A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5

CCR5 encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for HIV-type 1 (HIV-1). Varied HIV-1 susceptibility and time to progression to AIDS have been associated with polymorphisms in CCR5. Many of these polymorphisms are located in the 5′ cis-regulatory region of CCR5, suggesting that it may have been a target of natural selection. We characterized CCR5 sequence variation in this region in 400 chromosomes from worldwide populations and compared it to a genome-wide analysis of 100 Alu polymorphisms typed in the same populations. Variation was substantially higher than expected and characterized by an excess of intermediate-frequency alleles. A genealogy of CCR5 haplotypes had deep branch lengths despite markedly little differentiation among populations. This finding suggested a deviation from neutrality not accounted for by population structure, which was confirmed by tests for natural selection. These results are strong evidence that balancing selection has shaped the pattern of variation in CCR5 and suggest that HIV-1 resistance afforded by CCR5 5′ cis-regulatory region haplotypes may be the consequence of adaptive changes to older pathogens.

CCR5基因编码一类细胞表面趋化因子受体，与CD4分子共同构成人类免疫缺陷病毒1型（HIV-1）侵染宿主细胞的主要共受体。人群中CCR5基因的多态性与HIV-1感染易感性差异以及进展至艾滋病的时间进程差异显著相关。上述多态性位点多位于CCR5基因的5'端顺式调控区，提示该区域可能曾受到自然选择的作用。本研究对来自全球人群的400条染色体中CCR5基因该区域的序列变异进行了分型表征，并将其与同一人群队列中100个Alu多态性（Alu polymorphisms）位点的全基因组分析结果进行了对比。结果显示，该区域的序列变异程度显著高于预期，且呈现中等频率等位基因过量的分布特征。尽管不同人群间的CCR5单倍型分化程度极低，但其谱系却拥有较长的分支长度。这一结果提示该区域的演化模式偏离中性演化理论预期，且这种偏离无法通过人群结构差异予以解释，后续的自然选择检验也进一步验证了这一结论。上述研究结果为平衡选择塑造了CCR5基因的变异模式提供了强有力的证据，同时也表明：CCR5 5'端顺式调控区单倍型所赋予的HIV-1感染抗性，可能是人类针对古老病原体产生适应性演化的附带效应。