Department of Biochemistry, Faculty of Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell. 2016 Oct 20;167(3):657-669.e21. doi: 10.1016/j.cell.2016.09.025.
Individuals from different populations vary considerably in their susceptibility to immune-related diseases. To understand how genetic variation and natural selection contribute to these differences, we tested for the effects of African versus European ancestry on the transcriptional response of primary macrophages to live bacterial pathogens. A total of 9.3% of macrophage-expressed genes show ancestry-associated differences in the gene regulatory response to infection, and African ancestry specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 804 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting expression quantitative trait locus (eQTL). Finally, we show that genetic effects on the immune response are strongly enriched for recent, population-specific signatures of adaptation. Together, our results demonstrate how historical selective events continue to shape human phenotypic diversity today, including for traits that are key to controlling infection.
不同人群的个体在免疫相关疾病的易感性上存在很大差异。为了了解遗传变异和自然选择如何导致这些差异，我们测试了非洲裔和欧洲裔对原发性巨噬细胞对活细菌病原体转录反应的影响。共有 9.3%的巨噬细胞表达基因在基因调控对感染的反应中存在与祖先相关的差异，而非洲裔具体预测出更强的炎症反应和减少细胞内细菌生长。这些差异中的很大一部分受到遗传控制：对于 804 个基因，免疫反应中祖先影响的 75%以上可以用单个顺式或反式作用的表达数量性状基因座 (eQTL) 来解释。最后，我们表明，免疫反应的遗传效应强烈富集了最近的、具有群体特异性的适应性特征。总之，我们的研究结果表明，历史上的选择事件如何继续塑造人类表型多样性，包括对控制感染至关重要的特征。
