Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC-Frederick, Inc., NCI-Frederick, MD 21702, USA.
Am J Hum Genet. 2011 Sep 9;89(3):424-31. doi: 10.1016/j.ajhg.2011.07.024.
Differential expression of human leukocyte antigen C (HLA-C) allotypes is mediated by the binding of a microRNA, miR-148a, to the 3' untranslated region of some, but not all, HLA-C alleles. The binding results in lower levels of HLA-C expression, which is associated with higher levels of HIV-1 viral load among infected individuals. The alternative set of HLA-C alleles has several substitutions in the miR-148a binding site that prevent binding and HLA-C downregulation; these high-expression alleles associate with control of HIV-1 viral load. We show that the common ancestor of all extant HLA-C alleles was suppressed by miR-148a. Substitutions that prevent miR-148a binding arose by a sequence exchange event between an HLA-C allele and an HLA-B (MIM 142830) allele of a B(∗)07-like lineage. The event occurred 3-5 million years ago, resulting in an HLA-C variant that escape from miR-148a downregulation. We present evidence suggesting that selection played a role in the successful spread of the HLA-C escape alleles, giving rise to 7 of the 14 extant HLA-C lineages. Notably, critical peptide and KIR binding residues of the escape variants have selectively converged to resemble the sequence of their inhibited counterparts, such that the inhibited and escape groupings differ primarily by their levels of expression.
人类白细胞抗原 C（HLA-C）同种异型的差异表达是由 microRNA miR-148a 与一些但不是所有 HLA-C 等位基因的 3'非翻译区结合介导的。这种结合导致 HLA-C 表达水平降低，与感染个体中 HIV-1 病毒载量较高相关。另一组 HLA-C 等位基因在 miR-148a 结合位点有几个取代，阻止结合和 HLA-C 下调；这些高表达等位基因与 HIV-1 病毒载量的控制有关。我们表明，所有现存 HLA-C 等位基因的共同祖先受到 miR-148a 的抑制。阻止 miR-148a 结合的取代是由 HLA-C 等位基因和 HLA-B（MIM 142830）B（∗）07 样谱系等位基因之间的序列交换事件引起的。该事件发生在 300-500 万年前，导致了一种逃避 miR-148a 下调的 HLA-C 变体。我们提出的证据表明，选择在 HLA-C 逃逸等位基因的成功传播中发挥了作用，产生了现存的 14 种 HLA-C 谱系中的 7 种。值得注意的是，逃逸变体的关键肽和 KIR 结合残基选择性收敛，类似于其被抑制的对应物的序列，使得被抑制和逃逸组主要区别在于它们的表达水平。
