Deschamps Matthieu, Laval Guillaume, Fagny Maud, Itan Yuval, Abel Laurent, Casanova Jean-Laurent, Patin Etienne, Quintana-Murci Lluis
Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France; CNRS URA3012, 75015 Paris, France; Université Pierre et Marie Curie, Cellule Pasteur UPMC, 75015 Paris, France.
Unit of Human Evolutionary Genetics, Institut Pasteur, 75015 Paris, France; CNRS URA3012, 75015 Paris, France.
Am J Hum Genet. 2016 Jan 7;98(1):5-21. doi: 10.1016/j.ajhg.2015.11.014.
Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000-13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change-containing variation acquired from archaic hominins or adaptive variants in specific populations-improving our understanding of the relative biological importance of innate immunity pathways in natural conditions.
调控先天免疫的人类基因是研究微生物对宿主基因组施加的选择压力的宝贵工具。目前尚缺乏对选择性限制和适应性如何驱动先天免疫基因进化的全面、全基因组研究。利用千人基因组计划的全基因组序列变异，我们首先表明，与其余蛋白质编码基因相比，先天免疫基因在整体上是在更强的纯化选择下进化的。我们鉴定出一组处于最强选择限制下的基因，其中的突变可能使个体易患危及生命的疾病，如STAT1和TRAF3所证明的那样。然后，我们评估局部适应性的发生情况，并在先天免疫基因中检测到57个高得分的正选择信号，这些基因的变异与常见传染病或自身免疫性疾病的易感性有关。此外，我们表明，大多数针对编码变异的适应性变化发生在过去6000 - 13000年，即人类群体从狩猎采集转向农耕的时期。最后，我们表明，先天免疫基因比其余编码基因组呈现出更高的尼安德特人基因渗入。值得注意的是，在具有最高尼安德特人祖先基因的基因中，我们发现了TLR6 - TLR1 - TLR10基因簇，该基因簇在欧洲人中也包含功能性适应性变异。这项研究鉴定出了在宿主生存中发挥基本、非冗余功能的高度受限基因，并揭示了其他一些更容易发生变化的基因，这些变化包括从古代人类获得的变异或特定人群中的适应性变异，从而增进了我们对自然条件下先天免疫途径相对生物学重要性的理解。
