio Fozza, Salvatore Contini, Raffaella Buzzetti, Francesco Cucca, and Maurizio Longinotti ABSTRACT Single nucleotide polymorphisms (SNPs) in the T-cell receptor (TCR) gene segments might play a role in shaping the TCR repertoire. Three polymor- phisms have been described for the TCRBV20S1 gene segment, one of which is responsible for a nucleotide substitution at position 524, resulting in the introduc- tion of a stop codon. Individuals homozygous for this inactivating polymorphism (“null allele”) are unable to express TCRBV20 gene products. Using DNA restric- tion digestion analysis, we investigated the frequency of this polymorphism in 111 healthy Sardinian subjects. Inhabitants of the Mediterranean island of Sardinia are considered to represent a genetically isolated popula- tion. Our analyses revealed an incidence of 19.8% of homozygosity for the null allele, corresponding to an allele frequency of 0.45. Such an incidence, significantly higher than the one detected in 83 non-Sardinian Cau- casians (6%), is the most elevated so far reported in the literature. BV20 is a single member subfamily and the null allele produces a gap in the potential TCR reper- toire. Therefore, it is possible that an undetermined selective pressure could have played a role in determin- ing the high frequency of this inactivating polymor- phism in Sardinians. Alternatively, this finding could be related to a founder effect in this ancient island popu- lation. Human Immunology 68, 426 – 429 (2007). © American Society for Histocompatibility and Immuno- genetics, 2007. Published by Elsevier Inc. KEYWORDS: T-cell receptor repertoire; single nucleo- tide polymorphisms; TCRBV20S1; null allele polymor- phism; Sardinia ABBREVIATIONS BV variable -chain PCR polymerase chain reaction SNP single nucleotide polymorphism TCR T-cell receptor TCRBV T-cell receptor variable -chain INTRODUCTION The high variability of the T-cell receptor (TCR) is the leading mechanism by which T cells recognize antigen in the context of the major histocompatibility complex system. The generation of the TCR repertoire diversity occurs primarily through germ-line DNA random rear- rangement of V-D-J gene segments, N-region diversifi- cation, and junctional diversity [1, 2]. In addition to such somatic mechanisms, allelic variations arising from DNA polymorphisms in TCR gene segments are thought to contribute to the shaping of the TCR reper- toire, hence potentially influencing recognition of the peptide–major histocompatibility complex and, conse- quently, immune response. Recently, the map of several TCR single nucleotide polymorphisms (SNPs) has been extensively investigated. Significant heterogeneity in TCR SNP frequencies within and between populations clearly emerged from these studies [3, 4]. For instance, regarding the variability of silent variable -chain (BV) gene SNPs, the frequency of the nine variants producing nonfunctional BV segments varied significantly among population samples [4]. In particular, the inactivating C/T mutation at position 524 in the BV20S1 gene segment (the BV20S1 “null allele”) resulted significantly more frequent in Caucasian than in African-American individuals [4 –7]. Individuals homozygous for the so- called null allele are unable to express the TCRBV20 From the Institute of Haematology (S.B., C.F., S.C., M.L.), University of Sassari, Sassari, Italy; Chair of Medical Genetics (F.C.), University of Sassari, Sassari, Italy; and Department of Clinical Sciences “Polo Pontino” (R.B.), University “La Sapienza,” Rome, Italy Address reprint requests to: Claudio Fozza, M.D., Institute of Haema- tology, University of Sassari, Viale San Pietro 12, 07100 Sassari, Italy; Tel/Fax: + 39 079 228282; E-mail: claudiofozza@hotmail.com. Received October 31, 2006; accepted January 17, 2007. Human Immunology 68, 426 – 429 (2007) © American Society for Histocompatibility and Immunogenetics, 2007 0198-8859/07/$–see front matter Published by Elsevier Inc. doi:10.1016/j.humimm.2007.01.011