Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors.
Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors.
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DOI：
10.1016/j.ajhg.2015.11.015
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发表时间：
2016-01-07
影响因子：
9.8
通讯作者：
Kelso J
中科院分区：
文献类型：
--
作者：
Dannemann M;Andrés AM;Kelso J
病原体及其引起的疾病是人类进化史上最重要的选择力量之一。虽然适应性等位基因通常是由突变产生的，但基因渗入也可能是有益等位基因的宝贵来源。在欧洲和西亚生活了20多万年的古人类可能很好地适应了这种环境和当地的病原体。因此，可以想象，进入欧洲和西亚的现代人与他们杂交，从古代等位基因的渗入中获得了实质性的免疫优势。在这里，我们记录了现代人中三个toll样受体（TLR6-TLR1-TLR10）的集群，它们携带三种不同的古代单倍型，表明来自古代人类的重复渗入。其中两个单倍型与尼安德特人的基因组最相似，第三个单倍型与丹尼索瓦人的基因组最相似。toll样受体是先天免疫的关键组成部分，是抵御细菌、真菌和寄生虫的重要第一道免疫防线。异常高的等位基因频率和意想不到的群体分化水平表明，在该位点存在多个单倍型的局部正选择。我们表明，渐渗等位基因在现代人中具有明确的功能效应；仿古等位基因是TLR基因表达差异的基础，并且在大队列中与微生物耐药性降低和过敏性疾病增加有关。这为TLR6-TLR1-TLR10基因座的反复适应性基因渗入提供了强有力的证据，导致现代人疾病表型的差异。
Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. Here we document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neandertal genome, and the third haplotype is most similar to the Denisovan genome. The Toll-like receptors are key components of innate immunity and provide an important first line of immune defense against bacteria, fungi, and parasites. The unusually high allele frequencies and unexpected levels of population differentiation indicate that there has been local positive selection on multiple haplotypes at this locus. We show that the introgressed alleles have clear functional effects in modern humans; archaic-like alleles underlie differences in the expression of the TLR genes and are associated with reduced microbial resistance and increased allergic disease in large cohorts. This provides strong evidence for recurrent adaptive introgression at the TLR6-TLR1-TLR10 locus, resulting in differences in disease phenotypes in modern humans.