A Comprehensive Study of Polymorphic Sites along the HLA-G Gene: Implication for Gene Regulation and Evolution
A Comprehensive Study of Polymorphic Sites along the HLA-G Gene: Implication for Gene Regulation and Evolution
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DOI：
10.1093/molbev/msr138
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发表时间：
2011-11-01
影响因子：
10.7
通讯作者：
Donadi, Eduardo A.
中科院分区：
文献类型：
--
作者：
Castelli, Erick C.;Mendes-Junior, Celso T.;Donadi, Eduardo A.
HLA-G分子在免疫应答调节中起重要作用，并参与抑制T和自然杀伤细胞的细胞溶解功能和抑制异体T细胞的增殖。由于其免疫调节特性，HLA-G基因表达与同种异体移植物、自身免疫性疾病、感染性疾病和恶性疾病的预后有关。多项证据表明，HLA-G在5‘上游调控区（5’ URR）和3‘非翻译区（3’ UTR）的多态性可能影响HLA-G的表达水平。由于巴西人是世界上异质性最大的人群之一，在研究人群中已经检测到最广泛的HLA-G编码区变异性，因此预计巴西人将具有高水平的变异性和单倍型多样性。在此基础上，在巴西的100个健康骨髓供体中评估了5' URR、编码和3' UTR变异性，以及基因上的连锁不平衡模式和包含几个基因片段变异的扩展单倍型。HLA-G位点似乎呈现六种不同的HLA-G谱系，主要在调节区域的核苷酸上显示功能差异。在与转录因子结合位点重合或接近的5' UTR位置观察到差异，在3' UTR主要在已经报道的影响HLA-G mRNA可用性的位置观察到差异。我们报告了几条关于调节区域的平衡选择的证据，这可能表明这些HLA-G谱系可能与HLA-G表达谱的差异有关。
HLA-G molecule plays an important role on immune response regulation and has been implicated on the inhibition of T and natural killer cell cytolytic function and inhibition of allogeneic T-cell proliferation. Due to its immune-modulator properties, the HLA-G gene expression has been associated with the outcome of allograft and of autoimmune, infectious, and malignant disorders. Several lines of evidence indicate that HLA-G polymorphisms at the 5'-upstream regulatory region (5' URR) and 3'-untranslated region (3' UTR) may influence the HLA-G expression levels. Because Brazilians represent one of the most heterogeneous populations in the world with the widest HLA-G coding region variability already detected among the studied populations, a high level of variability and haplotype diversity would be expected in Brazilians. On this basis, the 5' URR, coding, and 3' UTR variability were evaluated in a Brazilian series consisting of 100 healthy bone marrow donors, as well as the linkage disequilibrium pattern along the gene and the extended haplotypes encompassing several gene segment variations. The HLA-G locus seems to present six different HLA-G lineages showing functional variations mainly in nucleotides of the regulatory regions. Differences were observed at the 5' URR in positions that either coincide with or are close to transcription factor-binding sites and at the 3' UTR mainly in positions that have already been reported to influence HLA-G mRNA availability. We report several lines of evidence for balancing selection acting on the regulatory regions, which may indicate that these HLA-G lineages may be related to the differential HLA-G expression profiles.