Sabeti Pardis C, Walsh Emily, Schaffner Steve F, Varilly Patrick, Fry Ben, Hutcheson Holli B, Cullen Mike, Mikkelsen Tarjei S, Roy Jessica, Patterson Nick, Cooper Richard, Reich David, Altshuler David, O'Brien Stephen, Lander Eric S
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
PLoS Biol. 2005 Nov;3(11):e378. doi: 10.1371/journal.pbio.0030378. Epub 2005 Nov 1.
The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Delta32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Delta32 arose within the past 1,000 y and rose to its present high frequency (5%-14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Delta32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Delta32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen at CCR5-Delta32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome.
C-C趋化因子受体5的32碱基对缺失（CCR5-Δ32）等位基因赋予对艾滋病病毒HIV感染的强大抵抗力。先前的研究表明，CCR5-Δ32在过去1000年内出现，并由于强烈的正选择，在欧洲升至目前的高频率（5%-14%），可能是由诸如中世纪的黑死病或天花等选择因素导致的。这一假设基于多条证据，包括该等位基因在欧洲以外地区不存在以及该位点的长距离连锁不平衡。我们利用密度更高的遗传图谱和广泛的对照数据重新评估了这一证据。我们发现，相对于基因组中的其他位点，CCR5-Δ32处的遗传变异模式并不突出。此外，使用更新的遗传图谱，我们估计CCR5-Δ32等位基因可能在5000多年前就已出现。虽然这些结果不能排除在C-C趋化因子受体5（CCR5）处可能发生了某些选择的可能性，但它们意味着在CCR5-Δ32处看到的遗传变异模式与中性进化一致。更广泛地说，这些结果对未来检测人类基因组中正选择迹象的研究设计具有普遍意义。
