Human leukocyte antigen‐C (HLA‐C) is a classical HLA class I molecule that binds and presents peptides to cytotoxic T lymphocytes in the cell surface. HLA‐C has a dual function because it also interacts with Killer‐cell immunoglobulin‐like receptors (KIR) receptors expressed in natural killer and T cells, modulating their activity. The structure and diversity of the HLA‐C regulatory regions, as well as the relationship among variants along the HLA‐C locus, are poorly addressed, and few population‐based studies explored the HLA‐C variability in the entire gene in different population samples. Here we present a molecular and bioinformatics method to evaluate the entire HLA‐C diversity, including regulatory sequences. Then, we applied this method to survey the HLA‐C diversity in two population samples with different demographic histories, one highly admixed from Brazil with major European contribution, and one from Benin with major African contribution. The HLA‐C promoter and 3′UTR were very polymorphic with the presence of few, but highly divergent haplotypes. These segments also present conserved sequences that are shared among different primate species. Nucleotide diversity was higher in other segments rather than exons 2 and 3, particularly around exon 5 and the second half of the 3′UTR region. We detected evidence of balancing selection on the entire HLA‐C locus and positive selection in the HLA‐C leader peptide, for both populations. HLA‐C motifs previously associated with KIR interaction and expression regulation are similar between both populations. Each allele group is associated with specific regulatory sequences, reflecting the high linkage disequilibrium along the entire HLA‐C locus in both populations.

中文翻译：

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来自巴西和贝宁的两个样本中的Hla-C遗传多样性和进化见解。

人类白细胞抗原C（HLA-C）是一种经典的HLA I类分子，可将肽结合并呈递给细胞表面的细胞毒性T淋巴细胞。HLA-C具有双重功能，因为它还与天然杀伤细胞和T细胞中表达的杀伤细胞免疫球蛋白样受体（KIR）受体相互作用，从而调节其活性。HLA-C调控区域的结构和多样性，以及沿HLA-C基因座的变体之间的关系，尚未得到很好的解决，很少有基于人群的研究探索不同人群样本中整个基因的HLA-C变异性。在这里，我们提出了一种分子和生物信息学方法来评估整个HLA-C多样性，包括调控序列。然后，我们应用此方法在两个具有不同人口历史的人口样本中调查了HLA-C多样性，一个样本来自巴西，其中欧洲占主要比例，另一个样本来自贝宁，其中非洲占很大比例。在HLA-C启动子和3'UTR非常多态性很少，但高度不同的单倍型的存在。这些区段也呈现了在不同的灵长类物种之间共享的保守序列。在其他区段中，核苷酸多样性比外显子2和3高，尤其是在外显子5和3'UTR区的后半部分附近。我们在整个HLA-C基因座上检测到平衡选择的证据以及这两种人群的HLA-C前导肽的阳性选择。这两个人群之间以前与KIR相互作用和表达调控相关的HLA-C基序相似。每个等位基因组都与特定的调控序列相关，反映了两个种群中整个HLA-C基因座的高度连锁不平衡。