Polymorphisms in the 5 '-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression

We present evidence of complex balancing regulation of HTR1B transcription by common polymorphisms in its promoter. Computational analysis of the HTR1B gene predicted that a 50 segment, spanning common DNA sequence variations, T-261G, A-161T, and -182INS/DEL-181, contained a putative functional promoter. Using a secreted alkaline phosphatase (SEAP) reporter gene system, we found that the haplotype -261G_-182INS-181_A-161 enhanced transcriptional activity 2.3-fold compared with the haplotype T-261_-182INS-181_A-161. Conversely, -161T reversed this, and the net effect when -261G and -161T were in the same haplotype (-261G_-182INS-181_-161T) was equivalent to the major haplotype (T-261_-182INS-181_A-161). Electrophoretic mobility shift experiments showed that -261G and -161T modify the binding of transcription factors (TFs): -261G generates a new AP2 binding site, while alleles A-161 and -161T exhibit different binding characteristics to AP1. T-261G and A-161T were found to be in linkage disequilibrium (LD) with G861C in a European ancestry population. Interestingly, G861C has been reported to be associated with several psychiatric disorders. Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies.

TCR{alpha} Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope

The underlying generic properties of {alpha}β TCRs that control MHC restriction remain largely unresolved. To investigate MHC restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (156Leucine) or HLA-B*3508 (156Arginine) showed a potent CTL response to the 407HPVGEADYFEY417 epitope from EBV. Interestingly, the response was characterized by highly restricted TCR β-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ β-chain was associated with distinct TCR {alpha}-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR {alpha}-chain usage determined the HLA restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR {alpha}-chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs.

Population mobility and indigenous peoples in Australasia and North America

This book draws together relevant research findings to produce the first comprehensive overview of Indigenous peoples' mobility. Chapters draw from a range of disciplinary sources, and from a diversity of regions and nation-states. Within nations, mobility is the key determinant of local population change, with implications for service delivery, needs assessment, and governance. Mobility also provides a key indicator of social and economic transformation. As such, it informs both social theory and policy debate. For much of the twentieth century conventional wisdom anticipated the steady convergence of socio-demographic trends, seeing this as an inevitable concomitant of the development process. However, the patterns and trends in population movement observed in this book suggest otherwise, and provide a forceful manifestation of changing race relations in these new world settings. © 2009 Informa plc