The Case for Selection at CCR5-Δ32

Abstract

The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Δ32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Δ32 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-Δ32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Δ32 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 atCCR5-Δ32 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.

Genetic variation and haplotype structures of innate immunity genes in eastern India

“…One possible reason is that the allele and haplotype frequencies of polymorphic loci in innate immunity genes in the study population has been reshaped by natural selection, perhaps because of their long and continued exposure to a high load of pathogens. Specific alleles in many human genes are now known to have been strongly selected in recent human history, especially in relation to exposure to infectious pathogens, such as CCR5 (Novembre et al, 2005;Sabeti et al, 2005) and FY (Hamblin et al, 2002). It has also been speculated that genes related to disease resistance are very likely to show evidence of recent positive selection (Wang et al, 2006), including resistance to infections -such as smallpox, malaria, yellow fever, typhus and cholera -that have become important causes of mortality after the origin and spread of agriculture (McNeill, 1976;Wolfe et al, 2007).…”

Scoring the collective effects of SNPs: association of minor alleles with complex traits in model organisms

“…Past studies of complex traits have met with great success in identifying a number of significant genetic variants, although such variants usually account for only a small fraction of the total trait variation and their functional roles typically remain unclear [1][2][3][4][5][6][7][8]. The focus on searching for a few major effect variants is under the null hypothesis in the field of population genetics that the majority of genetic variations are neutral.…”

Recent acceleration of human adaptive evolution

“…Because LD decays quickly over time, most ASVs are quite recent (14), compared with other approaches that detect selection over longer evolutionary time scales (15, 16). Many human genes are now known to have strongly selected alleles in recent historical times, such as lactase (17,18), CCR5 (19,20), and FY (21). These surveys show that such genes are very common.…”