Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön, Germany.
Research Unit for Evolutionary Immunogenomics, Department of Biology, Universität Hamburg, Hamburg, Germany.
Mol Biol Evol. 2021 Sep 27;38(10):4376-4387. doi: 10.1093/molbev/msab176.
A key component of pathogen-specific adaptive immunity in vertebrates is the presentation of pathogen-derived antigenic peptides by major histocompatibility complex (MHC) molecules. The excessive polymorphism observed at MHC genes is widely presumed to result from the need to recognize diverse pathogens, a process called pathogen-driven balancing selection. This process assumes that pathogens differ in their peptidomes-the pool of short peptides derived from the pathogen's proteome-so that different pathogens select for different MHC variants with distinct peptide-binding properties. Here, we tested this assumption in a comprehensive data set of 51.9 Mio peptides, derived from the peptidomes of 36 representative human pathogens. Strikingly, we found that 39.7% of the 630 pairwise comparisons among pathogens yielded not a single shared peptide and only 1.8% of pathogen pairs shared more than 1% of their peptides. Indeed, 98.8% of all peptides were unique to a single pathogen species. Using computational binding prediction to characterize the binding specificities of 321 common human MHC class-I variants, we investigated quantitative differences among MHC variants with regard to binding peptides from distinct pathogens. Our analysis showed signatures of specialization toward specific pathogens especially by MHC variants with narrow peptide-binding repertoires. This supports the hypothesis that such fastidious MHC variants might be maintained in the population because they provide an advantage against particular pathogens. Overall, our results establish a key selection factor for the excessive allelic diversity at MHC genes observed in natural populations and illuminate the evolution of variable peptide-binding repertoires among MHC variants.
脊椎动物病原体特异性适应性免疫的一个关键组成部分是主要组织相容性复合体 (MHC) 分子呈递病原体衍生的抗原肽。MHC 基因观察到的过度多态性被广泛认为是由于需要识别不同的病原体，这个过程被称为病原体驱动的平衡选择。这个过程假设病原体在它们的肽组（从病原体蛋白质组衍生的短肽池）中存在差异，因此不同的病原体选择具有不同肽结合特性的不同 MHC 变体。在这里，我们在一个由 36 种代表性人类病原体的肽组衍生的 5190 万个肽的综合数据集上测试了这个假设。令人惊讶的是，我们发现病原体之间的 630 对比较中，有 39.7%的比较没有一个共同的肽，只有 1.8%的病原体对共享超过 1%的肽。事实上，所有肽的 98.8%都是独特的单一病原体物种。我们使用计算结合预测来描述 321 种常见人类 MHC 类-I 变体的结合特异性，研究了不同病原体的肽结合特异性方面的 MHC 变体之间的定量差异。我们的分析显示，特别是具有狭窄肽结合谱的 MHC 变体，针对特定病原体的专业化特征。这支持了这样的假设，即这种挑剔的 MHC 变体可能在种群中被维持，因为它们对特定的病原体提供了优势。总的来说，我们的研究结果为自然种群中 MHC 基因过度等位基因多样性建立了一个关键的选择因素，并阐明了 MHC 变体之间可变肽结合谱的进化。
