School of Life Sciences, Institute for Immunology, State Key Laboratory of Membrane Biology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China.
Tsinghua-Peking Center for Life Sciences, Beijing, China.
Nat Immunol. 2024 Oct;25(10):1809-1819. doi: 10.1038/s41590-024-01944-4. Epub 2024 Sep 11.
Evolutionary pressures sculpt population genetics, whereas immune adaptation fortifies humans against life-threatening organisms. How the evolution of selective genetic variation in adaptive immune receptors orchestrates the adaptation of human populations to contextual perturbations remains elusive. Here, we show that the G396R coding variant within the human immunoglobulin G1 (IgG1) heavy chain presents a concentrated prevalence in Southeast Asian populations. We uncovered a 190-kb genomic linkage disequilibrium block peaked in close proximity to this variant, suggestive of potential Darwinian selection. This variant confers heightened immune resilience against various pathogens and viper toxins in mice. Mechanistic studies involving severe acute respiratory syndrome coronavirus 2 infection and vaccinated individuals reveal that this variant enhances pathogen-specific IgG1 memory B cell activation and antibody production. This G396R variant may have arisen on a Neanderthal haplotype background. These findings underscore the importance of an IGHG1 variant in reinforcing IgG1 antibody responses against life-threatening organisms, unraveling the intricate interplay between human evolution and immune adaptation.
进化压力塑造了种群遗传学，而免疫适应则增强了人类对危及生命的生物体的抵抗力。适应性免疫受体中选择性遗传变异的进化如何协调人类种群对环境干扰的适应仍然难以捉摸。在这里，我们表明，人类免疫球蛋白 G1（IgG1）重链中的 G396R 编码变体在东南亚人群中呈现出集中的流行。我们发现了一个 190kb 的基因组连锁不平衡块，其峰值与该变体非常接近，提示可能存在达尔文选择。该变体赋予了小鼠对各种病原体和毒蛇毒素更强的免疫弹性。涉及严重急性呼吸综合征冠状病毒 2 感染和接种疫苗个体的机制研究表明，该变体增强了病原体特异性 IgG1 记忆 B 细胞的激活和抗体产生。这种 G396R 变体可能是在尼安德特人单倍型背景上出现的。这些发现强调了IGHG1 变体在增强针对危及生命的生物体的 IgG1 抗体反应中的重要性，揭示了人类进化和免疫适应之间错综复杂的相互作用。
