Barreiro Luis B, Patin Etienne, Neyrolles Olivier, Cann Howard M, Gicquel Brigitte, Quintana-Murci Lluís
Centre National de la Recherche Scientifique FRE 2849, Unit of Molecular Prevention and Therapy of Human Diseases, Institut Pasteur, 25, 75724 Paris Cedex 15, France.
Am J Hum Genet. 2005 Nov;77(5):869-86. doi: 10.1086/497613. Epub 2005 Sep 29.
The innate immunity system constitutes the first line of host defense against pathogens. Two closely related innate immunity genes, CD209 and CD209L, are particularly interesting because they directly recognize a plethora of pathogens, including bacteria, viruses, and parasites. Both genes, which result from an ancient duplication, possess a neck region, made up of seven repeats of 23 amino acids each, known to play a major role in the pathogen-binding properties of these proteins. To explore the extent to which pathogens have exerted selective pressures on these innate immunity genes, we resequenced them in a group of samples from sub-Saharan Africa, Europe, and East Asia. Moreover, variation in the number of repeats of the neck region was defined in the entire Human Genome Diversity Panel for both genes. Our results, which are based on diversity levels, neutrality tests, population genetic distances, and neck-region length variation, provide genetic evidence that CD209 has been under a strong selective constraint that prevents accumulation of any amino acid changes, whereas CD209L variability has most likely been shaped by the action of balancing selection in non-African populations. In addition, our data point to the neck region as the functional target of such selective pressures: CD209 presents a constant size in the neck region populationwide, whereas CD209L presents an excess of length variation, particularly in non-African populations. An additional interesting observation came from the coalescent-based CD209 gene tree, whose binary topology and time depth (approximately 2.8 million years ago) are compatible with an ancestral population structure in Africa. Altogether, our study has revealed that even a short segment of the human genome can uncover an extraordinarily complex evolutionary history, including different pathogen pressures on host genes as well as traces of admixture among archaic hominid populations.
先天免疫系统构成了宿主抵御病原体的第一道防线。两个密切相关的先天免疫基因CD209和CD209L特别有趣，因为它们能直接识别多种病原体，包括细菌、病毒和寄生虫。这两个基因源于古老的基因复制事件，都有一个颈部区域，由23个氨基酸的七个重复序列组成，已知该区域在这些蛋白质的病原体结合特性中起主要作用。为了探究病原体对这些先天免疫基因施加选择压力的程度，我们对来自撒哈拉以南非洲、欧洲和东亚的一组样本中的这些基因进行了重测序。此外，还在整个人类基因组多样性样本中确定了这两个基因颈部区域重复序列数量的变异情况。我们基于多样性水平、中性检验、群体遗传距离和颈部区域长度变异得出的结果提供了遗传学证据，表明CD209一直处于强烈的选择约束之下，阻止任何氨基酸变化的积累，而CD209L的变异性很可能是由非洲以外人群中的平衡选择作用所塑造的。此外，我们的数据表明颈部区域是这种选择压力的功能靶点：CD209在全人群的颈部区域大小恒定，而CD209L的长度变异过多，尤其是在非洲以外人群中。另一个有趣的观察结果来自基于溯祖法的CD209基因树，其二叉拓扑结构和时间深度（约280万年前）与非洲的祖先群体结构相符。总之，我们的研究表明，即使是人类基因组的一小段也能揭示出极其复杂的进化历史，包括宿主基因上不同的病原体压力以及古代原始人类群体间混合的痕迹。
