Human Evolutionary Genetics, Department of Genomes and Genetics, Institut Pasteur, Paris, France.
Mol Biol Evol. 2011 Nov;28(11):3087-97. doi: 10.1093/molbev/msr137. Epub 2011 Jun 9.
Natural selection is expected to act strongly on immune system genes as hosts adapt to novel, diverse, and coevolving pathogens. Population genetic studies of host defense genes with parallel functions in model organisms have revealed distinct evolutionary histories among the different components-receptors, adaptors, and effectors-of the innate immune system. In humans, however, detailed evolutionary studies have been mainly confined to the receptors and in particular to Toll-like receptors (TLRs). By virtue of a toll/interleukin-1 receptor (TIR) domain, TLRs activate distinct signaling pathways, which are mediated by the five TIR-containing adaptors: myeloid differentiation factor-88 (MyD88), myeloid differentiation factor-88 adaptor-like protein (MAL), toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon (IFN)β (TRIF), toll/interleukin-1 receptor domain-containing adaptor protein inducing IFNβ-related adaptor molecule (TRAM), and sterile α- and armadillo motif-containing protein (SARM). Here, we have examined the extent to which natural selection has affected immune adaptors in humans, using as a paradigm the TIR-containing adaptors. To do so, we characterized their levels of naturally occurring genetic variation in various human populations. We found that MyD88 and TRIF have mainly evolved under purifying selection, suggesting that their role in the early stages of signal transduction is essential and nonredundant for host survival. In addition, the adaptors have been targeted by multiple episodes of positive selection, differing in timing and spatial location. MyD88 and SARM display signatures of a selective sweep that has occurred in all humans, whereas for the other three adaptors, we detected signatures of adaptive evolution that are restricted to specific populations. Our study provides evidence that the contemporary diversity of the five TIR-containing adaptors results from the intermingling of different selective events, swinging between constraint and adaptation.
自然选择预计会在宿主适应新的、多样化的和共同进化的病原体时对免疫系统基因产生强烈影响。对具有相似功能的模型生物宿主防御基因的群体遗传学研究揭示了先天免疫系统的不同组成部分（受体、衔接子和效应子）之间存在独特的进化历史。然而，在人类中，详细的进化研究主要局限于受体，特别是 Toll 样受体 (TLR)。TLR 通过 toll/interleukin-1 受体 (TIR) 结构域激活不同的信号通路，这些信号通路由五个含有 TIR 的衔接子介导：髓样分化因子 88 (MyD88)、髓样分化因子 88 样蛋白 (MAL)、toll/interleukin-1 受体域包含衔接蛋白诱导干扰素 (IFN)β (TRIF)、toll/interleukin-1 受体域包含衔接蛋白诱导 IFNβ 相关衔接分子 (TRAM) 和无菌 α 和 armadillo 基序包含蛋白 (SARM)。在这里，我们以含有 TIR 的衔接子为例，研究了自然选择在人类免疫适应性中的影响程度。为此，我们在各种人类群体中对其天然遗传变异的程度进行了特征描述。我们发现 MyD88 和 TRIF 主要受到净化选择的影响，这表明它们在信号转导的早期阶段的作用对于宿主的生存是必不可少的且不可替代的。此外，这些衔接子还受到多次正选择的影响，其发生的时间和空间位置各不相同。MyD88 和 SARM 显示出选择性清除已经发生在所有人类中的特征，而对于其他三个衔接子，我们检测到适应性进化的特征仅限于特定人群。我们的研究提供了证据表明，这五个含有 TIR 的衔接子的当代多样性是由不同的选择事件相互混合引起的，在约束和适应之间摇摆。
