Identifying Darwinian Selection Acting on Different Human APOL1 Variants among Diverse African Populations
Identifying Darwinian Selection Acting on Different Human APOL1 Variants among Diverse African Populations
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DOI：
10.1016/j.ajhg.2013.05.014
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发表时间：
2013-07-11
影响因子：
9.8
通讯作者：
Tishkoff, Sarah A.
中科院分区：
文献类型：
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作者：
Ko, Wen-Ya;Rajan, Prianka;Tishkoff, Sarah A.
疾病易感性可能是适应传染病的结果。最近的研究结果表明，在最近的非洲血统的个体中，慢性肾病（CKD）的发病率较高可能归因于APOL 1的血清抵抗相关（SRA）相互作用结构域编码区的两个风险等位基因（G1和G2）。这两个等位基因似乎是适应性产生的，可能是由于它们对人类非洲锥虫病（HAT）或非洲昏睡病的保护作用。为了探索APOL 1潜在功能变异的分布，我们研究了187个个体的核苷酸变异，这些个体分布在10个地理和遗传多样的非洲种族群体中，暴露于两个引起HAT的布氏锥虫亚种。我们观察到不寻常的高水平的非同义多态性的区域编码的功能域所需的裂解寄生虫。G2等位基因频率在所有人群中相似（3%-8%），G1等位基因仅在约鲁巴人中常见（39%）。此外，我们确定了一个单倍型（称为G3），包含在APOL 1的膜寻址域编码区的非同义变化，并存在于除约鲁巴以外的所有人群。连锁不平衡的远程模式的分析表明，最近的选择作用于G3单倍型在富拉尼从喀麦隆的证据。我们的研究结果表明，APOL 1中的G1和G2变异在地理上受到限制，并且可能有其他功能变异在非洲人群的HAT抗性和CKD风险中发挥作用。
Disease susceptibility can arise as a consequence of adaptation to infectious disease. Recent findings have suggested that higher rates of chronic kidney disease (CKD) in individuals with recent African ancestry might be attributed to two risk alleles (G1 and G2) at the serum-resistance-associated (SRA)-interacting-domain-encoding region of APOL1. These two alleles appear to have arisen adaptively, possibly as a result of their protective effects against human African trypanosomiasis (HAT), or African sleeping sickness. In order to explore the distribution of potential functional variation at APOL1, we studied nucleotide variation in 187 individuals across ten geographically and genetically diverse African ethnic groups with exposure to two Trypanosoma brucei subspecies that cause HAT. We observed unusually high levels of nonsynonymous polymorphism in the regions encoding the functional domains that are required for lysing parasites. Whereas allele frequencies of G2 were similar across all populations (3%-8%), the G1 allele was only common in the Yoruba (39%). Additionally, we identified a haplo type (termed G3) that contains a nonsynonymous change at the membrane-addressing-domain-encoding region of APOL1 and is present in all populations except for the Yoruba. Analyses of long-range patterns of linkage disequilibrium indicate evidence of recent selection acting on the G3 haplotype in Fulani from Cameroon. Our results indicate that the G1 and G2 variants in APOL1 are geographically restricted and that there might be other functional variants that could play a role in HAT resistance and CKD risk in African populations.