CCR5Δ32 evolutionary history

A new paper in PLoS Biology examines the recent evolution and dispersal of the Δ32 allele at the CCR5 locus (via Gene Expression). The introduction has a great paragraph summarizing the importance of the allele:

The CCR5 Δ32 mutation is a good example of an advantageous allele with a well-characterized geographic distribution. The Δ32 mutation currently plays an important role in HIV resistance because heterozygous carriers have reduced susceptibility to infection and delayed onset of AIDS, while homozygous carriers are resistant to HIV infection [1]. The mutation is found principally in Europe and western Asia, where average frequencies are approximately 10%, although the frequency varies within this geographic area. HIV only recently emerged as a human pathogen, so researchers were surprised when various sources of evidence showed strong selection in favor of Δ32 throughout its history. The age of the Δ32 allele has been estimated to be between 700 and 3,500 y based on linkage disequilibrium data [2,3], and recent ancient DNA evidence suggests the allele is at least 2,900 y old [4]. If Δ32 were neutral, population genetics theory predicts it would have to be much older given its frequency. The alternative explanation is that the Δ32 mutation occurred recently and then increased rapidly in frequency because of a strong selective advantage [2,5]. Quantitative studies have concluded that heterozygous carriers of Δ32 in the past had a fitness advantage of at least 5% and possibly as high as 35% [2,3]. Bubonic plague was initially proposed as the selective agent [2], but subsequent analysis suggested that a disease like smallpox is a more plausible candidate ([6-8], with reviews in [9-11]) (Novembre et al. 2005:e339).

This allele is one of the best-characterized recently selected variants in humans. Its selective advantage at least at some times in European history was huge, and it has a very recent origin (as assessed by linkage disequilibrium around the variant site).

Here we fit a simple population genetic model to the geographic distribution of Δ32 in order to infer features of the processes of dispersal and selection that shaped the historical spread of the allele. In particular we conclude that given current estimates of the age of the Δ32 allele, the allele must have spread rapidly via long-range dispersal and intense selection to attain its current range. We find the Δ32 allele is likely restricted geographically because of limited time to disperse rather than local selection pressures. In addition, we show that the data are consistent with origins of the mutation outside of northern Europe and modest gradients in selection (ibid.).

It's on its way to being a textbook case. At least in my textbook!

References:

Novembre J, Galvani AP, Slatkin M. 2005. The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele. PLoS Biol 3(11): e339. Full text (free)